he US Food and Drug Administration’s (FDA’s) controversial approval of the Alzheimer’s drug aducanumab (Aduhelm^TM) has kicked off a firestorm of debate, placing the Accelerated Approval Program (AAP) in the hot seat. The AAP seeks to balance the need for evidence of clinical efficacy with the need for access to novel drugs for seriously ill patients with no adequate options, a high-risk but potentially high-reward proposition.

While it is clear that FDA and drug sponsors must work together to proactively plan and diligently implement clinical trials for the collection of data sufficient to “convert” accelerated approval into traditional approval, equally important is ensuring that while clinical trials are pending, patients who receive AAP-approved drugs in the clinical setting fully understand the program, its limitations, and the tradeoffs they are making.

Under the AAP statute and regulations, FDA may grant approval of new drug products that meet the following criteria:

• They are for the treatment of a serious or life-threatening disease or condition.
• They provide a meaningful advantage over available therapy.
• They have an effect on a surrogate endpoint (such as a laboratory measurement) that is reasonably likely to predict clinical benefit, or on an intermediate clinical endpoint that is reasonably likely to predict an effect on survival or irreversible morbidity, as established through adequate and well-controlled clinical trials.

After AAP approval, to verify the drug’s predicted clinical benefit, applicants must complete confirmatory clinical trials. According to FDA regulations, these trials “would usually be studies already underway” and should be carried out “with due diligence.”

Delays in Confirmatory Trials Leave Patients in Limbo

Delays in commencing confirmatory trials should not come as a surprise. Lack of acceptable alternative treatments is a basic premise of the AAP; thus it is operationally and ethically challenging to conduct post-approval “controlled” clinical trials that withhold the AAP-approved drug for a portion of subjects. As a result, applicants may be required to test approved drugs in a patient population that does not fall within the label or that resides in a country where the drug has not been approved. In either case, the trial may not provide the definitive evidence sought, with additional time on the market for data analysis, regulatory action, and applicant/sponsor response. In its white paper “Strengthening the Accelerated Approval Pathway,” the Institute for Clinical and Economic Review (ICER) explains that despite the challenges implicit in conducting confirmatory trials and interpreting their results, the “FDA appears to have no formal process for exploring these issues with study sponsors following accelerated approval.”

For example, the drug hydroxyprogesterone caproate (Makena^TM) was approved under the AAP in 2011 to reduce the risk of pre-term birth. The drug was available for use prior to its FDA approval in compounded form after a small study conducted from 1999 to 2002 (the Meis trial) indicated efficacy based on the surrogate endpoint of gestational age. As a condition of accelerated approval, the applicant was required to conduct confirmatory trials to verify Makena’s clinical benefit to neonates. However, given its longstanding history of use as standard of care in the US, the confirmatory trial (the PROLONG trial) was conducted largely with subjects in Russia and Ukraine, whose risk of pre-term birth is lower than that of US patients. In 2019, the applicant announced that the PROLONG trial failed to confirm the drug’s benefit and, in 2020, FDA’s Center for Drug Evaluation and Research proposed to withdraw Makena from the market. Recently, however, FDA granted the applicant’s request for a hearing to review the proposed withdrawal, which is expected to focus on whether the drug is effective in a subgroup that looks more like the population studied in the Meis trial. In the meantime, the drug remains on the market, with apparent cautious support from two leading professional organizations, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM), and with many upset patients, some of whom recently sued the drug manufacturer.

Standardizing Patient Information on AAP Limitations

When drugs are available prior to FDA approval through clinical trials or the Expanded Access Program, information about the drug is made available to subjects/patients through the informed consent process and form, which is vetted by an institutional review board/ethical committee. In the clinical trial setting, in addition to providing information about the drug under investigation, the informed consent process and form are key in explaining the purposes of research and minimizing the risk of “therapeutic misperception”: the incorrect perception of subjects that a clinical trial is intended to benefit them individually.

After FDA approval, patients receive drug information from varied sources, including FDA-approved patient labeling (such as Medication Guides), manufacturers’ marketing communications, and communications with clinicians. However, information may be unclear or conflicting, in part due to the lack of regulatorily required AAP disclosure language in these patient-facing materials. According to ICER, in patient-facing materials “the basis for approval and the key uncertainties surrounding the product were also communicated inconsistently.”

Patient labeling and marketing communications could be further standardized with clear, easy-to-understand information on the AAP and how its approval standards may impact a patient’s care decisions. Likewise, incorporation of informed consent requirements into the AAP may help establish a baseline of understanding of the differences between the AAP and traditional approval, and help ensure that the baseline is maintained consistently, even if the drug becomes more familiar and widely prescribed by clinicians over time. Informed consent in the context of the AAP may be key in minimizing the risk of a different sort of “therapeutic misperception”: the incorrect perception of patients that an AAP-approved drug has been proven to be therapeutic.