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Background: Drugs and high-risk medical devices are increasingly likely to receive Food and Drug Administration (FDA) approval through expedited pathways, which has implications for informed treatment consent (i.e., consent in clinical practice)., Objective: To obtain expert opinion about the clinical and ethical implications of the increasing availability of new drugs and devices approved through expedited development and regulatory review pathways., Design: Qualitative study using individual semi-structured videoconference interviews., Participants: National leaders in medicine, ethics, and law (n=12) with expertise in medical product regulation, payor policymaking, bioethics, physician practice, patient advocacy, public health expertise/advocacy, clinical trials, the pharmaceutical and device industry, institutional review board oversight, and real-world evidence., Main Measures: Principal themes in 3 domains: expedited regulatory pathways, physician and patient understanding of and reliance on FDA approval, and informed treatment consent., Key Results: Respondents pointed out that more common use of expedited pathways translates to increased reliance on surrogate measures, some with uncertain clinical significance. While expedited development and review can have advantages, participants expressed worry that physicians were unaware when medical products were expedited and did not communicate about uncertainties in knowledge about new drug or device approvals effectively with patients. Many participants felt that informed treatment consent discussions about new drugs or devices should include some explanations of expedited pathways and use of surrogate measures., Conclusions: Experts identified advantages of expediting development and of FDA flexibility in applying its standards to new drugs and medical devices, but highlighted concerns that patients may not be adequately informed about the risks of shorter review times or about uncertainties in the evidence that result. There is a need to identify approaches to ensure effective clinical use of drugs and devices when approved through expedited pathways., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background/aims: The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018., Methods: We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated., Results: From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications., Conclusions: The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.

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.

Importance: The US Food and Drug Administration (FDA) can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics. Pharmaceutical companies can also agree to conduct nonmandated clinical trials as postmarketing commitments. However, when therapeutics are approved by the FDA without postmarketing requirements or postmarketing commitments, it is not well known how often pharmaceutical companies voluntarily conduct trials and report results monitoring safety or efficacy after approval., Objective: To characterize postapproval clinical trials sponsored by pharmaceutical companies of therapeutics initially approved by the FDA without clinical postmarketing requirements or commitments., Design, Setting, and Participants: This cross-sectional analysis included postapproval clinical trials conducted with at least 1 site in the United States sponsored by pharmaceutical companies of therapeutics first approved by the FDA from 2009 through 2012. Analyses were conducted June 11, 2018, to November 30, 2018., Main Outcomes and Measures: Postapproval clinical trials registered on ClinicalTrials.gov generating safety or efficacy data, characteristics including whether trials focused on approved or unapproved indications, study design elements, and rates of study completion and results reporting., Results: From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications, of which 37 novel therapeutics for 39 indications did not have postmarketing requirements or commitments for new clinical studies at the time of first approval. For 31 therapeutics (83.8%), there were 600 postapproval clinical trials sponsored by pharmaceutical companies. Most trials investigated therapeutics for new indications (363 [60.5%]) or expanded populations of the originally indicated disease (122 [20.3%]). Trials were often small (median [interquartile range] enrollment, 44 [21-131] participants), nonrandomized (359 [59.8%]), unblinded (455 [75.8%]), and lacked comparators (381 [63.5%]). Approximately half of the trials (311 [51.8%]) assessed at least 1 clinical outcome. Of 300 terminated or completed trials, 204 trials (68.0%) had reported results on ClinicalTrials.gov a median (interquartile range) 16 (13-25) months after their primary completion date. For the 96 trials (32.0%) without reported results, a median (interquartile range) 35 (13-62) months had passed since their primary completion date., Conclusions and Relevance: Pharmaceutical companies frequently conducted clinical trials after approval, even when there were no clinical postmarketing requirements or commitments at approval. However, most of these trials evaluated new indications or expanded patient populations rather than monitored approved uses, and nearly half of the trials remained incomplete more than 5 years after original therapeutic approval.

Background: Regulatory approval of novel therapies by the FDA does not guarantee insurance coverage requisite for most clinical use. In the United States, the largest health insurance payer is the Centers for Medicare & Medicaid Services (CMS), which provides Part D prescription drug benefits to over 43 million Americans. While the FDA and CMS have implemented policies to improve the availability of novel therapies to patients, the time required to secure Medicare prescription drug benefit coverage-and accompanying restrictions-has not been previously described., Objective: To characterize Medicare prescription drug plan coverage of novel therapeutic agents approved by the FDA between 2006 and 2012., Methods: This is a cross-sectional study of drug coverage using Medicare Part D prescription drug benefit plan data from 2007 to 2015. Drug coverage was defined as inclusion of a drug on a plan formulary, evaluated at 1 and 3 years after FDA approval. For covered drugs, coverage was categorized as unrestrictive or restrictive, which was defined as requiring step therapy or prior authorization. Median coverage was estimated at 1 and 3 years after FDA approval, overall, and compared with a number of drug characteristics, including year of approval, CMS-protected class status, biologics versus small molecules, therapeutic area, orphan drug status, FDA priority review, and FDA-accelerated approval., Results: Among 144 novel therapeutic agents approved by the FDA between 2006 and 2012, 14% (20 of 144) were biologics; 40% (57 of 144) were included in a CMS-protected class; 31% (45 of 144) were approved under an orphan drug designation; 42% (60 of 144) received priority review; and 11% (16 of 144) received accelerated approval. The proportion of novel therapeutics covered by at least 1 Medicare prescription drug plan was 90% (129 of 144) and 97% (140 of 144) at 1 year and 3 years after approval, respectively. At 3 years after approval, 28% (40 of 144) of novel therapeutics were covered by all plans. Novel therapeutic agents were covered by a median of 61% (interquartile range [IQR] = 39%-90%) of plans at 1 year and 79% (IQR = 57%-100%) at 3 years (P < 0.001). When novel therapeutics were covered, many plans restricted coverage through prior authorization or step therapy requirements. The median proportion of unrestrictive coverage was 29% (IQR = 13%-54%) at 3 years. Several drug characteristics, including therapeutic area, FDA priority review, FDA-accelerated approval, and CMS-protected drug class, were associated with higher rates of coverage, whereas year of approval, drug type, and orphan drug status were not., Conclusions: Most Medicare prescription drug plans covered the majority of novel therapeutics in the year following FDA approval, although access was often restricted through prior authorization or step therapy and was dependent on plan choice., Disclosures: Funding for this study was contributed by a student research grant awarded to Shaw and provided by the Yale School of Medicine Office of Student Research under National Institutes of Health training grant award T35DK104689. Ross reports research grants to Yale University from the U.S. Food and Drug Administration (U01FD005938, U01FD004585), Medtronic, Johnson & Johnson, Centers for Medicare & Medicaid Services (HHSM-500-2013-13018I), Blue Cross-Blue Shield Association, Laura and John Arnold Foundation, Agency for Healthcare Research and Quality (R01HS022882), and National Institutes of Health (R01HS025164), unrelated to this study. Dhruva has nothing to disclose. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Food and Drug Administration (FDA) and Centers for Medicare and Medicaid Services (CMS) rely on evidence from clinical trials when approving a therapeutic for marketing and insurance coverage in the US, respectively. No study has compared the quality and quantity of evidence examined by these agencies.To characterize evidence used by FDA and CMS to support marketing approval and National Coverage Determinations (NCDs), respectively, of novel therapeutics reviewed for CMS coverage from 2005 through 2016.A cross-sectional study of clinical trials described in FDA approval documents and CMS NCD memoranda. We compared the number of clinical trials used by each agency as well as the following characteristics among original clinical trials: study size, randomization, double-blinding, and control arm.Twelve medical products met our inclusion criteria. FDA approvals of these products were based on 22 pivotal trials. CMS NCDs were based on 27 original clinical trials; 14 clinical trials were used by both agencies. Between FDA pivotal and CMS original clinical trials, there was no significant difference in study size (P = .53), use of randomization (P = .75), double-blinding (P = .55), or control arm (P = .54). There was no statistically significant difference in median age between participants in trials reviewed by CMS versus those reviewed by FDA (62 vs 59 years, P = .26). The median time from FDA approval to publication of CMS NCD memorandum was 17 (interquartile range, 13-36) months.FDA approvals and CMS NCDs are based on a similar number and quality of trials, although trial participants are not reflective of the Medicare population, and the process of finalizing coverage determinations requires an additional 17 months.

Key Points: Question: When medical devices that had been cleared under the FDA's 510(k) pathway are subject to Class I recalls, how often did the predicates for these devices also have a history of recalls? Findings: In this cross-sectional analysis of 156 cases of 510(k)–authorized devices with Class I recalls from 2017 through 2021, 44.1% used predicates with Class I recalls. In addition, 48.1% of these devices were subsequently used as predicates to authorize descendant devices later subject to Class I recalls. The risk of a Class I recall was 6.40 times higher for descendants that used predicates with Class I recalls than for devices using Class I recall–free predicates. Meaning: Stronger safeguards are needed to prevent problematic predicate selection and ensure patient safety. Importance: In the US, nearly all medical devices progress to market under the 510(k) pathway, which uses previously authorized devices (predicates) to support new authorizations. Current regulations permit manufacturers to use devices subject to a Class I recall—the FDA's most serious designation indicating a high probability of adverse health consequences or death—as predicates for new devices. The consequences for patient safety are not known. Objective: To determine the risk of a future Class I recall associated with using a recalled device as a predicate device in the 510(k) pathway. Design and Setting: In this cross-sectional study, all 510(k) devices subject to Class I recalls from January 2017 through December 2021 (index devices) were identified from the FDA's annual recall listings. Information about predicate devices was extracted from the Devices@FDA database. Devices authorized using index devices as predicates (descendants) were identified using a regulatory intelligence platform. A matched cohort of predicates was constructed to assess the future recall risk from using a predicate device with a Class I recall. Main Outcomes and Measures: Devices were characterized by their regulatory history and recall history. Risk ratios (RRs) were calculated to compare the risk of future Class I recalls between devices descended from predicates with matched controls. Results: Of 156 index devices subject to Class I recall from 2017 through 2021, 44 (28.2%) had prior Class I recalls. Predicates were identified for 127 index devices, with 56 (44.1%) using predicates with a Class I recall. One hundred four index devices were also used as predicates to support the authorization of 265 descendant devices, with 50 index devices (48.1%) authorizing a descendant with a Class I recall. Compared with matched controls, devices authorized using predicates with Class I recalls had a higher risk of subsequent Class I recall (6.40 [95% CI, 3.59-11.40]; P<.001). Conclusions and Relevance: Many 510(k) devices subjected to Class I recalls in the US use predicates with a known history of Class I recalls. These devices have substantially higher risk of a subsequent Class I recall. Safeguards for the 510(k) pathway are needed to prevent problematic predicate selection and ensure patient safety. This cross-sectional study evaluates the frequency of new devices receiving US Food and Drug Administration approval through its 510(k) pathway based on predicate devices that had been subject to a Class 1 recall. [ABSTRACT FROM AUTHOR]

Background: Drugs and high-risk medical devices are increasingly likely to receive Food and Drug Administration (FDA) approval through expedited pathways, which has implications for informed treatment consent (i.e., consent in clinical practice).Objective: To obtain expert opinion about the clinical and ethical implications of the increasing availability of new drugs and devices approved through expedited development and regulatory review pathways.Design: Qualitative study using individual semi-structured videoconference interviews.Participants: National leaders in medicine, ethics, and law (n=12) with expertise in medical product regulation, payor policymaking, bioethics, physician practice, patient advocacy, public health expertise/advocacy, clinical trials, the pharmaceutical and device industry, institutional review board oversight, and real-world evidence.Main Measures: Principal themes in 3 domains: expedited regulatory pathways, physician and patient understanding of and reliance on FDA approval, and informed treatment consent.Key Results: Respondents pointed out that more common use of expedited pathways translates to increased reliance on surrogate measures, some with uncertain clinical significance. While expedited development and review can have advantages, participants expressed worry that physicians were unaware when medical products were expedited and did not communicate about uncertainties in knowledge about new drug or device approvals effectively with patients. Many participants felt that informed treatment consent discussions about new drugs or devices should include some explanations of expedited pathways and use of surrogate measures.Conclusions: Experts identified advantages of expediting development and of FDA flexibility in applying its standards to new drugs and medical devices, but highlighted concerns that patients may not be adequately informed about the risks of shorter review times or about uncertainties in the evidence that result. There is a need to identify approaches to ensure effective clinical use of drugs and devices when approved through expedited pathways. [ABSTRACT FROM AUTHOR]

Randomized controlled trials have long been the gold standard for evidence in medical product evaluation, but there is growing support for the use of real-world evidence (RWE). The authors review the benefits and limitations of RWE and discuss the implications for P&T committees. [ABSTRACT FROM AUTHOR]

The article focuses on issues related to cost-effective pricing of Alirocumab and another PCSK9 inhibitor, evolocumab, which were priced at more than 14,000 dollars annually following the U.S. Food and Drug Administration's approval in 2015. It highlights the failure of these high prices to meet conventional cost-effectiveness thresholds with enormous budgetary implications raised by the widespread PCSK9 inhibitor adoption.