Medications for serious or life-threatening conditions may receive accelerated approval from the U.S. Food and Drug Administration (FDA) by showing an effect on surrogate measures that are reasonably likely to predict a treatment’s clinical benefit. Post-approval confirmatory drug trials are then required to determine whether or not these effects translate into clinical improvements. In recent years, the number of drugs that have received FDA accelerated approval has increased.
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When drugs undergo the accelerated approval process, the concern is that the safety and efficacy of these agents are not well established. Additional concern exists because this safety and efficacy information may not be confirmed during three-year, post-drug-approval trials. Some clinicians believe the drugs undergoing the accelerated approval process may pose a greater risk to patients, while others look toward proved effectiveness, rather than just surrogate markers of efficacy.
In a recent study, researchers evaluated the characteristics of drugs that received FDA accelerated approval between 2009 and 2013.1 They reviewed publicly available FDA documents used in the preapproval trials that led to the accelerated drug approvals to determine the characteristics of the drugs receiving this approval. The FDA’s post-marketing database of requirements, commitments and matched, peer-reviewed publications was also used to obtain needed information. The study follow-up ended on April 7, 2017. Its design features a comparison of the preapproval and confirmatory studies. Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were also summarized.
During the evaluated timeframe, the FDA granted accelerated approval to 22 drugs for 24 indications, with 38 preapproval studies supporting 24 indications. Nineteen indications were for oncologic treatment. Of the required post-approval confirmatory studies, 19 of 38 (50%) were completed in a minimum of three years post-approval. Of these studies, most showed some treatment benefit, but relied on surrogate measures rather than clinical outcomes. Twenty-five of the 38 (66%) studies observed clinical efficacy, seven (18%) evaluated longer follow-up and six (16%) evaluated safety. The proportion of randomized studies did not differ before and after accelerated approval.
Efficacy was demonstrated for 10 of 24 (42%) indications in completed studies that used surrogate measures. As a result, the package inserts (e.g., drug labels) of these medications were updated. Of the 14 of 24 (58%) indications that had not completed all the requirements, at least one of the confirmatory studies did not demonstrate a clinical benefit, two (8%) were terminated and three (13%) were delayed by more than one year.
For the remaining seven indications (29%), studies were progressing according to target timelines. Clinical benefit had not yet been confirmed for eight indications that had been initially approved at least five years prior. The most common surrogate measure in the preapproval studies was disease response, because many drugs were cancer agents. Other surrogate measures included time-to-event outcomes, such as progression-free survival and time-to-sputum culture conversion; and change in baseline biomarker levels, such as liver iron concentration. Most requirements were for randomized clinical trials (n=25); the rest (n=13) were single-group studies, including long-term extensions of preapproval studies.
Among the 22 drugs with 24 indications granted FDA accelerated approval in the studied timeframe, efficacy was often confirmed in post-approval trials a minimum of three years after approval in most studies. The confirmatory and preapproval trials had similar study elements, including using surrogate measures as outcomes. Although this type of evaluation has many limitations, the information can be useful in evaluating post-marketing safety and effectiveness for use in patients.
Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.
- Naci H, Smalley K, Kesselheim A. Characteristics of preapproval and postapproval Studies for drugs granted accelerated approval by the U.S. Food and Drug Administration. JAMA. 2017 Aug 15;318(7):626–636. doi: 10.1001/jama.2017.9415.