Rapid Development of New and Affordable Medical Treatments
Current medical treatments for many diseases can be improved. Drugs used to treat diseases such as cancer, Alzheimer's, chronic fatigue syndrome, and long COVID have limitations, including high costs, limited access, toxicity, and limited efficacy. Yet, there are a host of promising interventions with some evidence for efficacy which are not being fully explored with definitive clinical studies.
Here is a case in point. Checkpoint inhibitors – drugs that unleash an anti-tumor immune response – represent a major advance in cancer care but sadly only a minority of patients respond to treatment. Thus, there is much opportunity to expand the number of patients with positive outcomes. Indeed, there is promising data that patients treated with these drugs live longer, if they also happen to be taking a number of commonly used medications (e.g. beta blockers and certain other blood pressure medications or anti-histamines used for allergies). There is also data that maintenance of vitamin B5, magnesium and manganese blood levels during immunotherapy treatment correlates with better outcomes. Importantly, animal model data suggests that these correlations may in fact be causal and that there is a plausible mechanism of action for these interventions. Moreover, acetaminophen or proton pump inhibitors (drugs used for acid reflux) usage is correlated with worse outcomes, suggesting that patients on checkpoint inhibitors may wish to avoid them. Clearly, to establish causality, prospective clinical trials are urgently needed, yet curiously such studies are not being aggressively explored.
What gives? Why are we not doing clinical trials to improve health outcomes worldwide? Basically, it comes down to dollars and cents.
A bit of history is in order. The National Institutes of Health (NIH), using our tax dollars, has been instrumental in funding laboratory research for decades but has largely left subsequent clinical trials to the pharmaceutical sector. This model has worked well, leading to the development of many miracle drugs. However, it has also left behind many untapped opportunities.
The reason is remarkably simple: clinical trials are expensive. Thus, only part of the vast body of ground-breaking laboratory work, that for which intellectual property (IP) / patent protection is guaranteed, has been singled out by pharma for further investment. The remaining therapies lie fallow: “potential untapped gems” that have never been followed through with clinical trials because nobody is willing to underwrite the costs involved. Why? In the absence of patent protection, no drug company wants to assume these costs because it cannot charge a premium price to recoup its investment in clinical studies. It is this strange dynamic that has resulted in a near-paralysis when it comes to fully exploiting basic research findings by NIH sponsored scientists.
Interventions cited above that could increase the efficacy of immunotherapy are examples of financial orphans, ideas that are not pursued by the for-profit sector due to insufficient financial incentive (Fig.1).
These ideas include repurposing of FDA approved generic (off-patent) drugs, generally recognized as safe (GRAS) supplements, lifestyle changes, and drugs for small or poorly reimbursable markets. The first three categories are immediately implementable, affordable, and are the focus of this commentary. Definitive clinical trials could be started quickly, in contrast to new drug development, which is time-consuming, expensive and for which toxicity is unknown.
Given that our current capitalist system does not incentivize pharma to harness the potential of financial orphans, we propose that the US government take on this mission by establishing and funding a national agency dedicated to this goal (Fig. 2).
The agency, tentatively named the Institute for Available Financial Orphan Therapeutics (IFOT), would complement pharma in developing new treatments, with patient impact and not return on investment serving as the primary driver for clinical development. IFOT’s singular goal would be to publish peer reviewed results on financial orphan clinical studies in order to change national treatment guidelines and obtain insurance coverage for such treatments.
We offer more details on IFOT structure and function. IFOT could be part of NIH, or it could exist as an independent organization, perhaps a new Federally Funded Research and Development Center (FFRDC), i.e., a private-sector entity with a unique relationship with its sponsoring federal agency. IFOT's major functions would include the following (Fig. 3):
Treatment Idea Generation and Prioritization: IFOT would curate existing information on financial orphans from various sources, including published pre-clinical and clinical papers, literature reviews, clinical trial protocols, and social media. This information would be used to construct a searchable database. Additionally, IFOT would support pre-clinical studies that may be critical to starting clinical studies. For example, in silico (dry lab) as well as wet-lab methods could be brought to bear on finding new indications for financial orphans. Promising candidates would be prioritized based on scientific and clinical evidence, as well as non-science related factors such as cost, physician interest, and feasibility. It should be noted that clinical development of financial orphans that fall in the off-patent drug class brings pharma’s discoveries to full fruition by finding new applications for off-patent drugs originally developed by pharma with patent protection for a specific indication.
Design and Oversight of Clinical Studies: IFOT would design and oversee clinical studies, collaborating with potential investigators and finalizing protocols. Various trial designs, including adaptive platform and decentralized studies using telemedicine, would be explored since community involvement would be critical for rapid patient enrollment and therefore impact.
Alongside clinical trials, real-world registry-based studies that use financial orphan treatments, perhaps through a network of caregivers in select clinics, could provide valuable early efficacy and toxicity data. Importantly, community caregiver engagement would take advantage of the wide availability and known safety profile of many financial orphan interventions, which is not the case for new drug development. For such an effort to bear fruit, IFOT would need to educate practitioners about financial orphan treatments outside of a clinical trial and address such issues as liability, compensation for caregiver time and intervention reimbursement.
Advocacy and Education: IFOT would ensure timely publication of trial data and actively market the data to caregivers. Educational events would be organized for patients, advocacy groups and caregivers and attention would be given to equitable distribution and access. A certification for caregivers around financial orphan intervention could be conceived. IFOT would engage with regulatory agencies like the FDA to simplify processes relevant to financial orphans and work with entities that set treatment guidelines.
Ensuring Drug Access and Reasonable Pricing: IFOT would collaborate with the private sector to ensure sufficient availability of drugs proven effective as financial orphans. It would monitor pricing to prevent unjustified increases and, if necessary, contract with manufacturers to produce the drug at a reasonable cost.
There are other benefits of establishing IFOT (Fig. 4).
Its activities could be leveraged by pharma for post-marketing studies, access to clinical outcomes data, and as a starting point for drug optimization or reformulation. The community caregiver network that IFOT would establish could rapidly gather data on interventions approved as an Emergency Use Authorization in a national emergency, such as a pandemic.
IFOT could accelerate its impact by partnering with and integrating fragmented and often under-resourced ongoing national and international efforts such as those at GlobalCures, Emory Morningside Center for Innovative and Affordable Medicine, Cures Within Reach, Anticancer Fund, Every Cure, CURE Drug Repurposing Collaboratory, REPO4EU, REMEDI4ALL and the National Health Service Medicine Repurposing Programme.
How might IFOT be funded and how much should the funding be? A strawman would be an annual budget of $1 billion, enough to explore in a timely manner the backlog of financial orphan opportunities in multiple diseases. Though this number may sound large, especially in today’s budget challenged and hyper partisan world, it is only 1% of pharma R&D spending and 2% of the NIH budget. Such an expenditure would allow pre-clinical and clinical development of ~50-100 new ideas per year. Funding sources could include a surcharge on generic drugs (labeled as a medical innovation fund), social impact bonds, and philanthropic entities. In addition, health insurance companies and self-insured health systems could save money if they funded treatments that replaced or augmented the efficacy of current expensive therapies, setting up a sustainable funding model. Pharma might contribute funds towards this effort to gain access to real world data (collected as part of a registry for studies that use on-patent drugs in combination with financial orphans) or for reputational reasons.
In conclusion, the creation of a unique national agency such as IFOT is not merely an opportunity but an imperative to unleash the full potential of financial orphans, propelling the rapid development of groundbreaking and accessible medical treatments for countless unmet needs. Patients worldwide eagerly await the transformative impact this initiative could bestow upon their lives.
About the Authors:
Vikas P. Sukhatme MD ScD is the Robert W. Woodruff Professor of Medicine and was dean of Emory School of Medicine from 2017 to 2023. He was previously the Victor J. Aresty Professor of Medicine at Harvard. Sukhatme has over 200 scientific publications in basic science and clinical research cited over 50,000 times. His longstanding interest in cancer currently centers on "outside-of-the-box" approaches for treating advanced cancer and preventing cancer recurrence using repurposed drugs. He is co-founder of a not-for-profit organization, GlobalCures, that aims to promote promising therapies for cancer not being pursued for lack of profitability. These ideas are being advanced at Emory through the Morningside Center for Innovative and Affordable Medicine, where Sukhatme serves as the director. He is a member of the Harvard Board of Overseers.
Vidula V. Sukhatme MS is an Instructor in the Rollins School of Public Health, Emory University. She is a co-founder of the Morningside Center and is the founding CEO of GlobalCures. She has a long-standing interest in repurposed drugs and other “financial orphans,” a phrase coined in a Health Affairs blog she co-authored in 2014.