Proposing an NIH High-Leverage Trials (HILT) Program

Introduction: An Opportunity in Plain Sight

While the US pharmaceutical industry excels at developing novel, patentable compounds, world-class trials of low-exclusivity treatments, such as dietary supplements and off-patent medications, are pursued neither by industry nor the NIH. In addition to missing opportunities to improve health for all Americans, this trial gap costs the public and the federal government hundreds of billions of dollars a year.

Because supplements and off-patent medications do not have economic mechanisms that lead pharmaceutical companies to run Phase III trials, there is an urgent need to develop reliable, large-scale evidence so that patients and providers can access these treatments.

Americans currently spend ~$70 billion annually on supplements, often acting on fragmented or inconclusive data. Simultaneously, hundreds of off-patent medications with known safety profiles sit on the shelf, untested for new indications because manufacturers do not have the legal exclusivity needed to justify the cost of large, conclusive Phase III trials, even in areas of very high unmet need.

"For drugs and therapies on patent, a patent holder has a strong interest in running randomized evaluations and navigating the drug through the FDA's approval process. By contrast, for drugs and therapies with no patent holder, no one has much interest in funding expensive randomized trials or working assiduously to move through the FDA regulatory process for rapid approval (or even slow approval)."

Jay Bhattacharya, Senate Testimony, 2020

To solve this gap and open up new treatments and dramatic cost savings, we propose the creation of an NIH High-Leverage Trials (HILT) Program for off-patent drug repurposing and supplements. HILT would fund and run definitive large scale trials and, when appropriate, advance regulatory approvals to ensure broad patient access.

Cutting Waste

There are already scattered examples that demonstrate the cost-saving potential of NIH running trials that industry players will not study.

In 2008, the National Eye Institute (NEI) funded the Comparison of AMD Treatments Trials (CATT) to compare Lucentis (macular degeneration treatment costing ~$2,000 per dose) vs Avastin (a structurally similar treatment, also under patent, but costing ~$50 per dose for this use). This is the type of head-to-head comparison that no commercial player had an incentive to run. The trial showed both drugs were equally effective, which transformed prescribing practices toward bevacizumab and OCT-guided therapy, and resulted in cumulative savings for Medicare Part B estimated at $40 billion (for context, NIH's entire annual budget is ~$50B).

By selecting trials with similar potential for high economic impact, HILT could generate savings for the general public, private payers, and public payers that would pay for itself many times over.

Improving Safety

Supplements are lightly regulated, which has both benefits and risks for patients. Access is generally good but high quality research is thin. A 2015 study showed that adverse events related to dietary supplements cause approximately 23,000 emergency department visits annually. Large-scale safety and efficacy trials on supplements will help guide the public towards safer and more effective supplements and clarify effective dose levels.

HILT would not promote supplements or repurposed drugs, but rather generate transparent and high-quality evidence, whether that evidence is positive, negative, or safety related. In high-risk contexts (such as probiotics in preterm infants), regulators have raised concerns about product quality and potential infectious complications, even though there are also potential indications of benefits. Well designed, large-scale trials can resolve safety and efficacy questions while offering clarity on dosing and quality.

Better Treatments

When a prescription medication approaches the end of its patent and exclusivity life, research investment vanishes, even if the drug has lots of promise for additional uses. Budish, Durvasula, et al. recently quantified this repurposing gap, demonstrating that the loss of exclusivity for a medicine leads to a near-total cessation of clinical trials for new indications, due to the collapse of private incentives (other research concurs).

Figure 1

Source: Budish, Durvasula, et al. (2024)

The market fails because these trials are very expensive, and even if the trial is successful and the company gets a 3-year indication-specific labelling exclusivity from the FDA (505(b)(2)), they cannot prevent other generic versions of the drug from being prescribed off-label for this new indication, which kills their potential profits. Therefore no private companies invest in these trials.

Their modeling of the repurposing cliff estimates that loss of exclusivity has resulted in 200-800 missing new uses for existing drugs. The authors calculate that the social cost of these lost opportunities is on the order of several trillion dollars. This market failure leaves patients with higher-risk or lower-efficacy products while potentially superior low-cost treatments are never tested and therefore never available or covered for patients. Solving this gap would bring new treatments to patients with dramatically lower costs and increased safety.

Creating a Solution

HILT will function as a funding, research, and regulatory advancement body, modeled in part on the successful Best Pharmaceuticals for Children Act (BPCA), in which NIH (via NICHD/PTN) identifies off-patent drugs, funds or sponsors trials, and submits findings to FDA for label changes. HILT would be an adult-population analog for supplements and off-patent therapeutics. HILT would build on and coordinate with existing NIH efforts (e.g., ODS and NCATS) while adding standing Phase III operations and end-to-end translation capacity (FDA + payer alignment).

HILT will:

• Generate "gold standard" evidence by moving promising unpatented compounds through large, well-designed Phase III trials.
• Define and study dosing and reference standards for supplements in trials, to provide clear consumer guidance and ensure that trial results are actionable.
• Validate low-cost alternatives to expensive therapeutics, providing the data necessary for CMS and private payers to reimburse cost-effective treatments.
• Serve as the non-commercial IND holder as needed, navigating regulatory pathways to enable access and coverage for patients.

Crucially, HILT would not increase or alter regulatory burdens on the private sector. Instead, it fills a void that the industry is not able to address, providing cost savings and better treatments to all Americans.

Mission and Operations

To accomplish its mission, HILT would:

• Develop staff and organizational expertise in the identification of supplements and off-patent medicines with a high expected-ROI from advancing large scale trials.
• Take advantage of extensive real-world safety data for many supplements and repurposed medications to design and fund or co-fund clinical trials with dramatically lower cost structures (e.g., telehealth-based designs).
• Create internal research programs and develop expertise in the unique economic and IP dynamics of supplements and off-patent therapeutics.
• Provide grant funding to non-commercial efforts to run trials with the ability to operate in the role of a program 'sponsor' in advancing trials and navigating existing regulatory pathways at the FDA.
• Establish partnership programs with industry to provide strategic or complementary funding that enables privately run large-scale trials.
• Collaborate with other NIH Institutes and programs to draw on disease-specific expertise when evaluating opportunities.
• Identify opportunities to run large-scale head-to-head trials (e.g., comparing multiple generic SSRIs or different forms of Vitamin D) that industry is often disincentivized from running. Precedents here include BPCA, Pediatric Trials Network, and PCORI.
• Launch research and develop expertise in quality testing and contaminants. Fund and publish methods, partner with established third-party certifiers (USP, NSF) and standards bodies, and create data standards.
• Align evidence generation with payer coverage to ensure patient access and availability.

Creation of HILT would likely build on and coordinate with existing programs at NIH's Office of Dietary Supplements (ODS) and NCATS's repurposing programs. These existing efforts provide benefits to patients but are not positioned to advance research through large scale trials and ensure that scientific, patient, consumer, manufacturer, prescriber, and payer incentives are aligned end-to-end.

Program Scale and Economics

HILT's goal is to minimize cost per decisive answer by focusing on compounds with extensive human safety history and by using pragmatic, embedded, and decentralized trial designs when possible. Compared with traditional pivotal drug development, which requires expensive infrastructure to evaluate the safety of novel compounds, this enables definitive trials to be run at substantially lower costs while preserving rigor.

HILT will be evaluated on output and outcomes: trials launched, cost per answer, downstream changes in coverage/labeling, new indications approved, impacts on consumer supplement spending patterns, and measured payer savings where utilization shifts to lower-cost generic options.

Establishing Legislation and Positioning for HILT

To be successful, the capabilities of HILT program should include:

• A permanent program office with staff aligned towards ROI and cost-per-decisive-answer (rather than a more traditional disease-area publication focus).
• Capacity to run Phase III pivotal trials with an orientation towards innovation on cost and approach, taking advantage of the advantageous safety data available for most of these candidates. This will require standing trial-operations capacity along with flexibility for external grantmaking, as appropriate.
• Regulatory capacity to act as a drug sponsor, including FDA engagement and submission. For successful therapeutics, the goal should be to achieve patient access and coverage, not simply publish evidence. The program should coordinate with CMS and private payers so evidence generation is aligned to eventual coverage decisions.

There are several ways that this program could be created and positioned for success within NIH:

• Expand BPCA: Expand BPCA authorities beyond pediatrics to a) cover repurposing research at all ages and b) add a focus on supplements. Potentially a straightforward political path that builds on the success of BPCA.
• New Institute: Create a new NIH institute, perhaps a National Institute of Supplements and Repurposing (NISAR). This would be a strong home for the program, enabling institutional capacity and expertise to develop and would potentially absorb some existing NIH programs. However, it may be a bigger lift politically.
• New NIH Center: Establish a joint Center for Supplements and Repurposed Therapeutics within NIH co-led by ODS and NCATS, with a dedicated budget line and explicit authority to a) act as non-commercial sponsor / IND holder, and b) submit data to FDA to support label changes or qualified claims.

Other pathways to establishing and situating this program are also possible.

Opportunities for Dramatically Cheaper Clinical Trials

Supplements and off-patent medications often have decades of public use and well understood safety profiles. This is a massive advantage relative to new drugs following the typical biotech and pharma approval pathway. Because extensive real-world safety history and/or previous pivotal trials reduce safety uncertainty, clinical trials for new indications have multiple opportunities to succeed at lower costs.

In collaboration with the FDA, HILT can develop experience and expertise in novel trial design models that are rare in traditional drug development. This will increase the speed and cost efficiency of HILT's programs and, as importantly, will create models for running Phase III trials more efficiently. Pharmaceutical development is a highly risk-averse industry and avoids innovation in pivotal trials to reduce regulatory complexity and risks of failure. Pharma is much more likely to pursue lower cost trial innovations at Phase III if precedents are demonstrated. HILT would be perfectly positioned to play this role.

Strategies for cost efficient clinical trials may include:

1. Embedded EHR-based randomized trials (RRCTs). This approach runs a trial "inside" routine health care. Patients are randomized within large health systems or networks, and most outcomes are pulled automatically from existing electronic health records and insurance claims (like hospitalizations or medication changes), rather than collecting lots of additional study-specific data for each patient at each site. This approach can help test repurposed drugs or supplements in real-world care. NIH's Collaboratory already has practical guides that show how to design and run these trials.
2. Decentralized telehealth trials. Patients interact remotely with trial staff and receive study medicines by mail or at local pharmacies. This avoids the massive per-patient costs charged by clinical research facilities -- costs that often make up the majority of a clinical trial program budget. Several large decentralized trials demonstrated feasibility of this model during the pandemic lockdowns, but pharma has been hesitant to pursue this model due to high risk-aversion.
3. Multi-arm, multi-stage (MAMS) or platform trials with shared controls. Compare several generic medications within an indication in one platform, drop futility arms early (for example, head-to-head SSRI or supplement trials). A single master protocol lets you reuse the same operational setup and monitoring for many comparisons.
4. Factorial designs to disentangle combos. 2x2 or 2x2x2 designs can test components and interactions without dramatically scaling participant numbers, for example, in migraine or metabolic supplement combinations.
5. Cluster/stepped-wedge trials. Trials where the unit is a setting rather than a participant. For example, to study artificial food dyes in schools, randomize schools or districts, rotate implementation (stepped-wedge), and use validated classroom behavior metrics. Can be much cheaper than typical site-based RCTs.
6. Coverage-with-Evidence Development (CED). For candidates with plausible payer coverage, co-design outcomes with CMS/private payers so positive trials can flow into CED or coverage updates.
7. Create a BPCA-style priority list. Formalize a "HILT priority list" for adult therapeutics (mirroring BPCA §409I), publish targets annually, and collaborate with FDA on trial and evidence pathways. EveryCure is a non-profit leader in therapeutic repurposing and has a multi-year contract with ARPA-H. They may be in a position to advise on trial opportunities and priority decision making.

HILT Is Distinct from Existing Agencies and Programs

HILT's role of bringing supplements and off-patent medications through Phase III trials and potentially regulatory approval is not accomplished by existing programs.

• BPCA (Best Pharmaceuticals for Children Act, NIH/NICHD & Pediatric Trials Network): an important pediatric-only precedent in which NIH identifies priority off-patent drugs, sponsors or funds studies, and supports FDA label updates. BPCA is limited to children and repurposed therapeutics, whereas the goal of HILT is to expand these mechanisms to adults, include supplements, and pursue larger trials for novel indications.
• ODS (NIH): coordinates supplement research, funds methods/standards (AMRM), databases (DSLD/DSID), and co-funds grants, but it's not set up to run or sponsor phase-3-scale trials nor to pursue label changes. Without these functions, it has limited impact for patients.
• FDA exclusivity programs: existing FDA incentive mechanisms which apply to non-patented drugs, such as the 3-year exclusivity for new clinical investigations, and 7-year orphan exclusivity, are insufficient and, as empirical studies clearly show, have not been able to address the repurposing gap.
• NCCIH & the NIH Pragmatic Trials Collaboratory: this work focuses on pragmatic trial methods and embedded trials across health systems, not a vertical mission to take supplements/off-patents through labeling or payer alignment.
• NCATS: has repurposing programs (e.g., New Therapeutic Uses) and convened an FDA workshop on off-patent repurposing that highlighted the lack of ROI for off-patents, but NCATS does not run a standing program to sponsor and complete large scale trials for generics or supplements.
• PCORI: comparative-effectiveness mission is complementary, but its scope is not designed to sponsor pivotal efficacy trials intended to establish new indications.
• AHRQ: generates evidence via systematic reviews and methods for comparative effectiveness through the Effective Health Care Program, not by sponsoring interventional trials to labeling.
• VA Cooperative Studies Program (CSP) runs large multicenter trials, but its remit is Veteran-focused and not organized around supplements/off-patent therapeutics or market-access alignment for the general US population.

Questions and Answers

Example Trials HILT Could Pursue