Volume XI Issue ii by Penn Bioethics Journal

Volume XI Issue ii Fall 2015

PENN BIOETHICS JOURNAL

Research Funding: Equity and Need

Rare Disease Funding, Global Research Funding, and A Conversation with Dr. David Fajgenbaum

Penn Bioethics Journal EDITOR-IN-CHIEF Ruchita Pendse MANAGING EDITORS Lucy Chen Claire Fishman Kurt Koehler Darby Marx Samip Sheth Girish Valluru

The Penn Bioethics Journal (PBJ) is the premier peer-reviewed undergraduate bioethics journal. Established in 2004, the Journal provides a venue for undergraduates to make contributions to the field of bioethics. Embracing the interdisciplinarity of bioethics, PBJ reviews and publishes original work addressing debates in medicine, technology, philosophy, public policy, law, theology, and ethics, among other disciplines. The biannual issue also features news briefs summarizing current issues and interviews with eminent figures in the field. Authors and the editorial staff alike have a unique opportunity to experience the peer-review process through the collaborative, rigorous review and preparation of the Journal. With an audience ranging from undergraduates to scholars in the field to the broader public seeking unbiased information, the Penn Bioethics Journal occupies a unique niche in the field of bioethics.

Email bioethicsjournal@gmail.com for more information about bioethics at Penn.

PUBLISHER Lucy Chen ASSOCIATE EDITORS Heather Kim John George Armstrong Daniel Klyde Jamie Atienza Sriharsha Kolla Sharika Bamezai Jessie Lu Alanna Cruz-Bendezu Jacob Morse Isabella Cuan Jack Norleans Jessica Davis Sagar Patel Jeremy Falk Pranav Reddy Ryan Fan Susannah Rogers Alys Ferragamo Danny Sample Michael Fortunato Rachel Shaw Rebecca Gelfer Samantha Snyder Josh Glahn Kevin Sun Elizabeth Gonzalez Olivia Webb Brian Hirsh Maelys Yepes Ed Jing

www.bioethicsjournal.com

Volume XI Issue i Spring 2015

Volume X Issue ii

PENN BIOETHICS JOURNAL

Contemplating Human Worth

Stem Cells, Selective Abortion, and A Conversation with Dr. Peter Reese

Data Interpretation in Health Care

DTC Genetic Testing and Neuroimaging

Also inside:

Conversations with Dr. Steven Joffe and Dr. Matthew Mendlik

ASSOCIATE PUBLISHERS Isabella Cuan Danny Sample Margaret Hanna Rachel Shaw The Penn Bioethics Journal is published twice a year by the undergraduates at the University of Pennsylvania in Philadelphia, PA.

FACULTY ADVISORS Autumn Fiester, PhD Anne Barnhill, PhD

Archived editions of the Journal and information about the submission process can be found on our website: www.bioethicsjournal.com. Permission must be requested for any kind of copying, such as copying for general distribution, advertising, or promotional purposes, creating new collective works, or for resale. Requests for these permissions or further information should be addressed to team@bioethicsjournal.com. Copyright ÂŠ 2016 Penn Bioethics Journal, all rights reserved. Philadelphia, PA. ISSN: 2150-5462

Contents

Letter from the Editor Ruchita Pendse Editor-in-Chief

Interview 4

Bioethics in Brief

Dr. David Fajgenbaum 10 University of Pennsylvania; Castleman Disease Collaborative Network

Articles

Physician-Assisted Suicide Legalized in California

Martin Shkreli and the Increased Cost of Daraprim

Planned Parenthood Controversy Revives Abortion Debate

Jeff Liu Auburn University

Self-Driving Cars: An Ethical Perspective

The Ethics of Global Research Funding

Updates to Previous News Briefs

Rare Disease Funding: A Rawlsian Approach to Orphan Drug Legislation

Ameen Barghi University of Alabama at Birmingham

Melanie Etherton University of Cambridge

Letter from the Editor

Ruchita Pendse Editor-in-Chief

Penn Bioethics Journal

Volume XI Issue ii

January 15, 2016

Dear Readers, It is a pleasure to present you with Volume XI, Issue ii of the Penn Bioethics Journal, entitled Research Funding: Equity and Need. The pieces in this issue consider the allocation of funds in drug research and development, and evaluate whether the pharmaceutical market, industry practices, and the regulatory and policy landscape are meeting ethical ideals. In our first article, Rare Disease Funding: A Rawlsian Approach to Orphan Drug Legislation, the authors defend legislation that incentivizes research into rare disease treatments against criticisms that the potential for impact is too small compared to investment in other diseases. The author of our second article, The Ethics of Global Research Funding, goes one step further, calling for more funds to be allocated toward research into neglected tropical diseases, and making the case for individual responsibility and action in this effort. I also want to draw your attention to the interview complementing the articles in this issue. The Penn Bioethics Journal sat down with Dr. David Fajgenbaum, an Assistant Professor of Medicine at the University of Pennsylvania and Executive Director of the Castleman Disease Collaborative Network, a ground-breaking organization with an innovative, crowd-sourced and patient-focused approach to the research and treatment of Castleman Disease, an orphan disease from which Dr. Fajgenbaum himself suffers. His experience with the system of research funding for orphan diseases as a provider, patient, and activist offers unique insight into the themes discussed in this issue’s featured articles. Finally, this issue includes our usual section on current events in bioethics, “Bioethics in Brief.” The past several months have seen a number of interesting bioethics issues emerge in the news. In the next several pages, you can find briefs on some of the most prominent bioethics stories since the summer of 2015: the passing of a physician-assisted suicide bill in California, the controversy over the astronomical increase in the price of the drug Daraprim by Turing Pharmaceuticals, the renewed abortion debate following the release of secret footage from conversations with Planned Parenthood executives, and the question of whether to program self-driving cars to kill people if a real-world trolley problem scenario were to emerge. While the first three briefs simply cover the latest emergences of long-discussed bioethics concerns – physician-assisted suicide, drug pricing, and abortion – the last brief about how to program self-driving cars foreshadows the kinds of ethical questions likely to be raised by continuing advances in the field of artificial intelligence, introducing practical implications to questions previously relegated to the thought experiments of philosophers. I invite you to take a look inside, and hope you find the questions considered within to be as captivating as the PBJ editorial staff has. For many of us, our undergraduate exploration of bioethics is just the first step of a lifelong journey in a field that promises a never-ending supply of thought-provoking, challenging, and often uncomfortable questions. We hope PBJ can offer our readers a glimpse into this beauty of bioethics. Happy reading! Ruchita Pendse Editor-in-Chief University of Pennsylvania C’16

Bioethics in Brief Physician-Assisted Suicide Legalized in California

Penn Bioethics Journal Volume XI Issue ii

On October 5, 2015, Gov. Jerry Brown signed a bill The End of Life Options Act also accounts for the granting terminally ill Californians the right to be prescribed a sensitivities of other parties involved in the implementation lethal dose of drugs. California has now joined the minority of of the bill. When Governor Jerry Brown signed the bill states including Oregon, Washington, Vermont, and Montana into law, he recognized it as “not an ordinary bill because that have legalized physician-assisted suicide (PAS) to protect it deals with life and death” (Brown 2015). Accordingly, the individuals’ choice in end-of-life decisions (Booker 2015). bill accommodates the social and moral concerns revolving The End of Life around end-of-life care. Option Act was introduced Any party or individual by Senators Lois Wolk and that does not want to Bill Manning on January participate can excuse 20, 2015 after Brittany itself and turn patients Maynard, a 29-year-old over to another healthcare cancer patient, swayed the provider (CA Senate Bill hearts of the Californian 128 2015). public. Uprooting the Additionally, insurance remainder of her life companies cannot deny to take control of her treatment in the state otherwise painful death, of California based on Maynard publicly moved a patient’s preferred to Oregon after being terminal care, nor can they informed of her terminal coerce individuals into illness (Maynard 2014). accepting PAS under any Maynard’s criticism of her circumstance. In addition, home state finally allowed the bill stipulates a strict Source: Kaiser Health News. the bill to pass after four residency clause to inhibit unsuccessful attempts between 1995 and 2008 (Asimov 2015). medical tourism and makes it illegal to ingest the drugs in a Despite popular support for the bill, many social public place (CA Senate Bill 128 2015). conservatives have taken issue with the new system, citing Finally, the bill requires an annual report to monitor the unlimited access and the slippery slope of eugenics as potential usage and socioeconomic breakdown of those utilizing the concerns. A closer look at the new legislation reveals measures system. Oregon’s Death With Dignity Act (DWDA) requires are in place to restrict the use of this law and to prevent its a similar yearly statement, which paints a picture far from abuse. Only adults, defined as individuals aged 18 or older, the slippery slope presented in arguments against PAS. Since with the “capacity to make [informed] medical decisions” will DWDA was passed in 1997, only 1,327 individuals were be considered for PAS. Additionally, the candidate must be written prescriptions under the law, with only 859 deaths due physically capable of self-administering the life-ending pills to ingestion (Oregon Public Health Division 2014). without assistance and have a prognosis of six months or The End of Life Options Act will take effect 90 days after fewer confirmed by an external physician (CA Senate Bill 128 the Legislature adjourns its special session on healthcare, 2015). which will likely be in January 2016 (McGreevy 2015). The process requires two unsolicited voluntary petitions by the patient at least 15 days apart, as well as a written petition References to the primary physician to establish intent. Furthermore, the Asimov, N. 2015. “Gov. Jerry Brown Signs Assisted-death Bill.” SFGate, October 6. written request must follow the format laid out in the bill Booker, B. 2015. “California Governor Signs Physician-Assisted-Suicide Bill and be signed by two witnesses. If there is any indication of Into Law.” NPR, October 5. mental illness or imbalance, the physician is responsible for Brown, J. 2015. Open Letter from Gov. Brown to Members of the California procuring an opinion from a board certified psychiatrist or State Assembly. October 5. psychologist to establish competence. Before a doctor agrees CA Senate Bill 128. 2015. End of Life Option Act. Health News. 2015. “Aid-In-Dying Advocacy Group Girds For Battles to provide the pills, the patient must be informed of the Kaiser After California Victory.” Kaiser Family Foundation, November 18. available alternatives including palliative care. The physician Maynard, B. 2014. “Brittany Maynard’s Legacy: One Year Later.” The Brittany is obligated to inform the patient multiple times that he has Fund. the right to back out at any time, including after he has already McGreevey, P. 2015. “After Struggling, Jerry Brown Makes Assisted Suicide Legal in California.” Los Angeles Times, October 5. received the drugs (CA Senate Bill 128 2015). Oregon Public Health Division. 2014. Oregon’s Death With Dignity Act.

Bioethics in Brief

Penn Bioethics Journal

Volume XI Issue ii

Martin Shkreli and the Increased Cost of Daraprim

In August 2015, a drug called Daraprim unexpectedly underwent a 5,000 percent price increase. Once sold for $13.50, Daraprim’s price was raised to a whopping $750 per tablet practically overnight after the 62-year-old drug was acquired by Turing Pharmaceuticals, a start-up founded and run by hedgefund manager Martin Shkreli. Daraprim is traditionally used to treat toxoplasmosis, a condition caused by a parasite that exists in almost a quarter of the U.S. population over age 12. For unborn children and for immunocompromised individuals like those with AIDS or specific cancers, the disease can be deadly (Pollack 2015a). Since Daraprim is the primary treatment for this condition, this price increase could skyrocket the annual cost of treatment for some of these individuals to hundreds of thousands of dollars—an unfathomable cost considering what patients were accustomed to paying. To make matters worse, the previous manufacturer of the drug had signed an exclusive deal with Walgreens in December 2014, making the network of 1,200 Walgreens’ specialty pharmacies the sole distributor of the drug (Russell 2015). Drug pricing has emerged as a frequent source of debate, and the Daraprim case serves as only the most recent example. Many pharmaceutical companies are controversially buying older drugs that have been on the market for years and relabeling them as “specialty drugs” in order to justify a significant price increase. Shortly before the Daraprim incident, Rodelis Therapeutics, another company, acquired cycloserine, a drug used to treat dangerous multidrug-resistant tuberculosis, and increased the price from $500 to $10,800 for 30 pills (Pollack 2015a). Although Rodelis has since rescinded the price, the fact that increases like these have occurred speaks to the unregulated power of pharmaceutical companies. Technically, Shkreli’s actions are not illegal, making him “an easy target for a problem that extends far beyond the confines of his ego: the rampant overpricing of life-saving medicine” (Allen 2015). But why do drug increases exist in the first place? Occasionally, price increases are attributed to shortages of drug elements. In most recent years, however, these factors have taken a back burner to the corporate culture that has motivated most drug increases of the 21st century. Some patent-holders are able to continue selling a drug at a higher cost because they pay generic companies to not make a generic version of the drug. Others, like Turing Pharmaceuticals, acquire the rights to a drug or buy out the manufacturer. Through slightly different tactics, these companies all essentially strive to decrease marketplace competition in order to amend prices without fear (Klugman 2015). Specialty drugs may only represent one percent of all prescriptions, but they account for about 20 percent of drug spending, according to the National Business Coalition on Health. Some experts even predict that the amount spent on these drugs will quadruple by 2020 (Russell 2015). Despite this popular trend, the public has viewed Shkreli’s actions as an egregious transgression of human rights. Because of this, he has essentially served as a platform for discussion: “With an easily dislikeable villain comes an easy shift in the national conversation toward pharmaceutical prices and predatory

practices that exploit the sick” (Hamblin 2015). The role of capitalism is a driving force in this debate, as many believe that the sole responsibility of business is to maximize profit (Miller 2015). Yet, this role is challenged from an ethical perspective that demands that the universal right to life be considered, especially with medications that treat life-threatening diseases. When allowing pharmaceutical companies to arbitrarily decide prices, especially for those medications that do not simply relieve symptoms but rather sustain life, many believe that dangerous territory is entered: “The more definitive the cure, the closer we are to asking, ‘What’s the value of a human life?’” (Appleby 2014). There is no concrete consensus among American citizens when it comes to how to regulate drug pricing. Pharmaceutical companies argue that presidential candidate Hillary Clinton’s proposal to implement a $250 cap on out-of-pocket payments for prescription medications “would turn back the clock on medical innovation,” and others contend that loosening the regulation for drug approval processes would more effectively alleviate price gouging (Hamblin 2015). Though Bernie Sanders and Elijah Cummings have called for a Congressional investigation, and Democrats and Republicans alike have spoken out about such pricing, it will be a challenge in the 2016 presidential race to determine an acceptable role for government in the drug industry and ultimately how to best enforce regulation on pharmaceuticals — the highest spender on government lobbying efforts (Klugman 2015). Though Shkreli’s intentions remained ambiguous for several months, Turing Pharmaceuticals has recently offered discounts of up to 50 percent to hospitals, as well as financial assistance to patients, in an attempt to provide the drug to those who need it (Pollack 2015b). Though the company still refuses to lower their initial $750 price, a $1-per-pill alternative has been proposed by San Diego-based Imprimis Pharmaceuticals, a company that mixes approved drug ingredients to fill individual patient prescriptions. Express Scripts, the nation’s largest prescription drug manager, has announced its support for the alternative medication through a partnership with Imprimis (Pollack 2015b). By processing prescription drug claims for employers and insurers, Express Scripts can dramatically increase accessibility and thus provide an affordable alternative to Shkreli’s controversial drug.

References

Allen, S. 2015. “Martin Shkreli is Big Pharma’s Biggest A**hole.” The Daily Beast, September 21. Appleby, J. 2014. “New hepatitis C drugs’ price prompts an ethical debate: Who deserves to get them?” The Washington Post, May 2. Hamblin, J. 2015. “Pharma Bro Is the Face of U.S. Health Care.” The Atlantic, September 23. Klugman, C. 2015. “Drug Price Hikes and The Misguided Profit Imperative.” Bioethics.net, September 25. Miller, M. 2015. “Pharma bro Martin Shkreli and the very American debate over maximizing profit.” The Washington Post, September 23. Pollack, A. 2015. “Drug Goes From $13.50 a Table to $750, Overnight.” New York Times, September 20. Pollack, A. 2015. “Top Prescription Plan to Offer $1 Alternative to $750 Pill.” New York Times, December 1. Russell, J. 2015. “Drug with jacked up price can only be found at some Walgreens. Why?” Chicago Tribune, September 25.

Bioethics in Brief

Planned Parenthood Controversy Revives Abortion Debate

Source: Associated Press.

Penn Bioethics Journal

References

Arons, J. 2011. “GOP: Money Is Fungible For Planned Parenthood, But Not Faith-Based Organizations.” ThinkProgress, April 14. Graham, D. 2015. “What Does the Planned Parenthood Video Show. ” The Atlantic, July 15. Harris, G. 2016. “Obama Vetoes Bill to Repeal Health Law and End Planned Parenthood Funding.” New York Times, January 8. Kliff, S. 2015. “A Government Shutdown Fight is Brewing. This One is Over Planned Parenthood.” Vox, September 10. Kliff, S. 2015. “The Planned Parenthood Controversy Over Aborted Fetus Body Parts, Explained.” Vox, August 4. “Public Funding for Abortion.” American Civil Liberties Union, accessed December 8, 2015. Rovner, J. 2009. “Abortion Funding Ban Has Evolved Over The Years.” NPR, December 14. Trott, B. 2015. “Planned Parenthood Revises Reimbursement Policy After Video Uproar.” Reuters, October 13.

Volume XI Issue ii

In July 2015, the nonprofit organization Center for Medical Progress (CMP) released a video of a secretly recorded discussion between Deborah Nucatola, the Senior Director of Medical Services at the reproductive health organization Planned Parenthood, and actors posing as middlemen for a fake scientific research company. In the video, the middlemen inquire about obtaining fetal tissue for medical research, and Nucatola explains that tissues are harvested to minimize tissue damage, describing in detail the treatment of the fetus in the process (Graham 2015). After this first meeting, CMP released several additional videos that revealed a number of secretly recorded meetings between other actors and Planned Parenthood officials. These videos portray the supposed donations by Planned Parenthood to actually be transactions of tissues for cash and depict the treatment of fetuses as inhumane and unethical. The release of these videos reignited a decades-long debate over abortion in the United States. Planned Parenthood officials in the videos appear callous in the manner they explain the extraction of tissues and haggle over compensation, which has led many conservative politicians to call to defund Planned Parenthood. The alleged sale of these tissues and resulting compensation has remained controversial. Nucatola insists that Planned Parenthood does not sell tissues while using tissue donation services. Instead, it intends to offer patients abortion services, contribute needed resources to the medical community, and receive fair compensation for extraction and shipping (Kliff 2015b). But in response to the public outrage, Planned Parenthood announced they would no longer accept reimbursement for fetal tissue donated for medical research after abortions (Trott 2015). The non-profit organization currently underwrites extracting and shipping costs of such tissues. However, the matter of extracting tissue and organs from aborted fetuses, even for the sake of medical research, is still a controversial topic for many. Critics argue that aborting with the intent of obtaining tissue or organs can result in modifications to the clinical procedure by which physicians perform the abortion, which is discussed by Planned Parenthood Official Mary Gatter in the second video (Kliff 2015a). Nucatola describes how the fetus is crushed above and below to obtain the best quality organs, giving rise to ethical concerns over whether the abortion procedure should be altered to obtain intact organs at the expense

of the fetus (Graham 2015). Additionally, there are psychological concerns regarding the effect of abortion perception on abortion frequency. Namely, a mother who wishes to abort the fetus might be further motivated to undergo an abortion if she knows that the fetal tissues can be donated for scientific research. Beyond these objections, staunch opponents of abortion view it as morally wrong: “There’s no way to make the use of fetal tissue in research acceptable: It will never be okay for the remains of aborted fetuses to be used for any purpose, research or otherwise” (Kliff 2015b). Discussion about fetal tissue procurement and research conduct has compelled legislators to review the federal funding of Planned Parenthood. Under the Hyde Amendment, effective since 1980, the use of federal funds for abortions is prohibited; however, the amendment is not actually a law but a “rider” that has been attached to other appropriations bills that need to be renewed yearly. Thus, the language of the original ban has been debated over the past few decades and has evolved to include exceptions in cases involving rape, incest, or endangerment of the mother’s life (Rovner 2009). State funding policy for abortions differs among states. Various states include all, some, or none of the exceptions mandated by the federal government, and 17 states do allow public funds to be used for abortions (“Public Funding for Abortion”). Planned Parenthood receives approximately $500 million in public funding, with federal funding consisting of Medicaid reimbursements and grants from the Title X Family Planning Program. This money cannot legally be allocated towards abortions; that funding is intended expressly for numerous other services that the organization offers (Kliff 2015a). However, some anti-abortion politicians argue that federal funding for nonabortion services enables the organization to dedicate more of its own funds towards abortions, thus indirectly funding abortions (Arons 2011). On December 3, 2015, Senate Republicans were able to narrowly pass a bill defunding Planned Parenthood and repealing parts of the Affordable Care Act. However, President Obama vetoed the bill on January 8, 2016, and Senate Republicans do not have the two-thirds majority required to override his veto (Harris 2016).

Bioethics in Brief

Penn Bioethics Journal

Volume XI Issue ii

Self-Driving Cars: An Ethical Perspective

Since the development of the first self-driving cars in the 1980s at Carnegie Mellon University’s Navlab, major companies such as Mercedes-Benz, General Motors, Renault, and Toyota have developed working prototypes. Autonomous cars resemble the cars we drive today, except with added features that allow them to “self-navigate” by automatically braking or self-parking. At the forefront of this global innovative market, Google is taking an additional step with its self-driving car. Google’s new prototype, released in December 2014, requires only that its passengers enter a destination into the car’s navigation system. Designed without a steering wheel, the self-driving car combines system sensors, radar, GPS, and mapping systems to take over the driving experience (Google 2015). Because an estimated 94 percent of automobile accidents are attributable to human error, the development of law-abiding, ultra-safe selfdriving cars promises to significantly reduce the number of annual car accidents. Yet, as long as self-driving cars share the road with human drivers, accidents will continue to occur. Though Google’s self-driving car has crash-avoidance features, how might it be programmed to act in a situation in which a crash is unavoidable (University of Alabama at Birmingham 2015; MIT Technology Review 2015)? For example, in a no-win situation, a self-driving car might have to “choose” between sparing its passengers at the risk of harming others, or sparing the greatest number of lives by sacrificing its passengers. If the car’s computer system can scan the oncoming vehicles to assess the number of passengers at risk, should it be programmed to do what’s best for its owner or to opt for the outcome that does the least harm? While a consequentialist perspective would favor programming the self-driving car to crash into the concrete wall to spare the greatest number of lives if the number of others were greater than the number of passengers, deontologists would condemn the active sacrificing of the car’s passengers (University of Alabama at Birmingham 2015). Although there is no readily available solution to this ethical dilemma, the ultimate outcome will have a tremendous effect on how, or even whether, selfdriving cars are socially accepted. The Toulouse School of Economics in France conducted a study that aimed to gauge public opinion about self-sacrificing cars by asking individuals about various scenarios. Public response was

Source: Google Self-Driving Car Project.

relatively unanimous in that individuals were comfortable with the idea of self-driving cars being programmed to reduce death tolls, so long as they did not have to own one themselves (MIT Technology Review 2015). The development of self-driving cars has raised additional ethical questions. If everyone were to adopt self-driven cars, nearly all accidents would be avoided, and the death toll would be significantly reduced. Yet, would it be ethically acceptable to impose the use of self-driving cars programmed with a specific algorithmic morality on the public? Should self-driving cars be programmed to assess situations on a more case-by-case basis, such as to act differently if children are on board (MIT Technology Review 2015)? Finally, there is the critical question of liability. Will the manufacturer be to blame in the event that an accident results in the death of a passenger? If a manufacturer were to sell vehicles with different settings of its moral algorithm, would the buyer or the manufacturer be liable in the case of an accident (Worstall 2015; Lin 2014)? As the market for self-driving cars gains momentum and political support, the question of algorithmic morality will become increasingly urgent.

References

Google. 2015. Google Self-Driving Car Project. Lin, P. 2014. “Here’s a Terrible Idea: Robot Cars With Adjustable Ethics Settings.” WIRED, August 18. MIT Technology Review. 2015. “Why Self-Driving Cars Must Be Programmed to Kill.” October 22. Worstall, T. 2014. “When Should Your Driverless Car From Google Be Allowed To Kill You?” Forbes, June 18. University of Alabama at Birmingham. 2015. “Will Your Self-Driving Car Be Programmed to Kill You If It Means Saving More Strangers?” ScienceDaily, June 15.

Updates to Previous News Briefs

Bioethics in Brief

In the Spring 2015 issue, we published a news brief on President Obama’s announcement of the Precision Medicine Initiative at his State of the Union address. The Initiative includes the creation of a $215 million national biobank with the hope of personalizing individual treatment through genomic data (White House 2015a). However, many privacy concerns developed following the release of this plan to personalize medicine (Klugman 2015). On November 13, 2015, the White House released a set of privacy and trust principles to provide a legal framework intended to minimize potential breaches in patient privacy. These principles were formed as an inter-agency effort with the White House Office of Science and Technology Policy, the Department of Health and Human Services Office for Civil Rights, and the National Institutes of Health. The principles’ formation included consultation with experts, bioethics literature, public opinion, and the policies of already existing biobanks. From this foundation, the group developed the following categories for privacy principles (White House 2015b): 1. Governance: Ensure participants have active roles in the Initiative, through collaboration with researchers or by having their needs represented and considered in decision-making 2. Transparency: Provide information to participants through all stages of the Initiative, and also make the information easily accessible and comprehensible to a diverse group of individuals. 3. Participant empowerment: Help individuals understand their own health data in order to make informed decisions 4. Respect for participant preferences: Dynamic and ongoing consent, in which individuals can change their decisions to participate at any moment 5. Data sharing, access, and use: Define data on different tiers, which vary in how open and accessible certain information can be, and explicitly ban selling any health data for advertisement purposes 6. Data quality and integrity: Commit to providing the most accurate information at all times. In addition to providing a legal and ethical framework for precision medicine, the interagency group also plans on developing administrative, technical, and physical safeguards for protecting genomic data (White House 2015b).

In the Fall 2014 issue, we published an article on the ethical implications of direct-to-consumer genetic testing, focusing on the company 23andMe. In November 2013, the Food and Drug Administration banned 23andMe from continuing to sell its direct-to-consumer genetic testing product. The ethical concerns were that individuals could misinterpret direct-to-consumer results, the unregulated industry was engaging in false advertising, consumers’ data protection and privacy were weak, and the company was using consumers’ data for medical research without undergoing the IRB-approval normally required of research using sensitive personal data (Pollack 2013). After two years, 23andMe is now back on the market providing lower-risk genetic tests. Instead of offering genetic testing for the individual consumer to weigh his or her risk of developing various diseases, the company is providing genetic testing on carrier status (Pollack 2015a; Pollack 2015b). The company decided to wait until now to release its carrier tests, which assess whether the consumer carries the recessive allele for 36 different diseases, including cystic fibrosis, sickle cell anemia, and Tay-Sachs. In addition to being back on the market, 23andMe has announced its intention to start developing medical drugs. Richard Scheller, former Vice President of Research and Early Development at Genentech has joined 23andMe to head this initiative (Pollack 2015b).

References

Klugman, C. 2015. “Precision Medicine has Imprecise Ethics.” Bioethics.net, February 18. White House, 2015. “Fiscal Year 2016: Budget of the US Government.” February 2. White House, 2015. “Precision Medicine Initiative: Privacy and Trust Principles.” November 9.

References

Pollack, A. 2015. “23andMe Will Resume Giving Users Health Data.” New York Times, October 21. Pollack, A. 2015. “FDA Reverses Course on 23andMe DNA Test in Move to Ease Restrictions.” New York Times, February 19. Pollack, A. 2013. “FDA Orders Genetic Testing Form to Stop Selling DNA Analysis Service.” New York Times, November 25.

Volume XI Issue ii

Update to “Direct-to-Consumer Genetic Testing: An Examination of Privacy and Security Concerns”

Penn Bioethics Journal

Update to “Data Security and President Obama’s Precision Medicine Initiative”

Interview

A Conversation with Dr. David Fajgenbaum Dr. David Fajgenbaum, MD, MBA, MSc is an Assistant Professor of Medicine at the University of Pennsylvania, Associate Director of the Penn Orphan Disease Center, Senior Fellow of the Leonard Davis Institute of Health Economics, and Executive Director of the Castleman Disease Collaborative Network. He is also battling Castleman Disease, a rare and deadly hematologic illness where the immune system attacks and shuts down vital organs, as a patient. Between relapses, he co-founded the Castleman Disease Collaborative Network (CDCN) in 2012 to accelerate research and treatment discovery for ideopathic Multicentric Castleman’s Disease (iMCD). The CDCN’s innovative approach is collaborative, crowd-sourced, and patient-focused and has initiated a paradigm shift in how doctors research and treat iMCD. He was named to Forbes Magazine’s 2015 30 Under 30 Healthcare list. Dr. Fajgenbaum received an MBA from Wharton, MD from University of Pennsylvania, MPH from University of Oxford, and BS from Georgetown University.

Penn Bioethics Journal

Volume XI Issue ii

Penn Bioethics Journal (PBJ): Could you describe your personal journey that has led to the work you do today?

Dr. David Fajgenbaum (DF): I was a third year medical student at Penn planning on becoming a clinical oncologist when I became deathly ill with idiopathic Multicentric Castleman Disease (iMCD), even though I’d been totally healthy my whole life. Over a couple weeks, I noticed my lymph nodes enlarging and experienced night sweats, fatigue, nausea, and vomiting. I was hospitalized immediately, had a retinal hemorrhage, went blind in my left eye, gained about 70 pounds of fluid, and experienced multiple organ failure. After surviving that first episode and spending seven weeks in the hospital, I relapsed about three weeks later with lifethreatening multiple organ failure. This time, the diagnosis was accurately made, and I was treated with chemotherapy. But before that, I had my last rites administered to me and thought that I was going to die from this unknown illness. Treatment was able to put me into partial remission, and I survived long enough for three or four weeks before I had another relapse requiring really intense chemotherapy. In total, I spent about four and a half months in the hospital fighting this disease. After becoming ill, I went back to medical school where I relapsed about 15 months later. At that point, I decided I wanted to dedicate my life to take down this disease, and for the last three years, I’ve dedicated everything I’ve done, and we’ve made a lot of progress. PBJ: Your work with Castleman disease has recently drawn attention to orphan disease research and funding. Can you comment on how you founded the Castleman Disease Collaborative Network (CDCN)1 and its short- and long-term goals? DF: What I first observed was that forward progress was moving way too slowly, as the disease was very poorly understood. It was completely unrealistic to think that the

Photo courtesy of David Fajgenbaum.

current state of research was going to advance nearly fast enough. We decided that we didn’t just want to stick with the traditional approach, which is generally to raise money among patients and loved ones and then invite researchers to apply and use this money however they wanted to. We didn’t want to rely on this two-step model. Instead, we wanted a three-step model, which we called the Collaborative Network Approach, where we identify physicians and researchers conducting Castleman research and connect them through online discussion boards as one of the first steps to build a community. Once we’ve built this community, we crowdsource or leverage the collective knowledge of the community to prioritize research. After prioritizing research, we go around the world and recruit the top people from around the world to do each one of those priority studies. Rather than letting people come to us to do research that they’re interested in, we use the world’s collective knowledge to determine what should be done, and we go out proactively to identify the right people to do it. It’s really a frameshift and new approach, but it’s built on the shoulders of previous and other rare disease organizations that have taken little pieces of this, which we’ve synthesized into our approach. PBJ: Do you think that the CDCN model can be applied to other rare diseases or even to academic medical research in general? DF: Absolutely, what we’ve done with Castleman Disease is to focus on identifying what causes the immune system to do what it does because if and when we figure out what’s wrong with the immune system, there’s a very high likelihood that there are drugs that already exist to target those pathways. Essentially, at all times we’re one study away from curing this disease, which is our primary goal. Our other goal, however, is to create a model to help knock out many more diseases.

Referring to the Castleman Disease Collaborative Network co-founded in 2012 by Dr. Frits van Rhee of the University of Arkansas for Medical Sciences and Dr. Fajgenbaum.

A Conversation with Dr. David Fajgenbaum PBJ: How does the scarcity of financial and scientific resources availed to rare disease research affect decision-making about resource allocation? DF: I definitely think that rare diseases are obviously going to have less funding than more common diseases, and that’s one part of the problem. I think a much bigger problem in biomedical research is in the efficiency of the use of funding that we do have. The two-step model that I initially spoke about did raise money and let people decide how to use it for research. It is just very inefficient. There’s a lot of redundancy in the research, and the research that people end up doing doesn’t even necessarily tie back to helping the patient or focus on patient impact. I think that it’s not just about funding but also about the way that we’re using and applying that funding.

PBJ: There is considerable discussion of the ethics of investing in rare disease research — even if everything goes well, it would only benefit a small group of people. The thought is that, given the realities of resource constraints, this has to be evaluated against the alternative of investing in research that could benefit a dramatically larger group of people. Can you offer your perspective on why we still should be investing in funding rare disease research?

DF: Since there is so little known about rare diseases, there is a much greater opportunity for changing the state of knowledge and resulting in an impact for patients. For example, in the case of heart disease, if you want to increase the survival by one year for every person who presents with heart disease, you would need to invest hundreds of millions to improve heart disease life expectancy by a year, as a very PBJ: Why do you think that previous rare disease general example. This is because so much has already been research efforts struggled with inefficiency? Your invested that the return on investment is going to a lot approach seems very logical, so what barriers inhibited smaller for a common disease, whereas if you look at a rare similar initiatives before? diseases, which are generally very poorly understood and ripe for innovation, applying a DF: I think that this inefficiency hundredth or even a millionth is really not just a rare disease of that money can have major What we have done is break breakthroughs. You can problem, but a problem for all biomedical research. For down the barriers between spend $20,000 on a study for common diseases you can Castleman Disease using flow patients and loved ones with cytometry, which has been done afford to be inefficient because you’re spending tens of billions for every other disease known physicians and researchers. of dollars and you’ll still come to man. It’s a simple and cheap out with enough breakthroughs. way to measure the numbers The problem is for less common diseases where there’s less of a certain type of cell, which can lead to a breakthrough money to spend and you can’t afford to be inefficient. The in identifying the cells that cause the disease and find an problems are magnified in the rare disease space. existing drug that can target those cells. You’ve gone from a The reason that I think it’s taken a while to get to disease that was untreatable to a perfect treatment just from this model is because physicians and researchers are the a $20,000 study. Though the number of patients is lower, ones with all the intellectual capital who know everything the delta in impact and the delta in life expectancy are huge about the disease. Patients and loved ones and those who with small dollar amounts invested. I actually think you have are more focused on impact than publications are not in a greater opportunity per dollar spent on a rare disease for position generally to be able to take the power out of the impact than you do if you spend it on a more common physicians’ and researchers’ hands because they don’t know disease. enough to be able to say “you’re doing the wrong thing” or “you should fund this instead of this.” What we have PBJ: Could you comment on public policy initiatives done is break down the barriers between patients and loved related to rare disease funding such as the Orphan ones with physicians and researchers and bring them all to Drug Act2 and how they’ve impacted Castleman the table with a very clear focus on impact. We don’t care Disease research or rare disease research in general? who publishes the paper and we don’t care who does the research. We just want the research to be done by the best DF: The Orphan Drug Act has done a lot for encouraging person and the right person. I think that genesis required pharmaceutical companies to pursue rare disease drug a physician-patient advocate to be able to bridge the gap. development. There is now one FDA approved drug3 just for Now that it’s been done, I hope that this model can be easily my subtype of Castleman Disease, which I believe is a direct shared with other diseases. result of the Orphan Drug Act. If not for the incentives

“

”

Referring to the Orphan Drug Act of 1983—a law passed in the United States to facilitate development of orphan drugs. Referring to Sylvant (siltuximab).

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A Conversation with Dr. David Fajgenbaum built into that Act, there is a chance pharmaceutical companies probably wouldn’t have developed it. There is also something called the 21st Century Cures Initiative4 which is currently going through Congress to help improve funding for all research and to improve to current way that the FDA reviews and approves drug applications. The idea is to modernize the FDA and to catch up to some of the more breakthrough techniques that exist for drug development. I think that’s tremendously important, not just focused on rare diseases, but it has the potential to increase funding across the board.

“ You have greater

opportunity per dollar spent on a rare disease for impact than you do if you spend it on a more common disease.”

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PBJ: There is a concern about public policies that have given too much monopolistic power to pharmaceutical companies in order to incentivize the development and production of rare disease drugs. Can you comment about whether this is truly as harmful as the critics of such policies claim?

DF: You can certainly charge a lot in the rare disease space. At the end of the day, if there’s only one drug approved, then it works the same way that monopoly pricing works for any other product. Without these financial incentives, there really is no incentive for pharmaceutical companies to develop these drugs. One of the things that I’ve discovered while getting more involved in the rare disease space is that every one of these pharmaceutical companies that has a rare disease drug that is really expensive (i.e. $10k+ per year) has a patient assistance program. Even if they charge a huge amount for a drug, the patient can essentially get back every dollar they pay out of pocket. The burden is placed on the insurance companies to pay off the bills. From a societal perspective, the burden is borne by society since the insurance company raises premiums and everyone pays a little more for their insurance due to these costs. When you think of it like that and the fact it’s being spread out among the population rather than any one person suffering from a disease, it becomes more palatable. As a society we’ve decided that we do care about people with rare diseases, and if someone would die of a rare disease, we want him or her to get treatment and save his or her life.

PBJ: Is there anything else you would like to say about Castleman Disease, the CDCN, or rare disease research in general?

DF: With our new strategic, crowd-sourced approach rather than the more individual, reactive approach, we’ve had some major breakthroughs. One of which is that we used to believe the disease was caused by lymph node tumors that turned on the immune system, but we discovered that the immune system caused the lymph node tumors to grow. Whereas before we thought chemotherapy was required to kill the tumors, we now know to use immunosuppressant drugs to prevent the tumors from growing. There are a lot of immunosuppressant drugs that already exist and are already approved, so this is a beautiful example of how breaking down how a disease works can lead to repurposing of already existing drugs to cure that disease. Another thing I want to say is that I was particularly harsh at the beginning of our conversation on biomedical research in general, and I think I’m so harsh because I sit on both sides of the aisle. I’m a research professor here at Penn, but I’m also a patient with a rare disease, so I’m deeply affiliated with both groups. I live in the research world and I see the great work that is done, but I also see the slow pace that it happens at. I also see the redundancy and inefficiency that occurs, and as a patient, I am terribly pained by that because I realize there are people just like me waiting for that breakthrough and for the drug that can ultimately help them. I’m not criticizing any one researcher, but I’m really criticizing the inefficient system for all of biomedical research. For rare diseases, we really have to make every dollar count because we can’t be wasteful since we don’t have a large number of people using millions of dollars to study them. Of course from the patient perspective, whether it’s for rare or common diseases, we better make every single dollar count because people like me are dying.

Interview by Ryan Fan.

Referring to the 21st Century Cures Act—legislation approved by the House of Representatives on July 10, 2015 and under review in the Senate.

Article

Rare Disease Funding: A Rawlsian Approach to Orphan Drug Legislation Ameen Barghi* and Jeff Liu+ Orphan drugs are treatments for chronically debilitating or life-threatening rare diseases, which are conditions that affect fewer than 200,000 people in the United States or fewer than five cases per 10,000 inhabitants in Europe. However, the costs for research and development of orphan drugs are enormous and the benefits uncertain. To protect pharmaceutical manufacturers against such risks and to incentivize investments in orphan drug development, governments worldwide have introduced legislation to help promote innovations in treatments for patients with rare diseases. Such legislation raises moral questions about the greatest common social good, moral equality, and resource allocation. The current bioethics literature, however, offers little guidance for settling conflicts between theories of justice that bear on the issue of orphan drug funding. This piece summarizes the national and international trends in health policy, examines some of the moral dilemmas facing governmental organizations when deciding whether to fund orphan drug research, and considers three commonly cited moral frameworks for resolving these dilemmas. Ultimately, the paper concludes that a Rawlsian approach to evaluating rare disease funding policy should be used, due to the limitations of applying a consequentialist framework. Background

people worldwide live with chronic, progressive, debilitating, and lethal RDs. Additionally, a significant proportion of RDs are genetic and affect children (many of whom do not live past adolescence). The approximately 7,000 RDs have no existing cures, which leads to low quality information among healthcare professionals and treatment inequalities (Global Genes 2014). Moreover, because many of these diseases are not taught in a traditional medical education, most general practitioners have had little experience with the diseases and cannot diagnose them.

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Difficulties for the Clinical Community It should be noted that many of the market deficiencies in RD experimentation are scientific in origin. For example, statistically weak sample sizes for clinical trials and modest knowledge bases around the diseases are obvious drawbacks. Also, the presentation of these RDs can vary from person to person and are often not recognized by most physicians. Thus, a specific drug, even if developed, may not be homogeneously efficacious. Patient recruitment for clinical trials is a challenge for even some of the most common RDs. Randomized, multisite clinical trials are often expensive and time-consuming. Among other factors, all of the above contribute to the research drought present in RDs (Haffner, Whitley, and Moses 2002).

*Ameen Barghi is currently a student at Oxford University reading for a Masters in Public Policy (MPP). He graduated May 2015 from the University of Alabama at Birmingham where he majored in Neuroscience and Translational Research. Ameen’s interest in bioethics stemmed from his involvement in his university’s Bioethics Team, which won the national championship in 2015. After his studies at Oxford as a Rhodes Scholar, Ameen will be attending Harvard Medical School where he hopes to further pursue philosophy in medicine. He can be reached at ameenbarghi@gmail.com. Jeff Liu is a J.D. candidate at Stanford Law School set to graduate in 2018. He graduated from Auburn University in 2015 with a B.S. in Chemical Engineering and a B.A. in Philosophy. He can be reached at liujeff1@stanford.edu.

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All healthcare organizations must decide which innovative pharmaceuticals to provide to patients, given limited resources. To help establish standardized priorities, in 1977, the World Health Organization (WHO) published advice for all countries, developing and developed, via the WHO Model List of Essential Medicines (Laing et al. 2003). The WHO defines essential medicines as “basic, indispensable and necessary for the health and needs of the population” (Organization 1977). Cost-effectiveness, demand, treatment efficacy, and other specific criteria help determine the inclusion list. Unfortunately, essential drugs often only meet the needs of the majority of the population, and they may neglect the minority – those with rare diseases (RD). We offer some reasons, both pragmatic and ethical, as to why attention in health care policy should be given to RDs. A rare, or orphan, disease is defined as a condition that affects fewer than 200,000 people in the United States (Congress 2002) or fewer than five cases per 10,000 inhabitants in Europe (Eurodis 2015). Together, these diseases impact the lives of approximately 60 million individuals in the United States and Europe (Haffner, Whitley, and Moses 2002). Though data for developing countries are scarce, it is estimated that 350 million

Orphan Drug Legislation Legislative Progresses The Orphan Drug Act The United States introduced the first piece of legislation for orphan drugs. In 1983, President Ronald Reagan signed the Orphan Drug Act (ODA) into law to promote the development and commercialization of drugs used to treat RDs and their symptoms. After pressure from advocacy groups such as the National Organization for Rare Disorders, the ODA provided several incentives for research and development, such as a sevenyear market protection for development companies, tax credits equaling half of drug development costs, grants for research and development, and expedited approvals for orphan drug programs (Haffner 1999). The market exclusivity granted to these drug firms was unlike anything in traditional patent law – it did not begin until the drug was approved by the Food and Drug Administration and was independent of any other patent status.

Rare Diseases Act In 2002, President George W. Bush signed the Rare Diseases Act into law, establishing the Office of Rare Diseases Research, part of the National Center for Advancing Translational Sciences at the National Institutes of Health. The Act allocated additional funding towards the development of new treatments for RDs, and the concrete establishment of a federal office reflected the growing concern for RDs among the public.

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Fresh Legislation

In the 113th Congress (January 2013 to January 2015), the U.S. House of Representatives introduced House Bill 3116, which was the Modernizing Our Drug & Diagnostics Evaluation and Regulatory Network Cures Act of 2013 (more succinctly, the MODDERN Cures Act of 2013). This bill aimed to expedite the development of novel treatments and therapies for patients with “complex conditions with limited or no treatment options,” like RDs. This piece of legislation, unlike its predecessors, encouraged partnerships between drug companies, research institutions, and private investors in the development of these novel tools. The Act also proposed a new drug class in the United States called “dormant therapies.” These essential RD drugs would get an additional period of patent protection (a 15-year period of data exclusivity after FDA approval) with the goal of facilitating the timeline for generic drug equivalent distribution in the market. Though the MODDERN Cures Act has neither been passed by Congress nor signed into law (Council 2014), it has paved the way for a more inclusive version, the 21st Century Cures Act. Most recently, with a bipartisan vote (51-0 unanimous vote in the committee), the House passed the 21st Century Cures Act (House Bill 6 at the 114th Congress), which is being considered in the Senate as of July 2015. The Act does several things to highlight the importance of medical research funding. This Act helps enhance personalized drug treatments that are targeted at individuals and their symptoms, not just general diseases; expedite clinical trials and make it more cost-effective for companies to showcase new drugs; and, most pertinent, create incentives for developing drugs for uncommon but deadly diseases. The Act also substantially ramps up funding for the National Institutes of Health and the Food and Drug Administration, two major research management bodies.

International Replicas Since the enactment of these key pieces of legislation, other international powers such as Japan, the EU, Australia, and Singapore have also instituted various versions of the U.S. orphan drug policy model. Though the international emulations of the ODA are extremely similar to their U.S. originals, they do contain some distinct differences. For example, in Japan, the prevalence limit for RD classification is < 0.04% of the Japanese population versus the approximate 0.1% in the U.S. (Shiragami and Nakai 2000). Both Japan and the EU granted orphan drug development companies a ten-year market exclusivity protection period, compared to the seven-year aforementioned U.S. period. The EU also removed orphan drug status from drugs that are considered unusually profitable to prevent companies from abusing the original intent of the RD policy (Lang and Wood 1999). In Singapore, legal guidelines were specifically targeted to facilitate RD drug imports (Franco 2013). Australia, with significant help from the U.S. FDA, created a RD model that provides fee reductions and expedites grant applications without the market exclusivity or tax breaks (Lavandeira 2002).

Ethical Considerations The ODA and related legislation have had an enormous impact on medical research and funding allocation. In the United States alone, 1,261 drugs received orphan status designation between 1983 and 2001, in contrast to the 10 that had received orphan status in the decade preceding the introduction of the ODA (Gericke, Riesberg, and Busse 2005). The ODA’s tremendous impact raises the question: is legislation creating special financial incentives for RD and orphan drug research just? Here, we offer a potential defense of the ODA, based on John Rawls’s Theory of Justice, and consider and reject two common moral arguments against the ODA.

A Rawlsian Argument for Orphan Drug Legislation In his magnum opus A Theory of Justice, John Rawls argues that policies for the regulation of the basic structure of society are subject to two principles of justice: the liberty principle, which guarantees maximum liberty for each so far as is consistent with equal liberty for all, and the difference principle, which permits departures from socioeconomic equality only if they benefit society’s least well-off group. Rawls claims these two principles of justice would be chosen by agents attempting to secure fair terms of cooperation for mutual advantage among free and equal persons, behind a “veil of ignorance.” The veil of ignorance is a theoretical construct behind which individuals are ignorant of their socioeconomic status and place in society. These factors, Rawls argues, are morally irrelevant. Thus, the introduction of the veil of ignorance serves as part of a thought experiment in which we choose principles of justice based on impartial rational principles, rather than principles that might serve our own interest groups. The liberty and difference principles are ones that no agent, choosing under conditions of rational choice, could reasonably reject (Rawls 2009). The difference principle neatly applies to the case at hand. Are the inequalities associated with the introduction of the ODA and related legislation, which give orphan drugs special legal status, morally permissible, and do they benefit the least well-off group

Orphan Drug Legislation in society? Though not always the case, the chronic, progressive and debilitating character of many diseases, coupled with the lack of available, effective treatment and diagnostic tools, certainly suggests that some patients with RDs are among the least well off with respect to healthcare access. Additionally, these patients may have low quality access to information or be subject to negative physical and social consequences of their illnesses. Thus, insofar as the ODA benefits patients suffering from RDs by incentivizing the development of better treatments, Rawls’s difference principle could justify treating the potential inequalities produced by such legislation, without appeal to the perhaps untenable notion of a “greatest common good.” This defense of the ODA and related legislation is, of course, not without objections. One might argue that patients with RDs do not necessarily constitute the least well-off group in society, because those suffering from severe common diseases might be worse off than those who possess a mild RD (a disease that possesses few symptoms, for example). Nonetheless, the Rawlsian approach offers a distinct alternative to common ways this issue is considered in the literature, avoiding the calculation and value additivity problems that plague consequentialist theories.

A Consequentialist Assessment

Moral Equality Critics of special legal protection for orphan drugs often appeal to moral equality, which emphasizes the natural equality of all rational beings. Given the opportunity costs of legislation granting special status to orphan drugs, such decisions seem to “imply that a patient with a more common condition, and who would benefit equally, is less worthy of receiving the treatment” (Hughes, Tunnage, and Yeo 2005). Reasoning this way, Christopher McCabe and colleagues suggest that the ethical dilemma regarding orphan drugs turns to the question of whether policymakers should value the health benefits of two individuals differently just because one has a common disorder and the other a RD (McCabe, Claxton, and Tsuchiya 2005). McCabe considers two hypothetical groups of people, group J (RD) and group K (common disease). All other patient characteristics are held constant except for cost: Group J’s treatment costs £1000 while group K’s treatment costs £100. Next, McCabe sets the healthcare budget at only £1000; either one of group J is treated or ten of group K. If group J gets treated, the system seems to implicitly value the treatment of members of J ten times more than members of K. Thus, McCabe concludes his hypothetical by asking, “Why should a person’s health be valued less, simply because the condition is not rare?” Though McCabe’s question is rhetorical, one can easily hold the opposing view, even under a consequentialist framework. A consequentialist would answer McCabe’s question by claiming that a person’s health would be valued less if it is utility-maximizing to do so” (i.e. it augments consequentialist gains). Since McCabe and the consequentialist seem to diverge on this point it suggests that moral equality, at least in McCabe’s terms, offers a distinct ethical consideration against special legal protection and funding for orphan drugs.

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Additivity Rejected But the deontological arguments of McCabe and the consequentialist share a common foundational assumption: the value of human lives is additive. This assumption generates the claim that treating group J (rare disease) involves valuing the lives of members of J ten times more than members of K (common disease). A conception of equality in which value adds across human lives has figured heavily in contemporary defenses of consequentialist (Cummiskey 1990) moral theory1 and is often expressed as an objection to deontological theories

1 For instance, in Kantian Consequentialism, David Cummiskey argues along these lines: “…persons also have a fundamental equality which dictates that some must sometimes give way for the sake of others. The formula of the end-in-itself thus does not support the view that we may never force another to bear some cost in order to benefit others. If one focuses on the equal value of all rational beings, then equal consideration dictates that one sacrifice some to save many”(Cummiskey 1996).

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About two hundred years before Rawls, Jeremy Bentham proposed a new moral theory of consequentialism. The good worth of an action, he wrote, should not be judged by its intentions, but rather by the utility of its consequences. Eventually, he correlated utility with happiness and concluded famously that actions should maximize the “greatest happiness for the greatest number.” This moral framework, now called utilitarianism or consequentialism, seems to motivate many policy decisions. Although legislative progress has been made to alleviate funding shortages for the study of RDs, the status quo distribution of research funding continues to strongly favor research and development of treatments for more common diseases. This distribution reflects a broadly consequentialist framework for thinking about public policy: given conditions of scarcity, public policy should be directed to produce the greatest good for the greatest number. If saving the life of one individual through effective healthcare policy is a moral good, then saving more lives must be an even greater moral good—or so the thought goes. Straightforward consequentialist thinking of this kind intuitively disfavors resource allocation toward orphan drug research: by definition, more people are affected by common diseases, and “the opportunity cost of supporting the use of ultra-orphan drugs necessitates that patients with a more common disease, for which a cost-effective treatment is available, are denied treatment” (Hughes, Tunnage, and Yeo 2005). At first, this utilitarian rationale seems sound. The cost to pharmaceutical companies is enormous, with estimates for the cost of developing a new drug over $1 billion. These

investments often come up empty, with only about one in ten new pharmaceutical compounds succeeding in the market (Gericke, Riesberg, and Busse 2005). Given the limited resources and significant investment of R&D, a closer analysis of the distribution of benefits and burdens of R&D funding, specifically that of the moral worth of individuals, complicates the consequentialist conclusion that R&D funding should be limited.

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Orphan Drug Legislation

that focus on moral rules, known as the paradox of deontological constraints2 (Alexander and Moore 2007). Our earlier discussion of consequentialist considerations also hinted at this idea: if X is a good, then more of X is better. But if we reject the assumption of value additivity—say, by assigning infinite worth to each human life—the conclusion does not follow. Indeed, many moral philosophers have rejected this assumption. Robert Nozick argues that “there is no social entity with a good that undergoes some sacrifice for its own good… only individual people… with their own individual lives,” and he argues that talk of an overall societal good undermines the essential separateness of persons (Nozick 1974). John Rawls also criticizes utilitarianism on the grounds that it treats all of society as if it were one person and it permits trade-offs that would make sense only if society were one person. The utilitarian assumes that the total amount of social benefit could outweigh the social cost incurred to some people, an assumption Rawls rejects: a cost to one person cannot be made up by a benefit to another person, because they are distinct persons.3 If the assumption of value additivity is rejected, considerations of moral equality may actually favor the ODA and related legislation. A refusal to allocate resources for orphan drug research penalizes those afflicted with a particularly rare medical condition. Rejecting such legislation leaves those with RDs subject to free market forces that disincentivize pharmaceutical companies from investing in rare drug research. To treat orphan drugs and treatments for common diseases by the same legal standard seems to sacrifice the minority, those with RD, to save the majority, those afflicted with more common diseases. In McCabe’s terms, this equates to treating any particular individual in group J (rare disease) as morally inferior to any particular individual of group K (common disease). Rejecting value additivity entails that only pair-wise comparisons, rather than aggregative ones, make moral sense. McCabe’s appeal to moral equality ultimately turns on an underlying consequentialist assumption--the assumption of the additivity of lives. Thus, the attempt to pivot from consequentialist analysis to considerations of equality does not represent a distinct ethical consideration. Moral equality does not support the rejection of the ODA.

Conclusion We present several arguments above that justify an increase in federal and state funding for research and development for RDs. Patients with RDs, we believe, appropriately fit the Rawlsian paradigm for augmenting the quality of life for the least well-

off group. Although the utilitarian rationale seems sound at first, we point to a framework of moral equality that rejects the value additivity of persons so as to shy away from the market forces that culminate in the marginalization of RD patients. We believe that individuals, with their basic legitimate claim to healthcare, have a right to a federal policy commitment to those needs. This right has been better protected in some countries than others and has great policy implications that can only result from a shift in allocation bundles for medical research in future legislation. Only further discourse and an increased awareness of the ethical issues that surround the topic at hand can lead to real-world action.

References

Alexander, L., and M. Moore. 2007. “Deontological Ethics.” Congress, United States. 2002. Rare Diseases Act, edited by Committee on Energy and Commerce. Council, National Health. 2014. “Modernizing Our Drug and Diagnostics Evaluation and Regulatory Network: The MODDERN Cures Act of 2011.” Cummiskey, D. 1990. “Kantian Consequentialism.” Ethics, 100(3): 586-615. Cummiskey, D. 1996. Kantian Consequentialism. New York: Oxford University Press. Eurodis. 2015. “What is a Rare Disease?” Franco, P. 2013. “Orphan Drugs: The Regulatory Environment.” Drug Discovery Today, 18(3):163-172. Global Genes Project. 2015. “Who We Are.” Gericke, C.A., A. Riesberg, and R. Busse. 2005. “Ethical issues in funding orphan drug research and development.” Journal of Medical Ethics, 31(3): 164-168. Haffner, M.E. 1999. “Orphan Drugs: the United States Experience.” Drug Information Journal, 33(2): 565-568. Haffner, M.E., J. Whitley, and M. Moses. 2002. “Two Decades of Orphan Product Development.” Nature Reviews Drug Discovery, 1(10): 821-825. Hughes, D.A., B. Tunnage, and S.T. Yeo. 2005. “Drugs for Exceptionally Rare Diseases: Do They Deserve Special Status for Funding?” QJM: An International Journal of Medicine, 98(11): 829-836. Laing, R., B. Waning, A. Gray, N. Ford, and E.T. Hoen. 2003. “25 Years of the WHO Essential Medicines Lists: Progress and Challenges.” The Lancet, 361(9370): 1723-1729. Lang, J., and S.C. Wood. 1999. “Development of Orphan Vaccines: An Industry Perspective.” Emerging Infectious Diseases, 5(6): 749-756. Lavandeira, A. 2002. “Orphan Drugs: Legal Aspects, Current Situation.” Haemophilia, 8(3): 194-198. McCabe, C., K. Claxton, and A. Tsuchiya. 2005. “Orphan Drugs and the NHS: Should We Value Rarity?” BMJ: British Medical Journal, 331(7523): 1016-1019. Nozick, R. 1974. Anarchy, State, and Utopia. New York: Basic Books. Organization, World Health. 1977. “The Selection of Essential Drugs: Report of the WHO Expert Committee: WHO.” Rawls, J. 2009. A Theory of Justice. Cambridge: Harvard University Press. Shiragami, M., and K. Nakai. 2000. “Development of Orphan Drugs in Japan: Characteristics of Orphan Drugs Developed in Japan.” Drug Information Journal, 34(3): 839-846. Taurek, J.M. 1977. “Should the Numbers Count?” Philosophy & Public Affairs, 6(4): 293-316.

2 The paradox expresses the following chain of reasoning: the deontologist, who focuses on moral rights and rules, holds that it is bad to wrong someone—it is bad if someone suffers wrong from someone else, and so, good to do what prevents it. Yet, there may be circumstances where preventing a wrong to person K will require wronging person J. So the deontologist must paradoxically conclude that, in such circumstances, it may be good to wrong someone because it is bad to wrong someone. For discussion of the paradox, see Alexander et al. 3 Other philosophers have made similar objections. In one passage, John M. Taurek writes: “Suffering is not additive… The discomfort of each of a large number of individuals experiencing a minor headache does not add up to anyone’s experiencing a migraine” (Taurek 1977).

Article

The Ethics of Global Research Funding Melanie Etherton* Our current system of global research funding contributes to great suffering, particularly among the least well-off. Existing drugs are too expensive for many to access. The resulting low market demand creates little incentive to research diseases chiefly affecting the poorest, despite their disproportionate contribution to global suffering. In this paper, I argue for a sufficientarian understanding of what it means to have a fair distribution of funding for research and development of new drugs. Using the work of Thomas Pogge, I propose we have an obligation to improve this system of drug innovation and establish three core criteria by which to assess proposals for doing so. Of the five proposals considered here, one is demonstrated to be harmful and the other four are shown to be insufficient. From this analysis, it seems unlikely that any one proposal can fulfill all criteria and effectively enable fair access to necessary drugs. We should therefore look to proposals in combination or from different domains in our efforts to lessen the global burden of disease. 1. What is wrong with global research funding today?

Disease R&D Investment (millions of pounds) Cancer 3438 HIV/AIDS 2067 Obesity 532 TB 157 Asthma 136 Malaria 96 Table 1: R&D investment for six selected diseases by the biomedical research arm of the US government in 2012 (National Institutes of Health 2015). Table created by author. The consequences of this funding disparity can be observed in the outputs of pharmaceutical research. Table 2 (below) lists the number of clinical trials for seven major NTDs from a database covering over 170 countries. Together, trials for these seven major NTDs represent just 0.67% of all trials in the database. Number of registered trials 843 120 106 53 46 37 11

Table 2: Data from ClinicalTrials.gov [search date: 12/11/2014]. Table created by author.

* Melanie Etherton graduated with a B.A. in Natural Sciences (Biological) from the University of Cambridge in 2015. She majored in Psychology and minored in History and Ethics of Medicine. She can be reached at me.etherton@gmail.com.

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NTD Malaria Leishmaniasis Dengue fever Trypanosomiasis (sleeping sickness) Schistosomiasis Lymphatic filariasis (elephantiasis) Onchocerciasis (river blindness)

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The current system of global research funding is inadequate as it fails to enable the development of affordable and effective ways to reduce the global burden of disease (GBD). In this paper, I focus specifically on tackling the GBD through drugbased interventions (henceforth “drugs”), including vaccines, treatments, and cures. Part of the GBD is caused by diseases for which effective drugs already exist: in 2012, pneumonia, malaria, and tuberculosis killed over 15,000 people every day (WHO Health Statistics 2015). Yet since drugs are typically priced 300–400% higher than their cost of production, often neither individuals nor governments in developing countries can afford to purchase them (Baker 2004). A key factor behind these high prices is the current system by which drug companies turn a profit despite their large original investment in drug research and development (R&D). When a company develops a new drug, it can claim a patent under the 1995 Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). This patent grants the company a 20-year market monopoly during which it can set high prices without fear of competition. TRIPS is currently enforced around the world, with the final deadline for compliance being 2016. The other main part of the GBD is caused by diseases for which no effective drugs exist. For example, existing drugs have little or no impact on the 17 key neglected tropical diseases (NTDs) identified by the World Health Organization (WHO) which affect over one billion people (WHO NTDs 2015). Since the high price of drugs results in low market demand among the poor, pharmaceutical companies have little incentive to research diseases chiefly affecting the poor – regardless of the impact of these diseases. One infamous 1990s estimate was that diseases causing 90% of the GBD attracted only 10% of the global drug R&D funding. Table 1 (top right) is a more recent illustration of this disparity.

The Ethics of Global Research Funding Overall, the current system of global research funding is inadequate as it fails to effectively alleviate the GBD. As a result, key diseases go under-researched and vital drugs are inaccessible. In the subsequent sections, I first defend a sufficientarian framework for a fair distribution of funding for new drugs. Then, in Section 3, I use Pogge’s work to argue that individuals have an obligation to improve the current system of drug innovation, establishing three core criteria for evaluating proposed mechanisms of doing so. In Section 4, I use these criteria to assess five popular proposals for improving the current system of global research funding. Since these criteria demonstrate four of the proposals to be insufficient and one to be actively harmful, I conclude by considering the implications of these criteria for approaching such issues in the future.

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2. What is a fair distribution of necessary drugs?

To evaluate proposals for making the current system of funding for new drugs more fair, it is first necessary to define what is meant by a fair distribution in this context. In this section, I propose and defend a sufficientarian understanding of what is meant by a fair distribution of funding for new drugs. I also lay out caveats to this approach, including the rejection of strict sufficientarianism and the importance of incorporating individual choice. The sufficientarian position states that we ought to distribute goods such that as many people as possible are at a sufficient, or ‘good enough’, level of advantage. Sufficientarianism does not value equality in and of itself, suggesting that the real issue of social justice is “never merely that some have more than others but that some do not have enough” (Arneson 2008). In the context of this paper, the system of global research funding will therefore be fair when as many people as possible have sufficient access to drug-based interventions. A central issue with the sufficientarian position is defining what this minimally acceptable level of access to drug-based interventions actually is. The positioning of this morally significant threshold is difficult and to some extent arbitrary. For the purposes of this paper, I propose a minimally acceptable level of access to drug-based interventions is access to drugs which would enable people to achieve minimal threshold levels of health, by prolonging life or improving its quality. Sufficientarianism is a more appropriate approach for considering issues of fair distribution in the context of drugs than prioritarianism, which suggests that “benefiting people matters more the worse off these people are” (Parfit 1997). However, prioritarianism faces problems because it allows people to accrue morally significant benefits, no matter how blissful their lives (Crisp 2003). For example, using a prioritarian approach, drugs which reduce hair loss are still recognized as creating meaningful benefits for their users: there is no cut-off point delineating when the benefits gained from a particular drug are so trivial that they cease to be important. A sufficientarian approach, however, enables consideration solely of drugs which significantly prolong life or improve its quality. Under sufficientarianism, there is much less risk of a system favouring funding drugs which provide only marginal benefits to users who are already relatively well-off.. I also argue that a sufficientarian framework is a more appropriate approach in this context than a utilitarian one. Under

utilitarianism, a distribution is fair if it creates the largest net benefit. This can create strong pragmatic arguments for changing the current system of global research funding; for example, ensuring people across the world have sufficient access to drugs in the present day reduces the risk of public health crises such as pandemics in the future (Kitcher and Flory 2004). However, I propose that such pragmatic arguments are insufficiently demanding. Instead, I focus on establishing how we may still have a duty to act even if it will not necessarily increase the net benefit. However, a strictly sufficientarian approach is still inadequate. Strict sufficientarianism places nudging one individual across the threshold of sufficiency above raising millions from a hellish life to a hugely more bearable, but still insufficient, standard. I therefore accept only a loose version of sufficientarianism: we cannot be sufficiently confident in our positioning of this threshold to justify choosing the one small benefit above large benefits to millions. My use of a sufficientarian approach to drug distribution also comes with two key caveats. First, a fair distribution of necessary drugs must ensure every person has sufficient access. Access to drugs, however, does not confer any responsibility to consume them. Approaches which attempt to define what is meant by a fair distribution must leave scope for individual choice: competent and uncoerced people should be free to trade off consuming necessary drugs with other benefits (Dworkin 2002). To give a medical example from a different field, a Jehovah’s Witness who refuses a blood transfusion can be seen as trading off their decreased physical health for an increase in mental or spiritual health. The second caveat is that definitions of a fair distribution of necessary drugs should also consider individuals’ responsibilities. For example, a person choosing a lifestyle which increases their likelihood of requiring drugs in the future could reasonably be expected to contribute towards the cost of these drugs now (Arneson 2008). However, since the extent to which people’s life decisions are truly uncoerced is a topic of much debate, this issue will not be considered further here (Cappelen 2005).

3. Arguments for action I propose that relatively wealthy citizens of developed countries have an obligation to improve the current system of drug innovation, such that all people have treatment options that enable them to reach threshold levels of health. I base this obligation in Thomas Pogge’s argument that as we participate in and utilize the existing system of drug R&D, we incur responsibilities towards those whom it systematically fails. In this section, I also consider Peter Singer’s argument that we should act to change the current system of global research funding because of our individual responsibilities towards other people. In this context, however, I argue that Pogge’s reasoning is more powerful, since it grounds our obligation to act in our involvement with the relevant institutions, rather than in abstract notions of beneficence. Lastly, I use Pogge’s argument to introduce criteria of effectiveness into the evaluation of proposals for changing the current system of funding. Pogge holds that our current global institutional order avoidably and foreseeably causes significant health-related suffering (Pogge 2008a). For Pogge, individual citizens therefore

The Ethics of Global Research Funding or subsidising drug distribution. Such an organization has the potential to save hundreds or even thousands of lives. Singer’s argument centres on the realisation that despite the differences in distance and immediacy between the two situations, they are morally identical: in both, there is an action which results in a life being saved and a duty of justice to take it. The force of this argument, if accepted, arises because it applies to almost all the money we spend. Viewed critically, few things can be considered of equivalent importance to a human life. Singer’s argument therefore applies to new suits but also new cars, holidays abroad, restaurant meals and almost every other aspect of modern life. If Singer’s argument is accepted, then it becomes a duty for us to give up many, if not all, of these personal expenditures in order to donate the money to organizations of the type described above. In the specific context of global research funding, however, I base my argument for action in Pogge’s arguments rather than Singer’s. This is because drug R&D is an area in which we can very often find clear links between our choices and their effects, as illustrated by the GE example above. To extend Singer’s analogy, Pogge characterizes the present situation of drug R&D as less like ‘coming across a drowning person’ than ‘actively pushing someone in.’ Under the current system of global research funding, we actively contribute to and benefit from the suffering of others. This therefore creates a much stronger obligation for us to help. Even when it is accepted that in some situations our connections to events are unclear and so our obligations are weakened, this still leaves the majority of us with an obligation to do far more than we are doing now. Using Pogge’s argument when evaluating proposals for improving necessary drug innovation and access shows the moral imperative for solutions to be effective. Ineffective solutions fail to fulfill our duties, since they are morally equivalent to doing nothing. My initial sufficientarian emphasis therefore needs to be balanced against a duty to use resources effectively. From these considerations, I propose three criteria for judging proposed mechanisms of improving the current system of necessary drug innovation and access. 1. Does it incentivize innovation? 2. Does it widen access? 3. Is it feasible and realistic? By establishing these three criteria it becomes clear that proposals which fulfill one criteria by making another impossible to fulfill need to be ruled out. This is because, ultimately, all three criteria must be met if the overall situation is to improve.

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4. Proposed Solutions In this section, I use the criteria established previously to critically analyze proposals for improving the current system of drug innovation and access. These five proposals were chosen for evaluation based on their current popularity in the literature. A. Encourage widespread use of compulsory licensing B. Confer particular duties upon the biomedical research community C. Use rewards based on human judgment D. Fund research and distribution of drugs through charitable donations E. Increase the prevalence of public-private partnerships

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violate duties of justice when they make choices which sustain this system. This argument focuses on individuals’ interactions with institutions, making it well-suited to considering issues of drug access and innovation. TRIPS was designed by and for wealthy nations: we reap the benefits of innovation driven by free market competition, but our wealth spares us from market exclusion brought on by monopoly pricing. As a result, our pharmaceutical industry is thriving: the pharmaceutical company Pfizer registered a net income of over £15 billion in 2013 (Pfizer 2014). Yet this same system of drug patents and monopoly pricing is contributing to death and suffering among the most disadvantaged, as outlined in Section 1. Pogge therefore argues that we have a strong obligation to change the system by which drugs are funded, developed and distributed. Mathias Risse disputes Pogge’s claims, contending that the global order is not fundamentally unjust since it “has caused amazing improvements over the state of misery that has characterized human life throughout the ages” (Risse 2005). The sufficientarian stance defended in Section 2 is critical for showing this argument to be irrelevant; a prioritarian view could not have refuted this argument. Under sufficientarianism, it does not matter if the current system is a fantastic improvement on previous systems: the current system is still leaving billions of people living and dying without the existence of important drugs, let alone easy access to a sufficient level of health. It is therefore legitimate to consider our current global system unjust and valid to argue for people’s duties to change it – even if the current system is an improvement on even more harmful previous systems (MacAskill 2014). Another counterargument to Pogge questions whether individuals can really be held responsible for institutionallymediated harms, given their complex and often indirect nature. I maintain that we can, however, generally understand the consequences of our choices. For example, we frequently engage with the company General Electric (GE) which, as the seventh-largest company in the world, supplies everything from the electricity in our homes to the energy for manufacturing the products we consume (Forbes 2015). Our tacit support – or lack of objection – legitimizes GE’s £430 billion Healthcare division’s choice to invest not in malaria drug R&D, but in CT scanners. When consumers are aware that viable alternatives exist, I argue that Pogge’s concept of indirect involvement is sound. Perhaps we need not even be immediately aware that viable alternatives exist; as Holm (1995) points out, it seems disingenuous to claim ignorance when it requires only minimal effort to learn more. An alternative argument for action to change the current system of global research funding comes from the work of Peter Singer. Singer’s basic argument can be stated simply: “if it is in our power to prevent something very bad from happening, without thereby sacrificing anything of comparable moral importance, we ought, morally, to do it” (Singer 1972). For example, in Situation A, a person must decide whether or not to jump into a pond and save a drowning person when doing so will ruin their new suit. In Situation B, a person must decide whether to buy a new suit or give the equivalent sum of money to an effective charity. For the purposes of this argument, this charity is assumed to be an organization effecting change within the current system of global research funding – be it through campaigning, funding research,

The Ethics of Global Research Funding Using an analysis based on the framework established above, the first proposal is found to be fundamentally flawed. The remaining four proposals are found to range from ineffective to promising, although none offer a single definitive solution. These proposals are evaluated in order of how effectively they fulfill the three criteria discussed above, from least to most promising.

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A. Encourage widespread use of compulsory licensing

Compulsory licensing (CL) allows governments of developing countries to inexpensively manufacture essential drugs without the patent owner’s consent (WTO FAQs 2015). Initially established under TRIPS, CL was strengthened by the 2001 Doha Declaration: “the TRIPS agreement does not and should not prevent members from taking measures to protect public health” (WTO 2001). CL has faced moral controversies as it pits people’s right to sufficient healthcare against companies’ intellectual property rights (IPR), leaving it unclear which should take priority and under what circumstances. While pharmaceutical executives, such as Bayer AG CEO Marijn Dekkers, view CL as “essentially...theft” (Knowledge Economy International 2014), public opinion has tended to differ: after Mandela appropriated antiretroviral therapies to treat South Africa’s HIV epidemic, a wave of public support forced pharmaceutical companies to reduce their prices by up to 90% (Berlinguer 2004). The approach outlined in this paper, however, sidesteps these controversies by considering pragmatic and moral issues together, and thus reveals that the problems with CL run far deeper. One might argue that a correctly-issued compulsory license would not affect a drug company: if people in that country do not buy the drug at market price, then there is no profit to be lost. This is not the case. CL both destroys any existing market for that drug within that country, however small, and also eliminates the possibility of the company and the government negotiating a reduced price (Resnik 2001). CL also undermines future international profits. Not only does the black market become flooded with cheap generic versions of expensive drugs, but one country’s decision to reject IPR makes other countries more likely to follow suit. For example, after the Indian government rejected Novartis’ patent for the cancer drug Gleevec in 2006, GSK withdrew Indian patent applications for two new antiretroviral treatments as it feared the setting of a precedent of patent breakdown (Sridhar 2008). Overall, CL actively discourages companies from investing in NTD drugs as it removes the possibility of profit. CL is therefore an unsustainable solution: the more it is used to improve drug access, the greater the innovation problem becomes. It thus should not play any further role in the efforts to tackle the GBD. Any use of CL to widen access to necessary drugs will ultimately cause more harm than good, as it undermines future investment in tackling the diseases of the people that it is intended to help.

B. Confer particular duties upon the biomedical research community Kitcher and Flory (2004) propose that members of the biomedical research community have particularly large obligations to redress the disparity in global research. In

particular, they argue biomedical researchers not only have a duty to research areas directly relevant to reducing the GBD, but also a duty to campaign for increased research funding to be directed towards these areas. Kitcher and Flory’s suggestions are both practically unworkable and logically flawed. First, individual scientists are generally tightly constrained by the market of available jobs. To argue that biomedical researchers should research particular areas, regardless of whether or not they have the time or money to do so, is unreasonable. Secondly, Kitcher and Flory construct their argument based on the flawed assumption of critical inputs coming from a small group of people (biomedical researchers). Yet without effective software developers, technicians, accountants, managers, waste disposal companies, scientific publishers and others, the efforts of the most talented biomedical researchers in the world would not translate into any reduction of the GBD. Kitcher and Flory fail to draw a principled line for whom their argument encompasses, making their case for specific duties for particular contributors unsound. Certainly, contributions from biomedical researchers will be vital in reducing the GBD. But even with the best intentions, focusing on allocating specific duties for the biomedical research community alone is both unfair and ineffective.

C. Use rewards based on human judgment Under the current patent system, a company with a desirable drug is rewarded by the market in proportion to the drug’s success. Such systems, which link rewards to market demand, are attractive due to their potential for obtaining large rewards from a single product. However, such systems also couple innovation to access and thus contribute to the problems outlined in Section 1. One alternative suggestion is to reward innovation based on a human assessment of the drug’s value to society. I raise two key practical problems with systems that attempt to incentivize innovation in this way, illustrating the impact of these problems with real-life case studies. The first practical drawback of systems giving rewards based upon human decisions is their vulnerability to human bias and error. In this context, certain diseases risk being considered less important due to moralistic judgements about the behavior of typical sufferers – for example HIV and its historical associations with homosexual activity (Cappelen 2005). People who make key decisions regarding necessary drugs are also likely to be susceptible to external pressure, as was the case of the £2 billion spent by pharmaceutical companies lobbying the US Congress between 1998 and 2014 (OpenSecrets 2015). The second key practical drawback of a system which rewards innovation according to human judgments is the near-impossibility of securing sufficient funding. With marketbased reward systems, people’s need is their incentive to pay. However, rewards based on judgement are removed from people’s immediate need. People would therefore have to be convinced to put money towards something without it directly yielding them a benefit, which is much harder to incentivize. It is therefore near impossible to establish large enough funds to incentivize an industry as expensive and high risk as pharmaceutical R&D in this manner.

The Ethics of Global Research Funding Case Study 1: Priority Review Vouchers Priority review enables drugs in the US to reach market more quickly, giving a head start on competitors and more time to sell under patent. While usually reserved for drugs with large therapeutic benefits, Priority Review Vouchers (PRVs) grant priority review and can be earned by patenting any drug aimed at a neglected tropical disease (NTD) (Ridley 2006). But seven years after their introduction into US law, PRVs have contributed little towards reducing the GBD. Following intensive lobbying from the pharmaceutical industry, the requirement for companies to ensure low costs for their NTD drugs was removed. Consequently, the few NTD drugs developed through the PRV scheme are unaffordable for those who need them most. For example, a six-month course of Sirturo, which earned a PRV in 2012 due to its effectiveness against multiple drug-resistant tuberculosis, currently costs between £590 and £2,050 (MSF 2014).

D. Fund research and distribution of drugs through charitable donations Increased donations to appropriate charities, both on individual and institutional levels, could be thought to tackle issues of access and innovation. The weak commitment of ‘charity’ fails to

Recent years have seen a proliferation of alliances between financial backers, usually public or non-profit institutions, and industry. As opposed to creating overarching changes to the entire patent system, these public-private partnerships (PPPs) are specific agreements between individual agents. An Advanced Market Commitment (AMC), for example, commits an organization to purchasing a certain amount of product and a pharmaceutical company to supplying that product at a particular (reduced) price. Establishing guaranteed demand enables further price reductions as companies compete for the contract to supply, which can in turn lead to further increases in demand. When a PPP called Gavi Alliance orchestrated distribution of the hepatitis B vaccine, the price eventually fell to just £0.15 per dose (Jarrett 2008). Analyses of PPPs suggest that they have significantly contributed to tackling issues of both access and innovation. Table 3 (below) shows that the increased rate of NTD drugs being approved correlates with an increased proportion of NTD drugs being funded via PPPs. Moran (2005) assessed pharmaceutical organizations on a range of measures: the health value of the final product (safety, efficacy, suitability, and affordability); innovation; drug development time; and cost-efficiency. In the majority of cases, PPPs were found to outperform industry or public groups working alone. Time period

Mean number of drugs for NTDs approved per year

% sponsored by Private industry

PPPs

Other

1975-1999

1.9

2000-2009

3.2

Table 3: NTD drug development data (Cohen et al 2010).

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Ultimately, due to issues with rewards based on human judgement, both PRVs and the HIF proved ineffective. These two case studies are not isolated initiatives, but instead illustrate the problems of purely judgement-based reward systems as a whole: they are overly susceptible to human biases and are generally unable to obtain sufficient funding. It is therefore highly unlikely that rewards based on human judgement can by themselves provide a way to effectively tackle the GBD.

E. Increase the prevalance of public-private partnerships

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Case Study 2: the Health Impact Fund The Health Impact Fund (HIF) was proposed by Pogge in 2005 as a complement to the current patent system. Under Pogge’s plans, companies could choose to register drugs with the HIF instead of patenting them, and would be paid a monetary reward proportional to the drug’s impact on the GBD. In exchange, the company would initially guarantee global supplies of the drug at production cost price, and later forgo patent rights (Pogge 2008b). Pogge believed the HIF could tackle issues of both innovation and access, creating a valuable and competitive market for NTD drugs and encouraging collaboration with generic manufacturers to ensure the maximum impact of these drugs on the GBD. Ten years after the HIF was first proposed, it is clear that the absence of viable funding mechanisms will prevent the HIF from ever being implemented. Pogge himself suggests that the HIF could be funded through reparations from governments of wealthy countries seeking to fulfil their moral obligations under his framework (discussed in Section 3 above) – but these reparations have failed to materialize. Securing sufficient funds to incentivize drug innovation through the HIF would require sustained political commitment from numerous wealthy governments. If we must wait for this before we start to tackle the GBD, we will be waiting a very long time (Wolff 2012).

fulfill the strong moral obligations to act established in Section 3. Furthermore, viewing charitable donations as not a duty, but a kindness creates serious practical issues. The ad hoc nature of charitable contributions makes them unreliable as a funding source for long-term projects like drug development. Viewing contributions as charitable, rather than obligatory, also results in donors imposing inappropriate restrictions on how money is spent. For instance, the US government contributed £13 billion to HIV/AIDS relief before 2008, but specified that at least one third of the money must be spent on abstinence-only educational programs, later described as “ineffective or even detrimental” (Ravvin 2008). Finally, an ad hoc funding system risks unfairly burdening those who do contribute. For example, the chairman of Merck hesitated to donate Ivermectin, fearing it would “discourage companies from doing research relevant to the Third World, since they might be expected to follow suit” (WHO Ivermectin 2015, Silverstein 1999). Without a clear structure to allocate and enforce obligations, agents who do involve themselves risk being unfairly disadvantaged (Sturchio 2001).

The Ethics of Global Research Funding 5. Conclusion Our current system of global research funding is a major contributing factor to death and suffering in our world today, particularly among the most disadvantaged. Working from this problem as outlined in Section 1 and Section 2, I defended a sufficientarian approach to understanding what is meant by a fair distribution of necessary drugs. In Section 3, Pogge’s work was used to argue that we have an obligation to change this situation, and establish three core criteria for evaluating proposed mechanisms of action. In Section 4, I used these criteria to evaluate five popular proposals: encouraging widespread use of CL; conferring particular duties upon the biomedical research community; granting rewards solely on the basis of human judgement; funding research and distribution of necessary drugs through charitable donations; and more public-private partnerships. My analysis revealed that some proposals, such as encouraging widespread CL, are counterproductive to improving drug innovation and access. This is a potent demonstration of the value of using appropriate ethical frameworks to assess proposals; by ruling out this unrealistic option early, we can consider more promising options. The remaining four proposals range from impotent to promising. None, however, were found to provide a complete solution. This analysis revealed no single, elegant solution to the problems of drug innovation and access. This paper focused only on drug-based approaches, whereas suggested alternatives range from more medical staff to improved sanitation, from better grassroots disease education to general economic development. More probable, however, is that there is no single solution. As we better appreciate the complexity and diversity of our R&D ecosystem, we increasingly realize that grand schemes and one-size-fits-all solutions are unlikely to work. The results of this paper therefore suggest the future instead lies in utilizing a range of strategies. By using a suitable framework to evaluate proposals, we can establish which proposals are both realistic to implement and fulfill all three criteria without creating bigger problems elsewhere. These viable, though partial, solutions can then be combined into context-dependent approaches. Accepting the absence of one clear solution is far from the end. Instead, it marks the beginning of our work to evaluate effective combinations of strategies for the future.

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