Analysis of Postapproval Clinical Trials of Therapeutics Approved by the US Food and Drug Administration Without Clinical Postmarketing Requirements or Commitments

Skydel, Joshua J.; Luxkaranayagam, Anita T.; Dhruva, Sanket S.; Ross, Joseph S.; Wallach, John R.

doi:10.1001/jamanetworkopen.2019.3410

Cited by 15 publications

(23 citation statements)

References 26 publications

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“…Using registries in this way to gather postapproval data on medicines will possibly be more effective than setting up and conducting (multiple) trials, which may have a longer lead-time. In a study including 600 nonrequired postapproval trials, the median duration of these trials was 37 (22–57) months [ 24 ]. The median duration of trials on cancer or hematology ( n = 437) was 43 (29–66) months.…”

Section: Discussionmentioning

confidence: 99%

Postapproval trials versus patient registries: comparability of advanced melanoma patients with brain metastases

Ismail

Sikkes²,

Wouters

et al. 2020

Melanoma Research

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Postapproval trials and patient registries have their pros and cons in the generation of postapproval data. No direct comparison between clinical outcomes of these data sources currently exists for advanced melanoma patients. We aimed to investigate whether a patient registry can complement or even replace postapproval trials. Postapproval single-arm clinical trial data from the Medicines Evaluation Board and real-world data from the Dutch Melanoma Treatment Registry were used. The study population consisted of advanced melanoma patients with brain metastases treated with targeted therapies (BRAF- or BRAF-MEK inhibitors) in the first line. A Cox hazard regression model and a propensity score matching (PSM) model were used to compare the two patient populations. Compared to patients treated in postapproval trials ( n = 467), real-world patients ( n = 602) had significantly higher age, higher ECOG performance status, more often ≥3 organ involvement and more symptomatic brain metastases. Lactate dehydrogenase levels were similar between both groups. The unadjusted median overall survival (mOS) in postapproval clinical trial patients was 8.7 (95% CI, 8.1–10.4) months compared to 7.2 (95% CI, 6.5–7.7) months ( P < 0.01) in real-world patients. With the Cox hazard regression model, survival was adjusted for prognostic factors, which led to a statistically insignificant difference in mOS for trial and real-world patients of 8.7 (95% CI, 7.9–10.4) months compared to 7.3 (95% CI, 6.3–7.9) months, respectively. The PSM model resulted in 310 matched patients with similar survival ( P = 0.9). Clinical outcomes of both data sources were similar. Registries could be a complementary data source to postapproval clinical trials to establish information on clinical outcomes in specific subpopulations.

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Section: Discussionmentioning

confidence: 99%

Postapproval trials versus patient registries: comparability of advanced melanoma patients with brain metastases

Ismail

Sikkes²,

Wouters

et al. 2020

Melanoma Research

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“…The primary outcome providing the highest level of evidence was recorded. For instance, for trials with multiple primary efficacy outcomes, we considered clinical outcomes the highest level, followed by clinical scales and surrogate markers [18]. A third reviewer (SSD) repeated all searches for trials that were determined to be unregistered, and uncertainties were discussed with the senior investigator (JSR).…”

Section: Methodsmentioning

confidence: 99%

Postmarketing commitments for novel drugs and biologics approved by the US Food and Drug Administration: a cross-sectional analysis

Wallach

Luxkaranayagam

Dhruva

et al. 2019

BMC Med

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Background Postmarketing commitments are clinical studies that pharmaceutical companies agree to conduct at the time of FDA approval, but which are not required by statute or regulation. As FDA increasingly adopts a lifecycle evaluation process, greater emphasis will be placed on postmarket evidence as a component of therapeutic evaluation. Therefore, the objectives of this study were to determine how often postmarketing commitments agreed upon by pharmaceutical companies at first FDA approval lead to new clinical trials and to establish the characteristics and rates of completion and dissemination of postmarketing commitments. Methods For new drugs and biologics approved in 2009–2012, we used public FDA documents, ClinicalTrials.gov, and Scopus, to determine postmarketing commitments and their characteristics known at the time of FDA approval; number subject to reporting requirements, for which FDA is required to make study status information available to the public (“506B studies”), and their statuses; and rates of registration and results reporting on ClinicalTrials.gov and publication in peer-reviewed journals for all clinical trials. Results Among 110 novel drugs and biologics approved by the FDA between 2009 and 2012, 61 (55.5%) had at least one postmarketing commitment at the time of first approval. Of 331 total postmarketing commitments, 33 (10.0%) were for new clinical trials; 27 of these were 506B studies subject to public reporting requirements, of which 12 (44.4%) did not have a recent (i.e., up-to-date) or closed (i.e., fulfilled or released) status provided publicly by the FDA. Although two postmarketing commitments were insufficiently described in FDA records to perform searches on ClinicalTrials.gov, nearly all (28, 90.3%) of the 31 remaining postmarketing commitments for new clinical trials were registered on ClinicalTrials.gov. Among the registered trials, 23 (23 of 28, 82.1%) were classified as completed or terminated, of which 22 (95.7%) had reported results. When considering all 29 completed or terminated clinical trials, registered or unregistered on ClinicalTrials.gov, only half (14, 48.3%) were published in peer-reviewed journals. Conclusions While only 15% of postmarketing commitments agreed to by pharmaceutical companies at the time of FDA approval were for new clinical trials, these trials were nearly always registered with reported results on ClinicalTrials.gov. However, only half were published, and despite FDA public reporting requirements, recent status information was often unavailable for 506B studies. Electronic supplementary material The online version of this article (10.1186/s12916-019-1344-3) contains supplementary material, which is available to authorized users.

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“…Studies about drugs targeting rare conditions have similar designs as those investigating drugs treating non-rare conditions in the post-marketing period. 28 Among novel therapeutic agents that received accelerated approval between 2000 and 2013, clinical benefit was often confirmed in post-marketing trials which had similar design elements to preapproval trials, including reliance on non-randomised designs, and surrogate endpoints. 22 Cancer drugs approved by the FDA based on the surrogate endpoint of response rate were often tested in post-marketing studies that captured other similar surrogate endpoints.…”

Section: Regulatory Agency-driven Research In the Post-marketing Periodmentioning

confidence: 99%

“…Most new drugs have industry-initiated post-marketing studies; however, the majority of these are conducted in therapeutic areas outside of the approved indication (or including participants that extend beyond the indicated population). 28 Such studies could be useful if they produce unbiased evidence on clinically relevant outcomes for the original approved indication and beyond. Instead, companies conduct post-marketing studies to seek approvals in new indications or expand their already-approved indications.…”

Section: Industry-initiated Research In the Post-marketing Periodmentioning

confidence: 99%

Generating comparative evidence on new drugs and devices after approval

et al. 2020

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Certain limitations of evidence available on drugs and devices at the time of market approval often persist in the post-marketing period. Too often, post-marketing research landscape is fragmented. When regulatory agencies require pharmaceutical and device manufacturers to conduct studies in the post-marketing period, these studies may remain incomplete many years after approval. Even when completed, many post-marketing studies lack meaningful active comparators, have observational designs, and may not collect patient-relevant outcomes. It is crucial for regulators, in collaboration with the industry and patients, to ensure that the important questions that are unanswered at the time of drug and device approval are resolved in a timely fashion during the post-marketing phase. We propose a set of seven key guiding principles that we believe will provide the necessary incentives for pharmaceutical and device manufacturers to generate comparative data in the post-marketing period. First, regulators and pharmaceutical companies (for drugs), notified bodies and manufacturers (for devices) should develop customised evidence generation plans, ensuring that future post-approval studies address any limitations of the data available at the time of market entry that would influence the benefit-risk profiles of drugs and devices. Second, post-marketing studies should be designed hierarchically: priority should be given to efforts aimed at evaluating a product's net clinical benefit in randomised trials compared with current known effective therapy, whenever possible, to address common decisional dilemmas. Third, post-marketing studies should incorporate active comparators as appropriate. Fourth, use of non-randomised studies for the evaluation of clinical benefit in the post-marketing period should be limited to instances when the magnitude of effect is deemed to be very large or when it is possible to reasonably infer the comparative benefits or risks in settings where doing a randomised trial is not feasible. Fifth, efficiency of randomised trials should be improved by streamlining patient recruitment and data collection through innovative design elements. Sixth, governments should directly support and facilitate the production of comparative post-marketing data by investing in the development of collaborative research networks and data systems that reduce the complexity, cost, and waste of rigorous postmarketing research efforts. Seventh, financial incentives and penalties should be developed or more actively reinforced.

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Analysis of Postapproval Clinical Trials of Therapeutics Approved by the US Food and Drug Administration Without Clinical Postmarketing Requirements or Commitments

Abstract: This cross-sectional study characterizes postapproval clinical trials sponsored by pharmaceutical companies of therapeutics approved by the US Food and Drug Administration (FDA) without postmarketing requirements or commitments.

Cited by 15 publications

References 26 publications

Postapproval trials versus patient registries: comparability of advanced melanoma patients with brain metastases

Postapproval trials versus patient registries: comparability of advanced melanoma patients with brain metastases

Postmarketing commitments for novel drugs and biologics approved by the US Food and Drug Administration: a cross-sectional analysis

Generating comparative evidence on new drugs and devices after approval

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