Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012 (original) (raw)
Related papers
Journal of Clinical Epidemiology, 2019
Introduction: Novel cancer therapies are often approved with evidence from a single pivotal trial alone. There are concerns about the credibility of this evidence. Higher validity may be indicated by five methodological and statistical characteristics of pivotal trial evidence that were described by the US Food and Drug Administration (FDA) which may corroborate the reliance on a single trial alone for approval decisions. Methods: We did a meta-epidemiologic evaluation of all single pivotal trials supporting FDA approval of novel drugs and therapeutic biologicals for cancers between 2000 and 2016. For each trial, we determined the presence of these five characteristics, which we operationalized as (1) large and multicenter trial (≥200 patients; more than one center); consistent treatment benefits across (2) multiple patient subgroups (in view of FDA reviewers), (3) multiple endpoints (including overall survival , progressionfree survival, response rate, health related quality of life) and (4) multiple treatment comparisons (e.g. multi-arm studies); (5) "statistically very persuasive" results (p-values <0.00125). Results: Thirty-five of 100 approvals were based on evidence from a single pivotal trial without any further supporting evidence on beneficial effects (20 randomized controlled trials and 15 single-arm trials). The number increased substantially from 1 approval before 2006 to 23 after 2011. Sixty-six percent (23/35) of the trials were large multicenter trials (median 301 patients and 63 centers). Consistent effects were demonstrated across subgroups in 66% (23/35), across endpoints in 43% (15/35), and across multiple comparisons in 3% (1/35). Very low p-values for the primary endpoint were seen in 34% (12/35). At least one of the corroborating characteristics was present in 94% (33/35) of all approvals, two or more were present in 54% (19/35) and none had all characteristics. Conclusions and relevance: Single pivotal trials typically have some of the corroborating characteristics, but often only one or two. These characteristics need to be better operationalized, defined and reported and whether single trials with such characteristics provide similar evidence about benefits and harms of novel treatments as multiple trials would do, needs to be shown.
BMJ open, 2015
To evaluate clinical trial registration, reporting and publication rates for new drugs by: (1) legal requirements and (2) the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge. Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration (FDA) for drugs approved in 2012, sponsored by large biopharmaceutical companies. Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications. Clinical trial registration and results reporting in ClinicalTrials.gov, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts (FDAAA), analysed on the drug level. The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99 599 research participants. Per drug, a median of 57% (IQR 32-83%) of trials were registered, 20% (IQR 12-28%) reported results in ClinicalTrials.gov, 56% (...
Outcome Assessments of Primary Endpoints of New Drugs Approved by the Fda (2011-2015)
Value in Health, 2016
Objectives: To assess the extent of use of endpoints based on survival, biomarker and clinical outcome assessments (COAs) consisting of Clinician-reported outcomes (ClinROs), Observer-reported outcomes (ObsROs), Patient-reported outcomes (PROs) and Performance outcomes (PerfOs) as primary endpoints in confirmatory studies of new drugs approve from 2011 through 2015. MethOds: New drugs approved between January 2011 and December 2015 were identified using Drugs@ FDA database. Labeling and medical review sections from FDA DAPs were reviewed to identify indication and the primary endpoint of confirmatory studies. ICD-10 codes were used to classify disease and the primary endpoints were classified based on the type of outcome assessment. Descriptive data were recorded in Microsoft Excel; frequency of measured characteristics was analyzed. Results: Of the 182 new drugs approved the majority of the approvals were for drugs related to cancer (27.5%), anti-infective (15.9%) and endocrine, nutritional and metabolic diseases (15.4%). ClinROs and biomarkers constituted 47.8% and 40.7% of the primary endpoints respectively. PROs, survival and PerfO constituted 13.2%, 14.3% and 1.1% of the primary endpoints respectively. PROs were commonly found to be the primary endpoint in diseases related to genitourinary (80%), musculoskeletal (66.7%) and digestive systems (50%). Approvals related to cancer drugs relied on ClinROs (76%), biomarkers (14%) and survival (36%) as primary endpoints. Only six approvals (3.2%) were based on primary endpoints that were composite of PRO and another type of outcome. cOnclusiOns: ClinROs and biomarkers are used as primary endpoints in the majority of confirmatory studies of recent FDA approvals. PROs were key to assess treatment benefit in diseases such as those related to genitourinary, digestive and musculoskeletal systems as per respective regulatory guidance.
Clinical Trials of New Drug Products: What Gets Compared to Whom
American Journal of Clinical and Experimental Medicine, 2015
Two of the most controversial aspects of phase III clinical trial design are the choice of the control group(s) and the choice of the outcome variable(s). Each of these choices has overlapping scientific and ethical ramifications, and the tension between maximizing scientific validity on the one hand, and protecting the rights and welfare of the human participants in the trial on the other, is the main source of the controversy. The intensity of the debate is increased whenever these choices are motivated not by scientific or ethical principles, but are driven by conflicts of interest. And so it comes to pass that in testing the safety and efficacy of new drug products, when study design choices are made more to achieve rapid market approval than to accurately assess safety and efficacy, thereby putting the welfare of both the trial participants and future patients at risk, the public and its advocates will recoil. In this paper, we study two issues of this kind: the use of placebo controls when an established intervention for the condition under consideration exists, and the use of surrogate outcome measures. There is a rich and growing literature on both of these topics and we will have little to contribute to a greater theoretical understanding of either of them. Our aim is to point to the ethical ramifications of these choices in the context of clinical trials of new drug products, and to suggest how these choices may be better made to serve public health interests. What is to come is portended by the observation that, "In the United States, the long tradition of leaving to the pharmaceutical industry the task of evaluating the efficacy and safety of its products has permitted manufacturers to make study design choices that largely determine the shape of the answers eventually provided by the trials" (Psaty and Weiss, 2007, p. 330).
Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results
JAMA internal medicine, 2016
Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research. To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results. Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product. For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval. Among 640 novel the...
The Journal of Clinical Pharmacology, 2007
The new drug application database submitted to the US Food and Drug Administration for drug approval (phases I-III or phases 1-3) is limited both in scope and size. Although randomized controlled trials, the hallmark of phase III trials, are the gold standard for the drug-approval process, they invariably have a number of limitations, including relatively small sample sizes, selective populations, short follow-up, the use of intermediate (surrogate) endpoints (almost always), and limited generalizability. The challenges of monitoring drugs once approved are also numerous. After approval by the Food and Drug Administration, marketed drugs undergo continued scrutiny, and this scrutiny is increasing because of problems that have surfaced with some drugs after their approval. Postmarketing research includes a variety of study designs and the use of registries and self-reporting of drug side effects. Along with this has come great confusion about what postmarketing research is and what a phase IV study is. Among the important strengths of phase IV research are the exposure of a broader range of patients to the drug under study, resulting in more &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;real-world&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; information about the drug&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s safety and efficacy, and consideration of a broader range of clinical endpoints. As a result, phase IV, or postmarketing research, has become an integral part of the drug evaluation process for a wide range of agents. The authors discuss the different types of study designs that are common under the phase IV terminology and provide some examples. They also discuss the use of registries and self-reporting of adverse events using the MedWatch System.
Pharmaceutical Statistics, 2011
, b on behalf of European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) The European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) engages more than 2000 statisticians through its ten national organizations. Amongst other things, EFSPI is involved in reviewing regulatory guidelines under development, including the draft FDA guideline on non-inferiority clinical trials. This review resulted in several critical comments relating to as follows: (i) the lack of one single standard for proving efficacy of new drugs implied by the guideline; (ii) the problems with the suggested 'fraction of effect to be preserved'; (iii) the formulation of the primary hypothesis in a non-inferiority trial aiming at indirectly demonstrating a new drug is superior to placebo; and (iv) the preference in the guideline for the fixedmargin method over the synthesis method in the analysis. The presumed implications of this guideline, if implemented as is, are (i) increased confusion of how efficacy could be demonstrated when placebo control is not available, (ii) more complicated communication between pharmaceutical industry and FDA because of the apparent disagreements on fundamental statistical matters, and (iii) illogical consequences in the approval process because of which order drugs are approved rather than how they fulfill the regulatory requirements. We believe that the area is not yet ready for such a prescriptive regulatory guidance and that further research and experience are required until the methodology can be finally agreed. A strategy needs to be developed by regulatory agencies together with drug industry and academia for a long term solution for this topic. Copyright