USE OF SURROGATE ENDPOINTS FOR FDA APPROVAL OF DRUG USES

To support efforts by the Food and Drug Administration (FDA) and other stakeholders to qualify the appropriateness of surrogate endpoints; further,

To support the continued use of qualified surrogate endpoints by the FDA as a mechanism to evaluate the effectiveness and safety of new drugs and new indications for existing therapies, when measurement of definitive clinical outcomes is not feasible; further,

To advocate that the FDA consistently enforce existing requirements that drug product manufacturers complete postmarketing studies for drugs approved based on qualified surrogate endpoints in order to confirm that the expected improvement in outcomes occurs, and to require that these studies be completed in a timely manner.

Rationale

Expedited approval programs provided by the FDA have resulted in substantial public health benefits, as illustrated by the use of surrogate endpoints to approve therapies for HIV and AIDS in the 1990s. More recently, these programs facilitated the approval of COVID-19 vaccines and treatments. During the pandemic, surrogate endpoints played a crucial role by providing early indications of effectiveness, allowing faster implementation during the global health emergency. The FDA provides four mechanisms to expedite the development and review process for drugs: fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation. The structure and requirements for each of these mechanisms differs as described in a 2013 draft guidance for industry. However, to qualify for any of these programs, a drug must (1) address an unmet medical need, (2) provide benefit over available drug treatments, and (3) be used in the treatment of a serious or life-threatening condition. Further, the FDA guidance states that these programs are “intended to help ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the therapies’ benefits justify their risks.” Processes used to ensure a favorable risk–benefit profile include, but are not limited to, requirements for postmarketing studies to evaluate safety and effectiveness of the drug in real-world scenarios. However, the accelerated approval program is the only program that includes postmarketing studies as a requirement. The FDA has discretion to require additional studies on a case-by-case basis for drug products approved via the other expedited mechanisms. Despite these safeguards, some features of these programs (e.g., smaller clinical trials, alternate trial designs, or limited-duration trials) can result in increased patient risk because less is known about a drug’s side effect profile and efficacy due to limited patient exposure. In addition, as with all drugs, safety assessments benefit from use of the drug in post-approval patient populations, which better reflect real-world use than the controlled environment of a clinical trial.

A significant concern with the use of surrogate endpoints is the potential lack of transparency in how these endpoints are communicated to the medical community and general public. While surrogate endpoints are essential for facilitating drug approvals, their limitations and rationale for use are not always clearly conveyed. Without comprehensive clinical outcomes data, this lack of transparency can lead to misunderstandings about the benefits and risks of a drug. To address these issues, two new guidelines, SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials)-Surrogate and CONSORT (Consolidated Standards of Reporting Trials)-Surrogate, have been specifically developed to enhance the reporting of trials that rely on surrogate endpoints.

Given that these drugs represent medical advances, their post-approval use can be extensive and, like all therapies, off-label use of these drug products is common. Unfortunately, prescribers and other clinicians are frequently unaware that an expedited pathway was utilized and that evidence limitations exist. This scenario raises significant concerns about whether there is sufficient clinician awareness to ensure appropriate and informed use of drugs approved via these pathways. Therefore, ASHP proposes unique labeling requirements, such as use of a logo or other visual mechanism, to temporarily inform clinicians about data limitations and provide guidance on appropriate use. This labeling would describe appropriate patient populations and monitoring parameters. Similar labeling requirements have been proposed for a new pathway under consideration for the development of antibiotics used to treat life-threatening infections. ASHP supports the approach but recommends that the increased labeling requirements be discontinued once the drug product manufacturer and FDA agree that sufficient data is available to support safe and effective use, or after the drug manufacturer completes any required postmarketing study commitments.

Given data limitations associated with approval of these therapies, ASHP advocates that the FDA be extremely diligent in ensuring that postmarketing commitments are met. Further, the FDA should use its existing authority as described under 21 CFR 314 subpart H and 21 CFR 601 subpart E if timelines or expectations for these commitments are not satisfactory. This authority allows the FDA to take legal action through penalties that include requiring labeling changes or rescinding marketing approval.

Finally, ASHP believes that research is needed to determine whether these expedited pathways are achieving the desired benefits, which include reducing the time and costs associated with drug product development, lowering overall healthcare costs, and increasing patient access to safe and effective drug therapies.