Leveraging Pharmacoeconomics and Advance Market Commitments to Reduce Healthcare Expenditures
Summary
By establishing a self-sustaining fund to incentivize pharmaceutical companies to develop new and improved treatment protocols using low-cost, off-patent and unmonopolizable therapies, billions of dollars in cost savings could be realized by US government payers and health insurers in a financially “de-risked” manner while improving quality of care —truly a win/win opportunity.
Currently, pharmaceutical companies do not develop medical therapies unless they can enforce a monopoly price using patents. As a result, thousands of low-cost therapies, such as repurposed generic drugs, nutraceuticals, plant medicines, medical diets, lifestyle interventions, and dose de-escalation protocols, lack private financial incentives for development. Clinically validating the safety and efficacy of these affordable treatments would help many patients while saving billions of dollars. Meanwhile, the largest pharmaceutical companies are earning trillions of dollars in revenue for new patented drugs that often provide limited or no added benefit to patients, while causing significant financial burden on patients and the taxpayer.
We can solve these misaligned incentives using new payment models such as interventional pharmacoeconomic (IVPE) randomized controlled trials (RCTs) that result in cost savings for healthcare systems, even if RCTs fail, by comparing the efficacy of low-cost therapies to expensive patented drugs. Further, outcomes-based financing mechanisms known as Advance Market Commitments or Pay-For-Success (PFS) contracts, can incentivize the successful development of new low-cost therapies, entirely funded by payer costsavings from reduced reliance on monopoly-priced drugs.
We propose that the National Institutes of Health (NIH), National Center for Advancing Translational Sciences (NCATS) work together with payers such as Centers for Medicare & Medicaid Services (CMS) and the United States Department of Veterans Affairs (VA) to transfer a fraction of their costsavings from IVPE RCTs and AMCs to create a self-sustaining “prize” fund for development of low-cost therapies under the 2010 America COMPETES Reauthorization Act.
With these new payment models, it is possible to create a scalable and sustainable business for a sponsor to develop affordable therapies, while improving patient outcomes and saving significant costs. For example, every 10,000 patients treated under an IVPE RCT + AMC contract comparing off-patent ketamine to patented esketamine, which could be more effective for treatment-resistant depression, would save payers at least $1.8 billion over 10 years until the expiry of the esketamine patent, part of which can be paid back into the fund. The IVPE + AMC contract can also provide revenues of at least $250 million to a sponsor of the clinical trials for development, FDA-approval, and post-approval (Phase IV) pharmacovigilance studies for ketamine (see Appendix).
Challenge and Opportunity
Patients urgently need more effective treatments that are readily accessible and affordable. For many Americans, treatments are prohibitively scarce or expensive, with an estimated 42% of newly-diagnosed cancer patients losing all of their assets within 2 years. As national health expenditures continue to rise and drug R&D productivity continues to stagnate, it is crucial to rethink private-public alignment by implementing improved incentive design systems to support better health and economic outcomes.
Generic medicines have substantial potential for addressing healthcare costs and improving R&D productivity: low-cost generic drugs saved the U.S. healthcare system $1.67 trillion in the last decade. Thousands of FDA-approved generic drugs—as well as 50,000+ nutraceuticals, plant medicines, diets, lifestyle interventions, and dose de-escalation regimens (collectively known as unmonopolizable therapies)—could be studied to treat diseases significantly cheaper and faster than developing new patented drugs. It costs an estimated $1 billion-plus and takes more than 10–15 years to get a newly patented drug to market, whereas it is significantly cheaper and faster to find new uses for existing drugs and other unmonopolizable therapies that have known safety profiles and mechanisms of action from their use over many years.
However, it is often not economically viable for pharmaceutical companies to pay for clinical trials assessing unmonopolizable therapies, which can be prescribed off-label at relatively low-cost. Generic-drug companies are protected by “skinny labeling” legislation, which makes it difficult or impossible to enforce patents for new uses of generic drugs. While pharmaceutical companies can reformulate generic drugs and re-patent them to charge a monopoly price, this might only be commercially viable if the reformulation is better than the original generic. And where a reformulation involves a combination of generic drugs, compounding pharmacies can prescribe the drug using the original low-cost generics.
Due to this market failure, there is a lack of funding for large and robust clinical trials for such low-cost therapies; the chance of the original formulation of a generic drug obtaining FDA approval for a new use approaches zero when it goes generic. The same problem applies to funding large clinical trials for nutraceuticals, medical diets, lifestyle interventions, and novel dosing regimens, where it is almost impossible to stop doctors and patients accessing these therapies. Patients who desperately need more treatment options are unable to realize the benefits that existing off-patent, unmonopolizable, or low-cost therapies might offer, and there may be significant harm to the public due to such gaps in patent incentives.
Increased direct grant funding for clinical trials can also create suboptimal outcomes. During the height of the COVID-19 pandemic in 2020, the Pepcid AC (famotidine) COVID-19 Study raised red flags weeks after a $21 million grant was awarded to study its effects as a potential therapy. Concerns over study integrity, outcome measures, and even administrative protocols were all brought to light. Ironically, such grant funding can lead to even more risk and wasted taxpayer funds, such as $150 million of federal funding on the dietary supplement curcumin studied in more than 120 clinical trials, with no tangible evidence that it is an effective treatment for any medical condition. Further, conservative estimates of publicly funded clinical trials for repurposing phospholipidosis-inducing CADs to treat COVID-19, including hydroxychloroquine, may be over $6 billion. Other than the large and pragmatic RECOVERY and TOGETHER trials initiated by the United Kingdom, which discovered that dexamethasone significantly reduced mortality in COVID patients on respiratory support, funding smaller, low-powered clinical trials did not lead to the development of significantly beneficial COVID therapies for patients. A risk-transferring market mechanism to fund large clinical trials would have been more efficient—or at least not have exposed taxpayers to the risk of failed clinical trials. IVPE RCTs are paid from cost savings, and AMC contracts only pay out when pre-specified requirements are met, so taxpayers and health insurers do not pay for any failures.
To quickly and affordably improve the lives of millions of patients, we propose that Congress should appropriate, and the Biden-Harris Administration should direct, the NIH, CMS, and VA with the support of the NCATS Repurposing Drugs program, to establish a self-sustaining fund utilizing IVPE RCTs and AMCs to fund clinical trials for affordable therapies generating cost savings (“IVPE + AMC Fund”), using their federal authorization to establish market rewards or “prizes” under the 2010 America Competes Reauthorization Act. Private health insurers are fragmented and have limited incentives to reduce the costs of the $4 trillion p/a US healthcare industry in order to justify the high premiums charged to their US customers, while providers earn more revenue by charging higher fees. However, there is some movement away from fee-for-service and towards PFS contracts and Value Based Pricing (VBP). There is also a significant risk of lawsuits (including personal liability for decisionmakers) under ERISA legislation and the Consolidated Appropriations Act of 2021, which impose a fiduciary duty on self-insured employers to reduce healthcare spend. Taxpayer-funded payers such as CMS, VA, United States Army and large self-insured employers can use IVPE RCTs and AMCs to incentivize development of low-cost therapies as a fiduciary and financial risk management mechanism. Their net cost savings would far exceed the cost of administering the IVPE + AMC Fund.
In particular, IVPE RCTs compare equivalence or superiority of a low-cost repurposed generic drug to an expensive patented drug normally funded by a payer. For example, there was a recent proposal to establish a self-sustaining IVPE fund to determine the optimal minimum dose for expensive oncology drugs to save costs while reducing side-effects. The price difference between the low-cost and expensive intervention can far exceed the cost of running the RCT, which means it pays for itself in cost savings, even if the RCT fails. And if the RCT shows the low-cost treatment provides at least the same standard of care as the patented drug, this can save payers billions of dollars until the patent expires. If some of these cost savings are transferred back into an IVPE + AMC Fund, this will create a scalable business model for developing new low-cost therapies.
The self-sustaining nature of the IVPE + AMC Fund could be demonstrated, for example, by providing market rewards up to $100 million (which can be pooled between federal agencies) to reimburse a sponsor recruiting patients into IVPE trials comparing low-cost and expensive therapies. The reimbursement amount should ideally be less than the cost of the expensive therapy and the resulting guaranteed payer cost savings from the low-cost therapy substituting the expensive therapy could be paid back to increase the size of the fund. The IVPE clinical trial would require ethics approval and provide valuable data to “de-risk” whether the low-cost therapy works, without requiring additional taxpayer support. AMCs then would act as a “pull” mechanism to reward sponsors of large Phase III Randomized Controlled Trials (RCTs) that result in FDA approval with higher reimbursement price for an otherwise low-cost therapy that would substitute the expensive therapy. For example, a sponsor can partner with a generic drug manufacturer to guarantee supply of a repurposed generic in return for sharing revenue under an AMC. The sponsor can then submit bioequivalence and efficacy RCT data under the 505(b)(2) pathway to obtain a new “label” for the new use, which also provides a 3-year period of data exclusivity. Alternatively, a sponsor can leverage the revenue from the AMC to develop a nominal reformulation (e.g. new mechanism of administration or dose) to disincentivize generic substitution and obtain a 5-year period of data exclusivity under the 505(b)(1) New Drug Application pathway. The sponsor can earn additional revenue from the sale of the repurposed generic or RCT data to other healthcare systems, with the payers backing the IVPE + AMC Fund receiving a lower price or royalties. Payer cost savings from substituting an expensive therapy with the lower-cost therapy can be paid back into the IVPE + AMC Fund to ensure long-term sustainability.
AMC contracts are already implemented in various other contexts to address market failures. For example, so-called Social Impact Bonds (SIBs), a type of AMC contract, have been used to help fund projects preventing homelessness and prisoner recidivism, with over $700 million in SIBs raised to date. Operation Warp Speed used AMCs to incentivize vaccine development through FDA approval and lab-to-patient stages. Similar methodologies to IVPE RCTs have also been used to prove that a low dose of bevacizumab (Avastin) could treat age-related macular degeneration rather than patented ranibizumab (Lucentis), which was estimated to save Medicare Part B $18 billion over 10 years.
Therefore, an IVPE + AMC Fund can generate billions of dollars in revenue from payers due to cost savings through the development of new low-cost therapies that reduce reliance on expensive therapies. It can also address misaligned incentives under the patent system by encouraging pharmaceutical companies to (1) “de-link” profits from maximizing sales of a monopoly-priced drug, (2) ensure that patented drugs are value for money rather than pursuing “evergreening” strategies such as patenting slight modifications of generic drugs to extend the period of monopoly pricing, and (3) pursue the most effective therapies rather than the most patentable. AMCs can also be used to incentivize development of low-cost therapies to address unmet medical needs if an expensive comparator treatment is not available or otherwise, the IVPE methodology can compare usual care.
A Market Failure Caused by a Tragedy of the Commons
Thousands of potentially safe and effective off-patent and low-cost therapies are currently ignored due to misaligned incentives under the patent system. Core to this tragedy is that the clinical trial data validating the safety and efficacy of treatment protocols is what is valuable to healthcare payers and patients, not whether the drug’s active ingredient is new. In essence, treatment protocols involving new uses for off-patent and unmonopolizable therapies are nonrivalrous and “highly non-excludable” public goods. The co-author Savva Kerdemelidis’s 2014 master’s thesis concluded that because the patent system provides inadequate incentives for the pharmaceutical industry to develop such “unmonopolizable therapies,” alternative “prize-like” incentives are needed. This allows payers to put a price on clinical trial data validating the efficacy of these new and more affordable treatment protocols.
Scaling the Development of Low-Cost Therapies with IVPE RCTs and AMCs
IVPE RCTs and AMCs (see definition in FAQ section) recognize that the value of a therapeutic intervention is not the cost of an active ingredient but the clinical trial data showing it is safe and effective in a particular patient population. To accelerate the development of unmonopolizable therapies through the clinical and regulatory pipeline, we propose that payers—specifically government agencies such as CMS and VA as well as health insurers responsible for pharmaceutical reimbursement (ideally a consortium of payers)—support IVPE RCT pilots to de-risk early-stage clinical research and the use of AMC contracts through the IVPE + AMC Fund. The AMC will incentivize a sponsor fund the Phase III studies need to obtain FDA approval and conduct post-approval (Phase IV) pharmacovigilance studies. It will be self-sustaining if a percentage of savings from the availability of low-cost therapies is paid back into the IVPE + AMC Fund.
The total amount of outcome payments under an AMC drawn from the IVPE + AMC Fund can be calculated with reference to the level of clinical impact or Quality-Adjusted Life-Years (QALYs) generated, disability-adjusted life-years (DALYs) reduced, or even future cost savings from allowing a low-cost therapy to be substituted for an expensive one or reduce hospitalisation costs. For example, the number of QALYs resulting from an approved unmonopolizable therapy can be calculated in advance by a committee of pharmacoeconomic experts under a similar process to the United Kingdom National Health System’s Subscription-Style-Payment (SSP) model for incentivizing development of new antibiotics. Under an SSP, a fixed amount is paid annually according to the total QALY value of the new therapy, as assessed by an elected, independent Medical Evaluation Committee. Similarly, CMS in Louisiana implemented a “Netflix-subscription” model to guarantee supply of low-cost generic drugs to treat Hepatitis C by agreeing to a fixed annual payment in advance. Pay-for-performance and value-based-payment (VBP) contracts are similar to AMC contracts and often negotiated with payers to provide more cost-effective delivery of healthcare services, where rewards are based on certain conditions being met. Accordingly, using AMC contracts to reward successful RCTs is not a novel mechanism that will require a significant administrative burden for federal agencies to implement. It may only require changing a few sentences in an existing VBP contract to refer to a repurposed generic drug or low-cost therapy.
The following example describes how the IVPE + AMC model works:
- A payer (e.g., CMS) agrees to an IVPE RCT with a sponsor comparing the equivalence or superiority of a repurposed generic drug or low-cost therapy to a patented drug (or expensive standard of care). The payer can reimburse the low-cost therapy at a higher price or per-patient price sufficient to cover the costs of the IVPE RCT. If the higher reimbursement is at a lower price than the patented drug or expensive treatment, it will guarantee cost savings for the payer, even if the RCT fails. If the IVPE RCT is successful, the payer agrees to a AMC worth, say, at least $100 million to purchase a minimum quantity of the repurposed generic drug in advance or reimbursing the sponsor at the higher price, subject to a sponsor obtaining FDA approval and being responsible for post-approval pharmacovigilance. Notably, because the IVPE RCT is funded from immediate cost savings due to the price difference between the low-cost therapy and patented drug, both parties are financially de-risked. (See Appendix 1 for an example of the IVPE + AMC model using the example of generic ketamine vs. patented esketamine to treat depression.)
- The sponsoring pharmaceutical company raises $50 million to conduct the clinical trials needed for FDA approval, on the basis of the agreement to transfer cost savings under the IVPE RCT and the $100 million AMC, subject to FDA approval and post-approval (Phase IV) pharmacovigilance studies showing continued safety and efficacy.
- If the IVPE RCT is successful and the generic drug or low-cost therapy is shown to be equivalent to or better than the expensive patented drug, the AMC is triggered: sponsors are guaranteed minimum sales of $100M and also have a “branded” generic or low-cost therapy with new label and data exclusivity for three years by filing an abbreviated new drug application (ANDA) with the FDA. A new drug application (NDA) with five years of data exclusivity is possible if the generic or low-cost therapy contains a new active ingredient. They can also obtain a method of use patent on the optimal treatment protocol, which provides some commercial benefit and leverage to negotiate AMCs with other payers. A payer’s cost savings from updating their reimbursement guidelines to substitute a low-cost generic drug for the expensive patented drug will exceed the $100 million outcome payments under the AMC, which can be used to top-up the IVPE + AMC Fund to make it self-sustaining. In the case that clinical trials fail, the sponsor loses their investment, unless payers agree to transfer part of their cost savings for the duration of the IVPE RCTs to reimburse the sponsor. This is truly a win-win arrangement to fund new RCTs with very limited commercial risks compared to traditional drug development. The main task is finding repurposed generic drugs or low-cost interventions that could reduce reliance on expensive patented drugs by having at least the same safety and efficacy. There are many low-hanging fruits that are already medically “de-risked” (see generic drug repurposing use cases section below).
Once the repurposed generic or low-cost therapy receives FDA approval and market authorization, the insurer can then market the approved therapy to prescribing medical doctors. Doctors in turn can prescribe the treatment protocol to their patients, who benefit from improved health. Moreover, this payment model that generates revenue from RCT data resulting in costsavings helps redress the conflict of interest and information asymmetry between government and healthcare payers and pharmaceutical companies, who are now incentivized to develop the most effective therapies for the lowest cost.
Financial and Health Impact of the IVPE + AMC Fund
According to the Office of Management and Budget and the Office of Science and Technology Policy, prize competitions benefit the federal government by allowing federal agencies to:
- Pay only for success
- Establish ambitious goals and shift technological and other risks to prize participants
- Increase the number and diversity of individuals, organizations, and teams tackling a problem, including those who have not previously received federal funding
- Increase cost effectiveness, stimulate private-sector investment, and maximize the return on taxpayer dollars
- Motivate and inspire the public to tackle scientific, technical, and societal problems
There are additional reasons why implementing a self-sustaining IVPE + AMC Fund as a prize-like “pull” incentive to reward development of low-cost therapies is more efficient and scalable than providing grant funding or “push” incentives (although the approaches can be complementary and push incentives can be superior when likely outcomes are known to the grantor). First, IVPE RCTs de-risk sponsors if the payer cost savings are shared by ensuring payer reimbursement of the low-cost therapy is sufficient to cover the costs of the RCT. Under an AMC contract, there is a transfer of risk from payers to the market: payers are not willing to take on the risk and expense of large RCTs, the responsibility of marketing to patients and doctors, and managing adverse events or product recalls. In turn, the market is comfortable taking on this risk and expense, as long as investors can obtain a standard rate of return (e.g., 10-20% p/a). Second, payers and government agencies are often not as well-qualified or equipped as the pharmaceutical industry, which has access to the most experienced staff and latest technological advances, including artificial intelligence. Third, grant programs have high administration costs, both for grantors and grantees, while the latter are not incentivized to deliver successful outcomes. By comparison, the markets are incentivized to fail fast and efficiently allocate capital to those best able to deliver results for the lowest cost. Lastly, repurposed off-patent and unmonopolizable therapies could outcompete patented drugs by providing improved health outcomes for a lower cost to payers. Pharmaceutical companies may also benefit from IVPE RCTs and AMC contracts versus developing novel molecules, due to decreased risk, costs, and time to market.
The IVPE + AMC Fund creates a clinical trial data marketplace that incentivizes the funding of large-scale clinical trials of unmonopolizable therapies such as low-cost generic drugs that can result in billions, if not trillions, of dollars in healthcare savings for health insurers and governments and, moreover, provide better treatment options and outcomes for patients. Those cost savings can then be reinvested in additional IVPE + AMC Funds to incentivize further development of treatment protocols. Accordingly, the IVPE + AMC model not only incentivizes investment in unmonopolizable therapies, it can also be used to generate a sustainable and scalable business model for additional investment into low-cost therapies that also help improve access to healthcare in the Global South.
Many Generic Drug Repurposing or Low-Cost Therapy Candidates Exist
Use Case 1: Metastatic Cancer
Hundreds of non-cancer generic drugs have already been tested by researchers and physicians in preclinical and clinical studies for cancer, some up to Phase II trials, and show promise. For example, repurposing the off-patent NSAID ketorolac as a prevention treatment resulting in 10% reduction in breast cancer recurrence would cost $5 million annually (100,000 cases at $50 per case for ketorolac and its administration). The savings could be over $1 billion annually (10,000 patients at approximately $100,000 per patient for the treatment of metastatic disease). These savings would be dwarfed by the cost savings available under an IVPE fund comparing low doses of expensive patented cancer drugs with their standard dose, which can result in fewer side-effects for patients, including nivolumab, abiraterone, trastuzumab, ibrutinib, paclitaxel, and pembrolizumab. The latter (Keytruda) is the top-selling blockbuster drug, with annual sales in excess of $15B; dosing Keytruda by weight could reduce use by 25% in approved indications such as lung cancers.
Use Case 2: Major Depressive Disorder & Treatment-Resistant Depression
Depression is the leading cause of disability in the United States for people between the ages of 15 and 44. An estimated 12-month prevalence of medication-treated major depressive disorder (MDD) in the United States was 8.9 million adults, and 2.8 million had treatment-resistant depression (TRD). A growing body of evidence has shown that infusions of generic ketamine can be a viable and affordable therapy for both forms of depression, which cost the United States over $320 billion in 2018. Generic ketamine has been used as a general anesthetic since the Vietnam War and costs less than $2 per dose. However generic ketamine is not authorized to treat any form of depression. The patented and FDA-approved s-ketamine or esketamine, has a price at $850 per dose and is used for TRD and MDD with suicidal ideation.
To date, many clinical trials show that generic ketamine is more effective. Moreover, a 2020 study indicated that esketamine is unlikely to be cost-effective for management of treatment-resistant depression in the United States unless its price falls by more than 40%. And recently, the UK payer NICE declined to reimburse esketamine. With approximately nine million American adults living with treatment-resistant depression, successfully repurposing generic ketamine using the self-sustaining IVPE + AMC Fund could save many lives through improved access and standard of care—and save healthcare payers hundreds of millions of dollars in monopoly prices.
Plan of Action
The IVPE + AMC Fund can be established through the America COMPETES Reauthorization Act of 2010 (P.L. 111-358), which encourages prize competitions by authorizing the head of any federal agency to carry out a competition that has the potential to stimulate innovation and advance the agency’s mission. In 2016, the 21st Century Cures Act (P.L. 114-255) directed the director of the NIH to support prize competitions that would realize significant advancements in biomedical science or improve health outcomes, especially as they relate to human diseases or conditions. IVPE + AMC contracts can act like a “prize-like” incentive that is designed to address market failures but also lower healthcare treatment costs for federal agencies (e.g., CMS or VA) by incentivizing the discovery and validation of evidence that low-cost interventions such as repurposed generic drugs may be equivalent to or more effective than expensive interventions such as patented drugs.
In short, we propose that the IVPE + AMC Fund be established and operate as follows:
The IVPE + AMC Fund is established through the America COMPETES Reauthorization Act of 2010 (P.L. 111-358) to support backing of IVPE RCTs by payers as a self-funding mechanism and authorize outcome payments of up to $100 million under an AMC for successful clinical trials of a repurposed generic drug, nutraceutical, and/or other low-cost unmonopolizable therapy to treat a specific indication of high unmet medical need and cost burden (e.g. cancer, treatment resistant depression, glioblastoma, Crohn’s Disease, Alzheimer’s).
The IVPE + AMC Fund is furthermore supported by Section 2002 of The 21st Century Cures Act (Division A of P.L. 114-255), which requires the director of the NIH, under authorities in 15 U.S.C. §3719, to support prize competitions for one or both of the following goals:
- Identify and fund areas of biomedical science that could realize significant advancements through a prize competition; and
- Improve health outcomes, particularly with respect to human diseases and conditions that are serious and represent a significant disease burden in the United States. The prize competition may also target human diseases and conditions for which public and private investment in research is disproportionately small relative to federal government expenditures for prevention and treatment activities and those diseases and conditions with potential for a significant return on investment via reduction in federal expenditures.
The director of the NIH elects a Medical Evaluation Board, which oversees and manages the prize purpose held by the IVPE + AMC Fund as follows:
- Determining the minimum reimbursement price to sponsors for patients receiving a low-cost therapy under an IVPE RCT which is less than the price of an expensive patented drug or intervention that it substitutes. Then determine the minimum purchase order or outcome payments under an AMC contract relative to total QALY / DALY improvement or cost savings, subject to large Phase 3 RCTs resulting in FDA-approval of the low-cost therapy, and further subject to ongoing safety and efficacy shown in Phase 4 pharmacovigilance studies.
- The Medical Evaluation Board will be required to collect information on the effect of the IVPE + AMC Fund on advancing biomedical science or improving health outcomes and the effect of the innovations on federal expenditures.
Initially, we propose that Congress should fund the NIH with $2 million to establish a pilot IVPE + AMC Fund program in partnership with the NIH Office of Acquisition Management and Planning and NCATS. The focus of this would be to create a menu of “de-risked” low-cost therapies suitable for reimbursement under an IVPE + AMC Fund, and feasibility studies to show projected cost savings for payers such as CMS and VA and patient access benefits based on existing NCATS translational efforts, including generic drugs or dose de-escalation interventions by comparing them to expensive patented interventions under the IVPE model. For example, for treatment of age-related macular degeneration, generic drugs such as bevacizumab (Avastin) could save Medicare Part B $18 billion over 10 years compared with ranibizumab (Lucentis). Or compare the cost of prescribing the generic fluvoxamine to treat Covid at $6000 per QALY with molnupiravir at $55,000 per QALY, substituting sirolimus for nab-sirolumus to treat locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumors (PEComa), or substituting sirolimus for everolimus in various cancers. Significant cost savings from IVPE RCT de-escalation studies comparing a lower dose of an expensive cancer drug to the standard treatment can fund the development of new unmonopolizable therapies. For example, this includes savings from low-dose nivolumab for head and neck cancer, low-dose abiraterone, and trastuzumab, ibrutinib, paclitaxel, and pembrolizumab for various other cancers, as noted above. The key to this pilot would be a sufficient evidence-based evaluation process to generate a menu of low-cost IVPE use cases. Ideally, at scale the IVPE + AMC Fund would cover a wide expanse of market failures, but we recommend the low-hanging fruit of repurposing generic drugs and dose de-escalation studies for specialist oncology drugs before expanding to other types of unmonopolizable therapies, including medical diets such as ketogenic diet, non-pharmaceutical, and lifestyle interventions that can reduce reliance on expensive therapies.
Conclusion
An IVPE + AMC Fund established under the America COMPETES Act can provide a more flexible, self-sustaining and cost-effective payment model for developing affordable and effective medical therapies, as opposed to the pharmaceutical industry’s traditional model of charging a monopoly price for new patented drugs. Establishing IVPE RCTs that compare low-cost treatments with expensive treatments generates immediate cost savings for payers from reduced reliance on monopoly-priced drugs as well as future cost savings if clinical guidelines are updated to recommend the low-cost treatment. AMC contracts incentivize FDA-approval and help correct misaligned incentives under the patent system by ensuring rewards are de-linked from maximizing the sales of a single monopoly-priced drug.
If our proposed self-sustaining IVPE + AMC Fund can be implemented, this will create new incentives to leverage the biotech innovations of the last 40 years and optimize the efficient delivery of healthcare, including genetic engineering, personalized medicine (informed by blood tests and low-cost DNA sequencing), artificial intelligence, decentralized clinical trials, and telemedicine. The pharmaceutical industry is not to blame if they can only rely on the patent system to obtain a return on investment for funding medical innovation. New outcomes-based payment models are needed to develop more affordable and effective treatments that can pull the practice of medicine into the 21st century and address significant health inequities.
Appendix
IVPE RCT + AMC Financial Model Example
This IVPE RCT + AMC financial model uses generic ketamine and patented esketamine as an example of how to leverage immediate and future cost savings by comparing a low-cost intervention to an expensive intervention to incentivize funding of RCTs for unmonopolizable therapies.
Advanced market commitments are a type of pay-for-success contract that guarantees a viable market for a product once it is successfully developed. Harvard economist Michael Kremer was the first to propose AMCs to stimulate private sector investment in innovations undersupplied by the market. In 2005, global foundations supported the creation of a detailed proposal by the Center for Global Development that described how an AMC might be structured. In 2009, the first AMC was launched, with $1.5 billion in funding for vaccines for diseases primarily affecting people living in poverty. Three vaccines have since been developed and more than 150 million children immunized, saving an estimated 700,000 lives.
Drug pricing can stay uniform if differential pricing is not permitted. Outcome payments under an AMC can be in the nature of a fixed annual “Netflix” subscription-style payment for the RCT data showing that the repurposed generic is safe and effective for the indication, and can be “de-linked” from sales of a drug. Alternatively, if differential pricing is permitted under applicable regulations and policy, then the repurposed generic drug could be priced higher in the new indication under an AMC.
Some of the most widely used prominent repurposed drugs include the following (not exhaustive):
| Drug name | Original indication | Disease name |
|---|---|---|
| Aspirin | Analgesia | Colorectal cancer |
| Gemcitabine | Antiviral | Cancer |
| Raloxifene | Osteoporosis | Breast cancer |
| Sildenafil | Angina | Erectile dysfunction |
Off-label drug use is when drugs are prescribed for a condition, a type of patient, or a dosage not officially approved by the FDA, which can be 20% of all prescriptions. Off-label drug use is generally not backed by the level of testing and data that allows FDA approvals, so patients do not have the guides and warnings that come from FDA-approved labels. Doctors and patients therefore do not always have enough information about the effects and dangers of the off-label use of the drug to make informed decisions. This can create a situation where patients are unknowingly at risk for dangerous, unexpected side effects. This validates the need for large Phase 3 RCTs to prove that drugs prescribed off-label can be prescribed for a new indication and granted a new label for that indication. In addition, health insurers often do not reimburse off-label use, which means patients are forced to pay out of pocket.
Large health insurers, particularly in the United States, often own hospitals and are not incentivized to reduce healthcare costs. This model will become unsustainable due to an aging baby boomer population and insurance premiums increasing faster than wages. To avoid this situation, payers have started to implement more outcomes-based contracts such as value-based pricing and bundled payments to incentivize innovation that reduces healthcare costs. Similarly, payers can agree to support IVPE RCTs to clinically validate a low-cost off-patent intervention by comparing it to an expensive patented intervention or paying an amount representing future cost savings or QALY gains for repurposing a generic drug under an AMC contract. Currently, payers do not put a price on the clinical trial data or treatment protocol information about which generic drug works in a new disease and the optimal dose, but only pay the marginal cost of the generic drug as a chemical. This is like only paying an electrician for the cost of a new $1 part, rather than for the knowledge of the specific part needed to fix an electrical fault, which is the valuable information that takes years of experience and would save your business thousands of dollars or more.
Repurposed generic drugs and unmonopolizable therapies such as nutraceuticals are de-risked because they have years of efficacy and safety data from successful Phase 1 safety trials and post-marketing Phase IV data in the case of generic drugs and being generally recognized as safe (GRAS) compounds in the case of nutraceuticals. IVPE RCTs de-risk early clinical trials, and an AMC would incentivize scale-up of supply of the repurposed generic drug and encourage sponsors to train doctors and patients to ensure more rapid uptake of this innovation.
Under an AMC, there can be a fixed annual payment or minimum sales commitment calculated with reference to determination of cost savings from substitution with expensive patented drugs and/or QALYs gained, similar to the subscription-style payment model for antibiotics in the NHS. The AMC means that the sponsor would also benefit from additional sales of the “branded” generic drug, so they would be incentivized to monitor its use and conduct standard Phase IV pharmacovigilance (and can also be liable for adverse events and recalls). Moreover, payer cost savings from the IVPE + AMC Fund program would far exceed the cost of monitoring or administrative burden.
Other than benefitting from immediate cost savings due to reduced reliance on expensive patented drugs, payers backing an AMC can negotiate a favorable price and guaranteed supply of the “branded” generic drug from the sponsor, whereas other payers would be forced to use an off-label version and expose doctors and patients to increased risk of liability. Sponsors would benefit from outcome payments under the AMC and additional sales of the “branded” generic. They can also leverage data exclusivity and traditional patent rights such as method-of-use patent for the optimal treatment protocol and reformulations to negotiate similar AMCs with other payers and also reduce the risk of generic off-label competition. The more payers backing the IVPE + AMC model, the more costsavings can be shared with free-riding. RCT data regarding optimal treatment protocols informed by genetic testing and other diagnostics can also be commercialized as a clinical decision support tool and trade secret. It is the intention of the authors to support the establishment of Public Good Pharma as a biotech company and clinical trial data marketplace owned by the charity Crowd Funded Cures, to carry out this business model.
The U.S. government should establish a public-private National Exposome Project (NEP) to generate benchmark human exposure levels for the ~80,000 chemicals to which Americans are regularly exposed.
The federal government is responsible for ensuring the safety and privacy of the processing of personally identifiable information within commercially available information used for the development and deployment of artificial intelligence systems
The United States is in the midst of a once in a generation effort to rebuild its transportation and mobility systems. Meeting this moment will require bold investments in new and emerging transportation technologies.
Employee ownership is a powerful solution that preserves local business ownership, protects supply chains, creates quality jobs, and grows the household balance sheets of American workers and their families.