PREMARKETING COMPARATIVE CLINICAL STUDIES

To advocate that Congress grant the Food and Drug Administration (FDA) authority to require premarketing comparative clinical trials when appropriate alternative agent(s) exist on the market, to elucidate the new agent’s role and place in therapy for the proposed indication; further,

To recommend that drug manufacturers include a summary of premarketing comparative study results in official product labeling, when available; further,

To advocate that Congress provide adequate funding to FDA and other agencies to support the additional tasks required by such premarketing comparative studies.

Rationale

In the past, new drugs were approved in the United States without a requirement to demonstrate efficacy or safety. Today, the FDA reviews new drug applications focusing on 3 major categories: the safety and efficacy of the drug for the proposed indication(s), appropriateness of the manufacturing process to ensure drug identity, potency, and purity, and proposed drug label information. Randomized controlled trials are the study design of choice to demonstrate the efficacy and safety of a new drug. Today, there is no requirement by the FDA that drug manufacturers conduct premarketing comparative studies due to a lack of legislation providing this express authority. A drug may be approved based on comparison to placebo alone, even if there are comparable treatment options available on the market. Demonstrated efficacy in placebo-controlled trials may overestimate the benefit of the drug and inadvertently lead prescribers to utilize a less effective drug, increases the risk for safety events and delayed time to care goals, and increased cost of care. Comparative clinical studies, when done in advance of approval consideration, may provide clinicians with critical information to stratify which patient populations are most appropriate candidates for a new drug in relation to therapeutic options already on the market.

Recently, the FDA has approved more drugs via expedited approval pathways, creating reliance on postmarketing studies to provide clarity on the role of the therapy in care, as well as for identification of undesirable treatment related effects. While postmarketing data is valuable, it is critical that potential efficacy and safety concerns be identified prior to drug approval where reasonable and applicable. Premarketing trials may not reveal all risks related to a drug, especially for those with adverse events that may take multiple years to emerge, adverse events that are relatively rare, or when used postmarket in more diverse or off-label populations. Postmarketing studies provide the best opportunity to identify such events. Currently, FDA industry guidance on the clinical studies section of product labeling notes that “active control clinical studies that imply comparative effectiveness” are among the study types to not include. The FDA should be granted the authority to require premarketing comparative clinical studies when appropriate, taking into account the potential impact of such therapies on patient care and timing to avoid approval delay when necessary, in order to ensure expedited availability for indications of unmet need. To ensure that the information in premarketing studies is of high integrity, consensus-driven, evidenced-based, and improves healthcare delivery and outcomes, the FDA could include the input of organizations such as the Pharmacy Quality Alliance, the Patient-Centered Outcomes Research Institute, and the Agency for Healthcare Research and Quality. Funding to allow for this expanded scope should be provided to support timely review and consideration of premarketing studies.