Jenerius A. Aminawung

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.).

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

Importance Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making. Objectives To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk. Design and Setting Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017. Exposures Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time. Main Outcomes and Measures A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications. Results From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02). Conclusions and Relevance Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.

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

Objective To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence. Design Systematic review. Data sources Drugs@FDA database and PubMed. Study inclusion All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both. Results Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively. Conclusions The quantity and quality of postapproval clinical evidence varied substantially for novel drugs first approved by the FDA on the basis of limited evidence, with few controlled studies published after approval that confirmed efficacy using clinical outcomes for the original FDA approved indication.

High Incarceration Rates Among Black Men Enrolled In Clinical Studies May Compromise Ability To Identify Disparities

In 1978 the federal government restricted research on prison and jail inmates in medical studies, the result of decades of unethical research in correctional institutions. We evaluated the impact this policy has had on studies of health outcomes in minority populations, particularly studies involving black men, who are disproportionately incarcerated. Specifically, we explored the effect of incarceration on follow-up rates of fourteen prospective clinical studies funded by the National Heart, Lung, and Blood Institute. We estimated that during the past three decades high rates of incarceration of black men may have accounted for up to 65 percent of the loss to follow-up among black men in these studies. The impact of incarceration was far less among white men, black women, and white women. These estimates suggest that the ability of those studies to examine racial disparities in health outcomes, as well as to understand the experience of this group, could be compromised. We believe that community-recruited subjects who are incarcerated should be allowed to continue participating in observational clinical research that poses minimal risk to participants.

Delay of Surgery for Melanoma Among Medicare Beneficiaries

IMPORTANCE Timely delivery of surgery for cancer affects health care quality and outcomes. However, population-based studies characterizing the delay of surgery for melanoma in the United States have not been performed. OBJECTIVE To assess the delay of surgery for melanoma by tumor-, patient-, and physician-level characteristics. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective cohort study of Medicare beneficiaries diagnosed as having melanoma from January 1, 2000, through December 31, 2009, using the Surveillance, Epidemiology, and End Results-Medicare database. We included all patients undergoing surgical excision of melanoma diagnosed by means of results of skin biopsy. EXPOSURES Anatomic location and stage of the tumor, patient sociodemographic characteristics, prior melanoma, Elixhauser comorbidities, and the specialties of the physicians who performed the biopsy and surgery. MAIN OUTCOMES AND MEASURES Surgical delay, measured as the time from the biopsy to surgical excision. We estimated risk-adjusted odds ratios (ORs) and marginal probabilities of delay with 95% CIs for each covariate using mixed-effects logistic regression. RESULTS Our cohort consisted of 32 501 cases of melanoma. Most of the patients were white (95.4%), male (63.1%), married (47.9%), and 75 years or older (60.8%) and did not have a prior melanoma (93.7%). Melanomas were most frequently located on the head and neck (40.5%) and staged as in situ disease (48.2%). More than three-quarters of cases (25 269 [77.7%]) underwent excision within 1.5 months of biopsy. Among those treated after 1.5 months (7232 [22.3%]), 2620 (8.1% of all cases) experienced a delay of longer than 3 months. The incidence of a risk-adjusted surgical delay longer than 1.5 months was significantly increased among patients 85 years or older compared with those younger than 65 years (odds ratio [OR], 1.28 [95% CI, 1.05-1.55]; P = .02), those with a prior melanoma (OR, 1.20 [95% CI, 1.08-1.34]; P = .001), and those with an increased comorbidity burden (OR, 1.18 [95% CI, 1.09-1.27]; P < .001). Melanomas that underwent biopsy and excision by dermatologists had the lowest likelihood of delay (probability, 16% [95% CI, 14%-18%]). The highest likelihood of delay (probability, 31% [95% CI, 24%-37%]) occurred when the biopsy was performed by a nondermatologist and excised by a primary care physician. Similar findings were observed for a delay longer than 3 months. CONCLUSIONS AND RELEVANCE Approximately 1 in 5 Medicare beneficiaries experience a delay of surgery for melanoma that is longer than 1.5 months. Those patients undergoing biopsy and surgery by dermatologists have the lowest risk for delay, highlighting potential opportunities for improved access to and coordination of dermatologic care.

Influence of a 21-Gene Recurrence Score Assay on Chemotherapy Delivery in Breast Cancer

BACKGROUND We performed an analysis to determine the relative contribution of the Oncotype DX (ODX) recurrence score (RS) results in adjuvant therapy delivery compared with traditional pathologic factors. METHODS AND MATERIALS We performed a retrospective review of women with stage I-IIIA breast cancer treated at the Yale Comprehensive Cancer Center from 2006 to 2012 with available ODX results. We constructed separate logistic models with the clinicopathologic factors alone and also integrating RS and compared these models using the likelihood ratio test and c-statistic to determine whether integration of the RS will result in better prediction of chemotherapy (CTx) delivery. RESULTS We identified 431 women with a median age of 58 years. The RS was low (< 18), intermediate (18-30), and high (> 30) in 56%, 37%, and 7%, respectively. CTx was delivered to 30% of the patients. Age, differentiation, lymphovascular invasion, and progesterone receptor (PR) positivity < 50% were associated with CTx delivery in multivariable logistic regression of clinicopathologic factors alone (P < .05). In the model integrating the RS, an intermediate or a high RS was the most influential factor for CTx delivery (odds ratio, 7.87 vs. 265.35, respectively; P < .0001). The PR results and grade were no longer significant (P = .74 and P = .06, respectively). The integration of the RS resulted in improved model fit and precision, indicated by the likelihood ratio test (ΔG2, 100.782; df = 2; P < .0001) and an improved c-statistic (0.720 vs. 0.856). CONCLUSION Gene expression profiling appears to account for a substantial amount of variability in CTx delivery in current practice. Further work is needed to ensure appropriate test usage and cost-effectiveness.

A Tool for Tracking and Assessing Chronic Illness Care in Prison (ACIC-P)

Chronic disease care is being transformed in correctional settings, given an aging inmate population, ongoing quality improvement efforts, litigation, and rising costs. The Chronic Care Model, established for chronic disease care in the community, might be a suitable framework to transform chronic disease care in prison, but it has not been systematically adapted for the correctional health care setting. We employed cognitive interviewing to adapt an extant survey used to measure the delivery of chronic illness care in the community, Assessment of Chronic Illness Care, for a prison setting. Results from the cognitive interviews and the modified Assessment of Chronic Illness Care–Prison (ACIC-P) instrument are presented in this article. Future studies will need to test the reliability and psychometric properties of the adapted ACIC-P.

History of Solitary Confinement Is Associated with Post-Traumatic Stress Disorder Symptoms among Individuals Recently Released from Prison

This study assessed the relationship between solitary confinement and post-traumatic stress disorder (PTSD) symptoms in a cohort of recently released former prisoners. The cross-sectional design utilized baseline data from the Transitions Clinic Network, a multi-site prospective longitudinal cohort study of post-incarceration medical care. Our main independent variable was self-reported solitary confinement during the participants’ most recent incarceration; the dependent variable was the presence of PTSD symptoms determined by primary care (PC)-PTSD screening when participants initiated primary care in the community. We used multivariable logistic regression to adjust for potential confounders, such as prior mental health conditions, age, and gender. Among 119 participants, 43% had a history of solitary confinement and 28% screened positive for PTSD symptoms. Those who reported a history of solitary confinement were more likely to report PTSD symptoms than those without solitary confinement (43 vs. 16%, p < 0.01). In multivariable logistic regression, a history of solitary confinement (OR = 3.93, 95% CI 1.57–9.83) and chronic mental health conditions (OR = 4.04, 95% CI 1.52–10.68) were significantly associated with a positive PTSD screen after adjustment for the potential confounders. Experiencing solitary confinement was significantly associated with PTSD symptoms among individuals accessing primary care following release from prison. Larger studies should confirm these findings.

Adherence to the International Committee of Medical Journal Editors’ (ICMJE) prospective registration policy and implications for outcome integrity: a cross-sectional analysis of trials published in high-impact specialty society journals

BackgroundRegistration of clinical trials is critical for promoting transparency and integrity in medical research; however, trials must be registered in a prospective fashion to deter unaccounted protocol modifications or selection of alternate outcomes that may enhance favorability of reported findings. We assessed adherence to the International Committee of Medical Journal Editors’ (ICMJE) prospective registration policy and identified the frequency of registrations occurring after potential observation of primary outcome data among trials published in the highest-impact journals associated with US professional medical societies. Additionally, we examined whether trials that are unregistered or registered after potential observation of primary outcome data were more likely to report favorable findings.MethodsWe conducted a retrospective, cross-sectional analysis of the 50 most recently published clinical trials that reported primary results in each of the ten highest-impact US medical specialty society journals between 1 January 2010 and 31 December 2015. We used descriptive statistics to characterize the proportions of trials that were: registered; registered retrospectively; registered retrospectively potentially after initial ascertainment of primary outcomes; and reporting favorable findings, overall and stratified by journal and trial characteristics. Chi-squared analyses were performed to assess differences in registration by journal and trial characteristics.ResultsWe reviewed 6869 original research reports published between 1 January 2010 and 31 December 2015 to identify a total of 486 trials across 472 publications. Of these 486 trials, 47 (10%) were unregistered. Among 439 registered trials, 340 (77%) were registered prospectively and 99 (23%) retrospectively. Sixty-seven (68%) of these 99 retrospectively registered trials, or 15% of all 439 registered trials, were registered after potential observation of primary outcome data ascertained among participants enrolled at inception. Industry-funded trials, those with enrollment sites in the US, as well as those assessing FDA-regulated interventions each had lower rates of retrospective registration. Unregistered trials were more likely to report favorable findings than were registered trials (89% vs. 64%; relative risk (RR) = 1.38, 95% confidence interval (CI) = 1.20–1.58; p = 0.004), irrespective of registration timing.ConclusionsAdherence to the ICMJE’s prospective registration policy remains sub-standard, even in the highest-impact journals associated with US professional medical societies. These journals frequently published unregistered trials and trials registered after potential observation of primary outcome data.