Probability of Regulatory Approval Over Time: A Cohort Study of Cancer Therapies.

PURPOSE: New cancer therapies are frequently evaluated in multiple disease indications. We evaluated whether the probability of achieving US Food and Drug Administration (FDA) approval for a new cancer therapy changes with time. METHODS: We identified a cohort of anticancer drugs with a first registered efficacy trial from 2007 to 2011 on ClinicalTrials.gov. We downloaded all clinical trials for each included drug from the initiation of efficacy testing to January 11, 2021. Each trial was categorized by cancer indication and assigned to investigational trajectories on the basis of unique drug-indication pairings. We performed a univariate Cox's proportional hazards regression to assess the probability of a trajectory leading to regulatory approval over time since initiation of the first efficacy trial for a given drug. RESULTS: We included 213 drugs in our cohort, of which 37 (17.4%) received FDA approval in at least one oncology indication. In our primary analysis, we found a 15% decrease in the probability of approval for every year since initiation of the first efficacy trial (hazard ratio [HR], 0.85 [95% CI, 0.73 to 0.99]; P = .032). We found a 45% increase in the probability of approval for the first trajectory launched for a given drug in comparison with all others (HR, 0.55 [95% CI, 0.33 to 0.91]; P = .021). CONCLUSION: Drug-indication pairings pursued years after initial testing for efficacy have lowered probability of affecting care. Clinical trial investigators, sponsors, and regulatory bodies may benefit from awareness of this trend when considering both early and late trajectory trials in a drug's development.

Timing for First-in-Minor Clinical Trials of New Cancer Drugs.

OBJECTIVES: To describe the delay for first-in-minor cancer clinical trials and its relationship with the Food and Drug Administration (FDA) approval. STUDY DESIGN: We used ClinicalTrials.gov to create a sample of pediatric-relevant cancer drugs starting efficacy testing in adults from 2006 through 2011. We characterized the delay between first-in-adult efficacy trials and first-in-minor trials. We also assessed the proportion of drugs evaluated in minors that failed to gain approval, the proportions that were not evaluated in minors before receiving the FDA approval, and whether shorter delay was associated with larger effect sizes or greater probability of regulatory approval. RESULTS: Thirty-four percent of the 185 drugs in our cohort were evaluated in minors; the median delay to clinical trials was 4.16 years. Of all drugs, 17% received the FDA approval, 41% of which were never tested in minors before licensing. Of the 153 drugs not attaining approval, 78% were not evaluated in minors. Earlier testing did not significantly predict greater response rates (P = .13). Drugs not attaining regulatory approval were evaluated significantly earlier (3.0 for drugs not approved vs 5.4 years delayed testing for approved drugs, P = .019). CONCLUSIONS: New cancer drugs were typically evaluated in minors years after adult efficacy evaluation. This delay likely eliminated some drugs lacking desirable pharmacology before pediatric testing. However, some drugs that were eliminated may have had activity in pediatric indications. Approaches for prioritizing drugs for pediatric testing warrants further consideration.

Completeness of clinical evidence citation in trial protocols: A cross-sectional analysis.

BACKGROUND: Human protection policies require assessment of how proposed clinical trials relate to prior and ongoing studies testing similar hypotheses. We assessed the extent to which clinical trial protocols cited relevant published and ongoing clinical trials that would have been easily accessible with reference searches. METHODS: We created a random sample of trial protocols using ClinicalTrials.gov, stratifying by industry and non-industry-sponsored studies. We then conducted reference searches to determine the extent to which protocols cited clinical trials with identical intervention-indication pairings that were accessible in PubMed and ClinicalTrials.gov at the time of trial initiation. FINDINGS: Of the 101 trial protocols evaluated, 73 had at least one identified citable trial. None contained statements suggesting a systematic search for relevant clinical evidence. Of industry-sponsored trial protocols with at least one identified citable trial, 7 of 23 (30.4%) did not cite any published clinical trials and 10 of 33 (30.3%) did not cite any ongoing relevant trials. Of the non-industry-sponsored trial protocols with at least one identified citable trial, 5 of 28 (17.9%) did not cite any published clinical trials and 14 of 19 (73.7%) did not cite any ongoing trials. CONCLUSIONS: Clinical trial protocols undercite accessible, relevant trials and do not document systematic searches for relevant clinical trials. Consequently, ethics review committees often receive an incomplete picture of the research landscape if they review protocols similar to those deposited on ClinicalTrials.gov. FUNDING: This study was funded by the Canadian Institutes of Health Research and the Greenwall Foundation.

Probability of Success and Timelines for the Development of Vaccines for Emerging and Reemerged Viral Infectious Diseases.

BACKGROUND: Anticipated success rates and timelines for COVID-19 vaccine development vary. Recent experience with developing and testing viral vaccine candidates can inform expectations regarding the development of safe and effective vaccines. OBJECTIVE: To estimate timelines and probabilities of success for recent vaccine candidates. DESIGN: ClinicalTrials.gov was searched to identify trials testing viral vaccines that had not advanced to phase 2 before 2005, and the progress of each vaccine from phase 1 through to U.S. Food and Drug Administration (FDA) licensure was tracked. Trial characteristics were double-coded. (Registration: Open Science Framework [https://osf.io/dmuzx/]). SETTING: Trials launched between January 2005 and March 2020. PARTICIPANTS: Preventive viral vaccine candidates for 23 emerging or reemerged viral infectious diseases. MEASUREMENTS: The primary end point was the probability of vaccines advancing from launch of phase 2 to FDA licensure within 10 years. RESULTS: In total, 606 clinical trials forming 220 distinct development trajectories (267 343 enrolled participants) were identified. The probability of vaccines progressing from phase 2 to licensure within 10 years was 10.0% (95% CI, 2.6% to 16.9%), with most approvals representing H1N1 or H5N1 vaccines. The average timeline from phase 2 to approval was 4.4 years (range, 6.4 weeks to 13.9 years). The probabilities of advancing from phase 1 to 2, phase 2 to 3, and phase 3 to licensure within the total available follow-up time were 38.2% (CI, 30.7% to 45.0%), 38.3% (CI, 23.1% to 50.5%), and 61.1% (CI, 3.7% to 84.3%), respectively. LIMITATIONS: The study did not account for preclinical development and relied primarily on ClinicalTrials.gov and FDA resources. Success probabilities do not capture the varied reasons why vaccines fail to advance to regulatory approval. CONCLUSION: Success probabilities and timelines varied widely across different vaccine types and diseases. If a SARS-CoV-2 vaccine is licensed within 18 months of the start of the pandemic, it will mark an unprecedented achievement for noninfluenza viral vaccine development. PRIMARY FUNDING SOURCE: McGill Interdisciplinary Initiative in Infection and Immunity (MI4) Emergency COVID-19 Research Funding program.