Medication affordability is a persistent public health problem in the US. Per capita US spending on prescription drugs totaled $1,024 million in 2017, $319 million (45%) more than the next highest country. ¹ An important contributor to this spending has been high drug prices, which can lead patients to skip or stretch out their prescriptions and forego other essential items. Such prices have been driven in part by new drugs. In 2017, the first gene therapies entered the US market. The chimeric antigen receptor-T cell (CAR-T) treatments tisagenlecleucel (Kymriah) and axicabtagene ciloleu-cel (Yescarta) were initially priced at $475,000 and $373,000, respectively,Reference Kleutghen, Mitchell, Kesselheim, Najafzadeh and Sarpatwari ² while the inherited retinopathy gene therapy voritigene neparvovec-rzyl (Lux-turna) was listed at $850,000 ($425,000 per eye).Reference Herper ³ Two years later, Novartis announced that it would charge $2.1 million for onasemnogene abeparvovec-xioi (Zolgensma), a gene therapy for spinal muscular atrophy.Reference Stein ⁴ Higher launch prices have similarly been observed for non-gene therapies as well. In 2019, the US Food and Drug Administration (FDA) approved two new drugs for sickle cell disease, crizanlizumabtmca (Adakveo) and voxelotor (Oxbryta), which each launched at about $100,000 per year.Reference Kolata ⁵

Other drugs have been the subject of substantial price mark-ups. The TNF-alpha inhibitor adalim-umab (Humira, first approved in 2002) and recombinant insulin (Lantus, 2000), have each more than doubled in list price since launch.Reference Hakim ⁶ One investigation found that price increases on existing drugs accounted for 60% of increased revenues between 2014 and 2017. ⁷

Particular concern has emerged because some of the new drugs and treatments emerging at high prices in the US, or that have been subject to some of the most substantial price increases over time, have benefitted in their development from critical public sector support.Reference Sarpatwari, Avorn and Kesselheim ⁸ Galkina Cleary et al. found that funding from the US National Institutes of Health (NIH), which had a budget of over $42 billion in 2020, ⁹ contributed at some level to all new drugs approved between 2008 and 2017.Reference Cleary, Beierlein, Khanuja, McNa-mee and Ledley ¹⁰ While many of these contributions were to the underlying basic science, a growing number of drugs can trace their existence to late-stage contributions originating from the public sector. Of all new small-molecule drugs approved between 2008 and 2017, a quarter were based in part on patents or other late-stage links to publicly supported research institutions.Reference Nayak, Avorn and Kesselheim ¹¹ If contributions from US taxpayers reduce the risk of private investment in development, should that be reflected in the price charged to US patients?

Such de-risking featured prominently in the three gene therapies approved in 2017. Tisagenlecleucel had its origins in work done by Dr. Carl June at the University of Pennsylvania.Reference Wilson ¹² It was only after his team published a National Cancer Institute (NCI)-funded pilot trial, which documented remission of chronic lymphocytic leukemia in a patient who had received that therapyReference Porter, Levine, Kalos, Bagg and Jun ¹³ that Novartis acquired the drug. ¹⁴ Development of axicabtagene cilolecleucel started at the NCI by a team led by Dr. Steven Rosenberg.Reference Richtel and Pollack ¹⁵ After publication of the results of treatment in 8 patients with advanced, progressive B-cell malignancies,Reference Kochenderfer, Dudley, Feldman, Wilson, Spaner and Maric ¹⁶ Kite Pharma executed a series of cooperative research and developments agreements with NCI to improve and advance the drug before ultimately acquiring it. ¹⁷ In the case of voritigene neparvovec-rzyl, grants from the National Eye Institute and non-profit sources supported a pilot trial,Reference Maguire, High, Auricchio, Wright, Pierce and Testa ¹⁸ after which university researchers formed the spin-off Spark Therapeutics to commercialize the therapy. ¹⁹ In each case, private investment played an essential role in supporting the pivotal clinical trials necessary for securing FDA approval. However, the manufacturers most prominently figured in the development programs after taxpayer-funded scientists worked through the challenging early stages.

Does such public support mean that Americans are “paying twice” for their medications? The COVID-19 pandemic has underscored this concern while also revealing the promise of more assertive governmentled drug discovery. By December 2020, Operation Warp Speed had spent $12.4 billion on COVID-19 vaccines.Reference Barone ²⁰ Of this funding, nearly $4.1 billion went to Moderna, including almost $1 billion for research and development costs, with the rest to advanced market commitments. ²¹ The NIH also served as an active collaborator in the phase III trial for the vaccine,Reference Baden, Sahly, Essink, Kotloff, Frey and Novak ²² which has proven to be extremely effective. Yet. despite extensive public support, the company is charging the federal government around $15 per dose.Reference Birnbaum, Rowland and Ariès ²³ Analysts forecast that Moderna’s revenues from its vaccine could total $32 billion in 2021 alone,Reference Dean ²⁴ and several Moderna executives have cashed out hundreds of millions of dollars in stock deriving its value primarily from public backing.Reference Lau ²⁵

To discuss the historical scope, opportunities, and challenges of public sector and non-profit contributions to drug development, including approaches to better account for public funding in the price of a drug resulting from that investment, the Program On Regulation, Therapeutics, And Law (PORTAL) in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital/Harvard Medical School convened a two-day Exploratory Seminar at the Radcliffe Institute for Advanced Study with experts in drug development and production, technology transfer, pharmaceutical policy, economics, and law. The six articles in this symposium issue stem from that meeting.

In the first article, Sampat traces the historical debate over public and private sector roles in drug development, summarizes evidence on the relative contributions of these sectors, and details a research agenda to identify optimal reforms to the existing system.Reference Sampat ²⁶ Marko and Miller follow with a case study on the development of photodynamic therapy and antivascular endothelial growth factor drugs — two revolutionary treatments for retinal diseases — highlighting the need for greater federal funding of “proof of concept” trials.Reference Marko and Miller ²⁷ Next, Baker critiques patent monopolies, proposing several ways that states and private actors can lower drug prices closer to free market levels, including importation, medical tourism, and state and philanthropic drug development funding.Reference Baker ²⁸ In the fourth article, Liljenquist et al. discuss the vulnerability of the US generic drug supply, calling for a greater role for non-profit drug manufacturers, which they argue can more freely engage in transparent, cost-plus pricing.Reference Liljenquist ²⁹ Kapczynski subsequently examines government patent use, identifying its strengths in contrast to Bayh-Dole “march-in rights” and how it could be implemented using the case of COVID-19 drug remdesivir (Veklury).Reference Kapczynski ³⁰ Finally, Mazzucato and Li identify four key problems with the pharmaceutical market — unmet needs, inefficient collaboration, high prices, and overly-financialization — and call for a fundamental reframing of the role of the state from market-fixing to market co-creation and co-shaping.Reference Mazzucato and Li ³¹

We hope this symposium issue will advance the debate on how to improve equitable access to prescriptions for drugs while promoting clinically meaningful innovation. This undertaking would not have been possible without generous support from the Open Society Foundations, Arnold Ventures, and Radcliffe Institute for Advanced Study.