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After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Number and design of pivotal trials supporting both supplemental and original indication approvals. From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

Topical onychomycosis therapy is commonly prescribed due to its tolerability and low incidence of side effects. There are limited data on adverse events associated with the newer topical onychomycosis drugs. The objectives of this study is to classify the most common adverse reactions associated with ciclopirox 8% solution, efinaconazole 10% solution, and tavaborole 5% solution. The United States Food and Drug Administration Adverse Event Reporting (FAERS) database was analyzed for the most common adverse reactions associated with ciclopirox 8% solution, efinaconazole 10% solution, and tavaborole 5% solution. Google Trends was used to examine public interest in these drugs and these data were compared with yearly adverse events in the FAERS database. The most common adverse reactions associated with ciclopirox 8% solution, efinaconazole 10% solution, and tavaborole 5% solution were drug ineffectiveness. Application site erythema and nail discoloration were reported with all three medications. Increased Google searches for efinaconazole and tavaborole were associated with increased in reporting of adverse events to the FDA. Topical antifungals are safe alternatives for patients who have contraindications to oral medications. For improved efficacy, physicians should confirm the diagnosis of onychomycosis and choose appropriate candidates before starting topical therapy. Patients should be given clear instructions on drug usage and counseled about the more common side effects, including application site reactions and nail discoloration.

Objective To evaluate the use of special expedited development and review pathways at the US Food and Drug Administration over the past two decades.Design Cohort study.Setting FDA approved novel therapeutics between 1987 and 2014.Population Publicly available sources provided each drug’s year of approval, their innovativeness (first in class versus not first in class), World Health Organization Anatomic Therapeutic Classification, and which (if any) of the FDA’s four primary expedited development and review programs or designations were associated with each drug: orphan drug, fast track, accelerated approval, and priority review.Main outcome measures Logistic regression models evaluated trends in the proportion of drugs associated with each of the four expedited development and review programs. To evaluate the number of programs associated with each approved drug over time, Poisson models were employed, with the number of programs as the dependent variable and a linear term for year of approval. The difference in trends was compared between drugs that were first in class and those that were not.Results The FDA approved 774 drugs during the study period, with one third representing first in class agents. Priority review (43%) was the most prevalent of the four programs, with accelerated approval (9%) the least common. There was a significant increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved agent (incidence rate ratio 1.026, 95% confidence interval 1.017 to 1.035, P<0.001), and a 2.4% increase in the proportion of drugs associated with at least one such program (odds ratio 1.024, 95% confidence interval 1.006 to 1.043, P=0.009). Driving this trend was an increase in the proportion of approved, non-first in class drugs associated with at least one program for drugs (P=0.03 for interaction).Conclusions In the past two decades, drugs newly approved by the FDA have been associated with an increasing number of expedited development or review programs. Though expedited programs should be strictly limited to drugs providing noticeable clinical advances, this trend is being driven by drugs that are not first in class and thus potentially less innovative.

Valid assessment of drug efficacy and safety requires an evidence base free of reporting bias. Using trial reports in Food and Drug Administration (FDA) drug approval packages as a gold standard, we previously found that the published literature inflated the apparent efficacy of antidepressant drugs. The objective of the current study was to determine whether this has improved with recently approved drugs. Using medical and statistical reviews in FDA drug approval packages, we identified 30 Phase II/III double-blind placebo-controlled acute monotherapy trials, involving 13,747 patients, of desvenlafaxine, vilazodone, levomilnacipran, and vortioxetine; we then identified corresponding published reports. We compared the data from this newer cohort of antidepressants (approved February 2008 to September 2013) with the previously published dataset on 74 trials of 12 older antidepressants (approved December 1987 to August 2002). Using logistic regression, we examined the effects of trial outcome and trial cohort (newer versus older) on transparent reporting (whether published and FDA conclusions agreed). Among newer antidepressants, transparent publication occurred more with positive (15/15 = 100%) than negative (7/15 = 47%) trials (OR 35.1, CI95% 1.8 to 693). Controlling for trial outcome, transparent publication occurred more with newer than older trials (OR 6.6, CI95% 1.6 to 26.4). Within negative trials, transparent reporting increased from 11% to 47%. We also conducted and contrasted FDA- and journal-based meta-analyses. For newer antidepressants, FDA-based effect size (ESFDA) was 0.24 (CI95% 0.18 to 0.30), while journal-based effect size (ESJournals) was 0.29 (CI95% 0.23 to 0.36). Thus, effect size inflation, presumably due to reporting bias, was 0.05, less than for older antidepressants (0.10). Limitations of this study include a small number of trials and drugs-belonging to a single class-and a focus on efficacy (versus safety). Reporting bias persists but appears to have diminished for newer, compared to older, antidepressants. Continued efforts are needed to further improve transparency in the scientific literature.

To describe the extent of late adverse event reporting by manufacturers to the US Food and Drug Administration's (FDA) Manufacturer And User Facility Device Experience (MAUDE) database as well as the distribution of late reporting among manufacturers and associations with device characteristics. Cross sectional study. The FDA MAUDE database, a central postmarket safety surveillance tool for US medical devices, from 1 September 2019 to 31 December 2022. Medical device manufacturers that submitted initial adverse event reports to the FDA between 1 September 2019 and 31 December 2022. Time in days between date manufacturer was notified of event and date of FDA receipt of adverse event reports, proportion of reports reported late (after the required 30 day window as required by FDA regulation), and distribution of late reporting among manufacturers and medical devices. 13 587 reports were of deaths, 1 552 268 of injuries, and 2 866 693 of malfunctions received by the FDA from 3028 unique manufacturers and 88 448 unique medical devices in the three and a half year period. Of 4 432 548 included reports, 71.0% (n=3 146 957) of adverse events were reported within 30 days (on time), 4.5% (n=197 606) were reported between 31 and 180 days (late), and 9.1% (n=402 891) were after 180 days (late). 15.5% of reports (n=685 094) had missing or invalid date data provided by the manufacturer. Three manufactures and 13 medical devices were attributed to 54.8% of late reports. Nearly a third of manufacturer reports of medical device adverse events were not demonstrably submitted to the FDA within the regulatory deadline, with most late reports being submitted more than six months after manufacturer notification. Most late reports were submitted by a small number of manufacturers. Late adverse event reporting may prevent early detection of patient safety concerns.

AbstractObjectivesTo characterize postmarketing requirements for new drugs and biologics approved by the US Food and Drug Administration (FDA), and to examine rates and timeliness of registration, results reporting, and publication of required prospective cohort studies, registries, and clinical trials.DesignCross sectional analysis.SettingPostmarketing requirements for all new drugs and biologics approved by the FDA between 1 January 2009 and 31 December 2012, with follow-up up to 15 November 2017.Main outcome measuresPostmarketing requirements and their characteristics known at the time of FDA approval, including FDA authority, study design, and study characteristics. Rates and timeliness of registration and results reporting on ClinicalTrials.gov and publication in peer reviewed journals of required prospective cohort studies, registries, and clinical trials.ResultsBetween 2009 and 12, the FDA approved 97 new drugs and biologics for 106 indications with at least one postmarketing requirement at the time of first approval, for a total of 437 postmarketing requirements. Postmarket study descriptions were short (median word count 44 (interquartile range 29-71)) and often lacked information to determine an up to date progress (131 (30%)). 220 (50.3%) postmarketing requirements were for new animal or other studies (including pharmacokinetic studies); 134 (30.7%) were for prospective cohort studies, registries, and clinical trials; and 83 (19.0%) were for secondary analyses or follow-up studies. Of 110 clinical trials, 38 (34.5%), 44 (40.0%), 62 (56.4%), 66 (60.0%), and 98 (89.1%) did not report enough information to establish use of randomization, comparator type, allocation, outcome, and number of patients to be enrolled, respectively. Of 134 required prospective cohort studies, registries, and clinical trials, 102 (76.1%) were registered on ClinicalTrials.gov; of 50 registered and completed studies, 36 (72.0%) had reported results on ClinicalTrials.gov. Among 65 completed studies, 47 (72.3%) had either reported results or were published a median of 47 months (interquartile range 32-67) after FDA approval. 32 (68.1%) of these 47 studies did not report results publicly by the time of their original FDA report submission deadline.ConclusionsPostmarketing requirements for new drugs and biologics were often briefly described and did not contain enough information to characterize study designs. Approximately three quarters of postmarketing requirements for prospective cohort studies, registries, and clinical trials were registered on ClinicalTrials.gov, and nearly three quarters of completed studies reported results or were published, suggesting that at least a quarter of these required studies are not being publicly disseminated.

In July 2012, the FDA Safety and Innovation Act created the “breakthrough therapy” designation to expedite development of therapies for serious diseases when evidence suggests substantial superiority over existing options. The authors discuss implications of the new designation. U.S. pharmaceutical regulations are based on the principle that patients should not be exposed to new prescription drugs until their efficacy and safety have been shown. Since 1962, the Food and Drug Administration (FDA) and Congress have balanced the efficient review of investigational drugs with the need to withhold judgment until sufficient evidence is available to clarify the benefit–risk relationship. Misjudging these competing interests in either direction causes important problems. On the one hand, the evidentiary hurdles of the FDA are often criticized by pharmaceutical companies and patient advocacy groups for slowing access to promising therapies. On the other hand, . . .

Background The United States Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) consists of adverse event (AE) reports linked to approved drugs. The database is widely used to support post-marketing safety surveillance programs. Sometimes cited as a limitation to the usefulness of FAERS, however, is the ‘Weber effect,’ which is often summarized by stating that AE reporting peaks at the end of the second year after a regulatory authority approves a drug. Weber described this effect in 1984 based upon a single class of medications prescribed in the United Kingdom. Since that time, the FDA has made a concerted effort to improve both reporting and the database itself. Both volume and quality of AE reporting has dramatically improved since Weber’s report, with an estimated 800,000 yearly reports now being logged into FAERS. Objective The aim of this study was to determine if current FAERS reporting follows the trend described by Weber. Methods Sixty-two drugs approved by the FDA between 2006 and 2010 were included in this analysis. Publicly available FAERS data were used to assess the ‘primary suspect’ AE reporting pattern for up to a 4-year period following each drug’s approval date. Results A total of 334,984 AE reports were logged into FAERS for the 62 drugs analyzed here. While a few of the drugs demonstrated what could be considered ‘Weber effect’ curves, a majority of the drugs showed little evidence for the effect. In fact, the general AE reporting pattern observed in this study appears to consist simply of increasing case counts over the first three quarters after approval followed by relatively constant counts thereafter. Conclusions Our results suggest that most of the modern adverse event reporting into FAERS does not follow the pattern described by Weber. Factors that may have contributed to this finding include large increases in the volume of AE reports since the Weber effect was described, as well as a concerted effort by the FDA to increase awareness regarding the utility of post-marketing AE reporting.

Background In recent years, an association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid has been detected in pharmacovigilance studies in European and Asian countries; however, no pharmacovigilance data have been published yet in the USA. Objective The objective of this study was to examine the relationship between bullous pemphigoid and DPP-4 inhibitors and other oral diabetes mellitus medications in the FDA Adverse Event Reporting System (FAERS). Methods Case/non-case analyses were performed in the FAERS using data from 2006 to 2020 to examine the reporting odds ratio (ROR) signal for bullous pemphigoid for all classes of oral diabetes medications. These analyses were performed under multiple conditions to control for bias: (1) comparison to all other drugs in the FAERS; (2) comparison to other diabetes medications; and (3) comparison to all other diabetes medications where only a single agent was implicated. Results A statistically significant ROR for bullous pemphigoid was found for DPP-4 inhibitors under all conditions: (1) 109.79 (95% confidence interval [CI] 101.61–118.62); (2) 74.46 (95% CI 60.58–91.52); and (3) 35.94 (95% CI 27.91–46.28). A larger signal was seen for non-US Food and Drug Administration (FDA)-approved (anagliptin, vildagliptin, teneligliptin) vs FDA-approved DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin), likely because of an overestimation of the ROR for non-FDA-approved drugs. The largest signal was seen under conditions 1 and 2 with vildagliptin (1) 1022.83 (95% CI 909.45–1150.35) and (2) 158.84 (95% CI 127.01–198.66) followed by anagliptin (1) 628.63 (95% CI 221.36–1785.24) and (2) 60.64 (95% CI 20.98–175.26), alogliptin, teneligliptin, linagliptin, sitagliptin, and saxagliptin. Under condition 3, the largest signal was seen with linagliptin 122.25 (95% CI 93.96–159.07). Both metformin and the sulfonylureas had a significant ROR under condition 2 [3.42 (95% CI 3.01–3.89) and 2.07 (95% CI 1.66–2.57) respectively]; however, this association was not present under condition 3 as only confounded cases occurred, and a large majority of reported cases had concurrent exposure to a DPP-4 inhibitor. Conclusions Our findings support an association between DPP-4 inhibitors and bullous pemphigoid. This association was maintained under controls to limit bias and falsely elevated signal, including controlling for disease state and cases with multiple drug exposures. Non-FDA-approved DPP-4 inhibitors had a larger ROR compared with FDA-approved DPP-4 inhibitors, likely owing to fewer reported adverse effects overall for non-FDA-approved drugs in FAERS.

As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported. To characterize the immunologic mechanisms underlying allergic reactions to these vaccines. This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. FDA-authorized mRNA COVID-19 vaccines. Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms. Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.