Sanket S. Dhruva

Strength of Study Evidence Examined by the FDA in Premarket Approval of Cardiovascular Devices

CONTEXT Medical devices are common in clinical practice and have important effects on morbidity and mortality, yet there has not been a systematic examination of evidence used by the US Food and Drug Administration (FDA) for device approval. OBJECTIVES To study premarket approval (PMA)--the most stringent FDA review process--of cardiovascular devices and to characterize the type and strength of evidence on which it is based. DATA SOURCES AND STUDY SELECTION Systematic review of 78 summaries of safety and effectiveness data for 78 PMAs for high risk cardiovascular devices that received PMA between January 2000 and December 2007 [corrected]. DATA EXTRACTION Examination of the methodological characteristics considered essential to minimize confounding and bias, as well as the primary end points of the 123 studies supporting the PMAs. RESULTS Thirty-three of 123 studies (27%) used to support recent FDA approval of cardiovascular devices were randomized and 17 of 123 (14%) were blinded. Fifty-one of 78 PMAs (65%) were based on a single study. One hundred eleven of 213 primary end points (52%) were compared with controls and 34 of 111 controls (31%) were retrospective. One hundred eighty-seven of 213 primary end points (88%) were surrogate measures and 122 of 157 (78%) had a discrepancy between the number of patients enrolled in the study and the number analyzed. CONCLUSION Premarket approval of cardiovascular devices by the FDA is often based on studies that lack adequate strength and may be prone to bias.

Variations Between Clinical Trial Participants and Medicare Beneficiaries in Evidence Used for Medicare National Coverage Decisions

BACKGROUND There is a paucity of data on the adequacy of the resources and tools used by the Centers for Medicaid and Medicare Services (CMS) in making national coverage determinations about services for beneficiaries. The objective of this study was to determine the extent to which clinical trials relied on by the CMS are applicable to Medicare beneficiaries. METHODS We performed a meta-analysis of data on 40 009 individuals from all 141 trials included in the technology assessments for the 6 cardiovascular disease meetings of the CMS advisory panel and compared them with the demographics of the Medicare population. RESULTS Medicare beneficiaries differ significantly from the cardiovascular clinical trial participants used to inform Medicare coverage decisions. Clinical trial participants, compared with beneficiaries, are more likely to be younger (60.1 vs 74.7 years), male (75.4% vs 41.8%), and non-US residents (60% vs 0%). The clinical trials, moreover, rarely included outcome stratification by age, sex, and race. CONCLUSIONS Participants in cardiovascular studies relied on by the CMS for coverage determinations differ substantially from the Medicare population. Data frequently are not available on relevant subgroup populations. Suggestions are made that address the need for data more relevant to Medicare beneficiaries by increasing enrollment of, and reporting on, women and elderly individuals in clinical trials and use of relevant data for coverage decisions.

CMS's Landmark Decision on CT Colonography — Examining the Relevant Data

The Centers for Medicare and Medicaid Services (CMS) recently decided to deny coverage of CT colonography for cancer screening, concluding that “the evidence is inadequate.” Dr. Sanket Dhruva and colleagues write that this is a long-overdue step toward meaningful validation of clinical-trial evidence in Medicare beneficiaries.

Setting a research agenda for medical overuse

Although overuse in medicine is gaining increased attention, many questions remain unanswered. Dan Morgan and colleagues propose an agenda for coordinated research to improve our understanding of the problem

Gender Bias in Studies for Food and Drug Administration Premarket Approval of Cardiovascular Devices

Background— Cardiovascular devices can have different safety and effectiveness profiles in men and women. The type and quality of sex-specific data reviewed by the Food and Drug Administration (FDA) before approval of these devices are unknown. Methods and Results— We performed a systematic review of the demographics, comments on gender bias, and analysis of results by sex for 78 high-risk cardiovascular devices that received premarket approval by the FDA between 2000 and 2007. FDA summaries of evidence did not report sex of enrollees in 34 (28%) of 123 studies. For studies reporting sex distribution, the study populations were, on average, 67% men. There was no increase in the enrollment of women over time. Explanations for the relatively low percentage of women often stated that the trials reflected either underlying disease distribution or referral rates for similar procedures or that the sex distribution reflected similar or previous trials. Forty-one percent of studies included a gender bias comment or analysis, and 12 (26%) of 47 of these analyses identified some difference in device safety or effectiveness by sex. Conclusions— There is a lack of sex-specific safety and effectiveness data for high-risk cardiovascular devices before FDA approval. The justifications for this lack of evidence may perpetuate the status quo. More rigorous FDA requirements for sex-specific data before device approval could present an opportunity to improve cardiovascular outcomes.

2016 Update on Medical Overuse: A Systematic Review

Importance Overuse of medical care is an increasingly recognized problem in clinical medicine. Objective To identify and highlight original research articles published in 2015 that are most likely to reduce overuse of medical care, organized into 3 categories: overuse of testing, overtreatment, and questionable use of services. The articles were reviewed and interpreted for their importance to clinical medicine. Evidence Review A structured review of English-language articles on PubMed published in 2015 and review of tables of contents of relevant journals to identify potential articles that related to medical overuse in adults. Findings Between January 1, 2015, and December 31, 2015, we reviewed 1445 articles, of which 821 addressed overuse of medical care. Of these, 112 were deemed most relevant based on their originality, methodologic quality, and number of patients potentially affected. The 10 most influential articles were selected by consensus using the same criteria. Findings included a doubling of specialty referrals and advanced imaging for simple headache (from 6.7% in 2000 to 13.9% in 2010); unnecessary hospital admission for low-risk syncope, often leading to adverse events; and overly frequent colonoscopy screening for 34% of patients. Overtreatment was common in the following areas: 1 in 4 patients with atrial fibrillation at low risk for thromboembolism received anticoagulation; 94% of testosterone replacement therapy was administered off guideline recommendations; 91% of patients resumed taking opioids after overdose; and 61% of patients with diabetes were treated to potentially harmfully low hemoglobin A1c levels (<7%). Findings also identified medical practices to question, including questionable use of treatment of acute low-back pain with cyclobenzaprine and oxycodone/acetaminophen; of testing for Clostridium difficile with molecular assays; and serial follow-up of benign thyroid nodules. Conclusions and Relevance The number of articles on overuse of medical care nearly doubled from 2014 to 2015. The present review promotes reflection on the top 10 articles and may lead to questioning other non-evidence-based practices.

Revisiting Essure — Toward Safe and Effective Sterilization

Essure, a female-sterilization device, is being reevaluated by an FDA panel 13 years after its original approval. Would concerns about its safety and effectiveness have been addressed earlier with better research and result dissemination?

Accelerated Approval and Possible Withdrawal of Midodrine

IN 1992, THE US FOOD AND DRUG ADMINISTRATION (FDA) introduced the accelerated approval process to allow earlier approval of drugs for serious or lifethreatening illnesses on the basis of surrogate end points. This approval requires the drug’s sponsor to agree to conduct postmarketing studies proving a benefit in clinical outcomes. Seventy-nine of the 90 drugs approved through this process through 2008 were for treatment of cancer, human immunodeficiency/AIDS, or inhalation anthrax. In 1996, midodrine hydrochloride, an 1-adrenergic agonist, was granted accelerated approval for treatment of symptomatic orthostatic hypotension with the guarantee that the drug’s sponsor would complete postmarketing studies to demonstrate clinical benefit. On August 16, 2010, noting that these studies had not been conducted, the FDA proposed to withdraw the medication. This withdrawal would be a landmark step in protecting the public’s health, as it is the agency’s first attempt to remove a medication marketed under accelerated approval that had not completed confirmatory trials. However, professional organizations, health care professionals, and patients appealed to the FDA to reverse its decision, and it did so on September 10. Reversal of this decision is worrisome. The approval of midodrine was based on a surrogate end point—an explicitly lower standard than for ordinary approval— and means that this product has been used in hundreds of thousands of patients without the sponsor demonstrating clinical benefit. The Code of Federal Regulations states that the FDA may withdraw a drug if “The applicant fails to perform the required postmarketing study with due diligence.” The FDA was acting in the public interest, as codified in law, by proposing withdrawal of this unproven medication with known risks including pilomotor reaction, urinary retention, and supine hypertension. Indeed, the drug’s sponsors have had 14 years to perform postapproval studies that provide meaningful clinical data. In the meantime, the drug has generated more than

Update on Medical Overuse

257 million in sales between 1996 and 2008, and the drug’s initial sponsor had market exclusivity until 2003. The drug’s manufacturers have had sufficient and repeated warnings concerning the need to conduct a clinical trial. In August 2007, the FDA notified the drug’s sponsors that if studies were not completed in a timely manner, the drug would be subject to withdrawal. One year later, the agency repeated its warning. In August 2009, the FDA notified the drug’s manufacturers of its requirement of 2 randomized, double-blind, placebo-controlled trials with a specific timeline including institutional review board approval by February 2010 and 100% enrollment by June 2010. The FDA firmly stated that the drug would be withdrawn if those requirements were not met. They were not, and the agency took the long overdue step of proposing withdrawal on August 16, 2010 (even after it allowed 5 generic manufacturers to market the medication over the past several years). In 14 years since accelerated approval of this popular drug, the initial sponsor has conducted 1 randomized trial of 24 patients, which showed no benefit and was never published. Although a senior vice president at one of midodrine’s manufacturers recently stated, “There is substantial evidence the drug does work,” he cited no data to support his statement. Midodrine’s approval rests solely on a 1996 study demonstrating an improvement in the surrogate end point of 1-minute standing systolic blood pressure. Although the company has had hundreds of millions of dollars in sales from the drug, it has not provided data that it is helping patients. Despite the company’s profits, when the FDA initially announced its plans to withdraw the drug, the company stated that it also wanted to withdraw the drug, for which it now lacks market exclusivity, because it did not make enough money from the product to warrant performing studies. Although anecdotal experience has led patients, health care professionals, and professional organizations to urge the FDA to reverse course, the fact remains that the drug’s sponsors have not shown any clinical benefit of midodrine in the 14 years since it was granted accelerated approval. If the FDA reverses its decision to withdraw a medication that has been on the market many years while the spon-

Evaluating sex differences in medical device clinical trials: time for action.

IMPORTANCE Overuse of medical care, consisting primarily of overdiagnosis and overtreatment, is a common clinical problem. OBJECTIVE To identify and highlight the most significant clinical articles published in 2013 related to medical overuse. EVIDENCE REVIEW A systematic review of English-language articles published in 2013 that related to medical overuse in adults. FINDINGS We reviewed 478 published articles that met our inclusion criteria. Of these, 126 were ranked most relevant based on quality of methodology, strength of results, potential effects on patient care, and the number of patients potentially affected. The 10 most relevant articles were selected using the same criteria. These 10 articles (organized into the categories overdiagnosis, overtreatment, and methods to avoid overuse) were reviewed and interpreted for their effect on clinical medicine. CONCLUSIONS AND RELEVANCE The literature on overuse of medical care is rapidly expanding. In 2013, both clinical trials and observational studies highlighted frequently overused or unnecessary care. Overuse of testing causes false-positive results and overdiagnosis. Negative test results do not appear to genuinely reassure patients. Overtreatment, with both medical therapies and procedural interventions, places patients at risk of unnecessary adverse events.