Med pub by Paul Streeto

inside:

FDA’s External Memory: Committees Push REMS ■ page 16

vol. 5, no. 8 | September 2010 | elsevier business intelligence | www.therpmreport.com

A July to Remember July 2010 featured one hot topic after another—Avandia, Qnexa, opioids, REMS, Avastin, Brilinta, Lovenox. We offer 10 themes to think about heading into the fall. n

page 6

Weighing the Regulatory Climate:

The Qnexa Review

c o l u m n s

Free Speech ...............................2 Common Sense ........................ 32 FDA Beat .................................. 34 CMS Beat ................................. 46 Pointed View ............................ 49

If you want to know how much the regulatory climate has improved at FDA since 2007, the agency’s approach to Vivus’ weight loss drug Qnexa is all you need to know. But if you want to know how fundamentally the regulatory model has changed, listen to what an advisory committee said in rejecting the application. n

page 34

Opioid REMS Takes Shape An FDA advisory committee rejected the agency’s carefully crafted class-wide opioid REMS proposal. But sponsors in the class should embrace it anyway. n

page 18

Brilinta: Imported Efficacy AstraZeneca won two strong votes in favor of approval of its clot busting drug Brilinta from an FDA advisory committee, despite a failure to show efficacy in North America. n

“The road to regulatory hell is paved with surrogate endpoints.”

page 26

–Avandia Advisory Committee member Gerald van Belle, PhD

d a s h board The Cost of Doing Business with FDA Pharma companies can only wish that their revenues were growing as fast as the cost of new drug application fees over the past decade. 1,600,000 1,400,000

Fee

1,200,000 1,000,000 800,000 600,000

Don’t Wait For The Next Issue! Now you can get RPM’s analytical coverage more rapidly on the web – www.TheRPMreport.com

400,000 200,000 0

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

SOURCE: FDA, The RPM Report

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Free speech

tktktktktkt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

index

by company

Abbott Laboratories Inc.................35

Features

A July to Remember: . Lessons from an Eventful Month at FDA. . . . . . . . . . . . . . . . . . . 6

Adolor Corp..................................34

FDA’s Brilliant Management of Avandia Re-Review . Provides Flexibility on Final Decision. . . . . . . . . . . . . . . . . . . . . 10

Apexus............................. 46, 47, 48

FDA Has Key New Constituency for REMS: Advisory Committee Members. . . . . . . . . . . . . . . . . . . . . . . . . . 16 Opioid REMS: Committee Rejects FDA Proposal, But Sponsors Should Embrace It . . . . . . . . . . . . . . . . . . . . . . . . 18 FDA’s Opioid REMS Proposal. . . . . . . . . . . . . . . . . . . . . . . . . 20 FDA Turns Back To CME as Opioid Control Tool. . . . . . . . . . . 22 Voluntary Education Does Not Work . . . . . . . . . . . . . . . . . . . 24 Phase IV Proof of Efficacy: A Brilinta Idea?. . . . . . . . . . . . . . . 26 Looking for a Reasonable Phase IV Trial for Brilinta. . . . . . . 28 How Low Can U.S. Efficacy Go? . . . . . . . . . . . . . . . . . . . . . . . 30 common sense

Avandia: How Do You Hold a Moon Beam in Your Hand? . . . . 32

Arena Pharmaceuticals................ 36 AstraZeneca PLC............................ 6 Bristol-Myers Squibb Co............... 39 Covidien Inc..................................18 Genentech....................................47 GlaxoSmithKline PLC.................6, 34 Orexigen.................................42, 44 Pfizer Inc....................................... 6

FDA BEAT

Weighing the Regulatory Climate: . Qnexa’s clues About the New Approval Model. . . . . . . . . . . . 34 The Qnexa Vote: Beyond the Bean Counting. . . . . . . . . . . . . 38

Purdue Pharma.............................18 Roche............................................ 6

CMS BEAT

340B: A Test Market for Health Care Reform?. . . . . . . . . . . . . 46 Health Care Reform’s Pricing Impact: 340B Purchasers See Initial 10% Decline in Brand Prices . . . . . . . . . . . . . . 48

Sanofi-Aventis..................26, 30, 34

POINTED VIEW

Wyeth...........................................35

Vivus Inc............................. 6, 25, 34

Orphan Drug Standards: . Systematic Flexibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

tm tm

“The road to regulatory hell is paved with surrogate endpoints.”

Advisory Committee member Gerald van Belle, Ph.D

Avandia safety review, July 14

A Tough Meeting Turns Out Well For FDA FDA’s two day review of the continued marketing of GlaxoSmithKline’s Avandia was a grueling and perilous event for the agency. The outcome of the meeting was probably as good as it could have been—a split vote with a majority choosing options that allow continued marketing of the drug. But the agency drew plenty of compliments for its handling of the process from committee members on all sides of the issue. “There’s been a lot written in the last few days and weeks about the FDA being broken. As someone who has worked with the FDA for over 20 years, I don’t believe it’s at all broken, and I think this meeting has been an enormous testimony of that. I don’t think it needs any reorganization from the outside. I think that perhaps some of the people inside the FDA might work on getting along better together, but maybe they can figure that out inside their walls.”

Marvin Konstam Tufts-New England Medical Center Avandia advisory committee, July 14

“I want to take a moment to congratulate the FDA for organizing what I think is the best possible meeting to have compared the studies’ quality.”

Richard Platt Harvard University Medical School Avandia advisory committee, July 14

“It is very nice to have a very transparent understanding of the discussions. It is reassuring to know that [FDA is] putting that much energy and heart into these very difficult questions.”

Elaine Morrato Anschutz Medical Campus Avandia advisory committee, July 14

“As I’ve joined the committee, my respect for the FDA has markedly increased. I think everybody is trying to do their best job, but we do have a responsibility to protect the public at large and that means although as much as I feel for the people who want this drug and want to lose weight, we have to protect the population at large.”

“I voted no, but it’s a no with a lot of explanations. I agree that the committee seems to be closer than perhaps it appears. But I think my no vote will allow further discussion with the FDA to address some of these issues. I wouldn’t be upset if it were approved.”

Kenneth Burnham MD Washington Hospital Center Qnexa advisory committee, July 15

“My yes vote comes with a lot of conditions, and I will not hold it against the sponsor if they interpret my yes vote as a no vote.”

Sanjay Kaul Cedars-Sinai Heart Institute Qnexa advisory committee, July 15

Lamont Weide University of Missouri-Kansas City Qnexa advisory committee, July 15

A Close Call on Qnexa On July 15, an FDA panel voted 10-6 against approval of Vivus’ weight loss drug Qnexa—but it felt more like 16 separate split votes. For a full transcript of the post-vote comments, see pp. 34 “I’ve been on many committees and I’ve never found a vote actually harder, and I think that in the comments you’re going to hear that the panel is probably closer despite the split vote.”

Alison Goldfine Joslin Diabetes Center, Research Division Qnexa advisory committee, July 15

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

Getting Tough on Opioids FDA presented a carefully crafted, thoroughly vetted proposal for a classwide REMS on long-acting opioids to its advisory committee, only to have a strong majority of the committee reject it as too weak. Sponsors, though, now know what the baseline is for postmarketing controls in the class. “Although I recognize the amount of work that FDA has done and the resources they put toward this proposal, I thought it did not have enough teeth. It did not go far enough in terms of requiring education for prescribers.”

David Craig Moffitt Cancer Center Opioid REMS advisory committee, July 23

FREESPEECH “In the briefing materials, the presentations and the constructing of the REMS, the FDA failed to adequately acknowledge what has brought us here, which is the education campaign, criminally conducted by Purdue in the 90’s, which led to the huge increase in use of dangerous – more dangerous than immediate release – extended release OxyContin.”

Sid Wolfe Public Citizen’s Health Research Group Opioid REMS advisory committee, July 23

“I want to echo what some others have said and commend the FDA for exercising their expanded authority under FDAAA to help address this public health problem. It is very critical. I commend them for the tremendous effort to obtain the extensive stakeholder input and feedback and their transparent consideration of that feedback. I voted ‘yes’ because I believe we cannot not act. This is a reasonable place to start.”

Elaine Morrato Anschutz Medical Campus Opioid REMS advisory committee, July 23

“I share many of the concerns of the committee members who voted no – particularly in regards to the failure to include immediate release opioids and the voluntary nature of the education… .I rationalize my [‘Yes’] vote because the proposal does include a caveat that this may need to become mandatory. I think this is a first step, a piece of a puzzle that includes a public health campaign and inter-agency collaboration.”

Carol Peairs Phoenix VA Health care System Opioid REMS advisory committee, July 23

US Approval With Proof of US Efficacy To Come? The July 28 review of AstraZeneca’s anti-clotting drug Brilinta focused on the question of how to handle the failure of the drug to show efficacy in US patients. The committee voted for approval—but there followed a lot of discussion about whether and how to confirm benefit in the US. “My recommendation to the FDA would be to require the sponsor to address this issue in a more coherent and systematic fashion. That is, to conduct a study post-approval where they take a substantial number of patients in the United States to address this issue….The issue that is driving this disparity has more to do with practice of care difference rather than the dose of aspirin. That needs to be addressed.

flexible tool for drug pipeline research, tracking and analysis.

Sanjay Kaul Cedars-Sinai Heart Institute July 28 advisory committee review of Brilinta

“I am not even clear how you maintain that the trial you can get to is ethical to do. If you voted to approve the thing for use in this country, with a hard outcome claim including CV mortality, how the heck am I supposed to get people to do another outcome trial like that?”

Norman Stockbridge Director, Division of Cardiovascular & Renal Drug Products Advisory committee review of Brilinta, July 28

It doesn’t seem open and shut or impossible to do the trial in the U.S. where, after all the results for the U.S. subgroup, was neutral or adverse. I don’t find it completely incompatible to think that you make the drug available on the basis of the overall results and see if the U.S. would like to check the U.S. outcome analysis. This requires a lot, however.”

Robert Temple Director, Office of Drug Evaluation I July 28 advisory committee review of Brilinta

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A July 29 advisory committee discussion of pediatric endpoints for pulmonary arterial hypertension trials will help determine whether Pfizer receives a six month pediatric exclusivity extension for sildenafil, the active ingredient in Revatio…and Viagra. The issue: whether FDA should change its formal study request to allow Pfizer’s completed study to qualify for the extension.

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“The goal here was to try and get useful information in children. There is a trial. It’s done. It’s in the can. We have not reviewed i …According to the current Written Request, the

sponsor’s development program does not meet its terms. It is conceivable to leave it in that state and reach a totally independent decision about whether or not something should go in the labeling. That’s not the agency’s policy about how to handle written requests, which are generally provided to reward companies that do provide useful data.

Norman Stockbridge Director, Division of Cardiovascular & Renal Drug Products July 29 advisory committee review of Revatio

“It’s a little bit hard to imagine calling the pediatric study a clearly negative trial. It’s not a fair characterization…. All Pfizer wants is to say PVRI should be included in the consideration of the totality of the data as a pre-specified secondary endpoint included in the total assessment, together with the fact that there’s adult data and together with the fact that the p-value on the pre-specified analysis on exercise was [favorable, but with a p value of] .056.”

Milton Packer Pfizer consultant; University of Texas Southwestern Medical School July 29 advisory committee review of Revatio

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Regulatory Policy

A July to Remember: Lessons from an Eventful Month at FDA July 2010 was the hottest month on record in Washington, DC—and it was even hotter for the FDA new drug regulatory group. The month featured one hot topic after another—Avandia, Qnexa, opioids, REMS, Avastin, Brilinta, Lovenox. Here are 10 themes to think about heading into the fall.

By Michael McCaughan

July 2010 may have been one of the busiest and most important months ever for the Food & Drug Administration’s new drug regulatory group. The advisory committee schedule alone may be unprecedented in the scope, whether you consider the significance of the products and classes affected, the implications for the issues discussed for the regulatory system itself, or simply the scale of the meetings themselves—with dozens of advisory committee members and significant participation by Center for Drug Evaluation & Research top managers at many days of meetings (and pre-meetings and post-meetings). To recap: FDA hosted half a dozen significant advisory committee meetings, looking at the future of a former blockbuster in the type 2 diabetes class (GlaxoSmithKline PLC’s Avandia), a class-wide Risk Evaluation & Mitigation Strategy for one of the biggest medication classes (the longacting opioids), the first of three eagerly watched weightloss drugs (Vivus Inc.’s Qnexa), a potential blockbuster anti-clotting drug (AstraZeneca PLC’s Brilinta), and the possible withdrawal of a major indication for an existing blockbuster oncologic (Roche’s Avastin in breast cancer). Even the one seemingly “insignificant” meeting—the July 29 review of Pfizer Inc.’s pediatric research proposal for Revatio—has the distinctly important (and provocative) subtext of involving a possible exclusivity extension

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

for Viagra. In addition to the formal advisory committees, FDA hosted a two-day meeting looking at all aspects of the REMS process, participated in a two-day cross-agency workshop on antibiotic testing standards, began the negotiation process for renewal of the Prescription Drug User Fee Act, and continued cracking down on compliance issues. Oh, and along the way, the agency made some pretty interesting approval decisions, most notably including Momenta’s generic version of the low molecular weight heparin brand Lovenox. So, from a medical perspective, FDA considered issues directly affecting the regulation of drugs for diabetes, infections, clotting disorders, weight loss, chronic pain, and breast cancer. That pretty much means FDA’s July schedule could have an impact on the entire US population. As for regulatory issues, how about the future of accelerated approval, the evolution of the new Risk Evaluation & Mitigation Strategy process, the handling of internal disputes, incentives for new drug development, and the future of the regulatory model itself? Yes, it was a big month—and you will find in depth coverage of many of these events in the current issue of The RPM Report. But we thought it would be useful to lay out some of the important themes we took away from the amazing month of July.

1. The REMS Process Remains Unsettled FDA’s new Risk Evaluation & Mitigation Strategy authority played a role in virtually ever major July event, culminating in the July 27-28 feedback meeting intended to help FDA better formulate guidance on using REMS in the real world. The lesson from July’s product reviews is that advisory committees are learning to love REMS—even as they express growing distrust in the ability of sponsors to control medicines in the real world. Similarly, FDA is wrestling with feedback from provider groups, consumers and payors about the impact of its early experiments with REMS. The two-day meeting on that topic at the end of July is likely to be just the beginning of a period of re-evaluation of the REMS process. This is truly a generational change in the regulatory model; 2-1/2 years into the new era, think of it as the toddler phase.

2. Get Used to Product Look-backs The Avandia and Avastin committees stood out as extraordinary examples of re-reviews of the risk/benefit profiles of approved drugs. Sponsors, however, should expect FDA lookback reviews to become a routine part of product lifecycles. In the case of Avandia, FDA’s new post-marketing safety tools are intended precisely to make sure that FDA can force sponsors to generate better data about real world outcomes in the post-marketing setting: more data means more Avandias. For Avastin, FDA is promising to push harder on accelerated approval products to get the confirmatory data (or remove the indication), especially in oncology.

3. Advisory Committees Are More Risk-Averse Than FDA That is a broad overgeneralization, but certainly helps explain two of the occasions where FDA got a surprising outcome: the rejection of Qnexa and a strong vote against the agency’s proposal for the opioid REMS. In both cases, committee members urged FDA to apply more rigorous controls up-front, rather than take a chance on a new product (Qnexa) or new program (the opioid REMS) that could cause headaches later on.

4. The Whistleblowers Are Back, but the Tune Is Different The Avandia meeting marked the return of some of FDA’s well-known internal gadflies to the public stage—most notably Associate Director for Drug Safety David Graham—and also the debut performance of a new one, Cardio-Renal Division medical officer Thomas Marciniak. The latter also played a

prominent role in the FDA presentation on Brilinta. However, while FDA’s internal dissenters can still grab the headlines, they may not have the same paralyzing impact on the pace and outcome of reviews as they did three years ago. FDA’s leadership more publicly embraced Graham during this Avandia re-review and let him make his case—but pressed ahead with the meeting and got (we believe) a good result. And Marciniak certainly didn’t hijack the Brilinta review, despite a clever and compelling presentation. In both cases, when it came time to make decisions, the committee asked FDA’s leadership for guidance—not the dissidents.

5. Made in the USA Counts At least when it comes to clinical data, it does. The Avandia re-review focused extensively on the reliability of the RECORD Trial, a massive study conducted mostly outside the US. Similarly, Brilinta’s data looked more brilliant outside the US than in North America—though the committee ultimately supported approval in the US anyway. AZ previously found itself defending skepticism about ex-US data for the RSV therapy Rezield which was rejected by the committee and received a complete response letter in late August calling for new trials in the US population. Don’t expect the concerns about the quality of international trials to die down any time soon.

6. The Era of the Observational Trial is (Almost) Here One recurring theme in Avandia, the opioid REMS and the REMS public meeting focused on the potential for FDA’s Sentinel active surveillance system to help provide better answers to questions about the risk/benefit profile of medicines (and the utility of controls on medicines) in the real world. The Avandia vote, in particular, felt a lot like a sign that the golden era of randomized controlled trials is winding down. The majority recommendation to continue marketing of the drug and complete post-marketing safety studies shows that RCTs are still what committees want to use as a basis for regulatory decisions. But that support is weakening—and it probably won’t be long before observational trials are more commonly accepted as the best way to develop post-marketing data for regulatory decisions.

7. So Is the Comparative Effectiveness Era The Brilinta database includes an 18,000-patient head-tohead trial suggesting superiority to Plavix, while the Avandia re-review focused extensively on comparisons to the other drug

Regulatory Policy

in the class Actos. The weighing of those datasets surely offers a taste of what is to come as federally directed comparative effectiveness research takes off in the years ahead.

model: in many cases, FDA’s outside advisors do have more experience with the new regulatory tools than the individual review teams involved in a specific application.

8. Advisory Committees are still Unpredictable

9. Conflict of Interest Is Still a Big Headache

FDA has always been skilled at managing advisory committees, and displayed all its skill in shaping the Avandia meeting. Though not as high profile, we think the oncology group probably did even better getting what it wanted from the Avastin committee. But both the Qnexa review and the opioid REMS outcomes clearly surprised the FDA managers running the meetings. That helps keep things fun, but it also underscores a reality of an era of change in the regulatory

The only fallout from the Avandia meeting (so far) that hasn’t played well for FDA are questions about the apparent failure of one or more committee members to disclose all relevant industry relationships. For any fair-minded observer, the “smoking gun”—an apparent failure by Thomas Jefferson endocrinologist David Capuzzi to disclose paid speaking engagements for GSK—is really a tempest in a teapot. Capuzzi may have been among the minority supporting no further

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

Regulatory Policy

action on Avandia, but he clearly didn’t have much impact on the overall outcome of the meeting. But that doesn’t mean the flap over his disclosure won’t have an impact on FDA. There was some hope that FDA could start to ratchet back on vetting of committee members; forget about that. Instead, we wonder whether FDA won’t find itself under pressure to devote yet more resources to the vetting process, since—in this case at least—it would probably have been relatively simple for FDA to determine on its own that there was a relationship between Capuzzi and GSK. After all, GSK is disclosing that publicly. Going forward, all those disclosures will be public, and we expect FDA will be expected to check the database to verify committee member CoI disclosures.

10. The Drug Center Management Looks Comfortable and Confident There were plenty of chances to see FDA’s top review managers in action during July—and plenty of occasions to marvel at their endurance, especially under the immensely trying circumstances posed by airing internal disputes over a product like Avandia, with the whole world watching. But as the month ended, at least, it sure seemed to us that FDA’s top managers remain comfortably and confidently in charge. If that impression is correct, the improving regulatory climate at FDA should continue to improve. rpm Comments? E-mail the author at michael.mccaughan@previsionpolicy.com

Advisory Committees

FDA’s Brilliant Management of Avandia Re-Review Provides Flexibility on Final Decision Going into the Avandia re-review, FDA looked stuck between a rock and a hard place. Coming out of the FDA advisory committee meeting, the agency has a full set of options to choose from that would likely be viewed as a credible outcome by the public. But possible surprises remain. By Ramsey Baghdadi The Food & Drug Administration’s top priority for the rereview of GlaxoSmithKline’s diabetes drug Avandia is to deliver a credible decision to the American public. The stakes are huge: not only for the sponsor (GSK) and the rest of the diabetes field (Takeda, Lilly, Amylin, Novo Nordisk, Merck, Bristol-Myers Squibb, AstraZeneca, etc.) but for the entire biopharma sector. A failure by FDA to handle Avandia well will re-energize advocates for a radical change to the drug safety regulatory model in the US. (See “Open Minds on Avandia?” The RPM Report, June 2010.) Going into the July 13-14 advisory committee review, delivering a credible decision seemed like a difficult task that bordered on insurmountable because of the highly charged politics and regulatory history of Avandia. Following the meeting, the goal of delivering a credible decision appears to be much more achievable. That didn’t happen by chance. FDA’s management of the joint advisory committee meeting was carefully planned and executed—nothing short of brilliant. The agency melded the combination of skills from experienced career officials who have made tough regulatory decisions in the past and the political savvy brought to bear by the new leadership at the agency. One result was an amazing two days. As Cleveland Clinic Cardiologist Steve Nissen summed it up in an interview after

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

the meeting: “That was great theater, wasn’t it?” But the theatrics of the two-day event shouldn’t overshadow what FDA was able to accomplish in the face of a drug safety wild card issue that threatens to throw the agency off course from the progress it has made in the past two years. The advisory committee played out in all its unpredictable glory—but the key deliverable remains a credible final action by FDA. And, thanks to the careful preparation FDA put into the committee meeting, that outcome looks very likely. The way the meeting was set up contributed greatly to a necessary end for the agency: it provided great flexibility to FDA in making a final decision on Avandia.

The Right Questions Getting the right answers often begins with asking the right questions. In the case of advisory committees, the crafting of the questions to the committee has always been a key piece of FDA’s preparations. The non-voting questions are critical because they shape how the committee will eventually vote, and the voting questions are viewed as the bottom-line outcome to all those who are watching. In short, the writing of the questions can be described as policy art. One senior FDA official says that the writing of the questions needs more attention. “An issue from my point of view

is: are we as skilled as we should be at writing the questions? There are very different and elaborate traditions at the various divisions in terms of how questions get written. It probably needs attention and maybe more than we’ve given it so far. A lot rides on those things.” With that in mind, the difference in the questions at the 2007 Avandia advisory committee and the questions in 2010 illustrates FDA’s increased sophistication in managing the final process of the advisory committee meeting, and underscores the nuanced drug safety tools at the agency’s disposal as a result of the 2007 FDA Amendments Act. In 2007, there were five questions—two of which required votes: (1) do the available data suggest a conclusion that Avandia increases cardiac ischemic risk in type II diabetes? (20 yes, 3 no) and (2) does the overall risk-benefit profile of Avandia support its continued marketing in the US? (22 yes, 1 no). The seemingly contradictory result—overwhelming support for the idea that Avandia increases risk of heart disease and equally overwhelming support for continued marketing—made it all but impossible for FDA to appear to be an effective public health regulator. Defending the seemingly contradictory advisory committee votes was all the more difficult because, as FDA noted in 2010, the committee changed the wording of the first question to include the word “suggest” rather than a more firm conclusion about risk—a subtlety lost in much of the more recent discussion of that outcome.) This time around, there were nine total questions, six of which were voting. More importantly, the question on whether to keep Avandia on the market or recommend withdrawal gave advisory committee members five options to choose from. Rather than framing the debate as a “yes” or “no” on marketing Avandia, FDA offered a multiple choice question ranging from eliminating restrictions altogether, through the status quo to applying new REMS tools, or outright withdrawal. Placing all options on the table was presented as a fair and neutral way to solicit advice, but also virtually ensured a split that would not box FDA into a corner. And, intended or not, FDA got a split vote. Question 8 read as follows: “What regulatory action does the panel recommend FDA take on Avandia? A) Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding risk of ischemic CV

events, or B) Allow continued marketing and make no changes to the current label, or C) Allow continued marketing and revise the current label to add warnings, or D) Allow continued marketing, revise the current label and add additional restrictions on use, or E) Withdrawal from the US market.” The committee voted as followed: A. Remove the warning—0 B. Status quo—3 C. Tougher warning—7 D. Restrictions on use—10 E. Withdraw the product—12 With that outcome, FDA can credibly argue that a majority of panelists (17) voted to keep the drug on the market with tougher warnings and/or restrictions on use. At the same time, however, the agency can also pull the drug from the market with supporting cover from the panel, saying the largest single bloc of members (12) voted to withdraw Avandia. Coming out of the meeting, it seems unlikely that FDA will opt for withdrawal, especially as that could prove more destabilizing for the agency as a whole. As one Drug Safety & Risk Management Advisory Committee member points out, Avandia has been used in so many patients that pulling it from the market without the consent of the committee could create confusion and a public health scare over why the agency was taking such extreme action. Still, the majority vote for withdrawal also gives FDA important leverage in negotiations with GSK if the agency chooses to severely restrict use of Avandia and the sponsor isn’t as cooperative as FDA would like. In addition to providing the agency with flexibility, the split vote demonstrated how difficult it is to interpret the mélange of available evidence: flawed randomized clinical trials, meta-analyses, and observational studies. FDA drug center leadership, particularly Center for Drug Evaluation & Research Director Janet Woodcock and Office of New Drugs Director John Jenkins, have argued that the evidence is not clear cut. (At the more extreme end of that view, Office of Drug Evaluation I Deputy Director Ellis Unger referred to meta-analyses during the committee meeting as “garbage in, garbage out.”) The panel’s interpretation of the incredible amounts of data

Advisory Committees

Exhibit 1

Commissioner Hamburg Sets the Tone

“Let me start by expressing my deep appreciation for the efforts of this advisory committee. I know that you have given up a great deal of time to help the FDA think through a series of important and challenging questions about the safety of rosiglitazone. You’ve submitted to a very complex screening procedure, applicable to all advisory committee members on all of our advisory committees, and you’ve had the pleasure of reading through many hundreds of pages of background materials and some pretty complex and technical stuff so I know that you’ve already been working very hard. And of course many of you have traveled from far and wide to be here in lovely Gaithersburg, and all of you have gotten up bright and early this morning to be here to start off what will be a very full two days of meetings and discussions. Today you’ll hear many hours of presentations from invited speakers and have the opportunity to ask them questions, and I strongly urge you to do so. Tomorrow, you’ll hear additional presentations and also from the public, and then you’ll have several hours to engage in discussions on a series of important questions. There’s been a lot of back and forth in the public and in the professional media and journals and meetings on all sides of this issue, but your job is to try to cut through all of that and to focus on the evidence. All of your comments, up to and including your votes, will help FDA as we move forward with our assessment of this important safety issue. My advice is that you keep an open mind, apply your sharpest scientific thinking, and bring your best judgment to the questions facing the agency. Follow the science wherever it leads, and the rest will fall into place. Many of you are clinicians, and you know how hard it is when a patient faces a choice of two different pathways for treatment and intervention for a serious condition, especially when there’s some level of uncertainty about the underlying questions. In that situation, you review all the facts, do your best to think clearly about them, and you give the best advice that you can. And that’s all that we’re asking you here today. Let me make one final comment. For some advisory committees, all of the FDA opinions line up nicely with each other. The issues are clear, and all of the agency’s scientists are in agreement. And as you know, that is not the case today. Rather than try to summarize or synthesize these competing perspectives into a set of bland documents or presentations, we thought it best for you to read their words for yourselves, hear from the key scientists of the agency directly, and factor their perspectives into your thinking. Doing so is hard work, I know that, but it will be immensely valuable to the agency. Everything that you’re doing over the next two days really matters. We wish you the best of luck in your discussions. We really appreciate the time and effort that you are putting in. The work of these advisory committees is invaluable to the agency and to ensuring that we can do the very best in fulfilling the mission of our agency to promote and protect the health of the public. Thank you very much, and I will let you now plunge into the important task before you. Thank you.”

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

and the final votes emphasized the disagreements over the interpretability of the data, giving FDA some absolution for not withdrawing Avandia altogether in 2007. In other words, no matter how FDA ultimately acts, it can emphasize that there is nothing black-and-white about the issue, no matter how some critics frame the decision.

Hamburg Strikes the Right Tone Setting the questions was key, but so was setting the tone for the meeting itself. The mood going into the first day of the advisory committee was extremely tense; a second postmarket review of a drug as big as Avandia was unprecedented. The internal disagreement over whether the drug should stay on the market or be withdrawn had played out publicly leading up to the committee meeting. In fact, a damaging story in the New York Times that came out the same day as the meeting alleged, with emails and testimony from a pending court case, assertions of a GSK cover-up of negative data and claims that FDA Office of New Drugs Director Jenkins had inappropriate contact with the company during FDA deliberations over the labeling. Moreover, almost all of the major players at FDA involved with the 2007 decision to keep the drug on the market and the 2010 controversy were present at the committee table giving the whole affair the aura of a battlefield in the pre-dawn hours, with separate army encampments stirring with activity. In a short, elegant introduction to the meeting, FDA Commissioner Margaret Hamburg defused much of the tension. (See Exhibit 1.) She started by noting it was very

Advisory Committees

rare for an agency commissioner to address an advisory committee “but with the amount of attention that this meeting and this issue has been receiving, I thought it important to speak with you for a few minutes as this session begins.” In her brief remarks, Hamburg thanked the committee for its hard work and submitting to extraordinary scrutiny as a condition of participation. A little acknowledgement goes a long way, of course, but in this case a reminder of shared mission was critical—as was the underscoring of the careful vetting process to protect the credibility of the committee process. Hamburg continued by acknowledged the broad public debate over the issue, and then delivered a widely quoted charge to the committee: “My advice is that you keep an open mind, apply your sharpest scientific thinking, and bring your best judgment to the questions facing the agency. Follow the science wherever it leads, and the rest will fall into place.” She then prepared the committee for what would prove to be its real task: adjudicating among several divergent views within FDA about the best approach to Avandia. “For some advisory committees, all of the FDA opinions line up nicely with each other,” Hamburg said. “The issues are clear, and all of the agency’s scientists are in agreement.”

“As you know, that is not the case today. Rather than try to summarize or synthesize these competing perspectives into a set of bland documents or presentations, we thought it best for you to read their words for yourselves, hear from the key scientists of the agency directly, and factor their perspectives into your thinking.” Hamburg also noted the immense amount of material presented to the committee, reinforcing the agency’s commitment to a fair and open scientific discussion—and subtly underscoring the theme that there is no simple answer.

Total Transparency and Messaging The level of transparency was a high point of the Avandia re-review and is sure to serve as a blueprint for future committee meetings focused drug safety controversies. According to an analysis by “The Pink Sheet”, there were 981 pages of background material, 606 presenters’ slides, 25 formal speakers, 4 sponsor presentations (1.25 hours), 11 FDA presentations (3.5 hours), 9 outside expert presentations (2.75 hours), 6 open public hearing presentations (1 hour), and 17 hours worth of total committee deliberations over two days. Several advisory committee members applauded the agency for the seemingly unprecedented amount of data and presenta-

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Advisory Committees

tions made to the panel. Said voting committee member Marvin Konstam, Tufts-New England Medical Center: “There’s been a lot written in the last few days and weeks about the FDA being broken. As someone who has worked with the FDA for over 20 years, I don’t believe it’s at all broken, and I think this meeting has been an enormous testimony of that. I don’t think it needs any reorganization from the outside. I think that perhaps some of the people inside the FDA might work on getting along better together, FDA presented a united but maybe they can front to those watching figure that out inside their walls.” that played to the pubTransparency was lic more like a group of a key piece of FDA’s scientists with differing messaging strategy interpretations of a vast as well. For example, amount of data than two the week before the rival factions within a govadvisory committee ernment agency bitterly was held, the agency brought in media to divided over the safety of take a sneak peak at a blockbuster drug. the agenda and questions. At the briefing, Woodcock explained the regulatory history of Avandia and the reason for the re-review. Although the full FDA briefing documents were not given to the media in advance, an index of the package was provided to journalists, and the CDER director went through the most important specific pieces of information within the documents that FDA wanted advisory committee opinions on. Moreover, the management of the actual meeting proceedings by panel chair Kenneth Burman, Washington Hospital Center, ensured the meeting ended in order for the outcomes of each day to make the evening news on the major television networks; CNN broadcast the final vote live to its viewers on the second day.

Visual Unity: The Drug Safety Team Back In The Fold One of the more effective visuals at the panel meeting was that of the drug safety officials, Gerald Dal Pan and David Graham, sitting with the rest of the FDA team. In fact, Dal Pan was seated next to Woodcock at the head of the FDA table. It served as a stark contrast to the 2007 meeting when Dal Pan and Graham appeared as a separate and seemingly unequal FDA team arguing that Avandia should be withdrawn. This time, FDA presented a united front to those watching

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

that played to the public more like a group of scientists with differing interpretations of a vast amount of data than two rival factions within a government agency bitterly divided over the safety of a blockbuster drug. In fact, Woodcock was careful to refer to Graham’s observational analysis of Medicare beneficiary data comparing the cardiovascular safety profile of Avandia to Actos as “our analysis” during the pre-meeting briefing with reporters.

More Surprises Likely In the end, all of FDA’s preparations for the two-day event paid off by giving FDA something it seemingly didn’t have before the meeting: flexibility. By any slice of the vote, the agency can deliver a decision that had strong support. But that doesn’t mean there won’t be negative headlines. For example, just one week after the meeting, FDA announced that it was asking GSK to put a temporary halt to the prospective TIDE trial comparing Avandia to Actos (“The Pink Sheet” DAILY, July 21, 2010.) “The FDA has instructed GSK to update investigators, institutional review boards and ethics committees involved in the TIDE trial regarding new safety information presented at the joint FDA Advisory Committee meeting held on July 13 and 14, 2010, along with information regarding the deliberations and votes of that meeting. This information can be used by investigators and IRBs to update existing informed consent information for current trial participants.” The halting of the trial could be the first step in pulling Avandia from the market or FDA may indeed be updating patient consent information—a key focus during the panel meeting regarding TIDE. Another unwelcome surprise: despite FDA’s best efforts, two committee members may have had conflicts of interest, first reported by Pharmalot and the Wall Street Journal. David Capuzzi, Thomas Jefferson University, has been paid by GSK in the recent past for talking on behalf of the company. Abraham Thomas, Henry Ford Hospital, has been paid by Takeda; both were voting members of the joint committee meeting. There are likely to be more surprises, whether they come from FDA, GSK or Capitol Hill. Nevertheless, FDA was able to take control of what it could: transparency of data and presenters, the makeup of the advisory committees, the development of the questions, and the run-of-show, among other aspects of the re-review. In doing so, FDA took a big step to restoring the credibility it lost in 2007 with the final outcome. That was the result the agency needed most. rpm

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Advisory Committees

FDA Has Key New Constituency for REMS:

Advisory Committee Members

FDA’s advisory committee members seem to be adopting the new postmarketing REMS authority with more enthusiasm than FDA’s own staff. Many of the advisory committee members – especially people who have served on the Drug Safety & Risk Management Advisory Committee – are jumping at the middle ground solution (between approval and rejection) offered by REMS. The Avandia re-review on July 13-14 demonstrated the strong appeal of REMS in a tough regulatory situation. By Cole Werble Duke cognition researcher Ruth Day and Colorado School of Public Health epidemiologist Elaine Morrato are part of an important new constituency for the Food & Drug Administration: a cadre of advisory committee members who are sending tough issues back to FDA and drug sponsors with instructions to find enhanced risk management and other post-marketing control solutions. Day and Morrato were vocal contributors to the July 13-14 re-review of cardiovascular safety issues with GlaxoSmithKline’s Avandia. They were two of the 10 committee members who voted for imposing a formal Risk Evaluation & Mitigation Strategy on Avandia as a condition for continued marketing. Day, a former member of the Drug Safety & Risk Management Advisory Committee and a frequent temporary voting member on other committees, said she would have voted for removal of Avandia from the market except for the option of extensive post-marketing controls offered by the new REMS authority. Day noted during the Avandia meeting that she has served on just about every Center for Drug Evaluation & Research drug advisory committee. “The only reason that I caved” and voted for post-marketing controls instead of market withdrawal, Day said, “is because I have a lot of knowledge and experience with the REMS package and I would recommend that something very tough be instituted” for Avandia.

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

Morrato, a current member of the Drug Safety & Risk Management Advisory Committee, similarly said her experience with REMS options led her to believe that a post-marketing program could include a firm acknowledgement by the patient and physician of a discussion of risk information. “I think the informed consent process which can be part of the requirements of REMS is an important addition. I am struck by the fact that the original 2007 warning changes actually had a big impact….I am struck with who is left on Avandia and why. Before I say we should take it off the market we need to do a better job of understanding why are there still patients taking it.” The votes and commentary during the meeting by Day and Morrato demonstrate the common thread of advice that FDA is getting from an influential group of advisors, who are applying REMS to situations faced by a wide variety of agency advisory committees. Day and Morrato were joined by seven other members who voted to keep the product on the market with stronger labeling to create a majority of 17 out of 32 voting members urging to keep the product on the market with more restrictions. Three members voted to leave the drug on the market with no changes to the current label. In a major swing from the 22-1 vote to keep Avandia on the market in July 2007, the largest single block of votes to the

multiple choice list of options offered by FDA at this meeting went in favor of removal of the product: 12 of the 32 members of the committee chose that option. However, several of the committee members voting for removal suggested that strict controls might suffice. One of the most forceful voices against the product’s safety record at the meeting, Thomas Fleming (statistician from University of Washington), voted for withdrawal but said that he could see the appeal of REMS controls as an alternative. “I wavered between Option D (REMS controls) and Option E (Withdrawal),” Fleming acknowledged.

Drug Safety Committee Members, Statisticians Are REMS Advocates A cadre of outside drug safety advisors is being assigned to special issue situations facing the agency, and they seem to come to the meetings with a predisposition towards REMS solutions. Fleming is also one of this relatively small group of advisors participating in many different advisory committee meetings. The agency only has a handful of pre-cleared and experienced statisticians to recruit for the large number of meetings that need them. If FDA wanted to limit the number of REMS programs being assigned to sponsors, it would would be hard pressed to accomplish that. The advisors who travel from committee to committee have learned to like the flexibility offered by REMS recommendations, and because the recommendations occur in public and are part of the public record it will be hard for FDA to pass over many of them. Even as FDA faces increasing pushback from providers who are unhappy with the top-down approach of some of the more far-reaching REMS, the agency is now facing this core of agency advisors who are inclined to pick rather elaborate programs as preferred paths for FDA and the sponsors to pursue. For Avandia, the suggestions for the REMS ranged from registries, to patient and physician attestation systems, to limitations on prescribing to specific medical specialties (endocrinologists), to use only in patients who have failed other therapy. The patient representative on the panel, Rebecca Killion, who repeated her 2007 vote to keep the product on the market, this time added a call for a strong physician education system on the risks associated with Avandia. Another compelling example of the importance of the new post-market controls to advisory committee members was the vote of Clifford Rosen (Maine Medical Center). Rosen was the

chair of the 2007 Avandia committee. He voted to keep the product on the market in 2007 with a simple call for “a warning … particularly for individuals with sever atherosclerosis on nitrates and insulin.” At the July 13-14 meeting, Rosen said he was pushed close to voting for removal. He described his vote for the “D” (REMS Option in FDA’s multiple choice question to the committee) as a very close call – “D-3/4.” “My argument is that that we need to have very tight control over the administration of this drug,” Rosen said. He noted that he is attracted to the opportunity that a REMS offers for collecting more data on Avandia. “I would like to see the FDA have a registry and that it be limited strictly to endocrinologists who can not only prescribe this drug but also collect data on those individuals who are still on rosiglitazone to find out what is really going on with those people and their long-term safety. The REMS option also appeals to advisory committee members as a way to finesse the issue of protecting access for a potentially small patient population who may benefit specifically from a questioned drug. Dale Hammerschmidt (University of Minnesota) also described himself as a member of the “D and a half club” – voting for the REMS but attracted by market withdrawal. “As a non-endocrinologist,” Hammerschmidt said, he was “concerned that there might be a small group of people out there who don’t do well on pioglitazone (Actos) for which this might be a good salvage drug and if we are going to leave that option available to people, I thought some sort of controlled access and monitoring would be important. For all of her strong pushing for a REMS at the recent Avandia meeting, Day is not new to that approach. She actually urged a risk management plan in 2007. Day told the first Avandia meeting that she felt that risk management programs were not getting enough attention. At that point, she felt that “about half of the committee” had any experience with those types of programs. She said that the sponsor also had a “quite underwhelming” risk management suggestion. The climate has changed dramatically at FDA and in the minds of its advisors. With strong advocates for REMS solutions providing very public outside advice, FDA is going to be getting a lot of recommendations like the Avandia vote in the future: don’t withdraw the product, control it. Approve the product, but only with a closely defined post-market program. rpm Comments? E-mail the author at cole.werble@previsionpolicy.com

REMS Strategies

Opioid REMS: Committee Rejects FDA

Proposal, But Sponsors Should Embrace It The combined Anesthetic & Life Support Drugs and Drug Safety & Risk Management advisory committees voted strongly (25-10) against FDA’s proposed class-wide educational REMS for long-acting opioids; but the vote does not stop the process. In fact, FDA may have achieved much of what it set out to do by just by proposing a class REMS in the area. By Cole Werble

The July 23 vote against the Food & Drug Administration’s proposed post-market education campaign for long-acting opioids was numerically large but only temporarily painful for FDA after 18 months of work developing a consensus among stakeholders for the program. The defeat is unlikely to be significant for FDA in the long-run. The agency came away from the two-day session of its Anesthetic & Life Support and Drug Safety & Risk Management Advisory Committees with the message of strong support for a post-market control program for the long-acting opioids. Office of New Drugs Director John Jenkins said after the meeting that the agency heard support for an opioid Risk Evaluation & Mitigation Strategy from all committee members, even those voting against the current FDA proposal. Jenkins pointed out that the agency looks more carefully at the reasons and explanations of votes by members rather than the vote itself. The agency’s first impression of the July 22-23 meeting: a strong endorsement of REMS for opioids; similarly strong advice to look again at ways to assure that education is taken seriously. More importantly, the agency has spent a year-and-a-half with drug sponsors in the class hammering out the type of program that would suffice for a class REMS. From a practical perspective, that work was an intensive education process informing sponsors what it will take to get a new product approved in the class. (See “The Opioid REMS,” The RPM Re-

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port, February 2010 and “Class-Wide REMS,” The RPM Report, June 2010.) The agency did not get an endorsement for its proposed class-wide approach, but any company seeking a new formulation opioid approval now has substantial warning what type of post-marketing program it will take to get through the FDA process. There are two products in the class (the market leader, Purdue Pharma’s OxyContin and new entrant from Covidien Inc., Exalgo) already under new REMS programs which closely mirror the proposed class program. In light of the vote of the advisory committee, those requirements are not going to go away. They can only get more restrictive.

FDA Opts for Softer Touch FDA’s proposal for the class wide REMS, publicly released a month ahead of the committee meeting, takes a relatively soft touch—requiring manufacturers to establish patient and prescriber education programs, but not requiring training as a condition of prescribing the drug itself. (See “FDA’s Opioid REMS Proposal.”) In addition, FDA proposed to limit the scope of the REMS to the long-acting opioid class, despite a strong internal argument that the scope should apply to all opioids.

The committee objected on both fronts, and it is possible that the agency would change its proposal. However, given the intense work done in preparing the proposal and the generally positive reception it received from manufacturers and health care providers, the agency seems likely to continue to follow the soft touch path for the time being—at least when it comes to making decisions about individual pending application. (The agency is accepting public comments on the REMS proposal through October; a final decision—and the complex task of implementing the REMS—will come sometime thereafter.) For manufacturers affected, the REMS will mean an ongoing cost of doing business, and a routine period of uncertainty surrounding the assessment of success. However, the proposal could have been far more onerous. Ideas considered and rejected (for now) by the agency include: • Registry of patients, physicians and/or pharmacists; • Inclusion of all opioids (not just long-acting ones) in the scope of the REMS; • Distribution restrictions or other interventions in the supply chain; • Tying DEA (Drug Enforcement Administration) registration to proof of successful education on opioid use. Instead, the proposed REMS will rely on physician and patient education with materials pre-approved by FDA as the key post-marketing control tool.

Stronger Options Already Rejected by FDA The agency considered but backed away from a physician registration and verification system at the point of dispensing to make sure that physicians are not over-prescribing longacting opioids. “FDA considered proposing that the REMS require individual prescribers or patients to enroll in a REMS program and real time verification of prescriber training at the pharmacy level, but decided that the proposed REMS should not include these requirements at this time,” FDA Division of Anesthetics & Analgesia Products Director Bob Rappaport, MD, said in a June 22 memo to the members of the advisory committees. The agency’s proposal is the product of a broad year-anda-half-long effort by the agency that entailed the work of 70 staff members broken up into eight working groups. The FDA team held three meetings over five days for stakeholders and a two-day offsite retreat. FDA proposed trying to walk a fine line on the education re-

quirement: stopping short of demanding proof of education of each prescriber but attempting to show that educational efforts have been undertaken seriously and have a positive effect on physician knowledge. CME providers appear well-positioned for the opioid effort as intermediaries which can assure FDA of the independence of training (distanced from the marketer) and as a way to entice physicians to participate. (See “FDA Turns Back to CME as Opioid Control Tool.”) The agency does not want to estabThe agency’s proposal lish a program at this point to test prescribis the product of a broad ers on their knowlyear-and-a-half-long edge of opioids and effort by the agency that selecting appropriate entailed the work of 70 patients and dosing/ staff members broken dispensing quantiup into eight working ties for opioid use. groups. Instead, FDA is proposing to throw that burden back on the drug marketers, who will be required through surveys and evaluation to show that their programs are having a positive effect on prescriber knowledge of opioid use. FDA does point out that an effective way to assure physician acceptance of the new education programs would be to tie Drug Enforcement Administration registration for controlled substances prescribing to successful completion of training. That, however, would take new legislative authority. The agency will not push for that authority for DEA at this point. The demonstration of the effect of the program on physician knowledge is also short of what FDA could have asked for from the sponsors. The agency could have asked specifically for data from tracking systems to show that opioid misuse has declined due to the REMS training effort. There is mention in one of the descriptions of the metrics that FDA expects during the evaluation part of the REMS that implies that sponsors will be responsible for data beyond physician understanding: FDA will expect information on “certain behaviors (such as nonmedical use of prescription opioids), adverse events (unintentional overdose, addiction, and deaths related to prescription opioids), and access to care.” The agency says that it will conduct separate observations

REMS Strategies

of opioid use data to see how well the education-based REMS works – i.e. how effectively it reduces inappropriate use. “FDA has initiated collaborations with a number of its Federal partners to develop metrics to monitor changes in prescribing behavior, non-medical use of opioids, and certain adverse outcomes (overdose, addiction, and death),” the agency noted. The agency is not going to require a patient registry; there are four million patients taking long-acting opioids and the burden to the system appeared too great to FDA. The agency is, however, going to try to work with medical societies and other groups to encourage the use of “pain treatment agreements” between patients and prescribers. FDA observed “these agreements are used by some prescribers to define the responsibilities of the patient regarding use of the opioid analgesic and the patient’s consent to appropriate monitoring of the patients medication use and behavior by the physician.” Finally, FDA also opted to limit the REMS to the long-acting opioids; specifically over-ruling one of its working groups which recommended that the program cover all opioids. In

the context of the “soft touch” approach, the agency may be wary of imposing a less restrictive program on some of the shorter acting products where it may see restricted distribution or other options as more appropriate.

Advisory Committee Not Satisfied, Pushes For More Teeth In Opioid REMS After all that work, the advisory committee vote had to be disappointing for the agency. Thirty-five outside advisors – including two-dozen temporary voting members selected to represent the broad scope of practitioners involved in the abuse and misuse issues surrounding opioids – voted decisively (25-10) against FDA’s approach. But the majority of advisory committee members rejecting FDA’s proposal attacked it as not being strong enough. They supported post-marketing controls in the form of a REMS – an important point not lost on FDA managers at the meeting, and one that sponsors should take to heart as well in working with FDA on specific applications. The “no” votes wanted FDA to create a program that would

FDA’s Opioid REMS Proposal Here is the proposed class-wide REMS developed by FDA and presented to the advisory committee.

Goal The proposed goal for the REMS would be: • Reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of long-acting and extended-release opioids while maintaining patient access to these medications. Adverse outcomes of concern include addiction, unintentional overdose, and death. This will be accomplished by educating prescribers in appropriate patient selection, dosing, and patient monitoring and by educating patients in the safe use, storage, and disposal of opioids.

Elements of the Proposed REMS In addition to the Goals, the REMS would include a Medication Guide, Elements to Assure Safe Use, and a Timetable for Assessment of the REMS. Medication Guides The Medication Guides would include “class” language regarding the safe use of all opioid drug products and may also include product specific information.

Elements to Assure Safe Use The proposed elements to assure safe use include prescriber and patient education. Prescriber Education Stakeholder comments and the available data suggest that prescriber and patient education will be the key components of a successful risk management program. Therefore, FDA is proposing that sponsors be required to develop an educational program that would educate prescribers about appropriate patient selection, dosing, and patient monitoring. Prescribers would also be trained to counsel patients on the safe use, storage, and disposal of opioids. FDA would encourage sponsors to develop the prescriber training in partnership with an appropriate, independent third party, and FDA would approve the training content. Sponsors would also be encouraged to explore appropriate incentives (e.g., CME credit) to encourage prescribers to undertake the training. Although prescribers would not be required to demonstrate evidence of training to prescribe these products, sponsors would be required to demonstrate that prescribers have been trained and that knowledge of

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appropriate use has improved via surveys of the prescribing community. Patient Education Sponsors would also be required to provide patient education sheets for prescribers to use in their interactions with patients, and sponsors would be required to encourage the prescribers to use these sheets when counseling patients. The content of these patient education sheets would be FDA approved. FDA considered proposing that the REMS require individual prescribers or patients to enroll in a REMS program and real time verification of prescriber training at the pharmacy level, but decided that the proposed REMS should not include these requirements at this time. FDA heard from commenters that a requirement for individual prescriber registration and real-time verification of training at the pharmacy before filling an opioid prescription could cause some prescribers and pharmacies to “opt out” of the program with potential adverse consequences to access to pain medications. More than 1 million prescribers are registered with the Drug Enforce-

REMS Strategies

require mandatory training and to a lesser extent to consider extending the program from long-acting opioids to immediate release products as well. That second change in the scope of the REMS would amount to a 10-fold expansion in the reach of the program, extending it from covering approximately 23 million Rxs for long-acting opioids to 258 million Rxs for longacting and immediate-release opioids. Typical of the explanations by committee members voting no: Drug Safety & Risk Management member Lewis Nelson (New York University School of Medicine) said “education will offer very little benefit. We really need to focus the REMS on different factions of people that are involved: clearly the prescribers and dispensers need to be trained and they need to be validated to be competent and capable.” Committee chair Jeffrey Hirsh (Oregon Health & Science University) said “I certainly support a REMS program. I think a critical element is missing in this proposal: the requirement for provider learning, definitive competencies, and assessment of those competencies so that we don’t come back eight years from now and say this is inadequate.” Temporary voting member Dennis Turk (University of

ment Administration to prescribe opioids. Approximately 700,000 of these prescribers prescribe long-acting and extended-release opioids. Approximately 66,000 pharmacies are registered with DEA. In the long term, linking the education to the existing DEA registration system would more efficiently ensure appropriate education of physicians, but would require legislation. FDA also considered whether the proposed REMS should include enrollment of patients in a registration system. Numerous comments at the public meeting and in the docket stated that a REMS that employs a patient registration system would be overly burdensome and create a stigma for pain patients that could adversely affect patient access to necessary medications. Nearly 4 million patients are prescribed long-acting or extended-release opioids annually, and enrolling this many patients in a patient registration system would be an enormous undertaking with unpredictable effects on patient access. For these reasons, FDA is proposing a more limited REMS at this time, but will carefully monitor the effects of the

Washington, department of anesthesiology and pain medicine) also offered support for a REMS and a call for more specifics on how the program would accomplish behavioral change among prescribers. “I strongly agree with the REMS process,” Turk declared. “However, I didn’t see any convincing evidence that anything that is being proposed in the current REMS plan is going to have any impact in actually making a change in the behaviors that we are concerned about.” Indeed, the final committee vote seemed to mirror the comments made by the past chairman of the committee during a presentation to open the second day. (See “‘Voluntary Education Does Not Work.’”) Jenkins told the committee during its deliberations that FDA had specifically considered a more restrictive program that would have entailed having every prescriber enrolled in a system for prescribing opioids with a real-time verification of adequate training. Jenkins noted that FDA was reluctant to create that type of system when the Drug Enforcement Administration already has a scheduled substance registration system for prescribers. Jenkins said the agency wanted to avoid

program and may consider further steps if the REMS does not prove effective in curbing serious adverse outcomes resulting from inappropriate prescribing, abuse and misuse.

Timetable for Assessment and Metrics All REMS are required to contain a timetable for assessment, and for a REMS of this size to address a problem of this complexity, assessing the effectiveness of the program as well as its impact on appropriate access to pain medications is critical. Understanding whether the proposed REMS, once implemented, has been successful in reducing serious adverse outcomes from the misuse and abuse of long-acting and extended-release opioids is important and will determine whether additional efforts or future REMS modifications are necessary. However, measuring the outcomes associated with the proposed REMS will be a challenge. The recommendations for assessing the proposed REMS include using multiple metrics and data sources that focus on

outcomes related to both extended-release products as well as all opioids. The existing databases are insufficient to adequately measure the impact of the REMS, and in addition to working to improve these databases FDA is exploring new data sources and methodologies for making better use of available data. To do this, FDA has initiated collaborations with a number of its Federal partners to develop metrics to monitor changes in prescribing behavior, non-medical use of opioids, and certain adverse outcomes (overdose, addiction, and death). In addition to these FDA initiatives, sponsors will be expected to assess the REMS, and FDA and sponsors will need to coordinate their efforts to provide the most complete evaluation. Sponsors will also be required to provide the support and resources necessary to improve the currently available data sources and to create novel and more efficient and effective metrics for measuring the impact of the REMS on abuse and misuse of opioid analgesics, as well as the impact on patient access to these products.

REMS Strategies

physician-patient interface. FDA can respond to the July 23 vote by demonstrating that FDA Needs To Show Impact From First REMS they can enforce education/training programs effectively. At Jenkins and other FDA officials at the meeting pointed out one level, the no-vote to the current proposal does not end the to the committee that FDA regulates drug sponsors and has process; it means that FDA must do a better job of selling the to work through control of the sponsor to try to address the ability to enforce the provisions in the proposal. The committee focused on ways to try to link the DEA registration system FDA Turns Back To CME as Opioid Control Tool or board licensure to Continuing medical education has been under attack in Washington in recent successful completion of years, criticized as representing a way around FDA’s control of medical opioid training. FDA ofpromotion. Now, FDA is turning back to CME as the keystone to controlling a ficials pointed out several tough drug overuse/abuse situation. times that those types of solutions to turning FDA-approved CME? That may be one outcome suggest some skepticism about the value of education in training take of the massive effort undertaken by the Food & CME in REMS—but also some interesting future the effort out of FDA’s Drug Administration to establish a class-wide directions that FDA-approved CME could take. Risk Evaluation & Mitigation Strategy for longThe FDA working group on physician educapurview and beyond its acting opioids. tion which reviewed the part of the program authority. Rather than focus on more restrictive ideas which eventually became the heart of the REMS One of the lessons of like patient registries and mandatory prescriber proposal had some qualms about the ability of this advisory committee certification, the agency is proposing a relatively CME providers to handle the education compo“soft-touch” REMS for the class, emphasizing nent. The nine-member working group, headed review for FDA has to be education over restriction. (See “Opioid REMS.”) by Division of Risk Management Deputy Director that the committees may FDA is going to try to walk a fine line on the Mary Willy, noted that it “considered concerns be inclined to ask FDA to education requirement: stopping short of deabout the current CME/CE system’s ability to do too much with REMS manding proof of education of each prescriber effectively teach” content that would improve but attempting to show that educational efforts health outcomes with opioids. However, the FDA programs, and yet at the have been undertaken seriously and have a posigroup noted that recent rigorous examinations same time underestimate tive effect on physician knowledge. of CME have created “a proposed framework for the power FDA has to And, in that context, the agency sees a improving the effectiveness of CME/CE, both at make REMS plans work. potentially critical role for continuing medical the macro-and micr0-level.” education and CME providers. The working group also discussed who would That entails primarily “FDA would encourage sponsors to develop create the content for the CME efforts. An indemonstrating how the the prescriber training in partnership with an dustry collaborative group would have the “the evaluation part of the appropriate, independent third party, and FDA resources and a vested interest in the subject,” REMS program works. would approve the training content,” FDA Divibut the working group shied away from that sugThat missing step may sion of Anesthetic & Analgesia Products Director gestion due to conflicts of interest.” Bob Rappaport, MD, said in a June 22 memo to “Another option is for FDA to develop the conhave helped to reassure the members of two agency advisory committent,” Willy’s group said. “This approach would the committee that the tees. “Sponsors would also be encouraged,” give FDA primary control over the information. agency now has a way to FDA said, “to explore appropriate incentives However, FDA currently does not have the necesensure that sponsors who (e.g., CME credit) to encourage prescribers to sary resources.” undertake the training.” The working group appeared to prefer a are implementing educaAt a time when industry-funded CME is under curriculum developed by an “expert panel, intion or training programs attack in Washington DC, the opioid REMS procluding representatives from specialty boards, are meeting the specifiposal suggests an intriguing possibility for CME medical societies, academia, FDA, and other cations of the program, providers: as intermediaries which can assure relevant government agencies.” That approach FDA of the independence of training (distanced would generate “the broadest perspective and typically through surveys from the marketer) and as a way to entice physiassembly of expertise and would be acceptable of patient and physician cians to participate. to the majority of stakeholders. However, it is compliance. Of course, that role is yet to be defined; the not clear who would pay for the panel’s time FDA has only recently advisory committee rejected FDA’s proposed and expertise.” REMS on the grounds that the “soft-touch” apFrom that working group discussion, FDA (late last fall) started proach would not work, so mandatory training opted for programs that would be reviewed by receiving the first evalucould still be the approach adopted in the class. the agency which would “approve the training ation reports from sponIn addition, the agency’s internal deliberations content.” sors. (See “Assessing creating a second, parallel registration system.

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REMS Strategies

“Voluntary Education Does Not Work” A lot of people spent a lot of time working on a proposal for a class-wide opioid REMS over the past 18 months. When an FDA advisory committee considered the plan, though, a very brief statement by a former committee chair may have helped undo a lot of that work. At least 70 Food & Drug Administration employees worked on the development of a proposed class-wide REMS for the long-acting opioid class. Two dozen pharmaceutical companies have been working in parallel trying to shape the proposal and provide input to the agency. After 18 months of internal deliberation, public stakeholder meetings, drafting and redrafting, FDA opted for a relatively soft touch, education focused

plan; the two dozen companies exhaled a sigh of relief. But when FDA brought the proposal to its advisory committee July 22-23, that approach was soundly voted down. The turning point: one brief public statement by former committee chairman Nathaniel Katz, early in the second day. Katz, invoking what he sees as a missed opportunity during his tenure as committee chair, urged the panel not to accept

“Since I chaired the first opioid risk management meeting now eight-and-half years ago, somewhere approaching 100,000 have died from prescription opioid over-dosing events. “What have we been doing all of this time? Innumerable forms of voluntary education, monitoring and surveillance – the essence of the current FDA and Industry Working Group proposals. “You just sat through a day of presentations describing the results of these approaches. Do you really need any more data to tell you that voluntary education does not work? I will remind you of the definition of insanity as attributed to Albert Einstein: doing the same thing over and over again and expecting the results to be different. “The days of prescribers not being trained how to safely prescribe an [opioid] prescription in the United States have to be brought to an end, by you, today. “In my view, you need to finally recommend mandatory prescriber training. “The days of millions of patients walking out of a pharmacy with potentially lethal medication and no training how to keep themselves and their community safe have to be brought to an end, by you, today. “In my view, you need to finally recommend mandatory patient training. “If you require training, you need a verification system in the pharmacy. It has been stated that this would excessively burden the health care system. That is incorrect. “Over the past year, our group, with some collaborators, has designed, built, tested and reported on technical performance and real-world usability of such a system and provided all this information to the FDA. Time prevents me from describing details. Suffice it to

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

“voluntary education” and to push for tougher controls. While it may be going too far to say that his brief comments swayed the committee, they did presage the tone of the panel’s conclusions. Katz has an academic appointment at Tufts and is also president of the drug development consulting firm Analgesic Solutions. Here are his July 23 remarks to the committee, as transcribed by The RPM Report.

say, that the system works; it is not burdensome; and it is not expensive. If we can do it, anybody else can do it. “You will hear a number of objections to such approaches. People will complain that these are registries which are inherently evil. These are not registries; they are databases – just like the databases that we are all in anyway. “People will claim that prescribers will flee form prescribing if they are required to participate in such programs. However, there are ample survey data to indicate just the opposite. “People will complain that we should not do anything without evidence. Guess what? There is no evidence. Nobody has been willing to fund this type of research. “This leaves you with two choices: you can do nothing and continue to count bodies; or you can recommend interventions that make sense and gather the evidence prospectively. That seems to be an easy choice. You should also know that many other interventions could have been presented: such as tamper-resistant prescription pads, automated prescription monitoring data checks, etc. “So, my recommendations to you are as follows: mandatory training of all prescribers and patients receiving long-acting opioids as part of the Elements to Assure Safe Use of the classwide REMS. “We have shown that this can be done. After a specified evaluation period, decide whether to expand to the rest of the opioids and whether to require any additional risk mitigation approaches. “When I bump into you again in eight-and-a-half years, I’d like you to have a clean conscience that you did the right thing.”

REMS Strategies

REMS: Risk Management’s Key Question – Do the Programs Work?” The RPM Report, March 2010.) There have been no major changes to REMS programs tied to those evaluations. Once the agency starts to make changes from the process, then future REMS education programs may be taken more seriously by the committees. The opioid advisory committee referred frequently to a previous risk management plan for OxyContin initiated in 2001 as showing little impact and being a weak control tool. However, that program was created before FDA gained the authority to impose metrics to oversee current plans via the Food & Drug Administration Amendments Act of 2007. The agency, in fact, asked the advisory committee in the last set of questions for advice on how to measure the impact of its proposed REMS. Coming at the end of a two-day meeting and after the committee had already voted that the proposal was insufficient, that part of the discussion did not get much attention. One of the members voting in favor of the agency’s proposal was Drug Safety advisory committee member Elaine Morrato (University of Colorado). Two weeks previously, Morrato led

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discussion by the Endocrinology & Metabolism Drugs Advisory Committee to vote against approval for the Vivus Inc.’s weight-loss product Qnexa. At that meeting, Morrato showed herself a forceful advocate for tougher REMS programs. (See “Weighing the Regulatory Climate: Qnexa’s Clues About the New Approval Model.”) At the opioid meeting, she noted that the education program was a good place to start and would have more impact than other committee members were indicating. “I voted ‘yes’ because I believe we cannot not act. This is a reasonable place to start. Educational training will be the foundation of any REMS and we should get going on it. “ Morrato added that she “also appreciated the perspective that the agency shared regarding the practicality and feasibility of executing a REMS within the FDAAA legislation that they are working with.” rpm

Comments? E-mail the author at cole.werble@previsionpolicy.com

FDA’s REMS Program:

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Regulatory Strategies

Phase IV Proof of Efficacy: A Brilinta Idea? AstraZeneca won two strong votes (each 7-1) in favor of approval of its clot busting drug Brilinta (ticagrelor) from FDA’s Cardio-Renal Drugs Advisory Committee on July 28. Standing between the drug and final FDA approval, however, is an unusual request from the advisory committee for a supporting Phase IV efficacy study in the same indication as the approval.

By Cole Werble

Can the Food & Drug Administration approve a product for a broad cardiovascular indication, label the new drug for that indication and then ask for a major confirmatory trial to show that the new compound actually works in the indication? That’s the regulatory conundrum that the agency’s CardioRenal Drugs Advisory Committee may be sending back to FDA following a July 28 review of AstraZeneca’s Brilinta (ticagrelor). The committee voted solidly (7-1 twice) for two acute coronary syndrome indications for Brilinta, AstraZeneca’s major pipeline product designed to compete with Sanofi-Aventis’ Plavix (clopidogrel) and Eli Lilly & Co.’s Effient (prasugrel). The votes were accompanied, however, with a highly unusual discussion and suggestion on post-market studies. (See “The Pink Sheet”, August 2, 2010.) Without taking a vote for a specific post-market trial for the product, the committee raised a call for post-approval efficacy trials to support the approval recommendations. Requests for Phase IV trials or observational registries to check for a safety issue or signal that cannot be resolved prior to approval have become almost de rigeur in some classes. FDA is now calling for mandatory Phase IV studies on about 80% of new molecular entities and 40% of all approvals. (See “FDAAA Impact (Year Two): More of Everything”, The RPM Report, June 2010.)

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Mandated post-market efficacy trials are a different matter. When called for by FDA, they are generally in the context of follow-up to an accelerated approval based on preliminary clinical work or a surrogate endpoint. The concept of postapproval efficacy trials for a broad use product to prove the approved indication is a novelty. Reading between the lines in the debate over the Phase IV efficacy study discussed at the advisory committee meeting, the threat of a demand from FDA for AZ to conduct such a study is remote. Still, the open debate at the meeting was confusing and detracted from the approval votes. More importantly, the July 28 discussion may provide a look into the future as committees are faced with more, large active comparator studies and try to grapple with aberrations within a large database. Those trials will only become more common in an era of comparative efficacy research.

Post-market Efficacy Trial: Response to Tough Call? Or Kaul to Action? Acting committee chairman Sanjay Kaul (Cedar Sinai Medical Center) led the call for a large post-market efficacy study. Concerned by weak, “wrong direction,” efficacy data in the U.S. portion (1,413 patients) of the large (18,624 patients) international comparative trial to the treatment standard,

clopidogrel, Kaul attached a specific request for Phase IV confirmatory efficacy to his vote for approval. (See “How Low Can U.S. Efficacy Go?”) The chairman described his request as part and parcel of the approval votes. At least three other advisory committee members talked about the benefits of doing follow-up work on the issues related to ticagrelor’s reduced efficacy in U.S. trials, though none of the other committee members spoke out as strongly for the idea as Kaul. The chairman was out ahead of the other members of the committee as an advocate and catalyst for the follow-up efficacy study (See “Looking for a Reasonable Phase IV Trial for Brilinta”.) FDA will have to determine how broad the committee consensus was for the further efficacy trials. Because there was no vote on the type of trail to recommend, that will be a pure judgment call by the agency. FDA will have to decide whether the post-market efficacy trial was supported by a majority of the committee or just pushed strongly and effectively by the committee chair. During the meeting, Kaul’s solution for approving a drug without U.S. efficacy proof seemingly caught senior FDA staff unawares and generated a spirited three-sided debate among Kaul and the top two decision-makers in the cardio-renal area: Office of Drug Evaluation II Director Robert Temple and CardioRenal Drug Products Division Director Norman Stockbridge. FDA expected the meeting would be difficult. Stockbridge introduced the challenge of weighing efficacy results from outside the US against much weaker effectiveness in the U.S. as an issue that he didn’t have the “foggiest idea” how they would handle. As the suggestion to repeat efficacy proof after approval emerged during discussion, it seemed like Stockbridge’s worst fears for the meeting were being met. FDA recognizes that it will be going to advisory committee more frequently in the future for advice of post-approval trials. The agency is already receiving advice that is troublesome and sometimes beyond the bounds of reasonable clinical work. (See “Phase IV Advice & Consent” The RPM Report, September 2009.) This is still very much a learning period for FDA and for drug sponsors. There will be more meetings like Brilinta where good outcomes for the sponsor emerge enmeshed in a tangle of post-market suggestions. If the recommendation for post-market proof of efficacy is viewed as crucial to the approval decision or continues to generate a spirited discussion within FDA, that bodes badly

for AZ receiving a final approval by the user fee date in midSeptember. A demand for Phase IV efficacy work on acute care treatment would also put AZ’s proposed large follow-up study under discussion with the TIMI Study Group at Brigham & Women’s Hospital in jeopardy. That study has been designed to look at a benefit from use of the product in the long-term with treatment beginning a year after the acute cardiovascular event. The sponsor may There will be more have to modify the meetings like Brilinta study to make it adwhere good outcomes dress some of the for the sponsor emerge committee’s postenmeshed in a tangle market expectations. of post-market That’s a tough challenge as the followsuggestions. up study addresses a different issue: not whether it works at the time of an acute coronary syndrome event but whether it is useful given as a maintenance therapy for stable coronary artery disease patients. At least one FDA analysis of the NDA data finds preliminary evidence to support anti-clotting activity after an extended period of time. FDA medical team leader Thomas Marciniak noted in his review of the NDA data that the efficacy curves on the time to major cardiovascular adverse events “do suggest that ticagrelor may have a long-term benefit and one that tracks differently” than existing platelet inhibition thienopyridines. AZ clearly wants to study that effect without having to graft a repeat efficacy determination in acute events back onto the study. Fortunately for AZ, it is unlikely that FDA will pursue the idea beyond kicking it around with the committee.

How Can You Approve Product and Ask For Repeat Study, Stockbridge Asks “My recommendation to the FDA,” Kaul said, “would be to require the sponsor to address” the inverse efficacy to the comparator in the U.S. population versus results in 41 of the other 42 countries in the major pivotal trial (PLATO). He urged a new efficacy investigation in “a more coherent

Regulatory Strategies

figure out what….who would be in, and what the endpoints would be?” Kaul: “The endpoint would be …cardiovascular death, non-fatal MI and non-fatal stroke. I would like to see this trial conducted in a U.S. population where the enrollment is over 50% in the U.S.” Stockbridge escalated the discussion of the Phase IV trials and pressed Kaul at length about the feasibility of his request. Stockbridge declared that a post-approval study to support an approved indication with a second efficacy study would not be ethical. “I am not even Looking for a Reasonable Phase IV Trial for Brilinta clear how you maintain that the trial you Sanjay Kaul (Cedar Sinai Medical Center), acting chair of FDA’s July 28 Cardio-Renal can get to is ethical Advisory Committee review of AstraZeneca’s Brilinta (ticagrelor) was the instigator and chief advocate of instructions to FDA to ask for a confirmatory efficacy study after approval to do,” the 20-year (See “Phase IV Proof of Efficacy: A Brilint a Idea?”). Other advisory committee members FDA veteran pointed discussed follow-up trials but not in the same terms. There are a lot of options from which out.” If you voted to FDA can choose. Here are some of the other thoughts on Phase IV trials from Cardio-Renal approve the thing for advisory committee members. use in this country, with a hard outcome Sanjay Kaul (Cedar Sinai Medi- We could tweak the sample size them not only look at aspirin dose claim including CV cal Center) – repeat of efficacy issues. I would like the FDA to but the possibility that patients mortality, how the trial with a substantial number of discuss this with the sponsor. And might benefit from the elimination I would also like to have language of aspirin from this regimen.” heck am I supposed U.S. patients. in the label to look at different to get people to do “My recommendation to the cohorts – look at the risk-benefit another outcome trial FDA would be to require the spon- profile of unstable angina and Henry Black (New York University like that?” sor to address this issue [wrong possible biomarkers to get a bet- School of Medicine) – study in a Te m p l e t re a t e d more representative U.S. patient ter idea where the effect is going direction of efficacy in the U.S.] population. in a more coherent and system- to be the most possible.” Kaul’s suggestion atic fashion. That is to conduct as an unusual but “I am puzzled and confused that a study, post-approval, where intriguing intellecthey take a substantial number Jonathan Halperin (Mt. Sinai the patients in the U.S. did not do tual question. He reof patients in the United States Medical Center) – follow-up on as well. I think the point that this to address this issue. I don’t think effect of aspirin concomitant use U.S. population was not really flected on the idea that this should be lumped with with anti-platelet drugs in general. representative of the U.S. populaopenly and by dotion is something that we should the trial that they have proposed: ing so took some of “I want to congratulate the consider. I don’t know what the carthe chronic stable angina trial. the controversy out [That trial] will not help to address sponsor on the overall quality of rot ought to be; it would be pretty the study design and execution. I hard to design a study to compare the issues. The issue that is drivof Kaul’s proposal. ing this disparity has more to do would also add a word of caution to it to something we don’t think is as Temple characterized with practice of care difference the FDA people here. There are very good. But I think that is going to be it as a suggestion that rather than the dose of aspirin. important unanswered questions something for the future.” would raise tough about aspirin. That needs to be addressed. Unless there is a mandate to practical challenges The endpoint would be…cardioMori Krantz (University of vascular death, non-fatal MI and investigate this issue going forfor the agency. Innon-fatal stroke. I would like to ward it will not happen once this Colorado) – small trial to assure stead of rejecting it see this trial conducted in a U.S. product is free, living in the market that efficacy is not going in wrong outright, Temple worpopulation where the enrollment place. To this day, we do not have direction in the U.S. “A smaller trial: you are not a study of aspirin plus clopidogrel ried the issue like a is over 50% in the U.S. It would not have to be nec- vs. clopidogrel alone in patients necessarily looking for superiority. cat with a mouse. essarily the same size [as the undergoing coronary intervention You are looking to see that it is not “It does not seem 18,624-patient PLATO Study] , or in patients with acute coronary going in the wrong direction…. It out of the question because we have the information. syndromes. I would like to see will be a hard thing to figure out.” that you could do a and systematic fashion…a study, post-approval, where they take a substantial number of patients in the United States to address this issue.” Kaul’s suggestion caught Stockbridge by surprise. Incredulous to Kaul’s request, Stockbridge broke into the post-vote discussion to press the chair to explain his post-approval recommendation: “What are you asking them to study?” The efficacy shortfall in the U.S population in PLATO, Kaul explained, “requires studying a population in the United States.” Stockbridge: “So it would be this same trial? I am trying to

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Regulatory Strategies

trial against prasugrel.” That would give AZ another active comparator and would be a way around the issue of repeating a failed efficacy comparison in the U.S. While prasugrel offers another active comparator, “I don’t know that you would want to” do a trial against prasugrel, Temple added, “that’s another question.” When Temple raised prasugrel as a potential comparator for an efficacy re-do, he had to know that he would get Kaul’s interest based on the advisory committee chair’s previous high visibility interest in the Lilly application. Kaul

was famously disinvited from the FDA advisory committee review of prasugrel. (See “The Prasugrel Backlash”,The RPM Report, April 2009.) Later in the discussion, Kaul jumped on the idea: “I like the idea of prasugrel vs. ticagrelor. The question I have is who is going to do it? The sponsor of prasugrel? Or the sponsor of ticagelor?” To which Temple rejoined wittily: “both; together.” “Whether you can design a non-inferiority trial or try to establish that you are not worse by a certain amount

How Low Can U.S. Efficacy Go? FDA faces an unusual decision on AstraZeneca’s Brilinta (ticagrelor). The efficacy comparison to standard anti-platelet treatment (Sanofi-Aventis/Bristol-Myers Squibb, Plavix, clopidogrel) turned noticeably against the AZ drug in the U.S. part of a large (18,624-patient) large multinational study. What should FDA do when it is asked to make a decision on use of a product in the U.S. and the worst results for a promising compound come from the U.S.? The Food & Drug Administration’s Cardio-Renal Drugs Advisory Committee is willing to look past weak efficacy results in the U.S. and recommend approval based on strong performance in non-U.S. trials. The committee twice voted 7-to-1 for approval of AstraZeneca’s Brilinta at its July 28 meeting. As FDA’s Office of Drug Evaluation I Director Robert Temple summarized the committee’s discussion and vote, the advisory committee looked past the U.S. data and voted not to withhold a promising therapy. “I think the advice we have been given is that they think on the whole there is good evidence that this drug works and if they had to bet it would be 60-40 or some reasonable expectation that it would work in the U.S.,” Temple said. “The way the results came out you do not know [if the drug works] to the extent you would like to, but you really like the idea of a drug that had a nice survival effect and you want to give people a chance to use it,” Temple continued. The agency summarized the U.S. efficacy deficit in the trials in analysis for the committee. The U.S. Brilinta patient population in the PLATO trial (707 patients) had major adverse cardiovascular events at a 12.6% rate compared to a 9.6% rate in non-U.S. Brilinta patients (8,626 patients) and 9.8% when the U.S. and non-U.S. groups were blended. The hazard ratio for Brilinta in the U.S. jumped to 1.27 compared to .81 in non-U.S. trials. As FDA medical team leader Thomas Marciniak, summarized in his memo for the committee briefing materials. “The U.S. has worse results with ticagrelor for all efficacy measures, including major adverse cardiovascular events, myocardial infarction, stroke, cardiovascular death and all-cause mortality and is an outlier for all of them except stroke.” Marciniak noted that strokes rates were higher with Brilinta than Plavix in all regions. Marciniak told the committee that the signs of an apparent mortality event in the full trial data should make a review want to be very impressed by the product but the discrepancy in the U.S. cools that ardor. Marciniak used a play on the pivotal trial’s acronym name (PLATO) to explain the ambivalence

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

of his response to the application. He said he came away with a cool “Platonic” relationship to the product when the full efficacy results would have suggested a “love fest.”

How Far Out of Line Can a Study Be? More pointedly, FDA Cardio-Renal Drugs Division Director Norman Stockbridge asked the panel after the vote what level of trial failure would it take in the U.S. to get them to reject a product. “I am curious,” Stockbridge said. The U.S.-non-U.S. difference between the efficacy result “is at least as extreme as any we have ever seen. I am wondering whether/what it would take before you would say ‘it is a subgroup, unplanned, but I am worried.’ What would it take? How far out of line would it have had to been?” One of the Cardio-Renal committee members, Henry Black (New York University School of Medicine), noted puzzlement also – but explained how his puzzlement led to a vote for approval. “I was very impressed with the overall result. I think we cannot deny a 50% reduction in events of mortality in particular,” Black said. “I am puzzled and confused that the patients in the U.S. did not do as well,” Black added. He suggested that the trial population in the U.S. might not reflect the appropriate treatment population. “I think the point that this U.S. population was not really representative of the U.S. population is something that we should consider.” For AZ, the outcome on July 28 was promising – pointing toward a probable FDA approval. The Cardio-Renal vote was also a form of redemption. AZ had a much less favorable review for another product earlier this year (the second generation respiratory syncytial virus product, Rezield). That product got a negative advisory committee review and a quick complete response letter from FDA due in part to a discrepancy between northern hemisphere and southern hemisphere results. The real answer on the efficacy issue is likely to come in the marketplace where A will have to sell a product that says something about less than favorable U.S. efficacy effects. And the comparator will begin to be available generically within two years.

Regulatory Strategies

remains to be seen,” Temple said.”I don’t know. It doesn’t seem open and shut or impossible to do the trial.” He noted that it would “take a lot” to come to that decision though. While Temple played with the post-market efficacy idea, Stockbridge continued to wrestle with it as a threat to FDA’s decision-making calculus.” I think it is extraordinarily awkward to put a hard outcome claim in the label – that applies to the United States, and then turn around and require someone to try to do an outcome trial in replicate.” Stockbridge reminded the committee that the agency expected a decision on whether the efficacy data (with its confounding U.S. trends) was sufficient. “If you are sure enough to give the drug the claim,” Stockbridge declared, “then you are sure enough not to be able to do the study.” Temple summed up the decision of the committee as fundamentally a vote not to withhold access to a medicine that worked well in trials outside the U.S.”I think the advice we have been given is that they think on the whole there is good evidence that this drug works and if they had to bet it would be 60-40 or some reasonable expectation that it would work in the U.S.” He noted that having “good evidence” is not the same as “knowing.” And the way the results came out you do not know to the extent you would like to but you really like the

idea of a drug that had a nice survival effect and you want to give people a chance to use it.” He also had one final suggestion for a referee on the issue of whether a sponsor could be required to undertake major efficacy work after approval. “That’s a “thorny” issue, Temple acknowledged, “We should ask the IOM whether we can do it.” At FDA’s request, the Institute of Medicine is already working on a study of the ethics of post-market studies and the types of trails that can be conducted in the post-market. (See “IOM Will Address Ethics in Safety Studies,” The RPM Report, June 2010.) Temple’s riposte indicates a little bemusement from the senior FDA staff ranks about the political reality that FDA has to seek outside help for decisions on follow-up studies. But there is also a balancing message: there are a lot of tough and unpredictable choices facing the agency in the future on Phase IV studies – some coming from their own advisory committees. Maybe it will be useful to throw some of them to a group like IOM. rpm

Comments? E-mail the author at cole.werble@previsionpolicy.com

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COMMON SENSE

Avandia: How Do You Hold a Moon Beam in Your Hand? FDA faces a tough decision on Avandia. Should it stay or should it go? There is bigger underlying issue: should the standard be different for pulling a drug than it is for approving the drug in the first place? It may be counterintuitive, but a different standard makes sense.

By Ian D. Spatz

Ian Spatz is the founder of the Rock Creek Policy Group, LLC, is a senior advisor to Manatt Phelps & Phillips, LLP, and is a contributing editor to the RPM Report.

The leaders of the Food & Drug Administration are facing a problem that may best be defined by paraphrasing a song from the Sound of Music. How do you solve a problem like Avandia? Talk about being between a rock and hard place! Let me stipulate up front that this column does not take a stand on the question of whether FDA should remove Avandia from the market or, as a majority of a recent advisory committee recommend, leave it on the market and strengthen its warnings and use restrictions. That’s a choice that is not only way above my pay grade but also way outside my health policy expertise. Instead, the Avandia story puts in sharp focus a policy and political problem for the FDA, its leadership, and the Obama Administration. How they navigate these problems will say a lot about the future of the FDA and the drug discovery and marketing process. First the politics. The easiest political decision for FDA is to withdraw the product pending further study to define its cardiovascular risks. While some physicians and patients may complain (and while the drug’s maker GSK will roar), most people don’t take Avandia and, therefore, most people will see the action as evidence that a “new” FDA is getting tough on those nasty drug makers and protecting the public health.

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

The alternative of leaving Avandia on the market will generate predictable challenges from self appointed drug safety advocates, disgruntled FDA staff, members of Congress, and many in the media. There will be more stories about how user fees cloud the FDA’s judgment, how drug safety officials lack clout with the agency, and how the drug’s maker pulled a fast one. Having said this, I don’t believe that FDA will necessarily take the path of least political resistance. This isn’t the agency’s way of doing things. A science based agency has to try to stick to the science. Given that the agency is made of humans, completely ignoring the politics, even at a subconscious level, is impossible. However, the FDA is filled with people who have bucked the politics before and, perhaps, kind of enjoy doing so. That leaves the issue of policy. The FDA is pretty clear on the standard it uses for new drug approval. Its web site states that the standard is “whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.” But how about the standard for drug withdrawal? Is it the same? Should it be the same? At that recent advisory committee meeting, the committee members

commonSENSE were asked whether they believed that, based on the data, Avandia should be withdrawn. However, each member was free to use their own standard in offering their opinion. It’s easy to say, as some at the FDA do, that the standard should be the same. However, there are good reasons it shouldn’t be the same. For one, a currently marketed drug is, by definition, already in wide use. Like Avandia, patients and their physicians are relying on it to deliver results and, for some, alternative treatments may not have been as effective or may have been associated with side effects. Withdrawal would mean taking away a treatment option. Second, unlike the well controlled, clinical trials that form the basis for new drug approvals, discussions about withdrawal are, as in the case of Avandia, often based in part on retrospective, non-controlled studies that invite debate on their strength as evidence. If a study that would not “count” toward FDA approval is part of the basis of withdrawal, isn’t that applying a different standard? Third, withdrawal is, most likely, the

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death of a compound and any hope of ever learning more about its uses. In contrast to a delayed or denied new drug application where a sponsor may have substantial incentive to do new studies to support approval, the sponsor of a withdrawn product likely lacks any incentive to do more. Part of this comes from the fact that withdrawal may come toward the end of a product’s patent life. Another factor is the stigma of a withdrawn drug. This stigma makes it unlikely that it could ever again gain clinical acceptance. Finally, withdrawal may raise practical and ethical issues in gaining participants for new trials. Is there a potential regulatory middle ground? Perhaps it is possible that the FDA could recognize that there is a de facto different standard for withdrawal especially in cases where there is no obvious evidence of massive fraud in the application or overwhelming danger. In such situations, FDA might consider using its Risk Evaluation & Mitigation Strategy authority to force physicians to document the need for the medicine and their reasons for rejecting alternatives. Doctors are likely to howl that the gov-

ernment is interfering in the practice of medicine. However, such a step would be far less interfering than withdrawing approval and denying their patients all access. It would also retain access for current patients and maintain a medicine as an option for new patients. However the FDA “solves” its Avandia problem, it is important that FDA do its best not only to be transparent about its reasons but also about the criteria it used to make the decision and will use to make future decisions about possible product withdrawals. Such transparency will help drug sponsors understand the risks they face when there is new, adverse evidence on marketed products. And, it will help everyone understand how the FDA continues to balance its roles as the protector of public health and the facilitator or medical acceptance of new medicines. Note: The writer represents pharmaceutical industry clients, but does not represent GSK, the maker of Avandia. rpm Comments? E-mail the author at ian.spatz@rockcreekpolicy.com

BIOPHARMACEUTICAL INDUSTRY INTELLIGENCE AND ANALYSIS

www.InvivoBlog.Blogspot.com

By Michael McCaughan

Weighing the Regulatory Climate: Qnexa’s Clues About the New Approval Model If you need evidence that the regulatory climate has improved at FDA since 2007, look no farther than FDA’s handling of Vivus’ weight loss drug Qnexa: FDA’s review team was ready to take a risk on the drug despite a number of safety signals that would most likely have killed a product three years ago. But if you want to know how fundamentally the regulatory model has changed, listen to what the committee said in rejecting the application. If you are looking for evidence of how much the regulatory climate at the Food & Drug Administration has changed since 2007, look no farther than the reaction of Endocrine & Metabolic Drugs Division Deputy Director Eric Colman after an advisory committee voted 10-6 against approval of Vivus Inc.’s weight loss drug Qnexa (topiramate/phentermine). “I was a little surprised that the vote went as it did,” Colman told reporters after the meeting. He said he had expected a more positive vote on approval. Indeed, that seemed clear enough from FDA’s presentation to the committee, both in its briefing materials provided before the July 15 meeting and in the agency’s presentation to the committee itself, which focused largely on approaches to labeling and managing potential risks for the drug in the post-market setting. Colman wasn’t the only one surprised. Vivus shares ran up upon release of the review documents, only to plunge after the no vote. But take a step back and consider what might have happened if Qnexa came up for review in 2007: **How would FDA have handled a drug for weight loss three years ago, if it included a signal of increased depression? Well, there was Zimulti, Sanofi Aventis’ rimonabant, rejected by a 14-0 vote because of potential psychiatric events. At the time FDA rejected the application, European regulators had already approved it; its subsequent withdrawal in Europe has been cited by agency review managers as vindication of the “safety first” mindset adopted by FDA. (See “Sanofi-Aventis’ Zimulti: Knowing When to Say When,” The RPM Report, August 2007.) **How about if the drug were associated with heart rate changes, the database included very few cardiovascular events,

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

and it so happened that all four myocardial infarctions occurred in the treatment group? Well, in the type 2 diabetes class, pretty much all new drug reviews were put on hold in 2007 to assure sufficient confidence in CV outcomes. Or, for that matter, look at GlaxoSmithKline PLC/Adolor Corp.’s constipation agent Entereg (alvimopan), a drug designed to act non-systemically in the gut that nevertheless stalled at FDA because of a small number of severe cardiovascular events in the treatment arm of one study. (See “Entering the World of REMS,” The RPM Report, July 2008.) **What if it was also a teratogen? Okay, there’s no obvious 2007 parallel, but given that the effectiveness standard itself hails from FDA’s handling of the teratogen thalidomide, it is safe to say that category of risk is not an easy one to overlook. In the case of Qnexa, the advisory committee was asked to discuss each of those red flag issues as potential risks of therapy—along with two others, cognitive side effects and metabolic acidosis—before voting on approval. Then consider the fact that 11 of the 16 members of the Qnexa panel spent the prior two days debating the fate of GlaxoSmithKline’s antidiabetic drug rosiglitazone (Avandia)— a drug approved based on compelling efficacy in lowering blood sugar that appears nevertheless to have poor health outcomes compared to other agents. Given all that context, maybe the truly surprising thing about the Qnexa review is not the “no” vote, but that fact that the FDA review team came into the meeting expecting a “yes.” There may be no clearer indication of how much the regulatory climate has improved for drug approvals since 2007 than in the attitude of FDA’s review team towards Qnexa.

The application triggers a number of hot button safety issues—suicidality, cardiovascular outcomes, and teratogenicity. The indication for weight loss clearly puts it in the category of “lifestyle” medications where the safety bar is high. The class itself has, as one committee member put it, a “checkered” history, given the withdrawal of Wyeth’s dexfenfluramine (Redux) a decade ago and the ongoing safety review of Abbott Laboratories Inc.’s sibutramine (Meridia). And yet FDA’s review team came into the meeting expecting a positive outcome. That underscores how much the regulatory climate has improved since 2007. But something else has changed since 2007 too: a new regulatory model is taking shape, tied to the new post-marketing safety authorities granted to the agency under the FDA Amendments Act. And for sponsors—not just those in the weight loss class—the real message of the Qnexa review is not that the agency is more approval oriented. Rather, the message is how challenging it is to manage drug development and regulatory reviews while the regulatory model itself is in transition.

The Paradox of Broad Market Potential The Qnexa panel illustrates a critical paradox facing sponsors in the emerging regulatory paradigm: the more broadly useful a new product will be, the more tempting it may be to put formal restrictions on the product to assure that use does not immediately take off in an uncontrolled, unmanaged fashion. That theme came up repeatedly in the Qnexa review. “This is a very effective drug,” noted Susan Heckbert (University of Washington). “It is likely to be used by large numbers of people because it is so effective. So I’m concerned about its use outside the intended population and its use for very long periods of time. I’m concerned about its use perhaps without adequate medical supervision, as we saw with phen-fen, where diet clinics were set up and people were getting the drug.” Consider the dilemma for the sponsor: Heckbert—like most of the committee—was enthusiastic about the effectiveness of the drug. But her very enthusiasm led her to worry about the potential for inappropriate use—and ultimately to a “no” vote on approval. (For a full transcript of the unusually thoughtful post-vote discussion among committee members, see “The Qnexa Vote: Beyond the Bean Counting.”) Then there was the committee’s sense that weight loss therapy needs a new model—one where obesity is considered a chronic condition, akin to hypertension and dyslipidemia, with drug therapy expected to continue indefinitely. That too should be music to sponsors’ ears, both as an

indication that FDA and its advisors are treating obesity as a serious medical condition (not merely a cosmetic issue), and as a sign that the commercial model that built Lipitor and Vasotec could apply directly in weight loss. But that sentiment, too, led to a desire to see longer term data and greater certainty about outcomes prior to approval—and reinforced the overall feeling on the committee that a slow roll-out is necessary. Committee member Lamont Weide (University of Missouri) described his “change in thinking over the years about obesity: I’ve come to think of it just as I do about blood pressure and lipids, such that it is a chronic disease that requires chronic therapy. Every agent that we have seen, when patients go off of it, they regain the weight. I can’t think of an exception to that. You can say they will change their lifestyle, but the reality is that when they go off of it they regain the weight.” That is, in fact, a great commercial model. Weide noted the testimony of clinical trial participants during the open public hearing: “You can hear from the audience that people want this and they are going to stay on it….I think this is going to be a lifelong therapy.” And that is the catch: “The real question is how safe is it and for how long?...I just feel uncomfortable with a year’s worth of data.”

An Avandia Hangover? Advisory committee members weren’t just concerned about protecting patients; they also stressed their concern about FDA’s credibility if a weight loss drug enters broad use and then triggers adverse events that force a withdrawal. “While I am very sympathetic to the desires of those who are seeking treatment options for this disease,” cardiologist Sanjay Kaul (Cedars Sinai heart center) commented, “I am also very concerned about the erosion of the public’s trust every time we approve a drug and don’t get it right the first time, either because the sponsors have not done due diligence and looked for that signal in the right population, or whether it is supposed to be used in the real world.” That perspective is understandable: after all, Kaul was one of 11 members of the Qnexa panel who spent the two prior days participating in an exhaustive re-review of the safety profile of GSK’s Avandia. It is tempting to say (as one FDA official did immediately after the Qnexa vote), that if it hadn’t been for the Avandia review, Qnexa would have been recommended for approval. One committee member—Katherine Flegal of the Centers for Disease Control & Prevention—explicitly said that “my views were colored by our experience with Avandia and the safety

FDABEAT concerns. We should deal with them before rather than afterwards.” Given how close the vote was and the ambivalence of several of the “no” votes, it is certainly reasonable to believe that the Avandia review cost Vivus dearly. Among the 11 Qnexa panelists who participated in the Avandia review, the vote was 8-3 against approval of Qnexa. Among the five members who joined the committee solely for the weight loss review, the vote was 3-2 in favor of approval. (See Exhibit.) That suggests a different way in which Qnexa was a victim of its own strong efficacy. The drug was submitted at essentially the same time as Arena Pharmaceuticals’ lorcaserin, but FDA took Qnexa to a committee two months earlier than Arena (which is slated for a September review). It seems likely that FDA’s decision to take Qnexa to the July panel reflected the review teams’ view that efficacy would not be an issue and that therefore it could move more quickly. As a result, it ended up going to the panel coincident with Avandia. However, it is probably a mistake to write off the “no” vote on Qnexa as simply a hangover from the Avandia debate. In fact, the selection of panelists for the Qnexa review suggests they were less risk averse than the overall Avandia panel. For one thing, the votes on Avandia among the 11 members who also participated in the Qnexa review skewed towards the less restrictive side of the options for handling the diabetes drug. Of the 12 votes in favor of pulling Avandia, only two were cast by committee members who came back for Qnexa. Four of the Qnexa committee members voted that Avandia can remain on the market only with restrictions (and generally urged significant restrictions) on the product. However, three of the Qnexa panelists believed Avandia could remain on the

Exhibit 1

The Avandia Effect? The eleven members of the Qnexa advisory committee who participated in the review of the safety profile of Avandia during the prior two days voted 8-3 against approval of the weight loss drug—even though they generally supported continued marketing of Avandia. The five Qnexa panel members who did not participate in the Avandia review supported approval, 3-2.

Qnexa Panel Members Who Also Reviewed Avandia (11) Committee Member

Avandia Vote

Qnexa Vote

Kenneth Buman, Acting Chair (Washington Hospital Center)

Continue Marketing (with stronger warning)

David Capuzzi (Thomas Jefferson University)

Continue Marketing (same warning)

Abraham Thomas (Henry Ford Hospital)

Pull It

Lamont Weide (University of Missouri)

Continue Marketing (with restrictions)

Alison Goldfine (Joslin Diabetes Center)

Continue Marketing (with restrictions)

Yes

Elaine Morrato (Anschutz Medical Campus)

Continue Marketing (with restrictions)

Sanjay Kaul (Cedars-Sinai Heart Institute)

Continue Marketing (with stronger warnings)

Yes

Katherine Flegal (Centers for Disease Control & Prevention)

Continue Marketing (with stronger warnings)

Susan Heckbert (University of Washington)

Pull It

Michael Proschan (National Institutes of Allergy & Infectious Diseases)

Abstain

Jessica Henderson, consumer rep (Western Oregon University)

Continue Marketing (with restrictions)

Yes

Qnexa Panel Members Who Did Not Review Avandia (5) Committee Member Thomas Bersot (UC-San Francisco)

Qnexa Vote No

Janet Cragan (Centers for Disease Control & Prevention)

Ed Hendricks (Private Practice)

Yes

Michael Rogawski (UC-Davis)

Yes

Melanie Coffin (Patient Representative)

Yes

SOURCE: The RPM Report

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

FDABEAT market with only an enhanced warning. That included the acting committee chair Kenneth Burman and the only cardiologist on the Qnexa panel (Kaul). One of the Qnexa committee members, David Capuzzi (Thomas Jefferson University), was among just three votes for the status quo (no change to Avandia labeling or marketing status). The eleventh Qnexa member, Michael Proschan (NIAID), abstained from the key Avandia vote. Add to that the fact that FDA’s Colman neatly defused the Avandia parallels in his opening comments. He began by thanking “the members who have endured the past two days and didn’t resign last night and go home,” joking that the agency “will be covering your therapy for PTSD.” After introducing the topic, he added: “You should be happy to know there is only one FDA presentation today,” by clinical reviewer Mary Roberts, and “I have never heard Mary argue with herself. So there should be a fair amount of harmony.” Those lighthearted remarks sent a clear message to the panel: this is not a case where the committee needs to settle an internal disagreement within FDA; instead this was to be a more straightforward product review. And, in its questions to the panel, FDA strongly indicated that it viewed the issue as how best to label and manage the risks associated with the drug—not whether the risks should preclude approval. The agency asked the committee to “comment on the significance” of each of the potential adverse effects in turn, and then to “discuss the need for monitoring, possible monitoring strategies, and contraindications for use.” The formula varied only for the discussion of teratogenicity—which Colman described as “perhaps most important” of the five issues for discussion. In that case, FDA asked the panel to discuss whether there is a potential teratogenic effect of topiramate (and it became clear quickly that FDA already believes there is) and then to “comment on how this risk should be managed in women of child-bearing potential.”

Meridia On the Panel’s Mind, Too Of course, it is impossible to know how the committee would have voted if it had approached Qnexa without the two-day Avandia review fresh in its mind. But it seems clear that the FDA review team didn’t see any reason to expect that outcome—even though the obesity products are handled by the same division that handles the diabetes drugs. But the bigger point is clear: the constellation of issues surrounding Avandia does very much apply to Qnexa and other potential broad market drugs. At the most fundamental level, the issue is that blockbuster drugs are built on simple, compelling and easy to verify sales messages—like, in the case of cholesterol, blood pressure or blood sugar, “lower is better.” However, in cases like Avandia

or Vytorin, outcomes data suggest that biology is more complex than that. (See “The Unsung Vytorin Vicitim,” The RPM Report, February 2008.) The parallel to the weight loss category is obvious: the commercial message (lower BMI is better) fits perfectly in the blockbuster marketing paradigm. But the Redux, Meridia and Zimulti experiences illustrate that weight loss alone isn’t enough to offset potentially troublesome side effects—and, indeed, that there is not yet a strong body of evidence that pharmaceutically driven weight loss actually produces health benefits the way pharmaceutically induced LDL reduction unequivocally does. Even without Avandia, the committee would likely have probed those questions—especially since a review of the cardiovascular safety of Meridia is the next item on its agenda. (The Abbott drug added a contraindication for use in high-risk patients after completion of the SCOUT study suggested a higher rate of CV events associated with treatment.) Weight loss drugs have a “checkered history,” Kaul noted during the review, and he asked FDA’s Colman in particular about what if anything the agency has learned from its analysis of data on Meridia’s cardiovascular safety profile. FDA plans to take that issue to a committee in September, and so Colman demurred, turning the question back to Kaul and the committee. Kaul also asked Colman to discuss the appropriate cardiovascular outcomes standard to apply to weight loss drugs, in light of standards promulgated by the agency for diabetes medicines. While that issue is clearly related to Avandia, it would likely have been discussed even without the immediate input of the July 13-14 re-review of the drug. “What is the FDA’s feeling about requiring the sponsor to rule out an unacceptable cardiovascular risk?” Kaul asked. “It seems to be an inconsistency in that we have that requirement for diabetic drugs and we don’t have that for weight loss drugs.” “The short answer is we don’t have a formal plan,” Colman said. “Obviously when the diabetes group was generating their guidance document for CV assessment, the question came up, given that obesity drugs, if they are approved, will be used by a large number of patients with type 2 diabetes.” “We have had those discussions. It hasn’t gotten to the point where we have formalized it in any kind of written statement. The question before us at this point is if you think, based on mechanism of action or the signals from the trials themselves that you would be concerned about an imbalance in cardiovascular risk then the question becomes do you think it should be done before or after approval. But we don’t have a formal policy.” “This is the dilemma we are facing here,” Kaul responded. “This is a highly selective patient population, with 44 pa-

FDABEAT tients with a history of MIs, and you know that cardiovascular disease and the risk factors for cardiovascular disease cluster with the disease indication, and we don’t have any information.” Kaul ended up voting “yes” on approval (albeit with significant caveats), but it was clear that several “no” votes were influenced by his line of questioning, reflected both as a desire for two-year data prior to approval and several comments requesting that the outcomes study be under way prior

to approval. (Committee members did not seem supportive of making CV outcomes assessments analogous to the diabetes class a pre-approval requirement.)

“Not Comfortable With the Amount of Data” In pressing Colman on the issue of CV outcomes standards, Kaul was playing a role that appears to be increasingly common for advisory committee members: serving as a sort of external institutional memory for the agency in applying its

The Qnexa Vote: Beyond the Bean Counting FDA’s Endocrinologic & Metabolic Drugs voted 10-6 against approval of Vivus’ weight loss drug Qnexa (phentermine/ topiramate) at this time. But committee members were almost unanimous in agreeing that it was a very close call, and their comments captured the nuance of the many issues FDA must resolve in the context of reviewing weight loss drugs in general and this application in particular. Below is our transcript of the discussion by each panelist about the reasons for their vote. By Michael McCaughan and Laura Helbling

Michael Rogawski, M.D., Ph.D. Chair, Department of Neurology, UCDavis

“Yes” on approval Clearly we need more information about this medication, but I think that the type of information we need, particularly with respect to teratogenicity, can’t be gained in a clinical trial setting. It can only be gained once the drug is on the market and large numbers of individuals are exposed to it. So, in terms of balancing the risks and the benefits here, I came to my conclusion to vote in favor of approval because it’s clear that these two components, as well as the combination, are indeed going to be used by patients because they are available. And it seems to me that the best use by patients would occur with the most information and with the proper labeling, the proper education and so forth. This would be done if the sponsor was marketing the drug and presenting the

drug combination to the public. So I think overall there’s a greater concern with respect to public safety if we have non-approval, because that means we don’t have the benefit of the additional information and education, risk-mitigation strategies and so forth being presented to the public.

Elaine H. Morrato, Dr.PH, M.P.H., C.P.H. Assistant Director, Children’s Outcomes Research Program, Anschutz Medical Center

“No” on approval I voted no, and actually many of my reasons are similar to what [Rogawski] just shared. I just erred on the no side in terms of risk management. I definitely agree that there’s a significant obesity epidemic in the United States, and therefore the public health and medical need is great for effective and safe pharmacotherapy options to be approved. I also agree that Qnexa

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was shown to be quite effective and met the FDA’s guidelines for weight loss. It needs to be remembered it was in the context of a very proactive active lifestyle modification and diet. But my concerns were the public health consequences given the long list of safety risks that were listed for the drug and this strong, pent-up market demand for effective weight-loss pharmacotherapy. The drug will be used by millions of patients over long periods of time, far exceeding the labeled indications for use and the duration of clinical experience that we have. [Obesity] is a chronic disease requiring chronic treatment, and while it’s always challenging when individual patients have personal success stories, I had to ask myself to balance that against initiating a huge public health. So I said no. Howeve,r I think there’s the opportunity to pay more careful attention to the REMS, in particular, and in addition to the registry trials and

FDABEAT new drug safety tools and standards. During the Avandia review, several panelists noted that they have developed broad experience looking at similar risk management problems across different product classes. (See “FDA has New Key Constituency for REMS: Advisory Committee Members.”) The discussion of cardiovascular safety in particular suggests that, rather than looking at the immediate impact of the Avandia re-review as an explanation for the Qnexa “no” vote, a better precedent might be the 2005 Pargluva review.

gathering more data, which I agree are very important. I think there could be more careful attention to a staged launch perhaps. There was no discussion really as to how the marketing would progress—if it would be very open to a very broad public or primary care [prescribers] as well as specialists. I’m wondering whether or not in a staged launch we could be more careful about how it gets out into the market in terms of specialists, weight-loss clinics, etc. where we know that those patients are more likely to meet the indicated use that they were seeking. The other piece I think that if it is to be approved, we need better, earlier assessment of knowledge, attitudes and behaviors [under the REMS] much earlier than 18 months. I would recommend that we actually seek quarterly understanding, the same way companies track market share and prescriptions. If you have those lists of doctors, you can also be tracking knowledge and behavior over time to make sure if there’s early intervention that needs to happen, you have the opportunity to do that. And I agree also with the FDA Maternal Health team’s recommendations:

In that case, the E&M advisory committee voted in favor of approval of Bristol-Myers Squibb Co.’s diabetes drug muraglitazar (Pargluva), despite a potential cardiovascular safety issue. Cleveland Clinic cardiologists Steve Nissen and Eric Topol (who has since left the Cleveland Clinic) published their own CV safety analysis in the Journal of the American Medical Association, warning that approval would be a catastrophic mistake. FDA subsequently deemed the product “approvable”—but with such onerous CV safety questions

if it is to be approved, it would be a Category X. And there needs to be attention paid to really think through the development and pre-testing of the medication guide. I know at this point if there’s an approvable letter, it’s very easy to say, “Let’s quick get some research together,” but I’m fearful that the time and attention to really develop it in a way that’s going to be effective would get short cut. So I’d want to make sure that it really is quantitatively tested in all of the risk groups, including special subpopulations, men, women, elderly and racial/ethnic subgroups.

Jessica Henderson, Ph.D. Consumer Representative and professor of Community Health, Western Oregon University

“Yes” on approval I did vacillate between “yes” and “no” because of the lack of long-term safety data and also the real-world applications that we are all worried about. But I voted yes because, number one, the sponsor did satisfy the criteria for the weight-loss benchmarks, but mostly what made me vote yes is the quality of life survey data. Five out of the eight

quality of life measurements were statistically significant in improvement, and as the consumer representative, I put a lot of credence into quality of life and the pursuit of life, liberty and happiness and a patient’s right to do that. So the quality of life data actually put me in the yes category.

Allison Goldfine, M.D. Assistant Director of Clinical Research, Joslin Diabetes Center

“Yes” on approval I’ve been on many committees and I’ve never found a vote harder. I think that in the comments you’re going to hear that the panel is probably closer, despite the split vote. I also thought there should be a controlled and staged launch. I would like to see that the outcome trials and longer-term trials are actually initiated, certainly coincident with the approval of the drug. I’d like to see the review of the two-year data before the approval of the drug. I would like to restrict patients initially who have established coronary artery disease, and potentially other very high risk individuals—certainly the elderly, certainly the cautions in youth that have been discussed.

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What concerned me most was the pregnancy issue, and that to me was very problematic because I don’t want a real-world trial where the vulnerable are not the ones who agreed to the risk exposure that was forced upon them. Yet I also clearly agree that you would not be able to get this data from a clinical trial design, and I think that’s what finally swayed me. Therefore, the risk management program and the registries and the careful assessment that these are established before the approval and that the mechanisms are in place are going to be essential. I was on the fence because of all of these lists of restrictions, in addition to some of the others that have been discussed, including serum bicarbonate monitoring, bone mineral density and others that were not as major as the pregnancy and depression issues.

Michael Proschan, Ph.D. Mathematical Statistician, National Institutes of Allergy & Infectious Disease

“No” on approval I also had a very difficult time. Part of my reason was that a lot of these potential problems are brain-related: depression, anxiety, memory, cognitive, and that always makes me worry a little more than with other kinds of problems, although I think there were other problems that certainly were brought up that I don’t think we have enough data to really be able to say whether they are serious issues or not. I think if we had had longer follow up, I probably would have voted the other way, but I just don’t feel com-

fortable with one-year follow up. In clinical trials, people often say well, “how do you know that it won’t cause cancer in 15 years?” The answer is: we don’t know. We do five-year trials; we don’t know whether it might cause cancer in 15. When you only do a one-year trial, I’m not willing to make that leap that in another year there might not be problems that reveal that these are very serious and they don’t go away.

Kenneth Burman, M.D. – acting chairman and Chief, Endocrine Section, Washington Hospital Center

“No” on Approval It is a “no” with a lot of explanations. I agree that the committee seems to be closer than perhaps it appears. But I think my no vote will allow further discussion with the FDA to address some of these issues. I wouldn’t be upset if it were approved with a lot of explanation. As we know, obesity is a major health problem, and all efforts to address this issue should be lauded. Qnexa does meet or exceed the agency’s requirement for efficacy. I don’t think there’s any issue there. The related topic though of course is that the patients will lose a percent of weight, 6 to 10 percent perhaps, and still may not reach their goal weight. But this will be helpful, especially in a longer-term program. On the other hand, the medication has serious potential adverse effects including potential teratogenicity, increased suicidal ideation, cognitive issues, decreased bicarb, tachycardia and possible renal stones.

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

Some of these side effects are serious and could be life threatening. And they have to be weighed against the potential of a relatively modest weight loss and its long-term health benefits. It is difficult if not impossible to weigh these issues since the clinical studies are only for about a year and these medications, if approved, will be used for a much longer time frame and in a much wider population, and it is difficult to extrapolate the potential adverse effects of this larger population. The doses of medication presently approved on the market are not identical to the doses in this medication, so it’s difficult to extrapolate from other studies using the medication when it’s used for seizures. I agree with the FDA recommendation that if the medication is approved, it should be tightly regulated. I agree with their specific recommendations for designating it category X, having a REMS program with details, a registry that is specific and detailed, and performing a prospective observational cohort study. I don’t have strong views regarding the lactation protocol. The question remains open in my mind whether it is worthwhile to approve a medication for moderate weight loss when it has significant potential issues. However, I could have voted yes and will feel more assuaged if a lot of these issues and restrictions are addressed, especially with regard to warnings for specific populations as mentioned.

FDABEAT Katherine Flegal, Ph.D. Senior Research Scientist, National Center for Health Statistics, Centers for Disease Control & Prevention

“No” on Approval I had a lot of different considerations here. I do think this drug fills a very important niche, as the sponsor points out, and it’s quite effective. I think my views were colored by our experience with Avandia and the safety concerns. We should deal with them before rather than afterwards. This is like a public health experiment, a large gamble, and I think widespread usage even in inappropriate populations is difficult to prevent. We have one-year information, but this drug will likely be used for a long time. It really addresses surrogate endpoints and there is minimal information on subgroup , even sex and ethnic groups. I would like to get more data on body composition. The use of this drug in itself would not improve [the overall epidemic of] obesity and I don’t think we really know if it would either save money or improve health on a population basis. I think that the risk management is a very difficult challenge that we need more information and research on how to really monitor this, how to control access.

Abraham Thomas, M.D., M.P.H Endocrinology Division Head, Henry Ford Hospital

“No” on approval Before I moved to Henry Ford, for six years I was the medical director of a weight management program at Brigham and taking care of thousands of patients with obesity. Current medications available are not very effective and have a lot of side effects. The sponsors did an

outstanding job of proving the efficacy, and this medication in terms of efficacy is far superior to anything that’s on the market. The concerns I have are with safety and, as previously mentioned, we want to make sure we avoid a situation where five years from now we’re back for an advisory meeting considering safety issues. There’s a few things that have to be addressed and I think it’s easier to be addressed before approval or at least start it before approval so that they can be finished soon after the medication is released. The first is cardiovascular disease. Most of us who treat obesity, when we use phentermine, use fairly precise criteria about which patients we shouldn’t give it to. We don’t give it to people who have a history of an MI, we don’t give it to people who have or are at risk of cirrhotic disease such as a stroke. Potentially, patients could get that. As part of a [post-marketing] trial, you’d have to use high-risk patients if you wanted to be able to do the trial within a time span that’s reasonable. Many of the patients in this study had high CRP levels, but that’s not unexpected because women who are obese will have high CRP levels. But if you were to look at their Framingham risk scores, they probably are quite low and their risk of an event is very low. The MIs that did occur were all in the treatment group. The youngest one was in their mid fifties, but in the sixties and two of them are men, in spite of the fact that men have the a very low proportion of representation in the study. So I think we should start a cardiovascular trial to look at outcomes in the higher risk population before release, so we have the

data within two to three years of release of the medication. The second thing is I’m very concerned about bone health. We were real surprised about bone health, the TZDs were a surprise and type two diabetes is a risk factor potentially for bone disease. This medication because of the acidosis could affect both spectrums of bone health, peak bone health in the younger generation because peak bone mass is developed through the mid-20s and then osteoporosis or fracture risk in the older subjects. I think this data could be accumulated as part if some of these studies are done for safety because you’ll have large numbers and hopefully also fracture data from the sponsor at a later point. The third thing is, the sponsor used a restricted-fat diet not a low carbohydrate diet. Most patients, when they’re going to use this, will pick a diet of their own in spite of what we tell them. So we do need to have some real world data. What happens when people are on a low-fat diet versus a high-fat diet? A ketogenic diet that’s high-fat like the Atkins diet may contribute to more issues of acidosis than a high carbohydrate diet. I think some data on that would be important to know what happens with acidosis. We do need more information about suicide risk. It took ten or twelve thousand patients for rimonabant to have that signal to be really clear. The meta analysis also needed a lot of patients for topiramate, so I think as the data being obtained for these other outcomes like cardiovascular disease, that data can also be obtained in terms of depression and suicidal ideation. And finally I think we have to get away from the concept of usage for

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short term. Obesity is a chronic disease. Blood pressure is a chronic disease. I would never go to someone who has high blood pressure and say “Your blood pressure is normal. now we stop all your medications in a year,” but yet with obesity we view it this way. So we have to look at the long-term safety of these medications so we can prevent weight re-gain.

Thomas Bersot, M.D., Ph.D. Professor of Medicine, UC-San Francisco

“No” on Approval Pretty much what’s been said. The reasons why I voted no: I realize that without a registry the issue with regard to pregnancy can’t be resolved. The staged launch is a good idea, but in the real-world, I don’t see how you really are going to be able to do that. We need more evidence in high-risk cardiovascular disease patients. And then there are two elephants in the room that no one has mentioned today, and those are [Arena’s] lorcaserin and the other drug that’s on its way to this committee [Orexigen’s Contrave] that have probably not as great of efficacy in terms of weight loss but maybe better risk factor profiles. But we don’t know that, and I would like to know more about all of these three compounds before making a decision about any particular one.

Lamont Weide, M.D., Ph.D. Chief, Diabetes & Endocrinology, University of Missouri

“No” on Approval It doesn’t surprise me that people who are treating people with obesity are starting to call it a chronic dis-

ease. You have to think that way. And I think when you think that way, then you look at the drugs differently, and you have to say “tell me what’s going to happen with my patients as I allow them to stay on the medication.” That is one of the things that bothers me. If with a year’s trial you have double the depression risk and you have some cardiovascular questions, I would like to see it extended. I would like to see the at-risk population be sicker, if you will, so that we can find out whether or not these safety concerns are going to be a major issue. I am really sick of taking medicines off of the market after they’ve been on a year or two because we’ve identified something that we didn’t know about. That really is some of what has given the FDA a reputation outside in the public. As I’ve joined the committee, my respect for the FDA has markedly increased, I think everybody is trying to do their best job, but we do have a responsibility to protect the public at large and that means –as much as I feel for the people who want this drug and want to lose weight—we have to protect the population at large. I think we just need longer term data with the people who are really going to be using it out there.

David Capuzzi, M.D., Ph.D. Professor of Medicine & Biochemistry, Thomas Jefferson University

“No” on Approval I voted yes, but I actually made a mistake. All the various concerns…my yes was predicated on the fact that these would all be met first, but I made a mistake. So it’s really “no” at this point.

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Sanjay Kaul, M.D. Director, Fellowship Training Program in Cardiovascular Diseases, CedarsSinai Heart Institute

“Yes” on Approval There’s a very fine line between a “yes” and a “no” vote, and thankfully the FDA pays more attention to the discussion rather than just counting the beans. My “yes” vote comes with a lot of conditions, and I will not hold it against the sponsor if they interpret my “yes” vote as a “no” vote. First of all, it should only be approved for low to medium dose, not for the high dose, because all of the safety signals appear to cluster in the high dose. The sponsor should be required to conduct a phramacodynamic study in the short term addressing the concerns that were expressed early on during the discussion, focusing specifically on commonly used medications including cardiovascular and over-the-counter medications. There should be a clinical outcomes study designed to rule out cardiovascular risk. It should be implemented within three to six months. The protocol should be to the FDA within three months, and the study outcomes should be available to the FDA for assessment within 3-5 years. It should be a conditional approval. If they don’t meet these conditions, the FDA should have the right to withdraw the approval. There is already a FDAAA program that enforces post-marketing requirements for assessing safety signals. I have no doubts about its effectiveness. I think it concentrates the sponsor’s mind if we impose moving forward a pre-approval requirement to evaluate cardiovascular risk and I think the FDA should seriously consider that

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as an option. There should be a strict contraindication in patients with arrhythmic heart disease, severe ischemic heart disease, patients with hypertensive heart disease including TI and stroke. And there should be a prominent warning mentioned for various effects particularly the drug interactions that have already been elucidated.

Ed Hendricks, M.D. Private practitioner

“Yes” on approval I agree that the population at large needs to be protected from dangerous drugs. However, one-third of that population is already obese and there’s a very large segment of the population who are headed that way. I think that Qnexa does meet the FDA efficacy standards. I think the sponsor did several different difficult clinical trials and did an outstanding job with producing the data. The data does show that in the target population, which were the obese patients, that the drug is reasonably safe and that we should approve it. I think it does fill a gap in our treatment spectrum. I think if the drug is disapproved, it will send a very bad message to the obese and the overweight and that will further drive them away from medical solutions to this problem to all the various quackery things that are out there. I hope the FDA doesn’t just go by the beans.

Melanie Coffin Patient Representative

“Yes” on approval I am a little surprised. I feel I can agree with some of the things that

have been said, I do agree that the drugs that are available right now don’t work well and they have really bad side effects. I do believe that the side effects that were listed here were reasonable with a doctor’s care. I disagree that these folks were in really good health. I think the sponsor did a great job including people with past mental illness, with depression, and comorbidities and I thought that it was much more real-world than some of the other studies that I’ve seen come through on other weight-loss drugs. I think that because these drugs as they stand alone are already on the market with higher dosage, you’re going to continue to run the risk of doctors prescribing them off-label. And you’re going to get higher instances with higher concentration. The funny stuff that’s on the market that does not go through FDA, people are clamoring for it hand over fist. I feel like we’re letting perfect get in the way of possible. If there are 100 drugs out there for high blood pressure for doctors and patients to choose from, there should be more than a half a dozen for obesity.

Janet Cragan, M.D., M.P.H. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control & Prevention

“No” on approval I also found it a very difficult decision. This drug is clearly effective and has the potential to change many people’s lives, and I really hate to be on record voting against that. But in the end, I couldn’t really justify widespread use with the reproductive outcomes concerns that we have. As I listened to the panel members discuss other adverse events, it actually

raised my level of concern rather than lessening it. I think there have been a number of excellent recommendations made by other panel members and I support those. I think the situation where the only way we’re going to resolve the reproductive risk if we can is to have a large number of women take the drugs and see what happens is the situation we’re in with human teratogenicity often. That is really difficult, but that’s just the nature of the situation.

Susan Heckbert , M.D., Ph.D. Professor of Epidemiology, University of Washington

“No” on approval In the open public hearing, we heard from several people that obesity is a very difficult disease to combat, and that’s why people are clamoring for medications. But because obesity is very difficult to combat, patients are often on very strong medications with a variety of different effects, and these medications interfere with a number of different biological pathways. They’re very highly effective. That was clearly demonstrated by the sponsor. But at the same time we have a number of signals of adverse effects that really can’t be ignored, that need more exploration. The ones I’m most concerned about are the suicidality risk, the potential for cardiovascular risk based on the mechanism of action for these drugs and the heart rate signal, and of course the teratogenicity. I do take Dr. Rogawski’s point that it won’t be possible to fully answer that teratogenicity question with clinical trials, but I think we do need more information about it as well as the other serious endpoints that I mentioned.

FDABEAT that Bristol abandoned development. (See “Shadow FDA?” The RPM Report, December 2005.) In hindsight, that decision marked the period when the cardiovascular safety outcomes bar went higher in diabetes—and also served as an unusually public rebuke of the work of an FDA committee. In that case, the panel was perfectly happy following the routine expectations for approval—only to be second-guessed in a leading medical journal and then over-ruled by FDA. In the case of Qnexa, the FDA review team seemed content to follow the letter of the agency’s 2007 draft guidance on weight loss drugs, which states that one year of data is sufficient as a basis for approval. The committee, however, expressed a clear desire to see longer term data before approval, and FDA’s Colman seemed to take that message to heart. “A lot of the committee members clearly were saying, ‘We are not comfortable with the amount of data you gave us. We need more data. We need longer data,’” Colman observed immediately after the meeting. “There is always this tension between how much data is sufficient to base an approval on, versus, ‘No, we need five years of data versus one year.’” “We just issued a draft guidance for the weight loss drugs a few years ago and we have in there one year,” Colman added. “The problem with guidance documents is they do get outdated very quickly, and this one may be on the cusp of another revision.” Colman noted that he does not expect to issue a revised/final guidance until after the pending weight loss drugs (Qnexa, lorcaserin and Orexigen’s Contrave) have been reviewed this year. But for other sponsors, the implication of the committee’s actions are clear: FDA may be back to trying to manage reviews as business-as-usual, with written guidance governing the process wherever possible—but advisory committees remain risk averse.

Seeking a “Staged Launch” The most important message for sponsors from the Qnexa review, however, is the centrality of risk management to the review process. Both the “yes” and the “no” votes kept coming back to the theme that Qnexa is going to appeal to a very numerous patient population—including inappropriate users. Committee member Elaine Morrato (Anshutz Medical Center) set the tone in her questions to the sponsor. “You have done a very thorough job measuring the efficacy,” she said. “It is my belief, though, that we should be applying the same scientific rigor that we do in the clinical development program also for defining and evaluating the risk management programs.” Given that the sponsor agrees with the agency about the

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

need to manage pregnancy exposure, she asked: “Have you incorporated learnings from other REMS programs in terms of pregnancy prevention?” The answer—from both the sponsor and the FDA—was, in effect, that those issues remained to be negotiated in the review. Morrato was not satisfied. “I think it is just very hard as a committee member to assess the sufficiency of the program when you only have about seven pages [in the briefing materials] out of 300 or so pages that talk about all the data,” she said. “We really don’t get to see the actual research plan and timing.” Good intentions are not enough, she stressed. “There is much experience that indicates that we have all good intentions when drugs launch and yet you don’t really have information that you would like afterwards...It makes it really difficult to react to some of the issues we have to react to as a committee when we don’t have some of that specificity.” After voting against approval, Morrato fleshed out her concerns. “I think there could be more careful attention to a staged launch perhaps,” she said. “There was no discussion really as to how the marketing would progress—if it would be very open to a very broad public or primary care [prescribers] as well as specialists.” “I’m wondering whether or not in a staged launch we could be more careful about how it gets out into the market in terms of specialists, weight-loss clinics, etc. where we know that those patients are more likely to meet the indicated use that they were seeking.” That theme was echoed in comments by several committee members, both for and against review. Immediately after the meeting, FDA’s Colman wasn’t quite sure what to make of that advice. “I’m not aware of a formal mechanism where you could” require a staged launch, he said. “There is restricted distribution, but that is a different kind of pathway.” A reporter asked Colman whether something like the program used for BioDelivery Sciences International Inc.’s fentanyl brand Onsolis would be a possible model. Colman’s response: “I’m not familiar with that program.”

A Split Committee? Not Really. The majority vote against Qnexa was certainly not an outright rejection of the product. In fact, a clear majority of committee seems eager to see the product on the market, provided it can be marketed safely. “When you listen to even the ‘no’ votes, you got the sense that a lot of people, they just have a little bit of hesitancy,” Colman said after the meeting. “They weren’t strongly against the drug, but they had some lingering concerns

FDABEAT that were enough to make them lean towards voting no.” Colman’s on-the-spot analysis is certainly an accurate interpretation. But the same could be said of the “yes” votes. Those voting in favor of approval did so with reservations—a strong sense of concern that widespread, unmanaged use of the agent could have dangerous consequences. “I think that…the panel is probably closer” in its view of the Qnexa application than the 10-6 vote indicates, said committee member Allison Goldfine (Joslin Diabetes Center) in explaining her “yes” vote on approval. “I’ve been to many committees, and I’ve never found a vote harder,” she said. “I also found it a very difficult decision,” said Janet Cragan (Centers for Disease Control & Prevention), who voted against approval. “This drug is clearly effective and has the potential to change many people’s lives. I really hate to be on record

voting against that.” Committee Chairman Kenneth Burnham (Washington Hospital Center) voted against approval as well, but added “I wouldn’t be upset if it were approved.” On the other hand, Kaul voted yes, and then said his vote comes with so many conditions “I will not hold it against the sponsor if they interpret my ‘yes’ vote as a ‘no’ vote.” Rather than describing the committee as split on approvability, it may be more accurate to say the committee was unanimously ambivalent about approval, eager for a middle ground between allowing broad use for weight loss and rejecting it outright. It is that push for a middle ground that other sponsors need to take to heart. rpm

Comments? E-mail the author at Michael.McCaughan@previsionpolicy.com

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By Michael McCaughan

340B:

A Test Market for Health Care Reform? The 340B program got a lot of attention from pharmaceutical industry lobbyists during the health care reform debate. Now it may be getting more attention from the commercial side of the business. Expanded discounts remains a legislative threat— but increased sales to “safety net” purchasers is also a business opportunity.

The 340B program is not exactly a high profile pharmaceutical market segment. The name, helpfully drawn from the section of the US Public Health Service Act that oversees a mandatory discount program for “safety net” providers, doesn’t really have a snappy ring to it. And the jargon of the program itself—“covered entities” purchase drugs at the statutory “ceiling price,” regulated by the Office of Pharmacy Affairs—does nothing to help. But, thanks to health care reform, plenty of people in biopharma companies are starting to pay more attention. That, at least, is one takeaway from the 14th annual 340B coalition conference in Washington DC last week. 340B has been around since 1993, and is—in principle, at least—a program that is supposed to help providers serve the uninsured by allowing them to purchase drugs at a deeply discounted price (basically the same price as is paid by state Medicaid programs, net of the rebates states collect by law from manufacturers). “Covered entities” are hospitals that serve large numbers of uninsured, as well as other special purchasers like family planning centers, TB clinics and hemophilia treatment centers. Why the new interest? For one thing, 340B was an important part of the legislative fight itself. The covered entities who purchase drugs at those deep discounts thought they had won a long sought victory to have the prices available on the inpatient side. (The program, for now at least, allows purchases only for drugs dispensed by outpatient clinics associated with hospitals or other covered providers.) Thanks in part to heavy lobbying by the pharmaceutical industry, that provision was stripped from the final legislation—

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

though the reform law did include language expanding the list of eligible entities. (See “Health Care Reform and the Biopharma Sector: A Complete Tactical Victory,” The RPM Report, April 2010.) And, since the reform law includes deeper minimum rebates under Medicaid, it also means deeper discounts on many products covered by 340B. (See “Taking Lumps from Health Care Reform,” The RPM Report, June 2010.) Since no legislative fight in Washington ever really ends, there remains interest in expanding 340B to the inpatient sector and some potentially important tweaks to the language that passed in health care reform to clarify exactly when orphan products will be exempt from 340B discounts.

Better Than “Best Price” But the interest in 340B post-reform probably has a deeper significance. At least, that is how Apexus VP Christopher Hatwig sees it. Apexus is a non-profit formed to serve as the Prime Vendor for the 340B program—an entity whose sole purpose is to negotiate even better prices than those mandated by law. Why would a manufacturer offer better prices, when the existing law already guarantees 340B the “best price” offered to any private purchaser? For the same reason manufacturers discount in other segments: market share. The 340B program now represents more than 14,000 purchasers with an annual spend of more than $5 billion on pharmaceuticals. And, thanks to the reform law, as many as 5,000 new entities are now eligible to join. For some manufacturers, at least, the potential to claim a preferred position in that market has been worth offering even deeper discounts. Apexus currently has 3,500 deeply discounted

CMSBEAT products on its Prime Vendor list, with an average discount of more than 15% off of the mandatory price for 340B. Still, with the health care reform law mandating even deeper discounts, you might think that manufacturers would be canceling those contracts rather than thinking about digging deeper. According to data presented by Hatwig, the average brand discount to 340B increased by 10.4% in the third quarter, reflecting the new Medicaid rebate formula. (See “Health Care Reform’s Impact on Drug Price.”) That means manufacturers will have to discount even more than that to participate in the Prime Vendor Program. It is certainly logical to assume that some companies, at least, will feel that enough is enough and they can’t go any lower on price. Hatwig acknowledges that is a potential concern, and says that one manufacturer has decided to stop participating in the Prime Vendor program in light of the new rebate requirements.

More Interest than Ever

But the attendance may also be a sign that manufacturers are seeing 340B as an opportunity to prepare for health care reform in the US. If the health care reform law is going to pay off for Big Pharma, it will do so over time—by giving the industry a bigger, faster growing market on the other side of the patent cliff. But only for manufacturers ready to go where the growth is. Hatwig, for one, believes that manufacturers realize that the federal government is only going to be an even more important partner in the long run, and see the 340B Prime Vendor Program as an opportunity to learn how to compete effectively in a government-administered marketplace. Add to that the fact that the market served by the 340B program includes uninsured individuals who may soon be gaining insurance through Medicaid or federally organized health exchanges, and it seems like a good time to get into the market. More importantly, as Hatwig puts it, 340B is too big to ignore. “If sales and market share are important, then you need these sales,” he said. Exactly. rpm

-9.68

% Change

But, he insists, all indications are that more manufacturers will participate in the long run. “I have never seen more interest in the Prime Vendor Program,” Hatwig said during a July Comments? E-mail the author at 20 session of the coalition meeting. michael.mccaughan@previsionpolicy.com There certainly seemed to be more industry folks in attendance at the coalition meeting than in years past. According to the coaliExhibit 1 tion, there were 870 attendees this 304B Price Declines year, up by 150 from 2009. Of those 870, 100 were from pharmaceutical 0 manufacturers, and a total of 245 were from pharmacy-related busi-3.28 nesses like wholesalers, consultants, law firms, etc. That’s only a slight -3 increase in manufacturer attendance, Generics -7.86 but a big increase in pharmacy-9.44 related firms, the coalition says. -10.43 Part of that could reflect the -6 -12.53 complexity of understanding the interlocking changes in the 340B program triggered by health care Injectable reform; one representative from -9 Genentech noted that he has atOverall tended the conference with one other colleague for years, but “this Brands year we have quite a number of -12 people here.” Genentech, in parOral ticular, needs to stay on top of some difficult challenges complying with the new rules governing treatment -15 of orphan drug prices for some SOURCE: Apexus, 340B Prime Vendor Program administrator covered entities.

Other

CMSBEAT Health Care Reform’s Pricing Impact: 340B Purchasers See Initial 10% Decline in Brand Prices How big an impact do the new Medicaid rebate rules have on prices? There’s no way to tell for sure, but price files analyzed for the 340B program offer a pretty good clue. Two things are clear about the changes to the Medicaid rebate program under health care reform. First, brand name manufacturers are paying a lot more in rebates than they were before enactment of the Patient Protection and Affordable Care Act in 2010. And second, it is devilishly hard for outsiders to know exactly how big an impact the changes have on any specific product or company. Manufacturers have disclosed the overall hit to revenues from the interlocking changes to the Medicaid rebate formula, and it is clear that the impact varies widely depending on product class and past pricing practices. (See “Taking Lumps from Health Care Reform,” The RPM Report, June 2010.) Data presented during the 340B Coalition conference in Washington, DC July 19-21 offer some insight into how big a bite the new rebate rules are taking out of pricing overall. (See “340B: A Test Market for Health Care Reform?”) The 340B program offers a unique perspective on prices because of its link to the Medicaid rebate law: the 340B program requires manufacturers to sell drugs to specific purchasers at a discount that is equivalent to the net price to Medicaid. Note the difference: Medicaid patients receive drugs purchased through commercial channels, and manufacturers pay a rebate to the state after the fact. 340B entities, on the other hand, buy drugs at a reduced price up front.

That price is known as the federal ceiling price—and, like everything else involving Medicaid rebates, it is supposed to be secret. But it is available to eligible 340B entities via a secure, government-administered website, and there is also a third party contractor—known as the 340B prime vendor—whose job includes making sure that hospitals and clinics that qualify for 340B understand the pricing trends at play. Hence the data presented by Apexus VP Christopher Hatwig during the coalition conference. Apexus is a non-profit formed to serve as the Prime Vendor for the 340B program. Because the start of the third quarter (July 1) marked the first update to ceiling prices since enactment of the health care reform law, his July 21 presentation marked an early opportunity to gauge the impact of the pricing changes. By Apexus’ analysis, brand name drug prices under 340B have declined by more than 10% on a weighted dollar volume basis. Overall prices under the program declined 9.44%, but that reflects a relatively modest drop in generic drug prices offsetting some of the bigger drop in brands. (See Exhibit 1.) Now, “ceiling price” isn’t a perfect reflection of the net Medicaid price, since it is updated quarterly and therefore trails behind the Medicaid rebate obligations accrued by manufacturers. It is an especially uncertain marker early in the health care reform era, since many of the changes

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

to the Medicaid rebate formula are still subject to interpretation. And one very important change—a new definition of Average Manufacturers Price—does not take effect until the third quarter. The new definition of AMP is intended to exclude some sales that may involve deeper discounts than are obtained by community pharmacy; as a result it is likely to increase AMP on average. That in turn will increase the size of Medicaid rebates (23.1% of a bigger number is a bigger rebate). But it will also likely increase ceiling price in some cases, since it raises the base price used to calculate the discounted price. Indeed, one pharmacy representative commented after the presentation that there is a danger that the third quarter prices could end up hurting purchasers, since hospital CFOs may look at the initial data as a basis for setting budgets for 2011—only to have prices drift upward as the AMP methodology adjusts. For manufacturers or others trying to use the 340B data to project pricing trends overall, the same caveat applies: the final impact of the changes to the legislation will likely take another quarter or two to sort out. In addition, the dollar volume weighting is specific to the 340B market; the product mix in the broader Medicaid market may be quite different. Still, it seems safe to say that brand drug prices under Medicaid are taking a 10% haircut thanks to health care reform.

Orphan Drug Standards: Systematic Flexibility The National Organization for Rare Disorders wants FDA to be a bit more rigorous in communicating its regulatory standards. The agency has always been flexible in determining how much evidence of safety and efficacy is necessary when it comes to orphan drugs; sponsors, investors and patients would benefit if that is more clearly spelled out. The National Organization for Rare Disorders is justifiably proud of our history as the principal force behind the effort that culminated in the 1983 Orphan Drug Act. And, NORD is just as equally proud of our current activities to advance the interests of Americans who have one of 6,000 rare disorders. I only have time to merely list some of NORD’s major initiatives over the past 13 months. 1. NORD organized a full-day Summit on orphan disorders at the Willard Hotel in May 2009, which was chaired by former FDA Commissioner Kessler and key participants included Dr. Janet Woodcock and Dr. Francis Collins. A summary of this Summit is available on the NORD website. 2. NORD, with the assistance of John Crowley, CEO of Amicus, one of NORD’s Corporate Council members, was responsible for organizing a Congressional Caucus on Rare and Neglected Diseases this year. 3. NORD was a key player involved in Section 740 of the FY 2010 Appropriations Act (the so-called Brownback/Brown amendment), which is the impetus for this hearing. 4. NORD suggested and supported that the FDA and the Center for Drug Evaluation and Research (CDER) establish its first position dedicated to issues related to the regulation of medicines for those with rare disorders, and in February FDA created the post of CDER Associate Director for Rare Diseases. 5. NORD worked for the passage of comprehensive health care reform, and

in particular, those two provisions of vital interest to those with rare disorders: eliminating pre-existing conditions and eliminating lifetime and annual insurance caps. To see that what was gained in Congress is not lost in the courts, NORD is currently participating in an amicus brief to defend the constitutionality of the health care reform law. 6. NORD, with the involvement of FDA Commissioner Hamburg and NIH Director Collins, set up a Task Force on rare disorders in January. In several meetings at which senior FDA and NIH officials participated, NORD has explored ways to facilitate the development of therapies for rare disorders, including holding a series of 4 focus groups, each separately meeting with representatives of patient organizations, the medical and scientific research community, the pharmaceutical industry and the financial investment community. 7. And, finally, on the seventh day, NORD rested. Both at the NORD Summit last May and at the NORD Task Force meetings, including focus groups, NORD has learned much and we want to share some of those key findings with FDA today.

By Frank Sasinowski

Sasinowski, a director of Hyman Phelps & McNamara, is the chair of the National Organization for Rare Disorders board. He delivered this statement during a Food & Drug Administration hearing on “Considerations regarding FDA review and regulation of articles for the treatment of rare disease,” June 29.

A Record of Success—but Much More to Accomplish First, over the 27 years since its enactment the Orphan Drug Act has proven a resounding success. This is best seen in the over 350 new medicines for more than 200 different rare disorders approved by

pointedVIEW FDA over the first quarter of a century of the law’s existence. However, what NORD learned at its Summit and in its Task Force proceedings is that there are still about 5,800 disorders for which there are no FDA-approved therapies. Perhaps most discouraging is that many affected with these rare disorders do not even see any research being conducted in their conditions. To NORD, this seems as though the proverbial low hanging fruit has already been harvested in the first quarter of a century of the law’s existence, while the vast majority of therapies are currently out of reach of those in need of an FDA-approved medicine. In sum, much has been accomplished by FDA, by NIH, by medical and scientific researchers, by the pharmaceutical industry, by the financial community and by patient advocates in these first 27 years, but much, much, much, much more beckons each of us to respond to the needs of those with rare disorders. Second, how best can each of us respond to those in need of therapies? As part of the NORD Task Force, NORD – with senior FDA and NIH officials – in April held a series of four focus groups to listen and learn what are the barriers slowing or barring the development of new therapies for rare diseases, especially the 5,800 rare disorders for which there are no FDA approved medicines. We had a separate focus group with each of the four major stakeholders involved in developing new therapies – the patient community, the academic research community, the pharmaceutical industry and the financial investment community. In those Task Force proceedings and at the NORD Summit, we heard many ideas. Several of those ideas would require new legislation and so those are beyond the scope of today’s hearing. What we at NORD heard which can be addressed by FDA is the benefit that would be gained from FDA action on the following two NORD recommendations: I. For a clearer, more granular expres-

sion of FDA’s historic commitment to exercise flexibility in its review of therapies for rare disorders; and II. For an FDA expression of ways to reduce regulatory uncertainty in the development and review of orphan disorder therapies. Let’s explore each of those.

NORD Recommendation I: For an FDA Statement of Policy on FDA’s Historic Flexibility in Regulating Orphan Drugs NORD heard, especially from the investment community and the pharmaceutical industry, that FDA delivers a consistent, repeated message that the statutory standards for safety and efficacy are the same for both rare disorders and prevalent diseases. What is not often heard is the companion portion that completes that statement which is that, while the statutory standards are the same, the FDA interpretation and application of those same standards have historically been tailored by FDA to the unique facts of each particular medicine under FDA review. Moreover, there are FDA regulations and guidances that express this flexibility. In addition, FDA actions on marketing applications eloquently embrace and express this concept of flexibility. This exercise of FDA scientific judgment in applying these statutory standards flexibly to various situations apparently is not being heard by some of the key stakeholders in this system. So, today NORD is asking the FDA to develop and issue a specific Statement of Policy on FDA’s role in regulating therapies for rare disorders, which includes an explanation and affirmation of the FDA’s historic position that FDA flexibly applies the standards of safety and effectiveness with respect to therapies for those with rare disorders. What we, NORD, have heard is that the investment community and pharma-

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

ceutical industry may benefit from such a formal, explicit statement of policy that will encourage investment in, research of and development of medicines for those with rare disorders, especially for those 20 million Americans with one of the 5,800 rare disorders for which there still is not a single FDA approved therapy. 1. FDA regulations and guidances In responding to the AIDS crisis that was becoming apparent around the same time that FDA was implementing the Orphan Drug Act in the mid-1980’s, FDA promulgated Subpart E of the IND regulations for “drugs intended to treat life-threatening and severely-debilitating illnesses.” FDA stated that the purpose of Subpart E is “to establish procedures designed to expedite the development, evaluation, and marketing of new therapies intended to treat persons with life-threatening and severelydebilitating illnesses, especially where no satisfactory alternative therapy exists. As stated in section 314.105(c) of this chapter, while the statutory standards of safety and effectiveness apply to all drugs, the many kinds of drugs that are subject to them, and the wide range of uses for those drugs, demand FLEXIBILITY in applying the standards. The FDA has determined that it is appropriate to exercise the broadest FLEXIBILITY in applying the statutory standards, while preserving appropriate guarantees for safety and effectiveness. “These procedures reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely debilitating illnesses, than they would accept from products that treat less serious illnesses. “These procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated.” (Emphasis added.) The regulation that was referenced in the Subpart E regulation is section 314.105(c), which even predates the Subpart E regulation and illustrates again FDA’s historic

pointedVIEW position on applying the same statutory standards in a flexible way depending upon the circumstances. Section 314.105(c) states that: “FDA will approve an application after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling. While the statutory standards apply to all drugs, the many kinds of drugs that are subject to them and the wide range of uses for those drugs demand FLEXIBILITY in applying the standards. Thus FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet them. FDA makes its views on drugs products and classes of drugs available though guidelines, recommendations and statements of policy” (emphasis added). An example of a formal regulatory policy or guidance that expresses this concept of “flexibility” in FDA’s application of the statutory standards of safety and efficacy is seen in the ICH E1A guidance. That FDAadopted international guidance stipulates the minimum quantum of safety exposures necessary for FDA to even accept a marketing application for review when the medicine is intended for a chronic condition. Most rare disorders are chronic in nature and not acute, and so this guidance applies to most rare disorder therapies. The guidance states that the minimum number of safety exposures to meet the statutory standard for safety are 1500 persons exposed to the investigational therapy with 300 to 600 of those exposed for at least 6 months and with at least 100 exposed for one year. However, the guidance states that these minimum safety thresholds do not apply to therapies for rare disorders. Importantly, the guidance then does NOT state what is required in the alternative, whereas it could have stated an algorithm such as at least 1% of the U.S. population with the rare disease must be exposed with half of them for

at least one year. No, instead the guidance relies upon the exercise of FDA’s scientific judgment to determine what is appropriate to meet the statutory standard for safety in each particular rare disorder therapy. 2. FDA actions on rare disorder therapy marketing applications Instead of reviewing many such precedents, NORD refers to but one recent example as illustrative. In March of this year, FDA approved Carbaglu for NAGS deficiency, the rarest urea cycle disorder, with only 10 patients in the U.S. generally at any time. In the FDA briefing document for the January 13, 2010 Advisory Committee meeting, FDA explained that while Congress in 1962 added a new statutory standard requiring that a drug prove its effectiveness, “FDA has been FLEXIBLE within the limits imposed by the Congressional scheme, broadly interpreting the statutory requirements to the extent possible where the data on a particular drug were convincing… Thus, evidence obtained from retrospectively reviewed case series could be considered as substantial evidence of effectiveness… The fact that the case series presented in this application is retrospective, un-blinded, and uncontrolled precludes any meaningful formal statistical analyses of the data. Under these conditions, any statistical inference from confidence intervals and/or p-values is uninterpretable and, consequently, should not be utilized to inform clinical decision making” (emphasis added). 3. Dr. Goodman’s June 23, 2010 Statement to Congress Dr. Jesse Goodman, FDA Chief Scientist and Deputy Commissioner for Science and Public Health, testified last week before the Senate Appropriations Committee Agriculture Subcommittee on “FDA’s efforts on rare and neglected diseases.” In Dr. Goodman’s commendable testimony he cites to the Carbaglu example

as well as several others to illustrate that “FDA is fully committed to applying the requisite FLEXIBILITY in the development and review of products for rare diseases, while fulfilling its important responsibility to assure that the products are safe and effective for these highly vulnerable populations. There are numerous examples of drugs approved for treating rare diseases where FDA’s FLEXIBILITY and sensitivity to the obstacles of drug development for rare diseases has brought forth a successful treatment” (emphasis added). 4. Personal example from meeting this month with FDA. In a meeting I had this month, the FDA told the sponsor at an End of Phase 2 meeting for a therapy to treat a very troublesome symptom of a very serious and common (that is, prevalent) disease that the sponsor had not only to prove the effectiveness of the drug to treat the symptom but also had to rule out that the drug did not increase unacceptably the risk of death in that patient population with this serious disease. FDA stated that the sponsor would have to show what increase in the risk of death could be excluded by reference to the upper 95% confidence interval. While we did not at that meeting arrive at an agreement on the size of the magnitude of risk that had to be excluded, even ruling out only a doubling of the risk of death would likely require a study of thousands of subjects for a long period of time. While I have been involved in scores, maybe hundreds, of therapies for rare disorders, I have never heard FDA express a similar requirement for a therapy for a rare disease. Why? This is likely because FDA is being flexible in interpreting and applying the statutory standards for safety and efficacy in that FDA knows that to require a similar type of showing for a therapy for a rare disorder would be impossible for almost all orphan drugs given the limited pool of potential subjects for

pointedVIEW clinical trials. The statutory standards are the same both for the prevalent disease and the orphan condition, but FDA rightly interprets and applies the standards in light of the disease and investigational therapy. In other areas FDA can exercise similar flexibility. For instance, where the potential number of subjects is limited, the degree to which FDA demands dose selection be optimized in preapproval studies may be reduced, as can be FDA’s requirements for validation of a patient reported outcome instrument in a rare disorder population or proof of the sensitivity, specificity and clinical meaningfulness of a primary endpoint. Given that each investigational therapy for a rare disorder will present unique features, NORD understands that the granularity of the requested statement of policy on rare disorder therapies may necessarily be limited. However, even cataloging the nature and scope of the orphan product precedents that illustrate FDA’s flexibility may enable key stakeholders to better understand FDA’s position. That is, even while FDA states correctly that the statutory standards are the same for prevalent and rare conditions, FDA will have a formal companion statement of the equally important and consistent FDA historic position that FDA will exercise its scientific judgment to interpret and apply those statutory standards in a flexible manner, tailored to each rare disorder therapy. NORD looks forward to the FDA issuance of an FDA Statement of Policy on FDA’s regulation of therapies for rare disorders and to the day when every FDA official who speaks to patients or to other stakeholders, including researchers and sponsors, about the FDA policies on regulating therapies for rare disorders does so in the complete and balanced way that Dr. Goodman did last week when he testified both that as to the identical statutory standards that rare disorder therapies must meet as well as to the historic FDA

flexibility in interpreting and applying those standards, exercising FDA’s scientific judgment in light of the particular circumstances of that unique rare disorder and specific investigational therapy.

NORD Recommendation II: Reducing Regulatory Uncertainty in the Development of Medicines for Rare Disorders In addition to the willingness of persons with rare, serious diseases to accept more safety risks and less rigorous evidence of effectiveness than for a prevalent disease or for a less serious disease or for one with some already approved therapy, and in addition to learning that some key stakeholders would benefit from a formal FDA statement of policy on FDA’s exercise of its flexibility, the other consistent message we at NORD learned from our research and interactions since the NORD Summit in May 2009 is that the development of therapies for rare disorders could additionally benefit from a reduction in regulatory uncertainty. It is axiomatic that the perfect is the enemy of the good. In the world of rare disorders, there is much that is often not known or not known well, starting with the etiology and pathophysiology of the condition, including its natural history, and ranging to a lack of agreement among even a small handful of world experts on the most common clinical manifestations of some conditions. Against this backdrop, it is entirely understandable that FDA on occasion will find it difficult to concur in advance with a development program, even the design of a registrational trial under a special protocol assessment. However, researchers, industry and FDA, as well as most importantly, persons with the condition, may find that sometimes a study needs to proceed because patients are suffering and can not wait for the perfect trial design with the ideal primary endpoint to be eventually determined or developed and consensually accepted.

September 2010 | www.theRPMreport.com | Elsevier Business Intelligence

Research resources in the universe of rare disorders are precious, with the most precious being the persons with the rare disorders who are heroically volunteering to participate in a trial, usually under conditions where there is less known than in trials of therapies for prevalent diseases about the safety and potential effectiveness of the investigational therapy from animal models, animal toxicology and early human trials. So, when these trials are conducted, sometimes with designs with which all parties may not be in full concurrence, including the FDA, great deference should be afforded the design of these trials and flexibility applied in the interpretation of their results. If such a principle were to be addressed and accepted by the FDA, much good would come of it. On behalf of all those with rare disorders, NORD commends the FDA on its stellar, worldwide leadership role on orphan product issues for the past 27 years, and NORD exhorts FDA to continue to embrace even more fully the historic flexibility FDA has long noted and exercised in FDA’s regulation of medicines for those Americans with rare disorders and to grapple with ways that can be managed by FDA to reduce the regulatory uncertainty in the development and review process. NORD commits to do all it can to continue to provide input to FDA on matters related to FDA’s vital responsibilities for the regulation of investigational therapies for each of the 30 million Americans with rare disorders, but especially for those more than 20 million who have the 5,800 rare disorders for which there are no current FDA-approved therapies. Finally, NORD would like to publicly and formally express NORD’s deep appreciation to the FDA for holding this hearing today on these critically important issues to so many Americans. rpm Comments? E-mail the editor at cole.werble@previsionpolicy.com

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