Under-reporting of cardiovascular events in the rofecoxib Alzheimer disease studies.

BACKGROUND: In September 2004, rofecoxib (Vioxx) was removed from the market after it was found to produce a near doubling of cardiovascular thrombotic (CVT) events in a placebo-controlled study. Its manufacturer stated that this was the first clear evidence of such risk and criticized previous analyses of earlier CVT risk for focusing on investigator-reported events. We studied contemporaneously adjudicated CVT events to assess the information on cardiovascular risk available while the drug was in widespread use. METHODS: Using an intention-to-treat analysis of adjudicated CVT deaths, we analyzed detailed patient-level data collected during 3 randomized placebo-controlled trials of rofecoxib versus placebo that had been designed to define the drug's possible role in the prevention or treatment of Alzheimer disease. All trials had been completed by April 2003. RESULTS: In the 3 studies combined, the data indicated that rofecoxib more than tripled the risk of confirmed CVT death (risk ratio = 3.57 [1.48-9.72], P = .004). This finding reached the P < .05 level of significance by June 2001. CONCLUSION: Intention-to-treat analysis of placebo-controlled studies of rofecoxib for Alzheimer disease demonstrated that the drug produced a significant increase in confirmed CVT deaths nearly 40 months before it was removed from the market. By contrast, published analyses of these trials were restricted to on-treatment analyses (ending 14 days after cessation of treatment) that did not reveal this risk. Intention-to-treat analyses of clinical trial data can reveal important information about potential drug risks and should be performed routinely and reported in a timely manner.

Use of US Food and Drug Administration Expedited Drug Development and Review Programs by Orphan and Nonorphan Novel Drugs Approved From 2008 to 2021.

Importance: The US Food and Drug Administration (FDA) has 4 programs that can be used alone or in combination to expedite drug availability: Accelerated Approval, Breakthrough Therapy, Fast Track, and Priority Review. Drugs using these programs can include novel drugs, which do not contain a previously FDA-approved active moiety, and orphan drugs, intended for diseases or conditions affecting fewer than 200 000 people; to date, no comprehensive evaluation of how these programs have been used in combination has been published. Objective: To assess how often and in what combinations expedited programs are used in the development and review of approved novel biologics and small-molecule drugs, stratified by orphan drug status and indication. Design, Setting, and Participants: This cross-sectional study evaluated all novel drugs that were FDA approved between January 1, 2008, and December 31, 2021. Main Outcomes and Measures: The main outcome was the frequency with which expedited programs were used and in what combinations, stratified by orphan drug status and drug type (small molecule vs therapeutic biologic). The unit of analysis was the novel drug-indication pair because a drug can be approved for multiple indications, each of which may use a different expedited program or differ in orphan drug status. Results: The study included 581 novel drug-indication pairs approved during the 14-year study period; 252 (43.4%) were orphan drugs, 139 (23.9%) were therapeutic biologics, and 442 (76.1%) were small-molecule drugs. Use of at least 1 expedited program increased from 11 of 26 drug-indication pairs (42.3%) in 2008 to 41 of 55 (74.5%) in 2021. Of the 363 approved drug-indication pairs using at least 1 expedited program, 225 (62.0%) were orphan drugs; at least 1 expedited program was used by 97 of the 139 approved biologic drugs (69.8%) and by 266 of the 442 approved small-molecule drugs (60.2%). Eighty-two of the 581 novel drug-indication pairs (14.1%) used the Accelerated Approval Program; of those, 65 (79.3%) were oncology drugs and 70 (85.4%) had an orphan designation. Conclusions and Relevance: The study showed that use of the FDA's expedited programs to bring novel drugs to market in the US increased from 2008 to 2021. The findings suggest that this trend is likely to continue.

Contents of US Food and Drug Administration Refuse-to-File Letters for New Drug Applications and Efficacy Supplements and Their Public Disclosure by Applicants.

Importance: Before reviewing drug applications, the US Food and Drug Administration (FDA) conducts "filing reviews" to assess whether they are complete enough for full review. If the applications are incomplete, the FDA issues refuse-to-file (RTF) letters identifying deficiencies. The FDA does not make these RTF letters public at the time of issuance. Why the FDA issues RTF letters and how often the letters and their contents are made publicly available are unknown. Objectives: To quantitatively analyze the FDA's reasons for issuing RTF letters and assess the public transparency of RTF letters and their contents. Design and Setting: This cross-sectional study analyzes RTF letters issued in response to new drug applications and efficacy supplements (applications for new indications or patient populations for already approved drugs) submitted to the FDA between January 1, 2008, and December 31, 2017. Statistical analysis was conducted in July 2019. Main Outcomes and Measures: Two types of information were extracted and cataloged from RTF letters: (1) the reasons why the FDA refused to file applications and (2) the FDA comments that, while not a basis for RTF letters, conveyed important information to applicants. The extent to which applicants publicly disclosed the FDA's refusal reasons were also assessed. Results: The study included 103 RTF letters containing a total of 644 identified FDA refusal reasons. Among the 2475 applications that the FDA received during the study time frame, 98 (4.0%) received RTF letters. Overall, 84.5% (544 of 644) of the refusal reasons were for scientific deficiencies; most reasons were related to drug efficacy and safety (196 [30.4%]) and drug quality (125 [19.4%]). The remaining 15.5% of refusal reasons (100 of 644) were for application organization deficiencies or legal issues. A total of 26.2% of the RTF letters (27 of 103) identified presubmission advice from the FDA that applicants did not follow; the most frequently ignored advice was related to clinical trial design (33.3% [9 of 27]), followed by product chemistry and manufacturing (25.9% [7 of 27]). Applicants publicly disclosed the existence of 16 of 103 RTF letters (15.5%); however, only 5.4% of applicant-disclosed reasons (35 of 644) matched the refusal reasons that the FDA had provided in the RTF letters. Conclusions and Relevance: This cross-sectional study found that the FDA refused to file applications for substantive reasons related to quality, safety, and efficacy, and applicants' disclosure of those reasons was incomplete. This work sheds light on the FDA's regulatory decision-making processes and the RTF reasons that could delay availability of therapies to patients.

Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study.

OBJECTIVES: To describe the content of non-public complete response letters issued by the US Food and Drug Administration (FDA) when they do not approve marketing applications from sponsors (drug companies) and to compare them with the content any subsequent press releases issued by those sponsors DESIGN: Cross sectional study. DATA SOURCES: All applications for which FDA's Center for Drug Evaluation and Research initially issued complete response letters (n=61) from 11 August 2008 to 27 June 2013. Complete response letters and press releases were divided into discrete statements related to seven domains and 64 subdomains and assessed to determine whether they matched. RESULTS: 48% (29) of complete response letters cited deficiencies in both the safety and efficacy domains, and only 13% cited neither safety nor efficacy deficiencies. No press release was issued for 18% (11) of complete response letters, and 21% (13) of press releases did not match any statements from the letters. Press release statements matched 93 of the 687 statements (14%), including 16% (30/191) of efficacy and 15% (22/150) of safety statements. Of 32 complete response letters that called for a new clinical trial for safety or efficacy, 59% (19) had matching press release statements. Seven complete response letters reported higher mortality rates in treated participants; only one associated press release mentioned this fact. CONCLUSIONS: FDA generally issued complete response letters to sponsors for multiple substantive reasons, most commonly related to safety and/or efficacy deficiencies. In many cases, press releases were not issued in response to those letters and, when they were, omitted most of the statements in the complete response letters. Press releases are incomplete substitutes for the detailed information contained in complete response letters.