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PERSONALIZED MEDICINE Right patient, right drug, right time, right dose, right price

❚ REGENERATIVE MEDICINE

Cell and gene therapies that have the potential to cure require new approaches to value assessment, payment and financing. In the second of a series, the Alliance for Regenerative Medicine identifies potential payment models, highlights key stakeholder concerns and identifies the barriers that must be overcome to enable their uptake across the health care system.

BY TED SLOCOMB, MICHAEL WERNER, TED HAACK, SATISH VALLURI AND BETH RADER Traditional payment and financing models may not be appropriate for curative treatments, some of which may require only a single administration.

New payment and pricing models must balance patient access and affordability and also adequately value curative therapies. Multiple options may be needed, and in some cases will need to be combined.

So what? A number of proposed reimbursement and financing models are available to address the potential uncertainty and economic disincentives that may be associated with curative therapies. Implementing them will be critical to ensuring patient access to those medicines and continued innovation in the field.

• Published July 2017

T

he next decade promises a wave of innovative and potentially curative gene and cell therapy products representing breakthroughs for patients with devastating and costly diseases, many of which lack current treatments.

Patients with certain forms of inherited blindness, rare genetic muscle and neurological disorders, hemophilia, untreatable cancers and other serious conditions may soon have transformative treatment options for the first time in the form of gene therapies, gene editing technologies and cell therapies such as CAR-Ts (chimeric antigen receptor T cells), and other types of regenerative medicines. As discussed in our previous article, many of these therapies are expected to provide durable and profound treatment effects with a single administration of therapy, effectively curing the disease or condition. However, traditional payment and financing models based on cost-per-unit of product or per procedure may be suboptimal to support adoption, patient access and continued innovation of these therapies.

These therapies are expected to deliver their benefits over a long period of time, ranging from several years to the remainder of a patient’s lifetime. However, under the current payment paradigm, the costs of many of these therapies will by necessity be incurred at the time of administration, as has occurred with the initial launches of in vivo and ex vivo gene therapy in Europe (uniQure NV’s Glybera and GlaxoSmithKline PLC’s Strimvelis, respectively).

Although these therapies offer the potential for improved health, quality of life, productivity and reduced costs, some stakeholders are concerned. For example, under routine payer therapeutic management techniques and existing benefit designs, patients worry access to life-saving medications may be unaffordable given anticipated high out-ofpocket costs. In addition, payers and providers have expressed concern that they could

Shutterstock: CI Photos

New Payment And Financing Models For Curative Regenerative Medicines

REGENERATIVE MEDICINE ❚

pay high up-front costs for therapies that will not yet have evidence to support the projected long-term benefits and for which the value cannot yet be fully characterized. Budget impact is also of concern to payers and providers, especially for therapies to treat a sizeable patient population.

In addition to ensuring patient access to new therapies, innovator companies, which invest substantial resources into the development, manufacture and launch of these therapies, are concerned that reimbursement systems will not fully account for the value these therapies provide.

All stakeholders (including patients, providers, payers, etc.) need new models of payment and financing for gene and cell therapies that address these key concerns.

There is no “one size fits all” and the variety of technologies and approaches means that multiple options may be needed, and in some cases would need to be combined.

The system needs to be flexible enough to accommodate different models. This article, the second in a series of three, will further describe the key payment and financing models that have been identified to date, examine their ability to address the concerns of various stakeholders, and identify the necessary steps to address barriers to implementation. (Also see “Curative Regenerative Medicines: Preparing Health Care Systems For The Coming Wave” - In Vivo, November 2016.)

Alternative Payment And Financing Models In most health care systems, the costs of curative therapies and the procedures necessary to enable their administration will be incurred and payable at the time of each administration, based on the amount of drug and/or the procedures needed to enable the therapy. In some cases, this “Up-Front” or “One-Time” payment model might remain acceptable for the payment for certain low-volume, or well-characterized curative therapies.

However, additional models have been proposed to address key stakeholder concerns regarding costs and uncertainty of outcomes should these therapies be indicated more broadly.

Several financing and payment models have been proposed to date as alternatives to one-time, up-front payment for single administration gene and cell thera-

pies. (See Exhibits 1 and 2.) In Exhibit 1, payment models refer to how the product is paid for, for example, the transactional flow of funds to provide payment for the product and/or service, and Exhibit 2 refers to the source of funding, for example, who pays for the therapy.

It is possible that some models could be combined. For example, pay-forperformance arrangements could be combined with a one-time payment or annuity/installment payment. Additionally, an annuity/installment payment obligation taken on by a payer or institution could be passed through to a re-insurer.

Risk pools could pay for gene and cell therapies via a periodic payment and/or pay-for-performance model, with patient assistance programs limiting patient outof-pocket cost exposure.

Payment And Financing Models – Key Considerations Each payment and financing model has attributes that address the needs and desires of some stakeholders better than

others. Patients and caregivers want their cost and risk exposure minimized, especially in the case of co-payments and co-insurance in multi-payer systems, where the burden on the patient could be substantial if new methods of offsetting patient cost-burden are not introduced.

Payers are concerned with the uncertainty of the long-term outcomes and the potential budget impact of potentially curative new therapies. Although an innovator may prefer to have the full value of the therapy recognized and compensated at the time of administration, payers, providers and patients may desire that the costs of a new therapy be spread over time like chronic therapies and, therefore, aligned with the delivery of health benefit.

Payment and pricing models that adequately balance access and affordability but also sufficiently value curative therapies should be prioritized. We propose the following criteria for evaluation and prioritization.

Preferred Models Should:

Payment and pricing models that adequately balance access and affordability but also sufficiently value curative therapies should be prioritized.

• Enable patient access to new therapies and minimize patient/caregiver economic burden. Gene and cell therapies typically target patients with serious, sometimes life-threatening, health conditions with significant health burden, morbidity and poor quality of life. Models that place undue economic burden on patients and their caregivers, by asking them to take on more than a reasonable co-payment or co-insurance burden, should be lower priority than other models.

• Ensure providers and institutions are not dis-incented to administer curative therapies due to up-front cost. Health care providers and facilities play a critical role in the introduction and adoption of innovative new therapies. Reimbursement and financing structures should not place an undue burden on providers and facilities with respect to working capital outlays at time of treatment, financial risk, or risk of outcomes for using new transformative therapies.

• Be feasible to implement in a time frame to promote product adoption. Changes in access, coding and payment policies and

❚ REGENERATIVE MEDICINE Exhibit 1

Payment Models For Novel, Curative Gene And Cell Therapy Products

PAY-FOR-PERFORMANCE

ANNUITY

PAYMENT DESCRIPTION MODEL

DISCUSSION/EXAMPLES

Installment payments spread over a pre-determined time period (e.g. monthly, annual for certain pre-specified number of periods or remaining life of patient). Payments may be based on or independent of amount of therapy dispensed on initial administration. (Wilson & Brennan 2014)

Mock Analysis of CAR-T Therapy including Lifetime Leasing model and Payment for Patients in Remission Only suggests that this could be an acceptable payment model for curative therapies. (www.nice.org.uk)

Payment terms would need to be developed that allow payers to spread out, under generally accepted accounting principles, high upfront costs of curative therapy over more of the years in which the benefits (and cost savings) of such interventions will be realized by both patients and payers alike. (Gottleib 2014) Payment amount adjusted depending on whether a prespecified health outcome is achieved. Net pricing mechanism can include discounts on future payments or rebates by innovator to payers. This model shares risk between the manufacturer and the payer and rewards manufacturers for maintaining patients’ health over a period of time.

Could include an annuity payment model tied to continued performance of the therapy based on a pre-specified outcome measure.

Strimvelis launch in Italy includes one-time payment with limited risk-sharing provision common to specialty drugs.

A pay for performance arrangement is currently in place for ChondroCelect from TiGenix, a tissue engineered product for the repair of knee cartilage. The manufacturer provides a full refund if the product fails in Year 1, 75% in Year 2 and 50% after three years. (Carr & Bradshaw 2016)

SOURCE: Alliance for Regenerative Medicine

systems may be required to enable new payment and financing models in order not to impede patient access to innovative new gene and cell therapies. Solutions that could be implemented within current public and private payer systems, or that could be implemented within a short period with limited changes or clarifications to coverage policies, should be prioritized over more complex solutions.

However, superior long-term solutions should be pursued even if they require significant changes to current systems.

• Recognize the value of innovation/ therapeutic advances. Innovation typically requires private sector investment of hundreds of millions of dollars and several years of discovery and development, sometimes a decade or more from concept to product. The value of this innovation is the development of products that may treat or even cure currently unmet medical needs. In addition, the production of novel gene and cell therapies based on biological materials,

sometimes utilizing the patient’s own cells as a starting point to develop an individualized therapy, can be far more complex and more costly compared with manufacturing traditional biological and small-molecule pharmaceutical products. Payment models must appropriately include the value of these therapies.

Below is a discussion of various payment and financing models and their application to cell and gene therapies.

Payment Models Annuity Payment Models Annuity payment models, also known as “periodic,” “amortization” or “leasing” models strongly fit most of the criteria for preferred models. Under these models, payments are made over time, thereby reducing large up-front costs. The benefits of these models includes the potential to reward innovation and to better align costs with the time period over which benefits are delivered to the patient, thereby reducing up-front budget impact to the payer or provider and reducing ini-

tial cost as a barrier to appropriate access for treatment-eligible patients.

However, implementation of a periodic payment arrangement for a one-time administered therapy is not without barriers.

These include the seller reaching agreement on payment amount (net present value of payments) and duration with the purchaser, whether that is the provider/ institution that administers the therapy and/or the payer. Payer accounting rules will likely need to change to comply with these payment arrangements.

Hospitals administering high-cost therapies could agree to payment terms with the drug manufacturer, and have a separate arrangement with the payer for appropriate payment to the health care provider. This would eliminate the requirement for the health care provider or institution to purchase the therapy at full, one-time cost and to bill the payer at full, one-time cost.

In addition, for patients with private insurance, the tendency of patients to switch plans (or become Medicare

REGENERATIVE MEDICINE ❚ Exhibit 2

Financing Models For Novel, Curative Gene And Cell Therapy Products FINANCING MODEL

DESCRIPTION

DISCUSSION/EXAMPLES

Re-Insurance

A financial arrangement that limits insurer or institution exposure to the risk of an unexpected price or volume threshold of high-cost treatments.

Commercial re-insurance carriers in the US offer insurance for transplant, specialty pharmaceutical and other claims over a certain threshold.

Commercially available re-insurance was successfully introduced and adopted to address high-cost solid organ and stem cell transplantation procedures.

Re-insurance for high-cost claims/patients is used by a majority of employers that self-fund health care for their employees. (Kaiser Family Foundation Employer Health Benefits Annual Survey 2016)

Similar to re-insurance, private payers, budget holders, employers and/or state governments put a certain percent of their member premiums or health care budget into a dedicated fund for specified high value medicines. If a patient’s medicine costs exceed a certain pre-determined threshold, monies will be paid out from this fund. This dedicated fund(s) could be managed by a non-profit third party, government or even a re-insurer. Federal/state governments could also create, and/or contribute and manage these dedicated funds to enable patient access to these high value medicines.

In Canada, an industry-wide agreement among the employer group plans spreads the impact of high-cost drug claims across all payers via a pool managed by a separate non-profit company.

(Canadian Drug Insurance Pooling Corporation)

Supplier Credit

Financial intermediaries could provide loans to payers or providers to address situations where there is an issue of near-term but temporary budget affordability in response to the availability of a new curative therapy.

Lease-like financing provided by makers of high cost medical imaging equipment to hospitals.

Patient Assistance/ Subsidy

Could include payer rebates or patient assistance programs to help cover patient’s out-of-pocket expenses up to their out-of-pocket limit.

Patient assistance programs (non-profits funded via grants from innovator companies) currently exist to assist patients with commercial insurance to pay for high-cost therapies.

However, patient assistance programs often exclude patients with government insurance for pharmaceuticals in the US.

Risk Pooling (With Carve Out)

The UK Cancer Drugs Fund is an example of a separate, centrally coordinated, government sponsored, funding mechanism for a class of drugs, with dedicated evaluation, funding and expenditure control mechanisms for the drugs considered for inclusion in the pool.

SOURCE: Alliance for Regenerative Medicine

eligible) could mean that a patient is covered by one insurer with the costs of treatment continuing to be paid for by a prior payer, unless a mechanism is developed for the payments to become portable with the patient. Other barriers include the potential impacts on statutorily mandated discounts.

A possible solution to these problems would be to divide the initial costs of the treatment up into smaller payments payable over time, perhaps without tying the payment to performance, survival

or continued coverage by the patient’s original plan. Also, an ongoing financial obligation could be made part of the patient’s pre-existing condition or covered under essential health benefits, to ensure continuity of coverage, as required by federal and state mandates. If many payers engage in these types of arrangements, the flow of patients, costs and benefits across plans should eventually balance out. In addition, mechanisms would need to be created to allow for ongoing patient-assistance if there is an annual

co-payment or co-insurance alongside annuity payments in the years following the one-time administration of a curative therapy. Medicare and Medicaid rules would likely need to be changed as well to accommodate new payment models.

Pay-For-Performance Based Models Performance-based risk-sharing agreements pay companies based on agreedupon performance of clinical outcomes.

These models are likely to be more easily implemented by payers – such as Medi-

â?š REGENERATIVE MEDICINE Exhibit 3

Ranking The Models PAYMENT MODELS

One Time *

Annuity

ARM Evaluation Criteria

Performance Based Payment

*

FINANCING MODELS

Re-Insurance

Risk-Pooling With Carve-Out

Enable patient access to new therapies, minimize patient/ caregiver economic burden.

Ensure providers not disincentivized to purchase and administer curative therapies due to up-front costs.

Could be implemented within current reimbursement systems or would require limited changes to existing laws and systems.

Recognizes value of innovation/ therapeutic advances.

Model strongly fulfills criteria

Model partially fulfills criteria

Not applicable/Not evaluable

*low volume products, e.g. for ultra rare disorders *higher volume e.g. specialty products SOURCE: Alliance for Regenerative Medicine

care and Medicaid – whose enrollees stay with the plan over longer periods of time. Depending on how they are implemented and under what financial terms, performance-based models strongly satisfy several of the key evaluation and prioritization criteria outlined above.

These arrangements may be attractive for innovators in cases where evidence/ predictors of durable effect are apparent in the short-term (several months to a couple of years) and may have already been characterized in clinical trials.

Several key challenges have been highlighted in the previous section, including innovator and payer/or provider agreement on the definitions of product performance, product value under uncertainty, and payment amount and schedule as well as potential impacts on statutory state discount programs if implemented in the US. Many products are likely to have data registries that patients will be strongly encouraged to participate in

for post-treatment follow-up, beyond post-marketing regulatory requirements, providing a means of data collection on product performance in aggregate and for individual patients that, with appropriate permissions and data safeguards, could be shared with all public and private payers in performance-based arrangements.

Financing Models Re-Insurance Re-insurance mechanisms could be adapted to curative therapies with limited need for change to coverage, coding or payment mechanisms. (See Exhibit 2.) In the absence of any changes in payment or finance models, re-insurance could be used with an up-front, one-time payment model to help offset any near-term budget impact for high-cost curative therapies.

Re-insurance could also be combined with a periodic or performance-based payment model, with the re-insurer taking on the payment obligation and benefiting from any rebates or refunds

should a patient fail a therapy.

Re-insurance mechanisms can be considered favorably in terms of limiting economic burden on the patient, ability to be implemented in a time frame that would not hinder product adoption, and ensuring providers and institutions are not disincentivized to administer curative therapies due to cost. Concerns include the possibility of increases in the cost or reduced availability of re-insurance due to a new market, and more frequent and higher claims costs due to curative gene and cell therapies.

Risk-Pooling (With Carve-Out) Risk-pooling mechanisms could work when there is stability in the health system, and transparency and alignment of interests of key stakeholders. Overall health system budget constraints and uncertainty regarding changes to the Affordable Care Act could remain an impediment to creating and funding such a pool in the US for patients appropri-

REGENERATIVE MEDICINE â?š

ate for curative gene and cell therapies.

Alignment on inclusion criteria for what product classes and products should be included in the fund, the cost threshold that triggers the payments and the valuation and payment for those products would need to be determined and aligned among key stakeholders. Risk-pooling focused on product classes or disease areas would need to be structured in such a way as to not place an undue incremental financial burden on patients in the form of excessive co-payments, lifetime coverage caps or increased future health premiums due to the presence of a preexisting condition.

The advantage of this model is that it offers budget predictability to payers/budget holders, prevents adverse selection, and no payer, including an employer, is adversely affected by having clusters of patients in their plan that require high-value cell and gene therapies. In addition, this method can be combined with various payment models (up-front with or without performancebased money-back guarantee or periodic payment with or without performance guarantee). This model allows individual payer autonomy on coverage decisions while decreasing financial risk.

Supplier Credit The supplier credit model could come in the form of a third party that would act as a financial intermediary between manufacturers and payers or providers.

The therapies would be sold directly to the third party (either a private entity or a fund set up by the federal government), then payment terms would be negotiated between the third party and the payer or provider.

This option could potentially work in conjunction with the annuity model to lower the risk of non-payment to the manufacturer and to help ensure payment is made when the patient changes insurance providers.

Patient Assistance/Subsidy Patient assistance programs and subsidies could potentially help cover patients’ out-of pocket expenses and reduce cost-burden to patients and their families. These programs are well established in the US, with a focus on

providing co-payment assistance or free drug for low-income patients with commercial insurance. While these mechanisms would not be unique to curative gene and cell therapies, adaptations or modifications of these programs, when

used in combination with the models outlined previously, could be part of a solution that mitigates affordability issues for certain patients. Challenges include adapting current programs to provide continued co-payment or co-insurance assistance to patients if an annuity payment model requires annual co-payments or co-insurance from the patient for continued payment by the payer.

Many products are likely to have data registries that patients will be strongly encouraged to participate in for post-treatment follow-up. That will provide a means of data collection on product performance in aggregate and for individual patients that, with appropriate permissions and data safeguards, could be shared with all public and private payers in performance-based arrangements.

Conclusions and Recommendations – Where Do We Go From Here?

There are several potentially viable models for addressing the unique challenges of payment and financing for innovative, curative gene and cell therapies, each with its own advantages and disadvantages, and challenges in implementation. If multiple options are enabled and adopted, such flexibility could serve the needs of a number of stakeholders and allow for payment and financing models to be selected and adapted to the particular application. Product characteristics, payer needs, current reimbursement mechanisms and innovator needs may vary case-by-case. Exhibit 3 highlights those models that we view as higher priority based on our evaluation using the criteria outlined previously. The last article in our series will further define the legislative and logistics barriers to implementation of these models and will propose more detailed approaches to overcoming these barriers.

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Ted Slocomb (tslocomb@audentestx. com) is VP, Commercial Planning, Audentes Therapeutics; Michael Werner (michael.werner@hklaw.com) is CoFounder and Executive Director, Alliance for Regenerative Medicine; Ted Haack is VP, LatticePoint Consulting; Satish Valluri is Director of US Patient Access, Pfizer; and Beth Rader is Director, Market Access Strategy and Payer Policy, BioMarin. The authors gratefully acknowledge the contributions of Donald Han, Pfizer; Eric Strati, Mesoblast; Azideh Golipour, Avrobio; and Lyndsey Scull, ARM.

❚ ADVANCED THERAPIES

Cell and gene therapies, among the most exciting developments in the life sciences industry, pick up more momentum with every passing month. The spiraling enthusiasm for treatments that will change how health care is delivered was captured by GE, GSK and other key players at a leading UK life sciences meeting in spring 2017.

BY ASHLEY YEO The tailwind behind cell and gene therapy, and regenerative medicine, blows ever stronger, with the larger companies now following the early lead taken by smaller innovators despite occasional clinical research setbacks seen in parts of the industry.

Industry majors present at the 2017 BioWales conference included GSK and GE Healthcare, which both observed that while science is making the breakthroughs, payment models for this transformative field of medicine need to be addressed rapidly.

So what? Confidence in the viability of the therapies is growing, even if the payer scenario is a possible block on growth up ahead. But if the full potential is reached, we will be watching the industry transform right before us.

• Published June 2017

T

here is perhaps no better place to highlight the benefits of regeneration than Cardiff Bay in South Wales.

On stage at the Millennium Centre to officially open the 2017 BioWales life sciences conference, Wales’ government business director Mick McGuire is recalling that 35 years ago, this 1,100-hectare area of the Welsh capital was desolate brownfields and derelict docklands. Today, besides the Millennium arts and conference center, it counts the modern National Assembly for Wales, TV studios and the Life Sciences Hub Wales (LSHW) among its stylish architectural statements, and is celebrated as urban regeneration triumph.

Similarly, in health care, increasing numbers of innovators are pressing for their research in cell and gene therapy and regenerative medicine to demonstrate equally groundbreaking effects in the medicines and therapy sectors.

This year’s BioWales showcased the progress being made in cell and gene therapy by some of the industry’s heavyweights and key stakeholders – GlaxoSmithKline PLC, GE Healthcare and the non-profit UK Cell and Gene Therapy Catapult. Completing an impressive quartet of keynote speakers, Pfizer Inc.’s UK managing director Erik Nordkamp spoke of the need for forward-looking life sciences ecosystems to ensure that the benefits of life science breakthroughs are not squandered.

Unstoppable Momentum While many of the basic questions regarding cell and gene therapy remain to be answered and companies are prone to gear changes, this industry sector’s momentum

Shutterstock: Sergey Nivens

Killer Cures: Industry Heavyweights Make Their Presence Felt In Cell And Gene Therapy

ADVANCED THERAPIES ❚

is undeniable and unstoppable. (Also see “Cell Therapy Manufacturing: Challenges Remain” - In Vivo, December 2016 and “Juno, Kite Stand By Their Products As Novartis’s Shift Renews CAR-T Concerns” - Scrip, August 31, 2016.) BioWales speaker Mark Briggs, PhD, observed that the public is demanding access to these therapies because the results so far have been so compelling.

Briggs, who is the senior program and research manager of cell therapy technologies at GE Healthcare Cell Therapy, observed that enthusiasm for cell and gene therapy is at a record high. This is despite setbacks of the kind experienced by chimeric antigen receptor T-cell (CART) and T-cell receptor (TCR) platform developer Juno Therapeutics Inc. In March, Juno ended development of its Phase II CD19-targeting CAR-T therapy JCAR015 for the treatment of acute lymphoblastic leukemia (ALL) because of patient deaths.

(Also see “Juno Ends JCAR015 Development In ALL, Cementing Third Place CAR-T Position” - Scrip, March 1, 2017.)

Bad news for that particular program, but not a hammer blow for the company or the wider industry; in fact, around the same time, another key player Kite Pharma Inc. was announcing encouraging safety and efficacy findings from Phase I trials of high disease burden patients treated with KTE-C19 (the investigational name of Kite’s lead product candidate, axicabtagene ciloleucel). Kite reported a death from cerebral edema in early May), but the company did not see that as limiting the therapy’s use or its ability to win approvals.

Measured Approach The manner in which disappointing trial news tends to be received indicates both a maturing of attitudes toward and also heighted expectations of cell and gene therapy. Julie Kerby, of the UK Cell and Gene Therapy Catapult, and head of the manufacturing development team, observed that sporadic setbacks now seem to be viewed in a more measured fashion.

Speaking to In Vivo at BioWales, she said, “In the early days, such news would have been significant, but my feeling, now that the industry has been around for some years and is so large, is that people understand the risks with these

“ You can’t be in this for the short term.

We are aware that we need to engage with payers early and often, but this is a long-term investment.”

– GSK’s Sven Kili, MD

novel therapies, especially in very ill patient populations.”

For Kerby, cell and gene therapy manufacturing is a “game changer,” given that it represents a complete shift in the way people are given medicine. “We are moving away from daily, weekly and monthly dosing regimes that treat symptoms, and towards a ‘one-treatment-cure’ approach,” she said. “That is really quite amazing.”

GSK’s Approach To Cell And Gene Therapy The next logical step for industry is to embrace the payer scenario. That is the view of Sven Kili, MD, vice-president, cell and gene and therapy development head at GlaxoSmithKline. GSK was a self-confessed “new boy on the block” as recently as early 2015, when the group revealed its commitment to cell and gene therapy, and later that year presented at the London Alliance of Regenerative Medicine meeting.

The GSK view then was that cell and

gene therapy solutions clearly showed the potential for lasting innovation, although they would not provide immediate benefits. GSK describes its participation in the industry as a long-term strategic move, starting with ultra-orphan diseases where there is high unmet need.

As understanding of the disease mechanisms grows, so does the potential for moving onto more common indications.

Kili advanced the story for delegates at BioWales. “We are finally rounding the corner with cell and gene therapy. We are now understanding the causes of disease, can manipulate cells and genes, and can make a long-term difference to patients’ lives,” he said. Patients receiving therapy are being followed up for long periods to allow understanding of the effects of their therapy.

GSK started work in cell and gene therapy in 2010, on entering an alliance with San Raffaele Telethon Institute for Gene Therapy (Milan, Italy). It has oncology collaborations with Adaptimmune Therapeutics PLC, of Oxford, UK, an alliance that is looking at a number of T-cell receptor therapies. And in March 2016, GSK entered a partnership with cell processing specialist Miltenyi Biotec Ltd (Surrey, UK). It continues to seek and develop new cell and gene therapies.

Kili stressed the importance of GSK keeping scale in all areas, including manufacturing, which was another reason for the agreement with Miltenyi Biotec. This industry is prone to rapid change. “The technologies we use now will probably not be those that we will be using in 10 years’ time,” he said.

GSK Projects Underway In a snapshot of cell and gene therapy projects underway at GSK, Kili referenced Strimvelis, approved last year as a gene therapy for ADA-SCID, a very rare immunodeficiency syndrome that annually affects just 14 to 15 children in Europe and a similar number in the US. A minimum 15-year follow-up is performed for this one-time therapy that has so far showed 100% survival. “It’s really exciting, but we’re just at the beginning.”

Another GSK project targets the rare cross-linked recessive disease, WiskottAldrich syndrome (WAS), in which boys are affected by bruising and bleeding

❚ ADVANCED THERAPIES

❚ A N ENHANCED UK ROLE IN CELL AND GENE THERAPY POST-BREXIT

A consensus is growing that the Cell & Gene Therapy Catapult and the new Cell and Gene Manufacturing Centre can help the UK carve out a particular role for itself as the country gives up its membership of the EU. In the post-Brexit phase, especially, the UK is urged by MPs, the MHRA and the industry alike to capitalize on research expertise and be opportunistic – particularly in the fields of ATMPs and cell and gene therapy. BioWales speaker Erik Nordkamp, managing director of Pfizer UK, supports this approach, but is wary about the increasingly competitive environment. He feels the UK needs to develop a better life sciences ecosystem, guard against an over-focus on cost containment, avoid bureaucracy, simplify systems, be pragmatic and realistic, and use up-to-date therapies in order to keep attracting the most modern therapies.

diathesis caused by a WAS gene mutation. Following gene therapy, GSK has seen the number of severe bleeds and severe infections reduce substantially.

“This therapy makes a massive difference to children’s quality of life and can even allow them to have normal interactions at school.” It too has seen 100% survival, and no abnormal side effects.

A third GSK project highlighted by Kili targets metachromatic leukodystrophy, which affects one in 40,000 children in the UK and leads to death at age 5-8.

A recent horizon scan showed that there are some nine advanced therapies approved in the EU. They are not yet household names (uniQure NV ‘s Glybera aside – for its price tag possibly as much as its science) and are normally intended for very small niche indications.

But many new companies are being formed: figures quoted by Kili revealed over 735 companies focused on cell and gene therapy around the world at the end of 2016. The US is leading the way in terms of new companies being formed. A lot of money is following them: into the EU last

year, close to €400 million ($432 million) was invested in these companies. Clinical trial numbers are increasing too, with over 800 underway globally (more of them in Phase I than Phase III, understandably).

And now, in what remains a young industry, big pharma and the larger health care industry players are increasingly making their presence felt. “This is important, as it sends a very clear signal that these types of therapies are viable and can make a difference to people’s lives. We see this as an area of exciting growth and development,” said Kili.

Payment Models Vital To Get Right But how are companies incentivized and rewarded for their efforts? The concept of a one-off treatment that has, say, 70 to 80 years of therapeutic effect, is difficult to factor in, Kili acknowledged. But industry has a responsibility: “We need to show value for money and to price responsibly, which means doing that in a way that payers and society can afford.”

When companies eventually branch out into the big diseases such as heart

failure and neuro diseases, for instance, the industry will certainly need to broach different methods of payment. “We have to take the long-term view – these therapies are expensive, and we as an industry need to find ways, including via more cost-effective manufacturing, to bring costs down,” said Kili.

But it’s a balancing act, and manufacturers need the financial incentives to do the research and develop the therapies.

“You can’t be in this for the short term.

We are aware that we need to engage with payers early and often, but this is a long-term investment, and we need to work with payers to develop new and unique ways of being reimbursed.” (Also see “Curative Regenerative Medicines: Preparing Health Care Systems For The Coming Wave” - In Vivo, November 2016.)

Kili is confident of one thing: “As reimbursement comes, investors will see how worthwhile these therapies are. We need to see a reset from the VCs too.” The VCs had been expecting Strimvelis to be priced at Glybera levels, “but we priced substantially lower,” said Kili. He added, “We are right at the beginning – but this is an area of health care that we are committed to.”

New UK Facility To Support Fast-Growing Cell And Gene Therapy Sector UK Cell and Gene Therapy Catapult head of manufacturing development Julie Kerby agrees: she says there is a “big conversation to be had” on payment models. One option is to pay annually for therapies over time to spread the burden, instead of using the one-off payment approach. “The industry is still very young, and right now, therapies look very expensive to make, but in the future, costs will come down,” she said.

Kerby told In Vivo that of the 22 UK facilities licensed by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, most were for smallscale processes. At present, the UK has six gene therapy manufacturers.

Some companies use CMOs, but this does not suit all players, especially those with a bespoke or unique process. Also, CMO capacity in the UK is becoming limited, and this is particularly a problem in the viral vector side.

The alternative is owner-operated

ADVANCED THERAPIES ❚

businesses, but this too comes with its own issues: the need for investment; the need to recruit expertise; and the struggle to simply keep ahead of the game and factor in advances in this fastest-moving sector of the industry. Companies must think about how they “crystal-ball” their facilities, Kerby said.

So she suggests a third option: companies can take space at the new Cell and Gene Therapy Manufacturing Centre at Stevenage (Hertfordshire, UK). The center, owned and run by the Catapult, will offer cleanroom, quality, stability and product cryo-preservation services. The facility, which was nearing completion in spring 2017, will have batch-to-batch segregation to prevent cross contamination, and will hold users to GMP (good manufacturing practice) guidelines.

The Centre hopes to get an MHRA license by the end of 2017 and to be delivering clinical material in 2018. It will be able to house multi-users, with each company owning its manufacturing space and having its own Quality Management System (QMS). It will initially have six modules, and 12 when fully occupied.

There is already a “huge amount of interest” – including from large companies and large pharma contact manufacturers, said Kerby, adding “This is a way for them to test the water with us.”

“It’s a total risk-based approach,” said Kerby, but it needs to be fit for purpose and to use lean solutions. “It was a bold decision by Innovate UK and the Catapult to initiate the center – it took a lot of far-sightedness, but that is the purpose of Catapults – to take risks and look into the future.”

She added, “World-leading research is coming out of UK universities, and we want to ensure that it doesn’t move away to the US or elsewhere.” A lot of companies in the cell and gene therapy space are quite small, with just 30 to 40 members of staff, and need a lot of support. (See box, “An Enhanced UK Role In Cell And Gene Therapy Post-Brexit.”)

It is foreseen that companies will stay at the center for two to three years at least, as these are “long-term endeavors”.

Companies need to generate clinical data to secure investment. Having to construct their own facility at the same time would slow them down. When the

time comes for them to leave the facility, they can take an identical copy of their QMS with them.

Kerby acknowledges that cleanrooms are a very expensive part of the operation, and that in the future, the industry might be able to dispense with them. “We’re still a way off that, but it’s something to aspire to.”

GE’s Focus On Turnkey Solutions GE Healthcare’s senior program and research manager Mark Briggs shares the enthusiasm for cell and gene therapy on several levels. While results from drug discovery can take 15 to 20 years to come through, results in cell therapy can be seen almost immediately.

In addition, these therapies – “the antibiotics of the future” in Briggs’ view

“ Creating a 21st century health care system requires all strands of the life sciences industry to work in collaboration and form new partnerships in fields like digital and medtech.”

– Pfizer UK’s Erik Nordkamp

– will help health care systems move from palliative to curative care, and as such will help lift some of the cost burden from the health care systems. But like Kili and Kerby, he acknowledges the challenges of reimbursement and notes the high costs associated with some therapies.

GE profiles itself as an integrator in the cell and gene therapy field, and aims to make the therapies robust, practical and viable. The group wants to help develop turnkey solutions and is building a suite of products that meet end-to-end workflow needs and allow cell manipulations to be done in a closed and safer manner.

During the past year, GE has announced: the acquisition of Biosafe SA, a supplier of integrated cell bioprocessing systems; a collaboration with Mayo Clinic – Vitruvian Networks – which provides cloud-based software systems and manufacturing services for cell and gene therapies; and a co-investment with the Canadian government in the BridGE@ CCRM Cell Therapy Centre of Excellence, to promote new technologies for the production of cellular therapies. (Also see “GE Healthcare Embraces Solutions Role In Growing Regen Med Sector” - In Vivo, January 2017.)

GE recently added to this with the acquisition of Asymptote Ltd, a specialist in cryochain technology for sensitive cellular therapies. This fills a critical gap in GE Healthcare’s end-to-end ecosystem and will enable the industrialization of these therapies.

In Briggs’ view, the industry still doesn’t have the basic tools and processes in place. “What we have been doing is repurposing equipment, techniques and processes from adjacent industries and from the clinic, and simply trying to apply them to cellular therapy. It’s an imperfect approach that won’t deliver cost-effective practical solutions. But at least we know where the issues are and can start to deal with them.”

He added, “Fundamentally, there needs to be a rethink in the way we approach this field: the academic or apprentice model, where an individual might see a process through to the end, needs to give way to a scientific management approach, implying a rethink in the way teams work with each other.”

To make operations cheaper, the indus-

❚ ADVANCED THERAPIES try needs to move away from cleanrooms, he said. GE is also seeking to exploit the digital era, in simple areas such as connectivity between systems, data logging, data integrity, customization of processes and pulling it together to enable predictions. “We need smarter more intelligent approaches,” said Briggs.

The Pfizer View: Opportunities Must Be Taken In Competitive Health Care Sector That view is echoed by Pfizer UK managing director Erik Nordkamp, but from the wider angle of entire health care ecosystems. The UK, especially, faces competition from countries that have a “joined-up, holistic approach.” Leaving the European Union additionally leaves the UK open to as-yet-unknown risks in the life sciences industries.

Creating a 21st century health care system requires all strands of the life sciences industry to work in collaboration and to form new partnerships, in fields like digital and medtech, that are truly transformative. The opportunities are there to be taken. But the UK, which in reality has a poor record in new medicines adoption, faces competition from countries that have a networked approach and have factored in future needs and opportunities – countries like Singapore, Israel, and Belgium, for instance.

Taking the example of Belgium, Nordkamp observed that a continued and open dialogue between the government and industry is already making for enhanced transparency. Belgium has secured fully 10% of EU pharma R&D expenditure, the Pfizer executive noted. “They are punching far above

❚ H EALTH CARE ECOSYSTEM HELPS WALES PUNCH ABOVE ITS WEIGHT

Several elements combine to make Wales one of the global health care networking and ecosystem hotspots. The Millennium Centre has become the regular venue for BioWales, which has developed into one of the UK’s leading life sciences events over the course of 15 annual conferences. The MediWales industry forum has played a big part in putting the local devices, diagnostics digital and biotech industries on the global map. The new Life Sciences Hub Wales (LSHW) serves as the life sciences’ front door to Wales and as a forum for industry, academia, health care professionals, investors, entrepreneurs and inventors. And the £100 million ($130 million) Welsh Life Sciences Fund has so far made 11 investments, while the Life Science Bridging Fund has supported 26 projects during their most vulnerable phases.

their weight.” Wales is another smaller country that has worked hard to develop effective health care networking (See Box, “Health Care Ecosystem Helps Wales Punch Above Its Weight.”)

Can the bigger countries take a leaf out of their book? “The UK needs to get the right people around the table. This doesn’t always happen. There needs be a strategic-level dialogue about ecosystems, in order to build trust, and create new partnerships for new ways of working,” said Nordkamp.

Science now requires such collaborative, networking approaches. Pfizer’s Centers for Therapeutic Innovation (CTI) are examples of new ecosystems that focus on translating new areas of promising science into clinical candidates.

Press The Reset Button In what should be read as a warning to health care stakeholders, Nordkamp said there is no room for complacency or a half-hearted approach. “The time to get this is right now. We need to press the reset button – the industry is under intense pressure to improve population health, and a holistic approach to health care is needed.”

Turning back to the UK once more, Nordkamp said there is a real opportunity for the UK to take advantage of the upcoming opportunities in advanced therapy manufacturing, but he advised less bureaucracy, simplified and faster processes, and wrapping services around offerings to attract new investment.

IV005112 Comments: Email the author: Ashley.Yeo@Informa.com

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❚ COMPANION DIAGNOSTICS

Personalized medicine is becoming the hallmark of care in oncology, but its use is also increasing in other therapeutic areas including inflammation, respiratory, infectious diseases and central nervous system disorders, as scientific understanding of these diseases advances. The expansion of companion diagnostics beyond oncology has impacts on dealmaking, clinical practice and the R&D pipeline.

BY JESSICA LEE, RAVI PATEL, DAVID RUCH AND KATYA MAGONOVA Takeda and AstraZeneca are investigating biomarkers with their latestage assets for Alzheimer’s disease and asthma, respectively, indicating that companion diagnostics have the potential to reach beyond specialty therapeutic and rare disease areas in the near term.

Multi-biomarker assays are an area of interest among pharmaceutical and diagnostics developers, and clinicians are interested in using them to inform their treatment decisions. inVentiv Health’s survey of practicing oncologists in the US finds that 90% believe multi-biomarker diagnostics will be accepted as the standard of care within the next three to five years.

E

xpanding personalized medicine beyond the oncology sphere offers significant upside, including targeted use in patients most likely to benefit as well as adding value to the health care system. However, there are unique development and commercialization challenges associated with pairing a therapy with a companion diagnostic. Proper preparation and expertise is required to avoid potential pitfalls, such as partnership challenges and education requirements for expanded audiences at launch. Additional considerations for a successful drug-companion diagnostic launch include demonstrating clear value to both providers and payers, both of whom are critical drivers of uptake.

Advancing personalized medicine is becoming the goal of many drug manufacturers, as is evident by the number of such therapies in clinical development. According to the FDA, more than 20% of new molecular entities (NME) approved by the FDA in the last three years – and 27% of the 22 NME approvals in 2016 alone – can be classified as a personalized medicine, not including previously approved therapies. Half of the personalized medicines approved in 2016 (three) were indicated in oncology. The others had indications for either infectious or rare disease. This trend signifies a major shift in the way drug companies are organizing and thinking about commercializing pipeline assets – likely as a way to differentiate therapies in crowded markets (e.g., oncology, hepatitis C) or demonstrate greater value due to their ability to selectively target appropriate patient populations most likely to benefit.

Dealmaking On The Rise Companion diagnostics that can help identify the right patient for the right drug at the right time are playing a major role in this shift toward personalized medicine in areas beyond oncology. An analysis of recent deals in diagnostics shows that companion diagnostics deals, as a percentage of all diagnostics partnerships (including

• Published March 2017

Gayle Rembold Furbert

Companion Diagnostics: Moving Beyond Oncology

COMPANION DIAGNOSTICS ❚

licensing agreements, asset purchases, joint ventures, etc.), have held relatively steady over the past five years, despite an overall decrease in the number of diagnostics deals.

For example, in January 2016, NanoString Technologies Inc., Medivation Inc. and Astellas Pharma Inc. announced a partnership to develop and commercialize a triple-negative breast cancer (TNBC) companion diagnostic for enzalutamide based on a cancer gene expression signature algorithm from NanoString, in a partnership agreement with a disclosed value of $22 million.

NanoString will modify its existing Prosigna Breast Cancer Assay, a multiplexed biomarker test, as a companion diagnostic for enzalutamide in TNBC, a form of breast cancer with relatively high unmet need.

Beyond oncology, NuSirt Biopharma and OWL Metabolomics forged a partnership to develop a blood-based companion diagnostic for NuSirt’s NS-0200, currently in Phase II trials for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), an increasing cause of liver transplantation. OWL Metabolomics’ approach to development of this companion diagnostic is to analyze a patient’s lipidomic signature over certain time intervals to measure specific markers of histopathological change in the liver.

Currently, liver biopsy is the gold standard in the diagnosis of NASH; OWL’s technology will utilize minimal blood draws (>0.5 ml), offering a significant benefit over surgery and its related potential complications. Development of NASH therapies is expected to address a major unmet need in a disease area with no approved therapies. Driven by a crowded pipeline and historically low success in NASH clinical trials, these companies are seeking to differentiate therapies and improve odds of trial success to ultimately evolve a new standard of personalized care.

Evolving Paradigms As companion diagnostics become more common, the traditional paradigm of “one biomarker, one disease” (such as treating an anaplastic lymphoma kinase [ALK] fusion in non-squamous cell lung cancer [NSCLC] with an ALK inhibitor) is expected to evolve to “multiple biomark-

ers, one disease” or “one biomarker, multiple diseases.” For example, the National Cancer Institute’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial is investigating this with a 24-arm study exploring the potential for treating cancer patients with currently available targeted therapies based on the molecular profiles of their tumors, regardless of a product’s specific indication (e.g., evaluating crizotinib in ALK-mutated breast cancer).

According to William Grady, MD, of the Fred Hutchinson Cancer Research Center and director of translational research at the University of Washington Medical School Gastroenterology Division, “The hope is that we’ll be able to better use targeted therapies by directing them to the molecular target in the cancer rather than by directing their use based on the tissue of origin of the cancer. However, what the NCI-MATCH trials are showing is that in only about 10% of the cases where the cancers have the predicted targets that should cause the cancer to be sensitive to the therapy are we seeing a clinical effect; in 90% of the cases that have the appropriate targets, the cancers are turning out to not be responsive.” He says more work is needed to better understand cellular and molecular pathways in cancer, but there is a high likelihood that a combination treatment approach with multiple targeted therapies will be able to attack the dynamic cellular features that change with time in cancer cells.

Multi-biomarker assays, similar to Foundation Medicine Inc.’s FoundationOne and next-generation sequencing panels, may help to fill the void in current understanding of molecular targets.

Grady continues, “What we’re discovering with functional assays is that some of the targets are completely unexpected, which means new possibilities for using other platforms to predict these targets.

These assays will be another way forward” toward understanding genomic and molecular characteristics of disease through retrospective analyses to match potential drug-molecular target pairs. For example, Ignyta Inc.’s STARTRK-2 trial is incorporating powerful technologies, such as next-generation sequencing and proprietary algorithm-based biomarker panels, to identify and characterize genetic or molecular variation (TrkA, TrkB,

TrkC, ROS1 and ALK) in cancer patients in combination with an investigational therapeutic, entrectinib.

Ignyta’s unique business model, in which it is developing both the drug and the diagnostic in-house, is enabling the rapid exploration of molecular biomarkers implicated in pan-tumor settings (i.e., NSCLC, colorectal cancer, salivary gland cancer and astrocytoma) in ways that may foreshadow the future of biomarker testing and companion diagnostics development.

Survey Results: Biomarkers’ Emerging Role In Clinical Practice Not only are multi-biomarker assays an area of interest among pharmaceutical and diagnostics developers, clinicians are interested in using these assays to inform their treatment decisions as well.

In a survey conducted by inVentiv Health Consulting with 85 oncologists (n = 30) and non-oncologists (n = 55), an overwhelming majority of oncologists (90%) stated they believed that multi-biomarker diagnostics will be the standard of care within the next three to five years, with 64% of oncologists believing they will be testing at least 60% of their patients with next-generation sequencing to make treatment decisions within the next three to five years. (See Exhibit 1.)

While oncologists reported high rates of familiarity with next-generation sequencing applications, the same was also true for non-oncologists. Among the 55 non-oncologists surveyed (i.e., rheumatologists, pulmonologists, neurologists and PCPs), only 9% reported low or very low familiarity with next-generation sequencing. Non-oncology physicians also anticipated using personalized medicine approaches in regular practice, with 79% expressing high or very high likelihood that they will be using biomarker assays in the future, if available.

An even higher number (85%) indicated that a diagnostic-therapy combination would increase their confidence in using the therapy because of the potential for increased efficacy, the availability of a new treatment option, the potential for greater patient satisfaction and safety, and increased confidence that the right patient will receive the right therapy. (See Exhibit 2.) Two-thirds of all physicians

❚ COMPANION DIAGNOSTICS Exhibit 1

Oncologists Say Multi-biomarker Diagnostics Will Become The Standard Of Care

Oncologists

90%

10%

■ Yes ■ No

Q:

Do you envision using multigene/multibiomarker diagnostic assays similar to FoundationOne, Oncotype Dx, Mammaprint, etc. as the standard of care in treatment decision making in the future (3-5 years)?

SOURCE: inVentiv Health

surveyed (including oncologists and nononcologists; n = 85) felt that personalized therapies with an associate companion diagnostic will be available for many conditions outside of oncology within the next five years. This high degree of anticipation and awareness of personalized medicine suggests that adoption of future novel biomarker-driven therapies is primed for rapid uptake. (See sidebar, Survey Points To Biomarkers’ Emerging Role In Clinical Practice.)

A Diversifying Pipeline Indeed, well-studied therapeutic areas with numerous treatment choices in inflammatory disease (e.g., rheumatoid arthritis, irritable bowel disease) and infectious diseases are likely to be fruitful areas for companion diagnostics development in the near future. This is in addition to those therapeutic areas that already have the attention of biopharmaceutical companies (i.e., Alzheimer’s disease and NASH) due to the absence of approved therapies. Analysis of the current companion diagnostics development pipeline shows that almost half of therapies currently in Phase III are associated with a biomarker diagnostic intended for use outside of oncology. (See Exhibit 3.)

For example, Takeda Pharmaceutical Co. Ltd.’s AD-4833, currently in Phase III for Alzheimer’s disease, is leveraging a growing practice from oncology – that is, testing for multiple biomarkers using a risk assignment algorithm, similar to Prosigna or Genomic Health Inc.’s Oncotype Dx, which can predict the risk of breast

and colon cancer recurrence using multiple genes. These types of assays have found a valuable niche among oncologists due to their ability to effectively help inform and guide treatment decisions for cancer patients, driven by inclusion in National Comprehensive Cancer Network (NCCN) guidelines. In addition to broad physician uptake, payers have supported the use of these assays through ensuring coverage in most commercial plans.

The goal of Takeda’s trial is to evaluate the safety and efficacy of AD-4833 in delaying the onset of mild cognitive impairment due to Alzheimer’s disease and to validate a risk-based biomarker algorithm for determining this, developed in conjunction with pharmacogenomics company Zinfandel Pharmaceuticals Inc. The assay is evaluating three factors: APOE, TOMM40 genotypes and age to produce a risk score for developing early onset Alzheimer’s disease. The disease is an increasing focus for this type of effort due to the large and growing patient population as well as efforts to better understand the underlying pathophysiology that leads to disease progression.

Key Considerations For Success Innovators seeking to successfully launch personalized medicine therapies must give thoughtful consideration to the development and commercialization of the associated companion diagnostic.

This often begins with the selection of the proper diagnostic partner. Careful coordination is required to develop a drug and diagnostic together. Often,

smaller, emerging companies may be the most at risk due to limited resources and knowledge of drug commercialization.

Key considerations in the partnership equation include: • Timing: When should we partner? How should we coordinate and manage the alliance?

• Capabilities: What capabilities should the ideal partner have? Do they have a track record of experience?

• Scale: Does the partner have financial stability/access to capital and have the ability to scale at launch?

It is also important to keep in mind that incentives for the drug developer and diagnostics partner are very different.

Often the primary benefit will go to the drug developer – that is, shortened time to approval and reduced development costs, greater revenues, differentiation as a personalized medicine, etc. Thus, therapeutics companies must carefully consider the investments they may need to make in biomarker strategy and partnership structure.

Early Planning Is Key With early planning and execution, the benefits of partnering with the right diagnostics developer can be tremendous, starting with the opportunity to tailor the drug development program and clinical trial design much earlier in the process.

Choosing a diagnostics partner too late

COMPANION DIAGNOSTICS ❚ Exhibit 2

Drivers For Increased Confidence In Using CDx Outside Of Oncology Improved efficacy potential

58%

New treatment options

45%

Patient satisfaction

35%

Improved safety potential

40%

Increased confidence that the right patient will receive the therapy

38%

0%

Q:

20%

40%

60%

80%

100%

What are potential drivers of your decision that may increase your confidence to prescribe a particular drug with an associated biomarker test?

SOURCE: inVentiv Health

Exhibit 3

Companion Diagnostics Pipeline 35

38% 2 2 1 2

# Of Clinical Trials With A CDx

30 25

■ ■ ■ ■ ■ ■

5 20

46% 2 2 2

15 10 5 0

0% 7

20

7

Phase I

Phase II

Phase III

Other Renal Metabolic CV CNS Oncology

= % Non-Oncology SOURCE: inVentiv Health

into clinical development runs the risk that the companion diagnostic assay won’t be developed, validated, and approved by the time of drug approval.

This can lead to potential confusion and inefficiencies during development and launch planning and, most importantly,

poor uptake and failure to realize the full commercial potential of the therapeutic.

Companion diagnostic development and optimization should be completed prior to pivotal trial initiation to increase the likelihood of simultaneous launch. Diagnostics companies may have different

expectations and it is important for both partners to gain alignment.

With or without a partner, making an early decision to utilize a biomarkerbased strategy may help reduce exposure to the risk of clinical trial failure and subsequently improve return on investment.

In the largest study of clinical drug development success rates to date (more than 9,500 phase transitions), a BIO Industry Analysis using data from Informa’s Pharma Intelligence’s Biomedtracker found that between 2006 and 2015, therapies that utilized biomarkers as inclusion or exclusion criteria had a three-fold higher likelihood of approval (25.9% from Phase I to approval) compared with drugs that do not have an associated selection biomarker (8.4%).

At launch, the adoption of personalized medicine is heavily dependent on stakeholder education, and detailed launch planning is key to preparing the market. Generally, launches with companion diagnostics include more customer stakeholders than the traditional drug launch. In addition to the traditional stakeholders (e.g., prescribers, nurses and payers, etc.), education of appropriate lab personnel is also required to ensure awareness of the companion diagnostic and help guarantee uptake of the novel therapy. This may require development of additional marketing materials or even coordination of sales teams to incorporate a laboratory call point.

Communication And Trust Drive Success Nothing is more important to a successful companion diagnostics partnership than excellent communication from start to finish – a key factor in which is trust.

Trust can be built or frayed around such issues as intellectual property sharing, the timing and strategy surrounding market development and educational initiatives, progress updates and the like.

Even differences in corporate culture can make it difficult for partners to communicate with each other effectively.

To mitigate these risks, it is vital to establish a regulatory communication plan at the outset. Partners should communicate with each other before and after each FDA interaction. Both drug

❚ COMPANION DIAGNOSTICS and companion diagnostics partners should consider and align on marketing strategies for pathology labs that will be involved in terms of investment, messaging, education, training and marketing materials. During the launch window, communication between the partners needs to continue to ensure optimal uptake.

As we’ve seen, personalized medicine is anticipated to continue changing treatment paradigms and evolve beyond oncology with the aid of companion diagnostics. A successful drug-companion diagnostic launch may be complicated and multifaceted, yet the benefits greatly outweigh the challenges. There are few other strategies that allow drug developers to reduce development time lines, increase the likelihood of R&D success, improve outcomes for patients and deliver greater value.

The challenges associated with the development and commercialization of personalized medicine can be minimized with proper and careful preparation, from development of biomarker strategy, to diagnostics partner selection and to engaging expanded stakeholder audiences – physicians, pathology labs, payers, patients, advocacy groups – at launch to ensure a therapy’s success.

Ultimately, companion diagnostics and personalized medicine have enormous potential to deliver significant value to patients and the health care system, benefiting all stakeholders.

❚ SURVEY POINTS TO BIOMARKERS’ EMERGING ROLE IN CLINICAL PRACTICE

According to InVentiv Health Consulting’s February 2017 survey: AMONG ONCOLOGISTS:

90%

believed multi-biomarker diagnostics will be the standard of care within the next 3–5 years.

64%

believed they will be testing about two-thirds of their patients with next-generation sequencing.

AMONG NON-ONCOLOGISTS

(including rheumatologists, pulmonologists, neurologists and PCPs):

Only 9%

reported low or very low familiarity with next-generation sequencing.

60%

believed that next-generation sequencing will be important or very important in informing treatment decisions in the next 3–5 years.

79%

believed there is a high or very high likelihood that they will be using biomarker assays for personalized medicine within the next 3–5 years, if available.

IV005045

Jessica B. Lee, PhD (jessica.lee@inventivhealth.com) is a director, Commercial Strategy and Planning, for inVentiv Health Consulting in San Francisco; Ravi Patel (ravi.patel@inventivhealth.com) is an engagement manager, Commercial Strategy and Planning, for inVentiv Health Consulting in New York; David Ruch (david.ruch@ inventivhealth.com) and Katya Magonova (katya.magonova@inventivhealth.com) are senior consultants in the Commercial Strategy and Planning practice for inVentiv Health Consulting, based in Boston and New York, respectively. The authors are members of the Commercial Strategy and Planning practice with inVentiv Health Consulting.

85%

stated that a diagnostic-therapy combination would increase their confidence in using the therapy due to: • Increased efficacy potential (58%) • Availability of new treatment options (45%) • Greater patient satisfaction (35%) • Improved safety potential (40%) • I ncreased confidence that the right patient will receive the right therapy (38%) AMONG ALL PHYSICIANS SURVEYED:

66%

believed that personalized therapies with an associated companion diagnostic will be available for many conditions outside of oncology within the next 5 years.

❚ CLINICAL TRIALS

Success rates are higher for clinical trials that incorporate selective pharmacogenomics and pharmacogenetics biomarkers, according to data from Informa’s Trialtrove. Given the challenges of designing and administering trials to secure regulatory approval in areas of unmet medical need, the data provide some basis for optimism in realizing the promise of targeted, personalized therapies that improve health outcomes for individual patients.

BY DORO SHIN Advanced genetically-based testing and diagnostic tools support success in drug clinical trials, according to data from Informa’s Trialtrove.

Phase III programs with PGX biomarkers scored a significant 76.5% success rate, while Phase III programs without these selective biomarkers had a rate of only 55%.

The data suggest that PGX tools have applicability to address one of the biggest challenges in clinical trial management today: patient recruitment and enrollment.

Further, incorporating PGX biomarkers in trials could boost prospects for regulatory approval.

• Published March 2017

A

lthough the standard of care for a disease (when one exists) generally has a well-established track record, it’s a one-size-fits-all remedy that may not be the best option for some patients. Medicine is entering a new era of personalization and the number of trials targeting specific subsets of patient populations continues to rise. The definition of “personalized medicine” or “precision medicine” varies, and can refer to an approach that incorporates insights on environmental and behavioral factors, in addition to a patient’s biology or genome, while informing disease treatment or prevention.

Some have a more specific view – personalized medicine leverages genetic profiles of patients to create tailored, more targeted interventions to better treat or prevent their conditions. This analysis will hone in on this arm of personalized medicine, exploring the current state of clinical research incorporating this strategy into drug development, and the potential effect of these approaches on the success of such trials.

The Course Of Clinical Research With Biomarkers Biomarkers, genomic and non-genomic, have been used within clinical trials to facilitate drug development for different purposes, such as to serve as indicators of a drug’s toxicity or efficacy or to identify specific patient populations for targeted treatments.

The latter has been enabled by the accomplishments of the Human Genome Project (1990–2003) – a complete sequence and map of all the genes in the human body.

With this better understanding of the human genome following the end of the project in 2003, the proportion of trials using pharmacogenetic or pharmacogenomic (PGX) biomarkers to target specific patients continually increased. Initially, trials that utilized PGX analyses to drive patient selection into a trial or into a cohort within

Gayle Rembold Furbert

One Size No Longer Fits All: The Personalized Medicine Trial Landscape

CLINICAL TRIALS ❚

a trial (patient stratification) hovered between 17% and 22% of all clinical research with biomarkers. From 2008 onward, the proportion continually increased until it comprised over half of biomarker research in 2016 captured

by Informa Pharma Intelligence’s Trialtrove. (See Exhibit 1.)

The largest percentage of clinical trials selecting or stratifying patients by PGX biomarkers took place in early- to midstage research. Due to their less frequent occurrence, trial hybrids were included in counts for the more advanced phase throughout this analysis (i.e., Phase I/II trials were counted as Phase II). Between 2003 and 2016, Phase II biomarker trials most frequently used PGX analyses for patient selection, followed by Phase I (36% and 31%, respectively). Only 29% of Phase III biomarker trials leveraged this strategy; however, interest has increased markedly in recent years, with the proportion jumping from 20% in 2000 to 53% in 2015, then 57% in 2016.

PGX-informed patient selection was least common in Phase IV biomarker research (13%). Seemingly, postmarket-

ing biomarker trials appear to be more focused on identifying novel biomarkers to indicate or predict therapeutic efficacy and/or drug toxicity, and not informing patient selection with genomics.

Since the completion of the Human Genome Project, more than 1,800 disease genes have been discovered, and over 2,000 genetic tests for human conditions now exist. However, not all diseases or conditions are associated with particular genetic mutations, and many are unable to reap the potential benefits of this approach. Oncology has seen a tremendous amount of activity, as well as benefit. Because cancer is a genetic disease, caused by errors in DNA that lead to uncontrolled growth of cells, it has been a frontrunner in incorporating targeted approaches into drug development activities.

Oncology The vast majority of research with PGXdriven patient selection does indeed involve oncology indications; a whopping 90% of these trials were for cancer research. Overall, breast cancer led with the largest number of trials selecting

patients based on PGX biomarkers, comprising 35% of all PGX biomarker selection trials. Non-small cell lung cancer (NSCLC) trails behind with nearly half the number of trials, followed by colorectal, non-Hodgkin’s lymphoma (NHL) and finally, melanoma. Breast cancer also holds the largest proportion of trials leveraging this strategy, and over 50% of all breast cancer research incorporates a genomic marker for patient selection. In contrast, the other top cancers use this personalized approach in 16% to 25% of their trials. (See Exhibit 2.)

For each of the top five cancers, the number of PGX biomarker selection trials starting each year grew, although some appear to have declined in recent years. Trial counts for nearly all cancer types seemed to decrease in 2016; however, this could partially be attributed to reporting bias rather than a true decrease in trial activity. The exception was NHL, which had an uptick of 13 trials between 2015 and 2016. Year-on-year, breast cancer consistently held the top ranking for the number of PGX selection trials initiated, while the other four had

Exhibit 1

Phase I–IV Trials Using Biomarkers By Trial Start Year, 2003–2016 60%

2500

50%

2000

30% 1000 20% 500

0

10%

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

Trial Start Year ■ Trials testing biomarkers only (n) ■ Trials using PGX biomarkers for patient selection (n) — % Biomarker trials using PGX for patient selection SOURCE: Trialtrove | Pharma Intelligence, 2017

2016

0%

Proportion

Trial Count (n)

40% 1500

❚ CLINICAL TRIALS Exhibit 2

6000

60%

5000

50%

4000

40%

3000

30%

2000

20%

1000

10%

0

Breast

Lung, Non-Small Cell

Colorectal

Lymphoma, NonHodgkin's

Melanoma

Proportion

Trial Count (n)

Top Oncology Indications Selecting Or Stratifying Patients By PGX Biomarkers

0%

■ Trials using PGX biomarkers for patient selection (n) ■ All trials (n) — Proportion (%)

SOURCE: Trialtrove | Pharma Intelligence, 2017

similar levels of activity until 2008 when NSCLC and colorectal broke from the pack. NSCLC trial starts continued to rise, outpacing colorectal, until NSCLC consistently held its second place ranking.

The trajectory of activity for colorectal initially positioned the cancer type for second place until its peak in 2010 and subsequent decline to levels similar to the trial activity of NHL and melanoma.

One likely contributor to the rising levels of genomic-driven cancer research is the establishment of the Cancer Genome Atlas (TCGA) program, a collaborative effort from the National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI) to generate comprehensive genomic maps of 33 types of cancer.

Although the program is nearing its end in 2017, the efforts of the TCGA, and other similar initiatives, will continue to inform targeted drug development and enable identification of additional therapeutic targets based on the expanding number of known genomic characteristics of various tumor types.

Non-Oncology On a much smaller scale, non-oncology indications have also explored targeted approaches, primarily split between the therapeutic areas of CNS (central nervous system) and infectious disease. However, the leader overall and in recent years was an autoimmune disease, cystic fibrosis.

Cystic fibrosis is the only non-oncology indication with a proportion of PGX biomarker selection trial activity similar to the top cancers, and 18% of all cystic fibrosis trials included this approach.

In sharp contrast, the remaining four diseases – HCV, Alzheimer’s disease, depression and HIV – only selected patients with PGX biomarkers for 1% to 5% of all their clinical research. (See Exhibit 3.)

While cystic fibrosis was the overall lead, the disease only attained this position in recent years, following the FDA approval of Vertex Pharmaceuticals Inc.’s Kalydeco (ivacaftor) in 2012 to treat patients with specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This uptick in trial activity for cystic fibrosis

was largely driven by trials including Kalydeco, or invacaftor containing fixeddose combinations. Prior to that, the top position oscillated among the top five non-oncology diseases, except for a brief period when HCV activity spiked in 2010 and 2011. In general, activity for indications outside of oncology has generally been minimal for most in recent years, rarely exceeding more than 10 trial starts in a year. Despite potential genetic causes and links for some non-oncology indications, targeted approaches have not been as heavily pursued. (Also see “Companion Diagnostics: The Expanding Reach Of Personalized Medicine” - this issue)

Key Destinations And Active Players As of February 2017, Trialtrove captured 4,133 active PGX trials, defined as those that are currently planned or ongoing (open, closed or temporarily closed to recruitment). Among active trials specifying at least one country as a site location, 909 are multinational, and as such, there will be instances where the same trial

CLINICAL TRIALS ❚ Exhibit 3

Top Non-oncology Indications Selecting Or Stratifying Patients By PGX Biomarkers 3500

20% 18%

3000

16% 14% 12%

2000

10% 1500

8%

Proportion

Trial Count (n)

2500

6%

1000

4% 500 0

2% Cystic Fibrosis

HCV

Alzheimer’s Disease

Depression

HIV

0%

■ Trials using PGX biomarkers for patient selection (n) ■ All trials (n) — Proportion (%)

SOURCE: Trialtrove | Pharma Intelligence, 2017

will overlap multiple countries. In typical fashion, the US is the most common playing ground by far with 1,890 trials.

Destinations in East Asia and Western Europe follow, with Japan (735 trials), France (547), China (536) and Italy (510) rounding out the top five.

Various regulatory agencies have put forth guidelines or created working groups to facilitate and encourage use of genomic biomarkers in drug development, which may help fuel the ongoing and planned trial activity in these locations. (See sidebar, Global Guidelines.)

The roster of key players in the personalized medicine field consists of a mixture of government, industry and academic or medical centers. With the US as a leading location, it’s no surprise to see that the National Institutes of Health (NIH) is the most prolific sponsor and/or collaborator with 465 active studies using PGX biomarkers for patient selection, primarily driven by the NCI branch. However, personalized medicine is only one of many priorities for the government agency as it comprises 20% of all its cur-

rently active trials. Roche, Novartis AG and AstraZeneca PLC follow, which is in line with each company’s strong oncology focus and the frequency of oncology trials targeting specific patient populations.

This approach appears to be a high priority for Roche – 36% of all its active clinical research leverages PGX patient selection biomarkers, which is the highest proportion among the top 20 sponsors/collaborators. The second highest proportion is held by the Dana-Farber Cancer Institute, an affiliate of Harvard Medical School and a Comprehensive Cancer Center designated by the NCI. (See Exhibit 4.)

Do Targeted Approaches Affect Drug Development Outcomes?

With the growing pursuit of personalized medicine and exploration of biomarkers to inform the appropriate treatment for patients, it’s worth reflecting on the past to determine whether this precision has an effect on the outcome of a drug development program, or the individual trial.

In an effort to measure clinical development success rates and strengthen bench-

marking metrics for drug development, a prior analysis leveraged data from Informa Pharma Intelligence’s Biomedtracker and Amplion Inc.’s BiomarkerBase to evaluate individual drug program phase transitions, defined as movement out of a clinical phase (i.e., advancing from Phase I to Phase II development), from January 1, 2008, to December 31, 2015. The analysis also considered a drug’s likelihood of approval (LOA), which represents the probability of reaching FDA approval from a current phase, calculated for a specified disease group based on the historical performance of drugs within the same disease group and development phase.

Among these company-sponsored, FDA registration-enabling development programs, the use of a selection biomarker does appear to be beneficial, raising both the probability of success as well as the LOA. From Phase I to FDA approval, a three-fold higher LOA was calculated for programs that utilized selection biomarkers (25.9%) in comparison with programs that did not (8.4%). In other words, programs using selection biomarkers had a

❚ CLINICAL TRIALS Exhibit 4

Top 20 Sponsors/Collaborators Of Active Trials Using PGX Biomarkers 2500

40% 35% 30% 25%

1500

20% 1000

15%

Proportion

Trial Count (n)

2000

10%

500

5% 0%

Na

tio

na

l In of stitu He te alt s h Ro ch e No MD v a An rti As s de tra rso Z en nC ec an a ce rC en te r Br i st ol P My fi z er er sS qu ib Me b rck Me Gl & a mo Co xo ri a Sm . lS i t hK l oa Ca n-K l i ne nc e t er ter Ce i n nt g er Ce l ge ne Da na - Fa rb er Ca A nc m er ge Re n Bo se eh a rch ri n ge UK r In ge lh eim Ba ye rA G Jap A an b bV es ie eM La i ni s Ta bo tr ke ur y o da an f H d W ea l el f th, are El i Li l ly

0

■ Trials using PGX biomarkers for patient selection (n) ■ All active trials (n) — % PGX/All active

Note: Active trials are currently planned or ongoing (open, closed or temporarily closed to recruitment).

SOURCE: Trialtrove | Pharma Intelligence, 2017

Exhibit 5

Effect On Completed Trial Outcomes Of Biomarker Use 70 60

Proportion (%)

50 40 30 20

Positive

■ PGX biomarkers for patient selection

Unknown*

Positive

■ Biomarkers only

Unknown* Non-Oncology

■ Non-biomarker trials

*Indeterminate designation is given to trials that reported an outcome that was neither clearly positive nor clearly negative.

Unknown is given to trials that have not yet reported full results for the primary endpoint(s).

SOURCE: Trialtrove | Pharma Intelligence, 2017

24.6 26.8 37.1

Negative Oncology

14.9 16.6 9.2

60.5 56.6 53.7

54.5 49.3 48.5

31.1 30.5 37.6

Negative Unknown*

All Therapeutic Areas

32.1 33.8 39.9

Positive

13.5 16.9 11.5

0

13.7 16.8 9.6

55.3 52.7 52.8

10

CLINICAL TRIALS ❚ Exhibit 6

Effect On Terminated Trial Outcomes Of Biomarker Use 70 60

Proportion (%)

50 40 30

9.7 18.8 15.4

54.8 54.7 62.7

29.0 20.7 20.2

6.5 7.4 3.9

55.5 45.4 54.7

en

14.0 18.3 16.8

30.7 38.5 29.6

ca cy

4.6 3.7 2.9

13.5 18.5 16.0

55.4 47.5 59.3

30.9 34.5 24.2

10

4.7 4.6 3.5

20

ec ts

t er se

en Sa fe

ty /

ad v

or

eff

lm ro l

effi Po

of

en

ca cy

e La ck

si po Ea rly

Sa fe

ty /

ad v

tiv

e

er se

ou

eff

tc om

ec ts

t lm ro l

en or Po

of

effi

tc om e tiv Ea rly

po

si

ad v ty /

Sa fe All Therapeutic Areas

La ck

ou

eff er se

en or Po

ec ts

t lm ro l

effi of

en

ca cy

e tc om La ck

ou e tiv si po Ea rly

e

0

Oncology

Non-Oncology

■ PGX biomarkers for patient selection ■ Biomarkers only ■ Non-biomarker trials

SOURCE: Trialtrove | Pharma Intelligence, 2017

1 in 4 LOA, whereas programs without selection biomarkers had less than a 1 in 10 LOA. All four phase transition success rates were much higher for programs that incorporated selection biomarkers in comparison with those that did not.

The largest percentage difference among the four phases of development was observed in Phase III transition success rates – Phase III programs using selection biomarkers had a rate of 76.5%, while programs without selection biomarkers had a rate of only 55.0%. (For a look at success rates see Personalized Medicine Infographic, this issue.)

Considering that the use of selection biomarkers seemingly has a positive effect on a drug program’s ability to transition to the next phase as well as its likelihood of approval, we also examined the effect on individual clinical trials. The dataset included Phase I to IV completed trials

sponsored by industry or large cooperative groups, comparing PGX biomarker selection trials with trials evaluating biomarkers only or no novel biomarkers, and the outcome analysis considered primary endpoints of the trial, classifying them into three categories: positive outcome/ primary endpoint(s) met, negative outcome/primary endpoint(s) not met, and outcome indeterminate/unknown (categories of positive, negative and unknown in Exhibit 5, respectively).

Each trial category reported positive outcomes for over half its completed research.

Although trials selecting patients by PGX biomarkers demonstrated the highest proportion of 55.3%, both non-biomarker and biomarker only studies were close behind with rates near 53%. Non-biomarker trials actually had the lowest proportion of trials reporting a negative outcome of 9.6%, versus 13.7% of PGX biomarker selection studies and 16.8% of biomarker only trials.

Although non-biomarker trials were over five times more likely to have a positive outcome compared with a negative outcome, there does appear to be a slight advantage across biomarker research in using genomic markers for patient selection. Trials using PGX biomarkers for patient selection were four times as likely to report positive outcomes, while those using biomarkers for other purposes were three times as likely. (See Exhibit 5.)

Completed Trials Exhibit 5 also provides a breakdown of the completed trials into oncology and nononcology indications; proportions shift slightly across categories and outcome types, with oncology less likely to report positive outcomes in comparison with non-oncology. Regardless of the indication, there still appears to be a benefit among biomarker trials in incorporating selection markers – studies matching

❚ CLINICAL TRIALS patients to therapy based on genomic markers continued to be around four times as likely to have a positive result, and biomarker only trials were still three times as likely.

One difference was observed in nonbiomarker cancer trials. Across all therapeutic areas, non-biomarker trials were over five times as likely to have a positive result, which was still the case for these trials in non-oncology indications. However, this apparent edge decreases for oncology, and PGX selection trials without any biomarkers were only four times as likely to have a positive outcome.

A limitation of this analysis is the fact that it is prone to reporting bias, including delayed or incomplete disclosure of trial results. Over a third of trials included in the analysis were classified as ones with indeterminate/unknown outcome. A portion of these trials may well fall into the positive category, but potentially a number of these trials have negative results that have not been reported to date.

Terminated Trials To further explore potential links between biomarkers and trial outcomes, we reviewed trials terminated due to reasons outside of strategic business decisions, specifically studies that prematurely ended based on early positive outcome, lack of efficacy, poor enrollment and safety/adverse effects. A total of 6,832 Phase I to IV trials have been terminated for at least one, or more, of these reasons as of March 2017, with poor enrollment as the most common reason for trial termination, speaking to the general challenges of patient recruitment. (See Exhibit 6.)

Although a key concern for all trials, recruitment could pose a larger issue for studies selecting patients based on PGX markers due to the specialized populations involved for these trials. A higher proportion of PGX biomarker selection trials did indeed terminate due to poor enrollment compared with biomarker only trials, but at a lower rate than nonbiomarker trials. As such, it appears that biomarker research in general is less prone to, but not exempt from, issues with recruitment rates, particularly for reasons outside of patient selection.

All three trial types had similar rates of trials terminating early due to an early

❚ GLOBAL GUIDELINES A sampling of global guidelines on the use of genomic biomarkers in drug development.

The US Food and Drug Administration established the Genomics and Targeted Therapy Group, within their Office of Clinical Pharmacology, to enable integration of genomics into the development, use and regulation of medication.

Guidelines have also been developed within the International Conference on Harmonization framework to harmonize activities among regulatory agencies in the US, European Union and Japan, including ICH E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories, ICH E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure and Format of Qualification Submissions, and ICH E18 Genomic Sampling and Management of Genomic Data.

Similarly, the European Medicines Agency released draft Guidelines on Good Pharmacogenomic Practice in April 2016, with the period for comments ending in September 2016.

positive outcome, which was generally a rare occurrence. The same is not true for the opposite side of the coin as non-biomarker trials were least likely to terminate due to lack of efficacy (24%), followed by PGX biomarker selection trials (31%). The advantage for targeted approaches, albeit slight, seems to lie with safety – trials with genomic markers were least likely to terminate due to safety/adverse effects.

Again, some differences are observed when limiting the dataset to oncology indications alone. A few proportions and trends remain largely unchanged; however, it appears that lack of efficacy becomes a larger issue for oncology trials without any biomarkers, and increases to nearly the same percentage as PGX biomarker selection cancer trials. In turn, the rate of non-biomarker cancer trials terminating due to poor enrollment decreases to a similar rate as studies with PGX driven patient selection. Shifts are more apparent with non-oncology indications, and PGX selection trials were most likely to terminate due to lack of efficacy. Also, issues with poor enrollment affected all biomarker trials equally, but they still terminated at a lower rate than non-oncology trials without biomarkers.

Conclusions While the traditional strategy of developing broad medical treatments for heterogenous patient populations has not been completely abandoned, personalized medicine approaches, and the acknowledgment that one-size-does-not-fit-all, are clearly being embraced across industry, government, and academic and cooperative groups. Luckily, the use of selection biomarkers to include or exclude patients into a trial does appear to have a positive effect on the success of the overall drug program, particularly for the drug’s likelihood of approval, although effects at the individual trial level are less clear. Considering the historically low rates of cancer drugs reaching the market, increased efforts to support this targeted approach for oncology should boost the odds of more effective options for more subsets of cancer patients in need.

IV005051 Doro Shin (Doro.Shin@Informa.com) is Thought Leadership Program Manager for Informa Pharma Intelligence.

❚ DRUG PRICING

2017 Fair Pricing Forum: The Message For Pharma CEOs Pharmas were in the minority at WHO’s Fair Pricing Forum, but ZS’ Ed Schoonveld says that other attendees sent some messages that pharma CEOs should heed.

BY ED SCHOONVELD

D

rug pricing continues to be a social and political dilemma that forms a divide with the drug industry on one side and the medical community, governments and patients on the other side. Frustration over the high cost of prescription drugs has resulted in a groundswell of government and private initiatives to increase transparency, analyze value through various frameworks or directly control pricing.

WHO’s 2017 Fair Pricing Forum On a global level, the World Health Organization (WHO) has taken an active role in shaping the debate by organizing the 2017 Fair Pricing Forum, an invitation-only meeting in May this year for members of governmental organizations, patient organizations, academia and the life sciences industry. Hosted by the Dutch Ministry of Health, the meeting prompted a productive dialogue among • Published June 2017

stakeholders, but also revealed a worrisome gap in the overall understanding of the drug industry’s economics. The pharmaceutical industry’s viewpoint was widely underrepresented with attendance capped at 15 pharma staff or 7%.

About half the 227 registrants were government representatives from countries across the world, with the balance being WHO staff, and representatives from patient organizations, academia, and various associations along with a handful of consultants, including yours truly.

The main issues discussed at the meeting were the supply and fair pricing of generics, voluntary collaboration among payers, new business models for R&D, and transparency on pricing and industry cost. The most controversial issues were funding of drug R&D and the principle by which drug prices are set. The analyses and comments in this article are focused on these topics.

Mind-set Of Governments, WHO And Patient Organizations At the beginning of the forum, the participants were polled on their opinions with respect to various issues. Here are the results for the ones that involve pricing of innovative prescription drugs and R&D. It gives a good sense of how the participants are thinking about the issues. Non-responders are not included in the responses shown.

It is encouraging to see that many think of therapeutic value as an important driver of what constitutes a fair price, but the majority of respondents indicated that price should be driven by payer affordability or cost of manufacturing. Given that almost half the attendees represented government payers, this is probably not surprising. Less than 5% of respondents considered return of investment for the innovator as a reasonable driver of price. (See Question 1, next page.)

The high cost of medicines is mostly deemed to be caused by the focus on profits by manufacturers and lack of gov-

DRUG PRICING â?š

1. What is a fair price?

All payers can afford Provides an attractive return for developer Reflects the therapeutic values of the medicine Covers the cost of bringing a medicine to market 0%

5%

10% 15% 20% 25% 30% 35% 40% 45%

2. Prices of some medicines have been considered too high.

What is driving this?

Developers’ costs are rising Governments have not taken adequate action Prices reflect buyers’ willingness to pay Prices are set to maximize profit 0%

10%

20%

30%

40%

50%

60%

70%

3. What is the most promising solution to the problem of pricing?

Companies agree to lower their prices Governments regulate prices based on R&D and manufacturing cost Governments issue compulsory licenses on patented medicines and compensate developers Government and other payers cooperate to increase their buying power 0%

5%

10%

15%

20% 25% 30%

35% 40%

45%

5%

10%

15%

20% 25% 30%

35% 40%

45%

4. Why should we explore new business models for R&D? To achieve affordable innovations by delinking R&D rewards from pricing To incentivize the pharmaceutical industry to respond to public health needs To meet the needs of countries at all levels of development To accelerate and improve R&D processes through open innovation 0%

❚ DRUG PRICING ernment intervention. Only few recognize that the rise in cost of drug development may have contributed to this. From the discussion, it was apparent that certainly a share of participants would like to go beyond government price control and place all health care and related research in the hands of government agencies. (See Question 2, previous page.)

An overwhelming majority of attendees feel that governments need to interfere in pricing, through direct control with a “cost-plus” type mechanism, government collaboration in price negotiations or even compulsory licensing. Even when considering the bias in the composition of the audience and the leading nature of the question, this is very concerning. Only 6% of responses favored the non-government intervention option, although there was clearly bias in the response options provided. (See Question 3, previous page.)

The last question was very biased as it was based on a premise of agreed need for change in the R&D model, which was rejected by most during the in-depth discussions. The general consensus seemed to be more toward favoring very limited government intervention by supplementing existing R&D efforts with incentives for specific disease areas where market conditions do not sufficiently entice new innovations, such as for anti-microbial drugs. (See Question 4, previous page.)

The WHO is challenging the use of “value-based pricing.” This is a clear contrast with most government payer systems, which tend to use some measure of demonstrated benefits and value in determining what these governments perceive as a fair price.

Results From The Discussions Although some participants seemingly preferred a “revolution” in terms of shifting R&D responsibilities to governments, most forum members appeared less interested in disrupting areas that work and more focused on finding solutions for areas with insufficient R&D investment incentives. Discussions related to antimicrobial resistance have demonstrated that the financing of additional incentives for globally oriented R&D efforts requires a sort of coalition or pooling of government resources across countries – a stumbling block that needs to be addressed foremost.

Much of the discussion focused on collaboration among governments following a recent effort between the Netherlands, Belgium, Austria and Luxembourg to jointly negotiate prices for hepatitis C drugs. The effort seems to have largely evolved into a joint health technology

assessment, while leaving actual negotiations mainly with the individual budget authorities in each country. As such, this initiative is progressing along a path similar to that followed by the European Network for Health Technology Assessment over the last 10 years or so.

Joint assessments can have some advantages to the industry in terms of a more consistent approach toward recognized benefits – for example, through an agreed-upon comparator or acceptable clinical endpoint.

Concerns For Pharma There’s a clear need for continued dialogue between governmental orga-

nizations, the industry and the patient community. Though much of the meeting’s dialogue was constructive and participants endeavored to find joint solutions, it revealed a large gap in the understanding of mutual perspectives, which stands in the way of meaningful solutions. Given each entity’s somewhat different responsibilities and interests, complete alignment is unlikely, but understanding each other’s perspectives will help us find responsible solutions that work in the long run.

Government and patient organizations have sent strong signals for increased transparency in pricing and drug industry economics. Even though transparency is unlikely to provide solutions, the industry needs to address transparency within a broader perspective of drug company investment and the economics environment to find solutions in other areas. Government representatives and the public often lack a fundamental understanding of drug development economics, leading to an unproductive fixation on actual production costs in pricing discussions.

Particularly, the WHO is challenging the use of “value-based pricing.” This is a clear contrast with most government payer systems, which tend to use some measure of demonstrated benefits and value in determining what these governments perceive as a fair price. A less understood component is that profit maximization is usually achieved where a product is priced to each country/customer at the perceived value and affordability. A drug that doesn’t reach a patient is of no value to society or to the drug manufacturer, either. The fundamental challenge of access to medicines for populations with lower affordability is the global community’s insistence in freedom of flow of goods and price referencing, which naturally leads to a single price for all, independent of geographic location, medical need and income status.

IV005117

Ed Schoonveld (Ed.Schoonveld@zs.com), Managing Principal and leader of the value and access solution area at ZS, is the author of The Price of Global Health, a textbook about global drug pricing and market access; the second edition was published in 2015.

❚ MEDTECH STRATEGIES

UK Medtech One Year Post-Brexit Vote: Still In The Land Of Uncertainty The UK’s Brexit and a failed Conservative Party election strategy last month weigh heavily on the minds of local medtech businesses, looking ahead nervously at the type of trade deal the UK might finally strike with the EU. They could be waiting awhile, because the When and What are still not yet apparent – never mind that the Why still rankles with many UK medtechs. That much is clear from a brand new survey of companies, which also reveals the primacy of NHS access.

BY ASHLEY YEO

W

ill the UK still leave the European Union, given the result of the June 8 2017 UK election and the slowlydawning realization about the levels of trade, policy and economic disruption – not to say damage – that the UK will subject itself to for years to come?

An Association of British Healthcare Industries (ABHI) “Question Time” panel this week decided that the answer remains yes, although now with signs of equivocation: on a panel of six political, legal, NHS and industry specialists, three were unable to commit whole-heartedly either way when asked the question; and the other three were perhaps not 100% forthright.

They don’t have to do the tricky nego• Published June 2017

tiating work, of course. Neither are they subject to humiliation, in the UK and overseas, whenever Brexit is mentioned.

But they are experts in gauging mood in the UK and its appetite for change: and on the former issue, there is growing uncertainty, while on the latter, there is real concern about just what would replace the EU’s freely-accessible medtech markets and potential lost business for home-grown companies. Never mind the misplaced hyperbole that preceded and followed the 2016 referendum.

It is one year after the UK voted to leave the EU, and not two weeks since the first meeting between UK “Brexit Minister” David Davis and his EU counterparts in Brussels. The big picture themes are just emerging. The detail must wait.

Medtech and health products are not yet

an agenda item, for instance. But at some point, they should be.

Simmering Unease Among Local Businesses Question Time panel chair Richard Phillips, ABHI director of healthcare policy, revealed that UK business unease in the post-vote period simmers with ever greater intensity. In an ABHI members’ survey that closed just this week, over 50% of respondents put Brexit as a top agenda item for their business. The survey, a follow-up from a similar poll by the association last May, also showed that, with the value of UK sterling languishing – especially against the Euro – rising manufacturing costs are starting to bite.

Sixty per cent of UK medtech businesses say they have seen a rise in pro-

MEDTECH STRATEGIES ❚

duction costs, indicating significant cost pressure in the system. But the picture is partly cloudy, as a net 20% of companies say they have seen an increase in export orders. Claims that the weaker pound will produce thriving export market opportunities are reportedly prone to exaggeration, however, and the survey’s findings do in fact point to a major imbalance in Brexit’s effects on the UK’s medtech import/export business.

Just 3% of UK companies polled want digression from EU medical device regulation – specifically the new EU Medical Device Regulation – MDR (EU) 745/2017 and its IVDR counterpart (EU) 746/2017.

A resounding 97% do not.

Panel Views – Hard Brexit Less Likely Now ABHI panellist Charles Mayo, a Simmons & Simmons corporate team partner, said that the election result makes a “hard Brexit” less likely. In its negotiations on Brexit, the UK should not be fazed by the first and second rounds of fire, he advised. Brussels-based EU regulatory specialist Steven Bridges, of SB Consulting, thought that the beginnings of the talks signified that the UK is at last confronting Brexit reality: the negotiations mean that some kind of trade deal between the UK and EU is marginally more likely than hitherto. He rates it at a 65:35 chance.

Prime minister Theresa May’s high poll lead at the start of the campaign was not pointing to the hung parliament, an outcome that surprised PB Consulting managing director Paul Bristow. For him, one positive outcome of the election result is that UK industry now feels empowered to speak up – many big manufacturing associations and Confederation of British Industry (CBI) are coming out strongly against a hard Brexit.

But he also feels there is no such concept as a “soft Brexit”, and that the Norway model of Economic Area (EEA) membership and access to the EU single market would be unpalatable to the minority Conservative government.

Bristow also observed that Conservative backbench MPs will suddenly have more of a voice on government issues.

Next comes the Great Repeal Bill, which could be a chance for health care businesses to raise profile. This and

The No. 1 concern of UK medtech companies is doing business with the NHS – ABHI June 2017 survey of members

Brexit discussions will dominate the unusually extended (two-year) parliamentary session, a prospect that must fill many with dread.

Left On The Sidelines Of Key EU Regulation Decisions It is highly doubtful that the two-year negotiation timeframe to complete Brexit can be adhered to. But if it is, a problem would arise for the UK medtech industry in that the MDR and IVDR, Regulation, would be effective after the UK’s EU withdrawal (in the MDR’s case on May 26 2020 and for the IVDR, two years later still).

The UK competent authority, the Medicines and Healthcare Products Regulatory Agency (MHRA), intends to keep following the MDR and IVDR, but these require some 60 pieces of secondary legislation; the UK government and MHRA would have no impact/influence on the drafting or content of these elements of the regulatory package, observed legal expert Alison Dennis, head of life sciences and healthcare at FieldFisher.

“Trade Comes With Trade-Offs” In any event, the UK will have to relearn how to negotiate trade deals – something that has been off its agenda for at least 44 years. As to the “financial settlement” that the UK must pay to the EU for leaving, this is now estimated at €40bn ($45.4bn) without the UK reneging on responsibilities: it is by no means a small figure, but maybe not as high as many had expected, said Bridges. But he added

that UK should learn that “trade comes with trade-off”. Tariffs can be expected for UK exports if no trade agreement is reached, but the non-tariff barriers may yet be worse.

It’s not all a one-way street, however.

Mayo noted that UK exports to the EU in 2015 were £230bn (43% of its exports); while EU exports to UK were valued at £290bn (53% of the UK’s imports).

Business Concerns Most Focused On The Here And Now For all that, the ABHI poll shows that the No. 1 concern of UK medtech companies is doing business with the NHS – 70% of respondents to the latest survey said so – whereas last year the figure was 46%.

This probably indicates that business is focused more on real and immediate problems than theoretical and future disruption.

The need for the UK to do new trade deals comes at a time of unprecedented levels of financial strain on the NHS, said Sarah Collen of the NHS’s European Office in Brussels. The NHS thus wants a minimal effect from Brexit. “We’re not prepared for or culturally ready for Brexit,” she said, adding that 10% of NHS clinicians are from the other 27 EU member states.

A new Brexit Health Alliance, cochaired by Sir Hugh Taylor, chair of Guy’s and St Thomas’ NHS Foundation in London, and Niall Dixon of the NHS Confederation), will have its inaugural meeting in July, with an expected focus on access to innovation and clinical networks, rare diseases, and the regulatory environment, among other themes.

But the Brexit process may be long and the transitional arrangements could last for years. The precedents are not good: Bridges observed that it took a full ten years for the MDR/IVDR to be negotiated – and that’s just a single piece of twin legislation.

The verdict from the ABHI panel for now is that Brexit will likely be followed through, subject to nothing hindering the process, like an economic recession, or no new referendum being called. But significantly, there are now question marks that were not there just a month ago. Uncertainty prevails still.

IV005127