Clearing the Path for New Uses for Generic Drugs

The labeling-only 505(b)(2) NDA pathway for non-manufacturers to seek FDA approval

Repurposing generic drugs as new treatments for life-threatening diseases is an exciting yet largely overlooked opportunity due to a lack of market-driven incentives. The low profit margins for generic drugs mean that pharmaceutical companies rarely invest in research, regulatory efforts, and marketing for new uses. Nonprofit organizations and other non-commercial non-manufacturers are increasing efforts to repurpose widely available generic drugs and rapidly expand affordable treatment options for patients. However, these non-manufacturers find it difficult to obtain regulatory approval in the U.S. They face significant challenges in using the existing approval pathways, specifically in: 1) providing the FDA with required chemistry, manufacturing, and controls (CMC) data, 2) providing the FDA with product samples, and 3) conducting post-marketing surveillance. Without a straightforward path for approval and updating drug labeling, non-manufacturers have relied on off-label use of repurposed drugs to drive uptake. This practice results in outdated labeling for generics and hinders widespread clinical adoption, limiting patient access to these potentially life-saving treatments. 

To encourage greater adoption of generic drugs in clinical practice – that is, to encourage the repurposing of these drugs – the FDA should implement a dedicated regulatory pathway for non-manufacturers to seek approval of new indications for repurposed generic drugs. A potential solution is an extension of the existing 505(b)(2) new drug application (NDA) approval pathway. This extension, the “labeling-only” 505(b)(2) NDA, would be a dedicated pathway for non-manufacturers to seek FDA approval of new indications for well-established small molecule drugs when multiple generic products are already available. The labeling-only 505(b)(2) pathway would be applicable for repurposing drugs for any disease. Creating a regulatory pathway for non-manufacturers would unlock access to innovative therapies and enable the public to benefit from the enormous potential of low-cost generic drugs.

Challenge and Opportunity

The opportunity for generic drug repurposing

On-patent, branded drugs are often unaffordable for Americans. Due to the high cost of care, 42% of patients in the U.S. exhaust their life savings within two years of a cancer diagnosis. Generic drug repurposing – the process of finding new uses for FDA-approved generic drugs – is a major opportunity to quickly create low-cost and accessible treatment options for many diseases. In oncology, hundreds of generic drugs approved for non-cancer uses have been tested as cancer treatments in published preclinical and clinical studies. 

The untapped potential for generic drug repurposing in cancer and other diseases is not being realized because of the lack of market incentives. Pharmaceutical companies are primarily focused on de novo drug development to create new molecular and chemical entities. Typically, pharmaceutical companies will invest in repurposing only when the drugs are protected by patents or statutory market exclusivities, or when modification to the drugs can create new patent protection or exclusivities (e.g., through new formulations, dosage forms, or routes of administration). Once patents and exclusivities expire, the introduction of generic drugs creates competition in the marketplace. Generics can be up to 80-85% less expensive than their branded counterparts, driving down overall drug prices. The steep decline in prices means that pharmaceutical companies have little motivation to invest in research and marketing for new uses of off-patent drugs, and this loss of interest often starts in the years preceding generic entry.

In theory, pharmaceutical companies could repurpose generics without changing the drugs and apply for method-of-use patents, which should provide exclusivity for new indications and the potential for higher pricing. However, due to substitution of generic drugs at the pharmacy level, method-of-use patents are of little to no practical value when there are already therapeutically equivalent products on the market. Pharmacists can dispense a generic version instead of the patent-protected drug product, even if the substituted generic does not have the specific indication in its labeling. Currently, nearly all U.S. states permit substitution by the pharmacy, and over a third have regulations that require generic substitution when available.

Nonprofits like Reboot Rx and other non-commercial non-manufacturers are therefore stepping in to advance the use of repurposed generic drugs across many diseases. Non-manufacturers, which do not manufacture or distribute drugs, aim to ensure there is substantial evidence for new indications of generic drugs and then advocate for their clinical use. Regulatory approval would accelerate adoption. However, even with substantial evidence to support regulatory review, non-manufacturers find it difficult or impossible to seek approval for new indications of generic drugs. There is no straightforward pathway to do so within the current U.S. regulatory framework without offering a specific, manufactured version of the drug. This challenge is not unique to the U.S.; recent efforts in the European Union (EU) have sought to address the regulatory gap. In the 2023 EU reform of pharmaceutical legislation, Article 48 is currently under review by the European Parliament as a potential solution to allow nonprofit entities to spearhead submissions for the approval of new indications for authorized medicinal products with the European Medicines Agency. To maximize the patient impact of generic drugs in America, non-manufacturers should be able to drive updates to FDA drug labeling, enabling widespread clinical adoption of repurposed drugs in a formal, predictable, and systematic manner.

The importance of FDA approval

Drugs that are FDA-approved can be prescribed for any indication not listed on the product labeling, often referred to as “off-label use”. Since non-manufacturers face significant challenges pursuing regulatory approval for new indications, they often must rely on advocating for off-label use of repurposed drugs.

While off-label use is widely accepted and helpful for specific circumstances, there are significant advantages to having FDA approval of new drug indications included in labeling. FDA drug labeling is intended to contain up-to-date information about drug products and ensures that the necessary conditions of use (including dosing, warnings, and precautions) are communicated for the specific indications. It is the primary authoritative source for making informed treatment decisions and is heavily valued by the medical community. Approval may increase the likelihood of uptake by clinical guidelines, pathways systems, and healthcare payers. Indications with FDA approval may generate greater awareness of the treatment options, leading to a broader and more rapid impact on clinical practice. 

Clinical practice guidelines are often the leading authority for prescribers and patients regarding off-label use. In oncology, for example, the National Comprehensive Cancer Network (NCCN) Guidelines are commonly used guidelines that include many off-label uses. However, guidelines do not exist for every disease and medical specialty, which can make it more difficult to gain acceptance for off-label uses. The Centers for Medicare and Medicaid Services (CMS) policy routinely covers off-label drug uses if they are listed in certain compendia. The NCCN Compendia, which is based on the NCCN Guidelines, is the only accepted compendium that is disease-specific.

Off-label use requires more effort from individual prescribers and patients to independently evaluate new drug data, thereby slowing uptake of the treatments. This can be especially difficult for community-based physicians, who need to remain up-to-date on new treatment options across many diseases. Off-label prescribing can also introduce medico-legal risks, such as malpractice. These burdens and risks limit off-label prescribing, even when there is supportive evidence for the new uses.

As new uses for generic drugs are discovered, it is crucial to update the labeling to ensure alignment with current clinical practice. Outdated generic drug labeling means that prescribers and patients may not have access to all the necessary information to understand the full risk-benefit profile. Americans deserve to have access to all effective treatment options – especially low-cost and widely available generic drugs that could help mitigate the financial toxicity and health inequities faced by many patients. For the public benefit, the FDA should support approaches that remove regulatory barriers for non-manufacturers and modernize drug labeling.

Existing pathways for manufacturers to obtain FDA approval 

The current FDA approval system is based on the idea that sponsors have discrete physical drug products. Traditionally, sponsors seeking FDA approval are pharmaceutical companies or drug manufacturers that intend to produce (or contract for production), distribute, and sell the finished drug product. For the purposes of FDA regulation, “drug” refers to a substance intended for use in the treatment or prevention of disease; “drug product” is the final dosage form that contains a drug substance and inactive ingredients made and sold by a specific manufacturer. One drug can be present on the market in multiple drug products. In the current regulatory framework, drug products are approved through one of the following:

Manufacturers can add new indications to their approved labeling without modifying the drug product through existing pathways. With supportive clinical evidence for the new indication, the NDA holder can file a supplemental NDA (sNDA), while an ANDA holder may submit a 505(b)(2) NDA as a supplement to their existing ANDA. As previously discussed, the drug product will likely be subject to pharmacy-level substitution with any available therapeutically equivalent generic. The marketing exclusivities that sponsors may receive from the FDA do not protect against this substitution. Therefore, these pathways are rarely, if ever, used by pharmaceutical companies when there are already multiple generic manufacturers of the product. 

Challenges for non-manufacturers in using existing pathways

Since manufacturers are not incentivized to seek regulatory approval for new indications, labeling changes are more likely to happen if driven by non-manufacturers. Yet non-manufacturers face significant challenges in utilizing the existing regulatory pathways. Sponsors must submit the following information for all NDAs for the FDA’s review: 1) clinical and nonclinical data on the safety and effectiveness of the drug for the proposed indication; 2) the proposed labeling; and 3) chemistry, manufacturing, and controls (CMC) data describing the methods of manufacturing and the controls to maintain the drug product’s quality. 

To submit and maintain NDAs, non-manufacturer sponsors would need to address the following challenges: 

  1. Providing the FDA with required CMC data. NDA sponsors must provide CMC data for FDA review. Non-manufacturers would not produce physical drug products, and therefore they would not have information on the manufacturing process. 
  2. Providing the FDA with product samples. If requested, NDA sponsors must have the drug products and other samples (e.g., drug substances or reference standards) available to support the FDA review process and must make available for inspection the facilities where the drug substances and drug products are manufactured. Non-manufacturers would not have physical drug products to provide as samples, the capabilities to produce them, or access to the facilities where they are made. 
  3. Conducting post-marketing surveillance. Post-marketing responsibilities to maintain an NDA include conducting annual safety reporting and maintaining a toll-free number for the public to call with questions or concerns. Non-manufacturers, such as small nonprofits, may not have the bandwidth or resources to meet these requirements.

Within the current statutory framework, a non-manufacturer could sponsor a 505(b)(2) NDA to obtain approval of a new indication by partnering with a current manufacturer of the drug – either an NDA or ANDA holder. The manufacturer would help meet the technical requirements of the 505(b)(2) application that the non-manufacturer could not fulfill independently. Through this partnership, the non-manufacturer would acquire the CMC data and physical drug product samples from the manufacturer and rely on the manufacturer’s facilities to fulfill FDA inspection and quality requirements.

Once approved, the 505(b)(2) NDA would create a new drug product with indication-specific labeling, even though the product would be identical to an existing product under a previous NDA or ANDA. The 505(b)(2) NDA would then be tied to the specific manufacturer due to the use of their CMC data, and that manufacturer would be responsible for producing and distributing the drug product for the new indication.

As a practical matter, this pathway is rarely attainable. Manufacturers of marketed drug products, particularly generic drug manufacturers, lack the incentives needed to partner with non-manufacturers. Manufacturers may not want to provide their CMC data or samples because it may prompt FDA inspection of their facilities, require an update to their CMC information, or open the door to product liability risks. The existing incentive structure strongly discourages generic drug manufacturers from expending any additional resources on researching new uses or making any changes to their product labeling that would deviate from the original RLD product. 

Plan of Action 

To modernize drug labeling and enhance clinical adoption of generic drugs, the FDA should implement a dedicated regulatory pathway for non-manufacturers to seek approval of new indications for repurposed generic drugs. Ultimately, such a pathway would enable drug repurposing and be a crucial step toward equitable healthcare access for Americans. We propose a potential solution – a “labeling-only” 505(b)(2) NDA – as an extension of the existing 505(b)(2) approval pathway. 

Overview of the proposed labeling-only 505(b)(2) NDA pathway 

The labeling-only 505(b)(2) NDA would enable non-manufacturers to reference CMC information from previous FDA determinations and, when necessary, provide the FDA with samples of commercially available drug products. Through this approach, the new indication would not be tied to a specific drug product made by one manufacturer. There is no inherent necessity for a new indication of a generic drug to be exclusively linked to a single manufacturer or drug product when the FDA has already approved multiple therapeutically equivalent generic drugs. Any of these interchangeable drug products would be considered equally safe and effective for the new indication, and patients could receive any of these drug products due to pharmacy-level substitution. 

We describe non-manufacturer repurposing sponsors as entities that intend to submit or reference clinical data through a labeling-only 505(b)(2) NDA. This pathway is designed to expand the FDA-approved labeling of generic drugs for new indications, including those that may already be considered the standard of care. Non-manufacturers do not have the means to independently produce or distribute drug products. Instead, they intend to show that there is substantial evidence to support the new use through FDA approval, and then advocate for the indication in clinical practice. This evidence may be based on their research or research performed by other entities, including clinical trials and real-world data analyses.

The labeling-only 505(b)(2) NDA pathway helps address the three major challenges non-manufacturers face in pursuing regulatory approval. Through this pathway, non-manufacturers would be able to: 

  1. Reference the FDA’s previous determinations on CMC data. Currently, a 505(b)(2) NDA can reference the FDA’s previous determinations of safety and effectiveness for an approved drug product. For eligible generic drugs, the labeling-only 505(b)(2) NDA would build on this practice by allowing non-manufacturer sponsors to reference the FDA’s previous determinations on any NDA or ANDA that the manufacturing process and CMC data are adequate to meet regulatory standards.
  2. Provide the FDA with product samples using commercially available drug product samples. Currently, it is up to the discretion of the FDA whether or not to request samples in the review of an application. With the labeling-only 505(b)(2) NDA, non-manufacturers would provide the FDA with samples of commercially available products from generic manufacturers. Given that the FDA would have already evaluated the products and their bioequivalence to the RLD during the previous reviews, it is not expected that the FDA would need to re-examine the product at the level of requesting samples, except potentially to examine the packaging and physical presentation of the product for compatibility with the new indication and conditions of use. The facilities where the drugs are made would remain available for inspection, under the same terms and conditions as the existing, approved marketing applications. 
  3. Manage post-marketing responsibilities. Since most post-marketing surveillance and adverse event reporting are drug product-specific, these obligations would continue to be the responsibility of the manufacturer of the physical drug product dispensed. With the labeling-only 505(b)(2) NDA, the non-manufacturer would not have product-specific obligations because they are not putting a new product into the marketplace. However, we anticipate the non-manufacturer would be responsible for the repurposed indication on their labeling, including but not limited to post-marketing surveillance as well as indication-specific adverse event reporting and reasonable follow-up.

Under the labeling-only 505(b)(2) NDA, the non-manufacturer sponsor would not introduce a new physical drug product into the market. The new labeling created by the approval would not expressly be associated with one specific product. The non-manufacturer’s labeling would refer to the drug by its established generic name. In that way, the non-manufacturer sponsor’s approval and labeling could be applicable to all equivalent versions of the drug product and would be available for patients to receive from their pharmacy in the same way that generic drugs are typically dispensed at the pharmacy. That is, with the benefit of pharmacy-level substitution, patients could receive any available, therapeutically equivalent drug products from any current manufacturer. 

Eligibility criteria

We envision the users of this pathway to be non-manufacturers that conduct drug repurposing research for the public benefit, including organizations like nonprofits and patient advocacy groups. The FDA should implement and enforce additional guardrails on eligibility to ensure that sponsors operate in good faith and cannot otherwise meet traditional NDA requirements. This process may include pre-submission meetings and reviews. The labeling-only 505(b)(2) NDA should be held to the FDA’s standard level of rigor and scrutiny of safety and effectiveness for the proposed indication during the review process.

The labeling-only 505(b)(2) would only be suitable for well-established, commercially available small molecule generic drugs, which can be identified as: 

  1. Drugs with a U.S. Pharmacopeia and National Formulary (USP-NF) monograph. The USP-NF monograph system ensures the uniformity of available products on the market by setting a consensus minimum standard of identity, strength, quality, and purity among all marketed versions of a drug. It is expressly recognized in the Federal Food, Drug, and Cosmetics Act (FDCA). The USP-NF strives to have substance and product monographs for all FDA-approved drugs. USP-NF monographs for generics are commonly available because the drugs have been on the market for a long time and are typically produced by multiple manufacturers. Drug products in the U.S. market must conform to the standards in the USP-NF, when available, to avoid possible charges of adulteration and misbranding. 

By statute and regulation, the FDA already allows for NDAs and ANDAs to reference the USP-NF to satisfy some CMC requirements, such as for specifications of the drug substance. As an illustration of the acceptance of the USP-NF, clinical trial protocols requiring the use of background therapy or supportive care, as well as trials testing medical devices requiring the use of a drug product, often will specify that any available version of the drug product meeting USP-NF standards can be used. We propose that products without USP-NF monographs, including certain newer drugs and drugs with especially complicated manufacturing processes that are not conducive to standardization, would not be eligible for the labeling-only 505(b)(2) pathway.

  1. Drugs with multiple A-rated, therapeutically equivalent products in the FDA Orange Book. The FDA does not regulate which specific products are dispensed or substituted for a given drug prescription. The listing of therapeutic equivalents in the Orange Book facilitates the seamless replacement of drug products from different manufacturers in clinical practice. Therapeutically equivalent drug products: i) have demonstrated bioequivalence to the RLD; ii) have the same strength, dosage form, and route of administration as the RLD; and iii) are labeled for the same conditions of use as the RLD. Therapeutic equivalents that meet these criteria are designated “A-rated” in the Orange Book. A-rated drug products are substitutable for any other version of that A-rated drug product, including the RLD itself. 

Implementation 

The labeling-only 505(b)(2) NDA pathway could be implemented through an FDA guidance document interpreting the current statute and regulations or through legislation that clarifies the FDA’s existing authority. Guidance documents contain the FDA’s interpretation of a given policy on regulatory issues. The FDA’s Center for Drug Evaluation and Research (CDER) could issue new guidance that allows for interpretation of the existing statute, thereby officially authorizing previous FDA determinations of acceptable CMC data to be referenceable for eligible generic drugs and adjusting drug sample requirements. Alternatively, the labeling-only 505(b)(2) could be enacted by Congress through a statutory change by incorporation into FDCA, which is up for reauthorization through the Prescription Drug User Fee Act (PDUFA) in 2027, or other congressional acts as appropriate. FDA guidance would be a faster pathway to adoption, while statutory authorization would offer additional safeguards for the continuance of the pathway long term.

The labeling-only 505(b)(2) NDA pathway could be funded through user fees, which are established by PDUFA for the cost to file and maintain NDAs. However, many nonprofit sponsors would not be able to afford the same user fees as for-profit pharmaceutical manufacturers. Relevant statutes will likely need to be updated to create a different fee schema for non-manufacturers who use the labeling-only 505(b)(2) pathway. In a similar spirit to reducing barriers to maintaining up-to-date labeling, the 2017 PDUFA update waived the fee for submitting an sNDA, which is how an existing RLD holder would update their labeling with new indication information.

Conclusion

Patients need new and affordable treatment options for diseases that have a devastating societal impact, and repurposing generic drugs can help address this need. Nonprofits and other non-manufacturers are driving these efforts forward due to a lack of interest from pharmaceutical companies. As momentum gains for generic drug repurposing, the U.S. regulatory system needs a pathway for non-manufacturers to seek FDA approval of new indications for existing generic drugs. Our proposed labeling-only 505(b)(2) NDA would eliminate undue administrative burden, enabling non-manufacturers to pursue FDA approval of new indications. It would allow the FDA to provide the public with the most up-to-date drug labeling, improving the ability of patients and physicians to make informed treatment decisions. This dedicated pathway would increase the availability of effective treatment options while reducing costs for the American healthcare system.

This action-ready policy memo is part of Day One 2025 — our effort to bring forward bold policy ideas, grounded in science and evidence, that can tackle the country’s biggest challenges and bring us closer to the prosperous, equitable and safe future that we all hope for whoever takes office in 2025 and beyond.

Frequently Asked Questions
Could the FDA make labeling changes for repurposed generic drugs without the process being driven by non-manufacturer sponsors?

The FDA does not have sufficient bandwidth or resources to meet the opportunity we have with repurposed generic drugs. To be the primary driver of labeling changes for repurposed generic drugs, the FDA would need to identify repurposing opportunities and also thoroughly compile and evaluate the safety and effectiveness data for the new indications. Project Renewal in FDA’s Oncology Center of Excellence is working with RLD holders to update the labeling of certain older oncology drugs where the outdated labeling does not reflect their current clinical use. The initial focus of Project Renewal is limited, and newly repurposed treatments are not included within its scope. For newly repurposed treatments, the FDA could evaluate the drugs and post to the Federal Register reports on their safety and effectiveness that could be referenced by manufacturers. However, this approach is burdensome as it would require a significant commitment of FDA resources. By introducing a motivated, third-party non-manufacturer as the primary driver for labeling changes, non-manufacturers can contribute expertise and resources to enable faster data evaluation for more drugs.

If a repurposed indication for a generic drug was approved through the labeling-only 505(b)(2) NDA pathway, would current manufacturers be required to update their labeling?

The pre-existing NDA sponsor could update their labeling to add the new indication through an sNDA that references the labeling-only 505(b)(2) NDA. ANDA holders would then be legally required to match their labeling to that of the RLD. The FDA should determine whether all current manufacturers would be required to update their labeling following approval of the new indication, and if so, the appropriate process.

Could drug repurposing and expanding the market for generics cause an increase in drug prices?

Generic drugs play a vital role in the U.S. healthcare system by decreasing drug spending and increasing the accessibility of essential medicines. Generics account for 91% of prescriptions filled in the U.S. Expanding the market with generics for new indications could lead to short-term price increases above the inflation rate for off-patent branded and generic drugs in some unlikely circumstances. For example, if a new use for a generic drug substantially increases demand for the drug, there is a short-term risk that prices for the drug or potential substitutes could rise until manufacturers build more capacity to increase supply. To mitigate this risk, generic manufacturers could be notified about potential increases in demand so they can plan for increased production.

Would off-label uses of drugs still be covered by healthcare payers if there is a pathway to seek approval for those uses?

Generally, healthcare payers are not required to cover or reimburse for off-label uses of drugs. Unless a drug undergoes utilization management, payers cover most generic drugs for off-label uses because coverage is agnostic of indication. Clinical practice guidelines are highly influential in the widespread adoption of off-label treatments into the standard of care and are often referenced by payers making reimbursement decisions. In oncology, many off-label treatments are included in guidelines; only 62% of treatments in the NCCN are aligned with FDA-approved indications. For example, more than half of the NCCN recommendations for metastatic breast cancer are off-label treatments. Due to the breadth of off-label use, we anticipate payers would continue to cover repurposed generic drugs used off-label, even if there is a pathway available for non-manufacturers to pursue FDA approval.

Would a labeling-only 505(b)(2) NDA sponsor receive any marketing exclusivities for the new indications?

We do not envision any form of exclusivity being granted for indications pursued via a labeling-only 505(b)(2) NDA. Given that the non-manufacturer sponsor would rely on existing products produced by multiple generic manufacturers, there is no new product to grant exclusivity. Even if some form of exclusivity were given to the non-manufacturer, it would be insufficient to guarantee the use of any particular drug product over another due to pharmacy-level substitution.

Advisory Committees for the 21st Century Recommendations Toolkit

From January 2024 to July 2024, the Federation of American Scientists interviewed 30 current and former Advisory Committee (AdComm) members. Based on these discussions, we were able to source potential policy recommendations for the executive level, for the executive level, that may assist with enhancing the FDA’s ability to obtain valuable advice for evidence-based decision-making. In this toolkit, we build off of those discussions by providing you with actionable policy reform recommendations. We hope that these recommendations catapult the Advisory Committee structure into one best suited to equip all AdComms with the necessary tools needed to continue providing the government with the best advice.

Download a PDF version of these recommendations on the left.

Recommendations and Best Practices for Actionable Policy Implementation

Voting for FDA Advisory Committees

Update Type: Process

Best Practices for Implementation 

The United States Food and Drug Administration can uphold their voting mechanism by updating their document entitled, “Guidance for FDA Advisory Committee members and FDA staff: Voting Procedures for Advisory Committee Meetings” to include language that clearly states a vote should be taken at all Advisory Committee meetings where a medical product is being reviewed. This guidance should also indicate that the absence of voting should only occur if an Advisory Committee meeting has been convened to discuss issues of policy. Further, this guidance should be considered a level 2 guidance as it falls into the category of addressing a “controversial issue”. To effectuate these changes, a notice of availability (NOA) may be submitted to the Federal Register for public input (public input is not a requirement before implementation). 

Potential Language to be Utilized for Guidance 

In an effort to continue to allow Advisory Committee members to provide unbiased, evidence-based feedback and uphold such an integral part of the Advisory Committee process, voting is hereby mandatory for all Advisory Committee meetings that are convened where the purpose is to review and assess the safety and efficacy of medical products. 

Involved Stakeholders

In order for this process to successfully occur, the FDA will need to amend their guidance with the aforementioned updates. Consideration should be given to incurred costs for personnel required to complete these updates. Personnel needed for these amendments may include, but are not limited to, the (a) Office of the Commissioner, Office of Clinical Policy and Programs, Office of Clinical Policy, (b) Center for Devices and Radiological Health, (c) Center for Biologics Evaluation and Research, and (d) Center for Drug Evaluation and Research.

FDA Staff, Leadership, and AdComm Disagreements

Update Type: Process

Best Practices for Implementation 

Implementing these recommendations will improve conflict resolution internally and between the Agency and Advisory Committee members. Best practices for implementation include (a) building the Scientific Dispute Resolution at FDA guidance into the official FDA onboarding process for new hires to raise awareness, (b) provide annual employee trainings in an effort to stay up-to-date with dispute resolution processes and procedures, and (c) develop a guidance that delineates the process for resolving conflicts between the Agency and Advisory Committees when there are differing opinions. 

Note: Guidance for resolving disputes between the Agency and Advisory Committees should be submitted to the Federal Register for public comment. Guidance should also include plain language that designates the avenue to be used for official decision notifications, the timeliness of these notifications after convenings have concluded, and circumstances in which the FDA cannot notify Advisory Committees that their decision is in direct opposition of the Committee’s vote (e.g., – if this notification would breach a confidentiality agreement with the applicant). Implementing a transparent process to communicate with AdComm members regarding differences between the Agency and the AdComm will assist in improving morale between both parties, but also encourage continued support of the AdComm.

Involved Stakeholders 

Successful implementation of these recommendations will require the capacity of human resources personnel and individual center leadership. 

Update Type: Regulatory

Best Practices for Implementation

Center leadership can assign FDA staff to make the necessary guidance amendments which should include the requirements for inclusion in the onboarding of all FDA employees. Staff should also be responsible for obtaining feedback on amendments from all necessary internal parties and submitting proposed amendments to OMB for review and addition to the Federal Register. Federal register comments will then be reviewed by FDA staff, guidance will be updated accordingly, and a final draft submitted to OMB for review. If approved, the final regulation will be published in the Code of Federal Regulations. Congressional involvement should not be necessary.

FDA Center leadership should delegate the task of creating an annual mandatory training program for all FDA employees to review this guidance in an effort to stay abreast of the procedures for dispute resolution. 

Involved Stakeholders 

FDA Center leadership, FDA staff, and the Office of Management and Budget (OMB) are the intended stakeholders for implementation of these recommendations. To incorporate this guidance into FDA regulations, Center leadership will need to assign FDA staff to amend guidance and submit to OMB.

Leveraging AdComm Membership

Update Type: Process

Expanding Committee Representation

Amplifying the Role of the Chair

Establishing Training and Regulatory Procedures for Incoming Members

Best Practices for Implementation

With respect to Committee composition, the FDA should consider adding patient representatives to all Committees that review medical products. The addition of a patient representative will ensure that the voice of the population who the medical product affects is heard. The FDA can select individuals best suited to fill these roles through connecting with patient advocacy organizations. If patient representatives are selected, the FDA should develop an onboarding program to familiarize the patient representative with basic knowledge of the federal regulation process. This program should educate the patient representative on (a) the types of questions presented to Advisory Committees, (b) how the FDA views the role of the patient representative in the process, (c) the internal review process for data that is submitted, and (d) other pertinent topics related to medical product regulation.

Leveraging the role of the Advisory Committee Chair can help the FDA fully optimize the use of their Committee. “Chairs possess extensive networks that could support the identification of permanent or temporary expert participants for AdComms” (Banks, 2024). Allowing Chairs the ability to identify relevant issues or products for their respective committees to review can provide an additional layer for the FDA to keep abreast of critical public concerns via appropriate committee evaluation (Banks, 2024).

Finally, while Committee members may be experts in their own right, training should be provided for all. The FDA should provide basic 101 training courses that can cater to the needs of members with various knowledge bases. Training should include information on the relationship between the FDA and Advisory Committee members, best practices for understanding statistical analysis, and the different types of clinical trial designs. Training should provide real-world examples of statistical analysis and trial design in use (this can be done by providing examples from prior medical product review). 

Involved Stakeholders

FDA Center staff (including statisticians and scientists for the development of training programs).

Conflict of Interest (COI) Auditing

UPDATE TYPE: PROCESS 

Best Practices for Implementation

To prevent recurring COIs, the FDA should develop a database of experts for various categories of expertise that can be selected to replace those with known COIs. This database should include names, contact information, credentials, all areas of expertise for each expert, and should link to public financial interest databases that can serve as a source for identifying conflicts (e.g., Open Payments, Dollars for Docs).

To prevent public confusion, the FDA should amend their Guidance for the Public, FDA Advisory Committee Members, and FDA Staff: Public Availability of Advisory Committee Members’ Financial Interest Information and Waivers to specify circumstances that warrant a COI waiver being administered. This will increase transparency and help Advisory Committee members and the public understand the reasoning in allowing members with conflicts to participate in meetings. This guidance can then be submitted to the Federal Register for public comment

UPDATE TYPE: PROCESS | REGULATORY

Best Practices for Implementation

Streamlining the COI process will assist the FDA with retention efforts for Advisory Committees while maintaining compliance with conflict of interest regulations. A digital system should be developed that allows Advisory Committee members to select whether their financial information has changed through the use of a dropdown or check box. This will prevent duplicative work and also contribute to a sustainable (green) process.

Involved Stakeholders

The Office of the Commissioner, Office of Clinical Policy and Programs, Office of Clinical Policy would be the interested stakeholder to issue updates to the COI policy and would work with the General Services Administration if necessary. 

The Role of Patient Advocacy in the AdComm Process

Update Type: Process

Best Practices for Implementation

Public comments are a crucial part of the regulatory process. The FDA should focus on increasing participation in this process, as well as notifying participants of what should be expected from the public comment period. By law, the FDA must allow a public comment period for all Advisory Committee convenings. To increase participation, the FDA should allow public comments to be vocalized in-person and virtually, in addition to the submission of public comments to the docket. 

Regarding Committee composition, please refer to Best Practices for Implementation under Leveraging AdComm Membership for information on the addition of patient representatives to Advisory Committees (see prior section above).

Patient engagement in the regulatory process is necessary to inform evidence-based decisions. While the FDA currently has ways to engage these communities through the use of public comment and initiatives such as Patient Focused Drug Development (PFDD), engagement should be an ongoing process. As mentioned, the FDA can develop and leverage existing relationships with public health agencies and advocacy organizations who can then serve as the liaison of feedback to the FDA. The FDA can also consider expanding their current initiatives and programs to engage communities twice a quarter instead of quarterly or annually. Consistent engagement in this form will help to establish trust between the FDA and the public who they serve, as well as give them the needed information from the communities who are most impacted from their decisions.  

Involved Stakeholders

Implementation of these recommendations and expansion of current initiatives will require the involvement of FDA Center leadership and Center staff.

Improving Public Awareness and Understanding of Advisory Committees

Update Type: Process

Best Practices for Implementation

The FDA should develop a monthly content plan to utilize its current interactive and social media outlets and disseminate information related to the role of Advisory Committees and their convenings, while also maintaining compliance with the FDA’s social media policy. The social media content plan should be centered around (a) what an Advisory Committee is, (b) how members are selected, (c) information regarding votes of Advisory Committees and how they are specific to safety and efficacy, but are not voting on the approval of a medical product, (d) discussing upcoming Advisory Committee meetings, their location, and inviting the public to participate via public comment, (e) sharing information about what a public comment is, requirements for making public comments, and how the FDA reviews them, and (f) sharing a webpage where the general public can input their personal email to be notified of upcoming Advisory Committee meetings.

FDA staff should develop a plain language disclaimer to be placed on all social media posts, meeting materials, and websites related to Advisory Committees. This disclaimer should illustrate that Advisory Committee members will provide unbiased expertise to assist the FDA with their decision. However, while the Committee’s vote is included in consideration for the decision, their vote is non-binding which leaves the FDA as the final decision maker for approval.

Finally, the FDA should identify state/local public health agencies, as well as advocacy organizations that they can potentially partner with to disseminate information more broadly. These agencies and advocacy organizations have strong relationships with various communities who should be engaged in the regulatory process. Developing a relationship with these agencies and organizations in an attempt to engage the community will assist the FDA with building connections and trust, as well as mutual understanding of Advisory Committee roles. Potential partners can be identified using the linked list under involved stakeholders. 

Involved Stakeholders

Implementation of these recommendations and expansion of current initiatives will require the involvement of FDA Center leadership, Center staff, Office of External Affairs (OEA) Web and Digital Media staff, Office of Information Management and Technology (OIMT), state/local public health departments, and advocacy organizations.

Note: These listings of state/local public health departments and advocacy organizations are intended to be used as a starting point in the identification of potential partners and not to be considered an exhaustive list.

For questions related to this toolkit, please contact

Cheri Banks
Health Regulatory Specialist
cbanks@fas.org

Grace Wickerson
Health Equity Policy Manager
gwickerson@fas.org

Improving Public Awareness and Understanding of Advisory Committees

From January 2024 to July 2024, the Federation of American Scientists interviewed 30 current and former Advisory Committee (AdComm) members. Based on these discussions, we were able to source potential policy recommendations that may assist with enhancing the FDA’s ability to obtain valuable advice for evidence-based decision-making. The results of these discussions are presented in case study format detailing the recurring themes that emerged and policy recommendations for improvement.

The FDA holds one of the most important roles as a federal agency which is to ensure public safety when approving vaccines, medical devices, and medicines. The approval of these products usually require extensive trials with data that supports their safety and efficacy. Considering that most of these decisions are complex and multifaceted, the FDA enlists the support of Advisory Committees to assist with their decision-making process. The primary role of FDA Advisory Committee members is to provide the FDA with informed advice and recommendations on issues spanning science, regulatory policy, and the evaluation of products under the FDA’s jurisdiction. Although AdComm members serve the FDA in an advisory capacity, their recommendations are non-binding. Therefore, they do not have the final say in the regulatory approval process. 

However, over the years, it has been made evident that the public is unaware of the role of Advisory Committees and ways in which they can engage with the FDA. In this case study, FAS hopes to share the current problem and actionable recommendations to combat public misconceptions regarding FDA AdComm roles and provide guidance on increasing FDA engagement with the public and other relevant stakeholders throughout the regulatory process.

Public Awareness Problems

While AdComm members are experts in their respective fields and volunteer their time to provide advice to the FDA, there are multiple factors that must be considered before making official decisions. The recommendations provided during Advisory Committee meetings are just one aspect that is considered for regulatory decision-making and do not guarantee an official approval or denial of a product by the FDA. During AdComm meetings, the FDA allows the general public to make public comments to the Agency and the AdComm regarding the topic that is being addressed. Despite this, members of the general public have expressed that, on many occasions, they are unaware AdComm meetings are occurring. This, in effect, deprives them of the opportunity to communicate directly with the FDA and the AdComm. Additionally, they feel the FDA fails to engage them in an adequate manner, thereby limiting opportunities for participatory engagement. It has also been noted that most members of the general public are unaware FDA Advisory Committees exist; and, for those who are aware, they are unclear about the capacity of their role within the regulatory process. 

For these reasons, the FDA must take measures to enhance public understanding in an effort to combat misinformation, educate, and raise awareness on the existence of Committees and their purpose.  

Communicating AdComms to the Public

Improving Public Awareness of Advisory Committees and their Role

Improving public awareness on the existence of FDA Advisory Committees and their purpose would assist the FDA with improving public trust and debunking myths and misinformation related to the approval of medical products. Advisory committees operate as an independent party and their recommendations assist with guiding regulatory decision-making. However, their recommendations are non-binding, and FDA leadership must consider additional factors before granting approvals or denials of medical products. 

To increase public awareness on Advisory Committees, it should be made clear that AdComm recommendations are not conclusive, as the FDA considers multiple factors in its official decisions. The FDA can leverage social media platforms to increase awareness and understanding of AdComms through the use of disseminating information via the use of ads and active social media engagement. A survey conducted by Pew Research Center states that eight in ten Americans believe social media platforms are an effective way to bring awareness. In addition, disclaimers should be included on all public facing materials referencing AdComms to indicate their purpose. Clearly communicating this to the public will dispel myths that AdComms make the final call on the approvals of medical products. 

Improving Communication about Advisory Committee Meetings

Encouraging public participation for Advisory Committee meetings will help foster a collaborative and engaged general public who can contribute valuable life experience to the regulatory process. FAS has identified ways in which the FDA can better communicate with the public to inform them of Advisory Committee meetings. First, the FDA can develop a webpage that allows people to receive notifications of upcoming AdComm meetings. The FDA can also establish relationships with state and local public health agencies, as well as advocacy organizations to spread awareness. Through these relationships, the various agencies and organizations can use their networks to disseminate widespread information on AdComm meetings. Public health agencies and advocacy organizations can gauge the best ways in which these communities would like the FDA to engage with them. This understanding of the communities they serve makes them an ideal partner for fostering continuous engagement.  

Policy Recommendations

In an effort to improve public awareness and understanding of AdComms, the potential policy recommendations are as follows: 

Conclusion

Advisory Committees are essential to the FDA regulatory decision-making process. It’s imperative that their role is understood by them and the general public to best move the needle forward. While the FDA currently allows the public to provide public comment at Committee meetings, that alone cannot be considered engaging the community. The FDA must create new opportunities for interpersonal communication which will create an environment of mutual trust and understanding between both parties.

The Role of Patient Advocacy in the AdComm Process

From January 2024 to July 2024, the Federation of American Scientists interviewed 30 current and former Advisory Committee (AdComm) members. Based on these discussions, we were able to source potential policy recommendations that may assist with enhancing the FDA’s ability to obtain valuable advice for evidence-based decision-making. The results of these discussions are presented in case study format detailing the recurring themes that emerged and policy recommendations for improvement.

The regulation of medical products is the responsibility of the Food and Drug Administration (FDA). To ensure effective decision-making regarding these products, the FDA recognizes the importance of patient advocacy and the perspectives of patients. In 1988, the FDA initiated the patient engagement process through the Office of Aids Coordination, and within five years, the first patient representative was appointed to an FDA Advisory Committee. Since then, the FDA has significantly enhanced its methods of engaging patients, caregivers, and patient advocates. This includes the establishment of various offices, programs, collaboratives, listening sessions, public guidance, and more.

The Evolution of Patient Engagement at the FDA

The FDA employs several avenues to engage patients in the regulatory process. Some avenues include the Patient Engagement Advisory Committee (PEAC), public comment, the Patient Focused Drug Development Initiative (PFDD), the Patient Listening Session Program, Patient Engagement Collaborative (PEC), and the Patient Representative Program (PRP). This list does not cover all the ways in which the FDA engages patients and advocates but provides an overview of the key operations involved in patient engagement efforts. 

The Patient Engagement Advisory Committee is the only Committee that is completely composed of caregivers, patients, and patient representatives from various organizations, as a way to ensure that the lived experiences of these populations and their opinions are included in the deliberations and regulatory decision-making of medical products. Public comment is a requirement by law for federal agencies, allowing the public to provide feedback on proposed actions or new rules and regulations. Public comment is also sought during Advisory Committee meetings to gather information and perspectives from the public. PFDD meetings provide a platform for the FDA to obtain insights from patients on specific diseases and their treatments. To identify the issues most important to patients, the FDA has a series of guidance documents that are used specifically for PFDD meetings. 

The Patient Listening Session Program facilitates informal meetings between patients, their representatives, and FDA staff. These sessions cover a range of topics, including treatment preferences, quality of life, unmet medical needs, and the impact of diseases and their symptoms. The PEC offers a forum for patients, caregivers, and advocates to discuss patient engagement operations. Lastly, the PRP allows patients, caregivers, and advocates who serve as special government employees the opportunity to provide advice to the FDA’s Commissioner or a designated representative on matters related to medical devices and their regulation.

Although there are various avenues for patient engagement and advocacy participation in the medical product regulation process, there are also ways in which these avenues can be expanded or improved.   

Patient Advocacy Problems

For many years, patients and their caregivers have not seen significant or sustainable treatments that have been developed to treat many illnesses and diseases. Some treatments have proven to be ineffective yet still made it to market approval. On the other hand, there are treatments that met safety and efficacy standards but were not approved. There are also those treatments that are simply not affordable to the populations that need them most. In many of these scenarios, the patient representative voice was lost as they did not have the option to express their concerns or perspectives on certain treatments with decision makers. This further confirms that the role of patient advocacy and allowing space for the patient representative voice is crucial to the regulation process of medical products. 

At the moment, the patient voice is not always heard because there are some FDA Advisory Committees that do not have a patient representative.

While the role of patient advocacy is crucial, it is important to note there should be boundaries in which patient perspective is considered for decision-making. Although patients and their advocates seek treatments that better address their needs, this desire can sometimes obscure their judgment concerning long-term treatment effectiveness. Frequently, patients and their supporters present powerful arguments to Advisory Committees and the FDA for approval of particular medical products which can lead to expedited medical product approval in the absence of supportive evidence. 

The endorsement of eteplirsen, which was intended for the treatment of Duchenne muscular dystrophy (DMD), illustrates this point. Despite a 7 to 3 vote by the FDA’s Advisory Committee against approval due to insufficient evidence of its benefits, opposition from the FDA’s Center for Drug Evaluation and Research’s former leader resulted in the drug’s authorization. This sparked substantial internal and public criticism and led Dr. Ellis Unger from the FDA’s Office of Drug Evaluation to challenge the approval decision. Dr. Unger emphasized that “patient-focused drug development is about listening to patient perspectives about what matters to them; it is not about basing drug approvals on anecdotal testimony that is not corroborated by data.”

This approval was perceived by many as having been heavily influenced by patient advocacy and raised concerns about potential long-term implications for patient health. It also signaled a need to further examine both patient education and the appropriate limits of patient involvement in the regulatory process. This could have been mitigated had there been a list of criteria in place to be followed for public comment. 

Incorporating Patient Perspectives

The Food and Drug Administration (FDA) is committed to understanding the balance of benefits and risks acceptable to patients as they relate to medical products. The FDA defines the role of patient representatives that serve on Advisory Committees as “Special Government Employees” who provide direct input to agency staff and share valuable insight on their experiences with various diseases, conditions, and devices while gaining access to confidential information. These representatives are selected by the FDA to serve on Advisory Committees using a specific set of criteria including, but not limited to: 

This criteria ensures the FDA will understand the patient perspective as it relates to various medical products and ensures those selected to serve on Advisory Committees are knowledgeable about the areas in which they are aiming to provide guidance. Currently, there are some FDA Advisory Committees that do not have a patient representative. Further, the patient representatives serving on committees do not always have voting privileges. The absence of consistent voting privileges for some patient representatives on Advisory Committees and not having a standing patient representative on all committees hinders these individuals from providing an official stance on behalf of the community they represent. Additionally, public comment plays a significant role at Advisory Committee meetings by permitting individuals—including patients, caregivers, and advocacy organizations—to highlight concerns and propose solutions that may not have been previously considered by decision-makers. This process also helps the committee and agency gauge patient acceptance or opposition related to medical products, thereby enhancing their ability to make decisions that more accurately reflect public needs. 

When Sarepta was seeking approval of eteplirsen for the treatment of DMD, a patient advocacy organization brought hundreds of patients, caregivers, and other advocates to the Advisory Committee convening so they could make a public comment to the Committee and the agency. Shortly after, the drug received a swift approval. Although it presented much controversy within the agency and the public, it showed how influential patient advocacy can be. Personal lived experiences, compelling stories of debilitating illnesses, and experiences with current treatment have the ability to impact regulatory decision-making. 

The role of patient advocacy continues to be important in the Advisory Committee process and FDA regulatory decision-making process because it is crucial to assisting with decisions that affect the American public. Patient advocacy can be presented in the form of patient representatives that serve on Advisory Committees, those who make public comments during Advisory Committee convenings, and various outreach programs by advocacy organizations. The role of advocacy gives patients and caregivers support, promotes and protects their rights, and allows broader visibility for the issues that are most important to them. All of these avenues for patient perspective are important to understand how treatments perform, the current needs of the patient population, and how to tailor care for these populations by truly understanding their condition, diagnosis, and current management. Therefore, their voice is critical to truly understanding how various medical products will benefit their population, how they will access and afford these products, and how they will fill an unmet medical need.

Policy Recommendations

In an effort to better leverage Advisory Committee membership, the potential policy recommendations are as follows: 

Conclusion

The landscape of disease burden and associated symptoms is ever-evolving. To ensure the FDA is best prepared for this changing landscape, patient advocacy and amplifying the patient voice should be considered vital to the development and regulation of medical products. Involving those who are the most impacted by these products is essential. The FDA can further promote the patient perspective and advance patient-centered health through incorporating patient representatives on all Committees that are reviewing medical products, making patient engagement an ongoing process, hosting town halls for patients to allow a broader audience the opportunity to voice opinions, and having dedicated staff to sort through public comments from patients.

FDA Staff and Leadership Disagreements and the Role of the AdComm in the Regulatory Process

From January 2024 to July 2024, the Federation of American Scientists interviewed 30 current and former Advisory Committee (AdComm) members. Based on these discussions, we were able to source potential policy recommendations that may assist with enhancing the FDA’s ability to obtain valuable advice for evidence-based decision-making. The results of these discussions are presented in case study format detailing the recurring themes that emerged and policy recommendations for improvement.

The FDA relies on its scientific staff and Advisory Committees to provide conclusions from trial and study data, which aid in the process of regulating and approving medical products. However, there are instances when disagreements arise between the agency’s scientists, statisticians, Advisory Committees, and leadership on the accelerated or full approval of medical products. The resolution of these disagreements present a growing concern about FDA leadership overruling the expert opinions of scientific staff and proceeding with official approvals, thus undermining staff expertise, decreasing agency morale, and potentially diminishing public trust.

When Disagreements Between FDA and AdComms Arise 

The Federal Advisory Committee Act governs the FDA’s Advisory Committees and establishes a process in which the FDA can seek expert advice on various issues related to science, regulatory policy, and the evaluation of products under the FDA’s jurisdiction. When the FDA has differing opinions on safety and efficacy requirements of medical products, certain products may be referred to an Advisory Committee for further data review by an impartial entity. To aid in this matter, the FDA has developed guidance detailing the process for assembling Advisory Committees. Since the resources required for convening these committees are significant, the FDA ensures there is substantial uncertainty or disagreement regarding the data. Advisory Committees will discuss the evidence and provide feedback with the goal of producing the most optimal evidence-based resolution. This part of the regulatory process is crucial to the agency’s regulatory decision-making as it involves unbiased parties and leads to transparency, upholding public safety, and maintaining public trust. However, there are times that FDA leadership disagrees with the votes of their Committees and proceeds with controversial approvals. One example of this scenario was approval of the drug Aduhelm. Aduhelm, which was marketed as a treatment for Alzheimer’s, received an overwhelmingly negative vote from the Advisory Committee to move forward with its approval for market distribution. Ten of eleven Committee members stated the data did not support adequate efficacy for approval. Nonetheless, the FDA granted accelerated approval, sparking resignations from a third of their Committee and outrage amongst the public. This disregard for expert opinion was viewed as the FDA exhibiting an approval bias, a perspective the public currently maintains of the FDA. 

In 2023, various organizations and coalitions, such as Doctors for America, Jacob’s Institute of Women’s Health, National Center for Health Research, TMJ Association and more publicly expressed concerns regarding the FDA’s leadership and their approach to drug approvals through a letter addressed to the FDA’s Chief Scientist, Dr. Namandje N. Bumpus. They highlighted FDA leadership had ignored claims by scientific staff that safety and efficacy standards were not being met for the drug Elevidys. Manufactured by Sarepta Therapeutics, Elevidys was granted accelerated approval by FDA leadership. Dr. Bumpus responded to this letter defending the FDA’s approval of Elevidys by referring to the agency’s comprehensive review of the data and consideration of the potential risks of the approved treatment, nature of the disease and its impact on patients, and the limited amount of therapies available. However, the response did little to quell public scrutiny of the controversial approval. Critics were apt to point out that the FDA had a record of approving products in this manner. Years prior, the FDA had approved the drug Eteplirsen for the treatment of duchenne muscular dystrophy (DMD), despite the objections of their scientific staff which disclosed a lack of evidence for the efficacy of this treatment. Criticism was also directed at FDA leadership suggesting the approval of some medical products were potentially due to favoritism toward companies seeking approval.

Resolving Internal FDA Disagreements

While it is acknowledged that the FDA must consider technological and political implications alongside scientific evidence in decision-making, it is essential to address the concerns of these organizations and coalitions. As part of an ongoing project to reform the FDA’s Advisory Committee system and assist the FDA with getting the advice needed to make the best evidence-based decisions, FAS engaged in discussions with current and former Advisory Committee members to seek their input on resolving disagreements between FDA staff and leadership. These conversations highlighted the breach of trust between the FDA, its staff, and the public.

Quotes from Experts

“FDA leadership needs to make is clear what data was used and why they’re moving forward when there is opposition”

“Disagreements should be addressed by a non-biased source because it affects the public safety.”

“There will be times where there are disagreements between staff and leadership. However, there’s a critical need for transparency within the FDA about why decisions are made. These are not decisions about evidence only. Ever.”

“Disagreements should be a matter of public scrutiny. There should be transparency that doesn’t jeopardize confidentiality.”

The FDA’s Commissioner has acknowledged the lack of trust within the institution and expressed a commitment to address the issue. There are many reasons for the lack of trust. However, one reason stems from the FDA’s approval of medical products despite clear opposition from its scientists and sometimes Advisory Committee members.

This raises the question of how the FDA intends to address these internal disagreements, which have the potential to impact the health and safety of the American public. Currently, the FDA has implemented a program called Scientific Dispute Resolution (SDR) to handle such conflicts. This document was initially developed in 2009 and recently updated in 2021 with the purpose of outlining the process for communication regarding internal scientific disputes within FDA Centers. It defines scientific disputes as disagreements that arise from the interpretation of science and the resulting decisions. This definition clearly distinguishes the circumstances in which the guidance should be utilized to resolve discrepancies between FDA scientists, statisticians, and their respective Center leadership. The guidance offers valuable examples of best practices for resolving formal and informal scientific disputes within the agency. Some of those best practices include, but are not limited to: 

However, it should be noted these best practice recommendations are not obligatory and their adoption is left to the discretion of the individual Centers. Furthermore, the document provides a process by which any of the internal parties involved can appeal the resolution of their dispute if they find it unsatisfactory through the Office of Research  Integrity at Health & Human Services (HHS).

Policy Recommendations

To increase morale and improve the approach and resolution of internal disagreements within the agency, the policy recommendations are as follows:

  1. Ensure that all FDA staff and leadership are fully cognizant of the existence and details of the Scientific Dispute Resolution at FDA guidance and the process for submitting disputes for review.
  2. Incorporate the Scientific Dispute Resolution at FDA guidance into FDA regulations
    1. Note: To incorporate this guidance into FDA regulations, the FDA will propose the regulation for OMB review. OMB will review and open the regulation up for public comment through the Federal Register. Responses to comments will be developed, and a final draft submitted to OMB for review. If approved, the final regulation will be published in the Code of Federal Regulations (Congressional Research Service, 2013). The involvement of Congress will not be necessary.
  3. Amend the Scientific Dispute Resolution at FDA guidance to dictate the mandatory execution of best practices within the dispute resolution process.
    1. This guidance should identify additional non-biased parties (that may not be government-affiliated) to provide impartial guidance on complex scientific matters affecting public safety. 
  4. Develop guidance that clearly explains a transparent process to communicate effectively with AdComm members regarding decision making when parties have opposing viewpoints
    1. Implementing a transparent process to communicate with AdComm members regarding differences between the agency and the AdComm will assist in improving morale between both parties, but also encourage continued support of the AdComm.
    2. This recommendation is also supported by a survey conducted by 3D Communications with 400+ AdComm members where 94% of members concurred that the FDA should develop a process to communicate their reasoning for decisions in opposition to Committee recommendations (3D Communications, 2024).

Conclusion

While FDA leadership ultimately holds the authority to grant approvals, it is crucial that the perspectives of all experts are duly considered. This includes the valuable input from the agency’s scientists, statisticians, and advisory committees. To regain public trust and restore integrity, it is imperative to first rebuild trust internally among the dedicated public servants within the FDA. Adoption of the aforementioned recommendations would start the trust-rebuilding process and lead to increased safety and precaution measures when approving drugs and medical devices.

Leveraging AdComm Membership

From January 2024 to July 2024, the Federation of American Scientists interviewed 30 current and former Advisory Committee (AdComm) members. Based on these discussions, we were able to source potential policy recommendations that may assist with enhancing the FDA’s ability to obtain valuable advice for evidence-based decision-making. The results of these discussions are presented in case study format detailing the recurring themes that emerged and policy recommendations for improvement.

The FDA relies on its scientific staff and Advisory Committees to provide conclusions from trial and study data, which aid in the process of regulating and approving medical products. Discussions have been centered around how to appropriately leverage the membership of Advisory Committee experts to assist with areas of difficulty surrounding the safety and efficacy of medical products. Nonetheless, the methods by which these systems currently generate the evidence the Government needs can be improved. This case study focuses on five key areas we believe can assist in fully utilizing the capacity in which AdComms serve and improve overall engagement with AdComms membership.

AdComm Membership Problems

Advisory Committees serve as the core for expert engagement in the Food and Drug Administration’s (FDA) decision-making processes and are composed of medical professionals, industry representatives, patient advocates, and scientific experts. Their primary role is to provide the FDA with informed advice and recommendations on issues spanning science, regulatory policy, and the evaluation of products under the FDA’s jurisdiction.

The intricacies of being an effective AdComm member, however, have been somewhat overlooked. Conversations with current and ex-members have highlighted areas for enhancement that would strengthen the function of AdComms and enrich the advice provided. Feedback indicated a lack of transparency in the FDA’s recruitment methods for committee positions, insufficient orientation or training for new members, limited understanding of regulatory procedures among members, and an onerous conflict of interest protocol that served as a deterrent for some members who were asked to return or renew their membership. 

Pathways to Improving AdComms Membership

Committee Composition

The composition of Advisory Committees vary depending on the charter that has been set in place. In some cases, committee composition has been set by law. However, where there is flexibility in determining the composition of a committee, consideration should be given to all categories of expertise that should be included and diversity of voices that are selected to participate in these meetings. Committee composition should reflect the diversity of the world and populations of whom their recommendations could potentially affect. For this reason, discussions with current and former Advisory Committee members indicated the need for three additional areas of expertise that should be included on all Committees. Insights discovered that all Committees should include a patient representative who has the knowledge from lived experience and understanding of how treatments affect day-to-day life. This recommendation was further corroborated by a 3D Communications survey conducted with 400+ FDA AdComm members where results indicated that 48% agreed there should be a patient and consumer representative on all Committees. Members also stated that pharmacists should be included because drugs and devices eventually pass through their hands to give to patients. Pharmacologists should serve on the Committee due to their clinical application knowledge of drugs and devices. Finally, a roster of temporary members should be created for varying categories to use when additional expertise is needed on a Committee because of a conflict of interest or when a certain skillset or knowledge base is lacking on the current Committee. 

Role of the Advisory Committee Chair

The FDA describes the purpose of an Advisory Committee chair as one who will “preside at committee meetings and ensure that all rules of order and conduct are maintained during each session”. The chair also has the responsibility of ensuring all recommendations and advice from AdComm members are clear and evidence-based. Moreover, the role of the chair should be used to enhance the overall committee experience as well as be of service to the FDA. Despite these requirements, there’s an underutilization of the chair’s role in terms of communication and stakeholder coordination, as evidenced by the chair not being listed as a primary point of contact for the Advisory Committee and a lack of coordination amongst stakeholders.

Chairpersons are usually selected due to their critical domain knowledge, understanding of best practices, ability to identify risks and keep members engaged, and expansive relationships within their industry. Maximizing the chairperson’s role requires discussion on how to utilize their valuable domain knowledge and professional networks. Chairs possess extensive networks that could support the identification of permanent or temporary expert participants for AdComms, aiding the FDA’s mission to recruit top talent for guidance. This would ensure the FDA’s continued success in recruiting the brightest minds in the industry to assist with providing advice. Additionally, chairs should have oversight in identifying relevant issues or products for their respective committees to appraise, which can provide another layer for the FDA to keep abreast of critical public concerns via appropriate committee evaluation. 

Training

Training is a significant part of many Federal Government service positions. However, besides ethics and conflict of interest trainings, there is no set training program in place for most new Advisory Committee members. Considering Advisory Committee members come from different professional backgrounds with varying levels of expertise, the FDA should develop an onboarding training program to assist with acclimating all new AdComm members into their roles. Many former and current AdComm members mentioned that no formal training was provided as part of the onboarding process. Some members who were new to the FDA AdComm process or who were not physicians or scientists stated they had no knowledge of statistical analyses, clinical trial design, or how the FDA views the role of the AdComm in the regulatory process. 

A foundational training, covering these aspects, would greatly benefit those members such as consumer and patient representatives who may lack this shared base of expertise. An investment in such an onboarding experience would promote stronger rapport among members and guarantee their preparedness in analyzing scientific and technical submissions.

Quotes from the Committee
“There should be basic training for all laypeople on the committee. This would help to prepare them for fulfilling their duties.”
“There should be an orientation that explains the relationship between the advisory committee and the FDA, and how the FDA thinks about this process.”

Learning about the FDA Regulatory Process

The Food & Drug Administration (FDA) was established with the purpose of regulating drugs and medical devices to ensure their safety and effectiveness for all citizens in the United States. Many Advisory Committee members join these committees without basic knowledge of the FDA’s regulatory process. During FAS’ discussions with current and former AdComm members, approximately 71% of members stated that basic knowledge of the regulatory process and how the FDA makes their decisions was unknown to them.

Providing AdComm members with an introductory course on the FDA’s regulatory process could enhance their comprehension, potentially allowing them to make more effective contributions and informed clinical decisions (based on their occupation). Although the FDA provides some online resources about its processes, like FAQs and guidelines, an expansion of this material should be considered for inclusion in AdComm orientation activities.  

Conflict of Interest (COI) Process

18 U.S.C. 208(a) prohibits Advisory Committee members who are designated as special government employees (SGE) from serving on federal advisory committees or any other Federal Government form of service that will have a “direct or predictable effect” on their financial interests. Similarly, the FDA describes a conflict of interest as an occurrence “when an individual selected to serve on an advisory committee has financial interests that may be impacted by the individual’s work on the advisory committee”. The auditing process for conflicts of interest is designed to confirm that the members of the advisory committee maintain impartiality and ensure the integrity of public health safety. Prior to any committee gathering, the FDA mandates that each participant, classified as either an AdComm member or SGE, complete an FDA 3410 form that reveals all financial connections that could be seen as potential COIs.

However, the process of what happens after the 3410 form has been completed is ambiguous. In 2007, the FDA submitted draft guidance to the federal register for comment entitled, Guidance for the Public, FDA Advisory Committee Members, and FDA Staff on Procedures for Determining Conflict of Interest and Eligibility for Participation in FDA Advisory Committees in an effort to determine if there is an inappropriate COI that should exclude members from participating in a committee meeting. Moreover, the official guidance is not easily accessible. Another draft guidance was developed with a detailed listing of considerations to be given when examining conflict of interests can be found in the FDA’s draft guidance on Procedures for Evaluating Appearance Issues and Granting Authorizations for Participation in FDA Advisory Committees.

Discussions with current and former AdComm members about the COI auditing process sparked varying views regarding whether flexibility should be exercised for COIs. 82% of members concurred that while they recognize the necessity for such a system, it tends to be overly demanding due to repetitive paperwork, especially when their circumstances remain unchanged. The strenuous nature of this routine has even deterred some from continuing their membership each year and remains a key aspect as to why members choose to end their service.

Despite having a COI process in place, there are loopholes that allow members with conflicts of interest to remain as voting members for specific AdComm meetings. A certain incident involved an Advisory Committee where 10 members who had financial ties to the sponsor were allowed to participate in an AdComm meeting. These individuals ultimately took part in endorsing the TriClip G4 System by Abbott and unanimously agreed that its benefits outweighed the potential risks. To further complicate matters, this information was not disclosed to the public at the time of approval.

While the COI process has resulted in members being rightfully disqualified from meetings due to actual or apparent conflicts, there is room to refine how these conflicts are identified and the standards employed to judge permissible COIs.

Policy Recommendations

In an effort to better leverage Advisory Committee membership, the potential policy recommendations are as follows:

Committee Composition

Role of the Chair

Training and Regulatory Process

COI Auditing Process

Conclusion

Advisory Committees are pivotal to maintaining trust with the public. It is essential for public safety to ensure that the most qualified experts are selected to serve on these Committees and that they have the tools to provide the FDA with informed and evidence-based recommendations. In an effort to increase public health safety, the FDA should enhance the AdComm structure by expanding the chair’s role, creating training programs for all new Advisory Committee members, and revising the conflict of interest procedures.

The Future of Voting for FDA Advisory Committees

From January 2024 to July 2024, the Federation of American Scientists interviewed 30 current and former Advisory Committee (AdComm) members. Based on these discussions, we were able to source potential policy recommendations that may assist with enhancing the FDA’s ability to obtain valuable advice for evidence-based decision-making. The results of these discussions are presented in case study format detailing the recurring themes that emerged and policy recommendations for improvement.

Advisory Committees (AdComms) serve as the core for expert engagement in the Food and Drug Administration’s (FDA) decision-making processes. These committees are composed of medical professionals, industry representatives, patient advocates, and scientific experts. Their primary role is to provide the FDA with informed advice and recommendations on issues spanning science, regulatory policy, and the evaluation of products under the FDA’s jurisdiction. Public meetings led by the FDA with these committees are instrumental in facilitating transparent deliberation between the FDA, the advisory body, and the American public. This practice helps to cultivate a collaborative environment between the FDA, the AdComms, and the public. AdComm recommendations are integral to strengthening public trust and reinforcing the FDA’s credibility. This relationship is corroborated by aligning the counsel of these independent entities with the FDA’s regulatory actions.

Key Problems Facing Advisory Committees

A critical component of the AdComm structure is its voting mechanism, a method by which hand-selected experts offer expert advice or recommendations on questions that have been proposed by the FDA to assist with informing its formal, regulatory decision-making. These questions include a broad range of topics, from evaluating post-market safety data to assessing pre-market product risks and benefits, and gauging whether a product should be approved or withdrawn from the market. The outcomes of the votes serve as barometers for the AdComms official stance on products and provide the FDA with a comprehensive and collective viewpoint. However, the recommendations proposed by AdComms are suggestive rather than prescriptive; ultimately, leaving the final decision to FDA leadership. 

Recent patterns indicate a reduction in the convening of AdComm meetings. In 2010, 55% of FDA-approved drugs were referred to an advisory committee. By 2021, the percentage of FDA-approved drugs with an advisory committee referral had dropped to 6%. The decline of meetings eliminates opportunities for evidence-based evaluation and deliberation that could potentially affect the health and well-being of Americans. Furthermore, the diminishing of these crucial interactions between the FDA, AdComms and the public exacerbates the lack of trust and erodes transparency. Interestingly, while most committees present definitive votes that are supported by explicit justifications for either approving or rejecting items under review, FDA Commissioner Robert Califf has suggested in multiple interviews that AC votes can be useful but are not mandatory for every meeting. This viewpoint raises concerns about the potential removal of voting from the reform agenda, which could undermine AdComms capacity to evaluate intricate topics that affect the American public consumer base. In addition, a survey conducted by 3D Communications with 400+ current and former AdComm members asked about the importance of voting. Results showed that 95% of AdComm members believe that voting should be retained when reviewing the benefits and risks of medical products. Reform discussions have materialized due to these factors, in addition to the FDA’s accelerated approval of Adulhelm (aducanumab) despite clear AdComm opposition. Demand for reform is inevitable and many are urging for there to be an increased number of AC meetings and a thorough reorganization of advisory committee operations and voting protocols. Such reform is not only administrative but also symbolic. This type of reform confirms that decisions affecting public health should be informed and shaped by multidisciplinary expertise. Additionally, it re-establishes the pivotal role of public input in regulatory affairs, which is an indispensable component to maintaining the American public’s trust.

Significance of AdComm Voting

In response to this call for AdComm reform, a project spearheaded by FAS has sought feedback from AdComm members regarding their views on the significance of voting. The intention of engagement is to understand members’ experiences as experts and their perspectives on voting by asking the following questions:

These questions aimed to measure the variability in voting mechanisms across committees and the value members place on voting. Results from 30 participants demonstrate a consensus on the critical role of voting in formulating committee recommendations, with 87% of committee members indicating a five (very important) as their stance on the importance of voting.

Policy Recommendations

To uphold the FDA’s integrity and regain public confidence, retaining voting at AdComm meetings is essential in addition to other recommendations to enhance the advisory committee process. The recommendations are as follows: 

Conclusion

The recommendations of FDA Advisory Committee members are a pivotal component to the FDA’s regulatory decision-making process. Maintaining the voting protocol for Advisory Committee meetings is essential as members strive toward the continued provision of precise, impartial, and evidence-based counsel to the FDA. This voting mechanism guarantees the inclusion of each member’s perspective and ensures that an official committee stance is taken, offering the FDA definitive and straightforward guidance.