Nicholas S. Downing

Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012

IMPORTANCE Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US Food and Drug Administration (FDA) has not been evaluated. OBJECTIVES To characterize pivotal efficacy trials (clinical trials that serve as the basis of FDA approval) for newly approved novel therapeutic agents. DESIGN AND SETTING Cross-sectional analysis using publicly available FDA documents for all novel therapeutic agents approved between 2005 and 2012. MAIN OUTCOMES AND MEASURES Pivotal efficacy trials were classified according to the following design features: randomization, blinding, comparator, and trial end point. Surrogate outcomes were defined as any end point using a biomarker expected to predict clinical benefit. The number of patients, trial duration, and trial completion rates were also determined. RESULTS Between 2005 and 2012, the FDA approved 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. The median number of pivotal trials per indication was 2 (interquartile range, 1-2.5), although 74 indications (36.8%) were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3% [95% CI, 86.4%-92.2%]), double-blinded (79.5% [95% CI, 75.7%-83.2%]), and used either an active or placebo comparator (87.1% [95% CI, 83.9%-90.2%]). The median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270-1550). At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8% [95% CI, 27.2%-40.4%]). Pivotal trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45.3% [95% CI, 38.3%-52.2%]), clinical outcomes for 67 (33.3% [95% CI, 26.8%-39.9%]), and clinical scales for 36 (17.9% [95% CI, 12.6%-23.3%]). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status, and accelerated approval. CONCLUSIONS AND RELEVANCE The quality of clinical trial evidence used by the FDA as the basis for recent approvals of novel therapeutic agents varied widely across indications. This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents.

Regulatory Review of Novel Therapeutics — Comparison of Three Regulatory Agencies

BACKGROUND The upcoming reauthorization of the Prescription Drug User Fee Act focuses on improving the review process for new drug applications at the Food and Drug Administration (FDA). METHODS Using publicly available information from the FDA, the European Medicines Agency (EMA), and Health Canada, we compared the time for completion of the first review and the total review time for all applications involving novel therapeutic agents approved by the three regulatory agencies from 2001 through 2010 and determined the geographic area in which each novel therapeutic agent was first approved for use. RESULTS There were 510 applications for novel therapeutic agents approved from 2001 through 2010--225 by the FDA, 186 by the EMA, and 99 by Health Canada; among the applications, there were 289 unique agents. The median length of time for completion of the first review was 303 days (interquartile range, 185 to 372) for applications approved by the FDA, 366 days (interquartile range, 310 to 445) for those approved by the EMA, and 352 days (interquartile range, 255 to 420) for those approved by Health Canada (P<0.001 for the comparison across the three agencies). The median total review time was also shorter at the FDA than at the EMA or Health Canada (P=0.002). Among the 289 unique novel therapeutic agents, 190 were approved in both the United States and Europe (either by the EMA or through the mutual recognition process), of which 121 (63.7%) were first approved in the United States; similarly, 154 were approved in both the United States and Canada, of which 132 (85.7%) were first approved in the United States. CONCLUSIONS For novel therapeutic agents approved between 2001 and 2010, the FDA reviewed applications involving novel therapeutics more quickly, on average, than did the EMA or Health Canada, and the vast majority of these new therapeutic agents were first approved for use in the United States. (Funded by the Pew Charitable Trusts.).

Mortality, Hospitalizations, and Expenditures for the Medicare Population Aged 65 Years or Older, 1999-2013

IMPORTANCE In a period of dynamic change in health care technology, delivery, and behaviors, tracking trends in health and health care can provide a perspective on what is being achieved. OBJECTIVE To comprehensively describe national trends in mortality, hospitalizations, and expenditures in the Medicare fee-for-service population between 1999 and 2013. DESIGN, SETTING, AND PARTICIPANTS Serial cross-sectional analysis of Medicare beneficiaries aged 65 years or older between 1999 and 2013 using Medicare denominator and inpatient files. MAIN OUTCOMES AND MEASURES For all Medicare beneficiaries, trends in all-cause mortality; for fee-for-service beneficiaries, trends in all-cause hospitalization and hospitalization-associated outcomes and expenditures. Geographic variation, stratified by key demographic groups, and changes in the intensity of care for fee-for-service beneficiaries in the last 1, 3, and 6 months of life were also assessed. RESULTS The sample consisted of 68,374,904 unique Medicare beneficiaries (fee-for-service and Medicare Advantage). All-cause mortality for all Medicare beneficiaries declined from 5.30% in 1999 to 4.45% in 2013 (difference, 0.85 percentage points; 95% CI, 0.83-0.87). Among fee-for-service beneficiaries (n = 60,056,069), the total number of hospitalizations per 100,000 person-years decreased from 35,274 to 26,930 (difference, 8344; 95% CI, 8315-8374). Mean inflation-adjusted inpatient expenditures per Medicare fee-for-service beneficiary declined from

Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010

3290 to

Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review

2801 (difference,

Analysis of Machine Learning Techniques for Heart Failure Readmissions

489; 95% CI,

Avoidance of Generic Competition by Abbott Laboratories' Fenofibrate Franchise

487-

Coronary Catheterization and Percutaneous Coronary Intervention in China: 10-Year Results From the China PEACE-Retrospective CathPCI Study

490). Among fee-for-service beneficiaries in the last 6 months of life, the number of hospitalizations decreased from 131.1 to 102.9 per 100 deaths (difference, 28.2; 95% CI, 27.9-28.4). The percentage of beneficiaries with 1 or more hospitalizations decreased from 70.5 to 56.8 per 100 deaths (difference, 13.7; 95% CI, 13.5-13.8), while the inflation-adjusted inpatient expenditure per death increased from

Publication of Pivotal Efficacy Trials for Novel Therapeutic Agents Approved Between 2005 and 2011: A Cross-sectional Study

15,312 in 1999 to

Innovation, Risk, and Patient Empowerment: The FDA-Mandated Withdrawal of 23andMe’s Personal Genome Service

17,423 in 2009 and then decreased to