Food And Drug Administration Advisory Panel Research Articles

US FDA Advisory Panel Members’ Assessment of Premarket Approval Process and Suggestions for Improvement

The manufacturing and marketing of medical devices is regulated by the US Food and Drug Administration (FDA), and the FDA premarket approval (PMA) process evaluates the safety and effectiveness of medical devices. The PMA process includes a detailed scientific, regulatory and quality system review and is critical to ensure that novel devices are safe, effective, and meet the needs of patients. To survey current voting members serving on panels of the FDA's Medical Devices Advisory Committee to better characterize panel decision-making and identify steps for improvement. This qualitative survey study included 36 questions that were mailed to FDA device panelists regarding their opinions on the influence of sources of information, pivotal trial design, quality of evidence, panel composition and internal deliberative process, time allocation, and impartiality of the FDA. The survey was mailed to the members of all 18 FDA device panels in January and February 2017. Data were collected from January to May 2017 and analyzed from 2018 to 2019. Respondents read and returned the aforementioned paper survey, while nonrespondents did not. The main outcomes included panel members' perceptions, and their implications for process improvement. χ2 or Fisher exact tests were used to test differences between subgroups. Of 64 of 92 panel members who responded (69.6%), 38 of 64 (59.4%) were male, 3 of 63 (4.8%) were Black respondents, 46 of 63 (73.0%) were White respondents, and 36 of 60 (60.0%) were in academic practice. The mean (range) panel service was 6.8 (1-22) years with 3.9 (1-19) meetings attended. Overall, respondents considered information presented by the FDA unbiased, and 28 of 61 (45.9%) believed that pivotal trials were frequently well-designed, 55 of 62 respondents (88.7%) suggested FDA consult panel members preemptively regarding trial design and 54 of 64 (84.4%) regarding the device label. Most indicated that prior FDA approval of another device serving the same medical purpose (43 of 62 [69.4%]) or approval in other countries with comparable regulatory regimes, such as Canada and Europe (39 of 62 [62.9%]), would make them more likely to recommend approval. Respondents rated written information (50 of 60 [83.3%]), live presentations (43 of 58 [74.1%]), and prior professional knowledge (41 of 60 [68.3%]) as the most important sources of information in deciding whether to recommend approval. Additionally, 52 of 58 respondents (89.7%) recommended that a panel member-only executive session would allow more clarity and honesty in deliberations, and 33 of 59 (55.9%) believed a three-fourths majority appropriate for recommending approval, which would be a deviation from the current system in which an overall vote is reported without designation of a vote threshold. In this survey study of FDA device panel members, respondents wanted improved study designs, more relevant clinical data, including from other countries, involvement of panelists in study design and device label development, and inclusion of an executive session. Demographically, panels could be made more diverse.

Overview of 2024 FDA Advisory Panel Meeting on the TriClip transcatheter tricuspid valve repair system

Tricuspid regurgitation (TR) is common and associated with significant mortality and morbidity. Because the effectiveness and safety of medical and surgical treatments are limited, there is a significant unmet need for the treatment of this disease. Therefore, there is a growing market for percutaneous devices that offer safer, less invasive, and more effective treatment options in this patient population. On February 13, 2024, the US Food and Drug Administration (FDA) convened a meeting of the Circulatory System Devices Panel to discuss the safety and effectiveness of the TriClip Transcatheter Valve Repair System (Abbott, Santa Clara, CA, USA). Several important points were discussed, including newly published data from the TRILUMINATE Pivotal study, the use of patient-oriented outcomes for device approval, and a discussion about training requirements and rollout plans when approving a breakthrough device. In this manuscript, we summarize the data presented by the sponsor and FDA and describe the deliberations and discussions during the meeting.

Controversial Approval of New Drug to Treat Alzheimer's Disease.

Aducanumab (Aduhelm), the first new drug to treat Alzheimer's disease since 2003, has received accelerated approval from the Food and Drug Administration (FDA).This drug's approval has been highly contentious in the medical and scientific community owing to contradictory study findings and the FDA's advisory panel not recommending its approval.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease.

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease.

Nonadjunctive Use of Continuous Glucose Monitors for Insulin Dosing: Is It Safe?

With the increasing accuracy of continuous glucose monitors (CGM) have come calls for the Food and Drug Administration (FDA) to label these devices as safe for nonadjunctive dosing of insulin. However, there is evidence that these devices are subject to sporadic, unpredictable, large errors. A text analysis of reports to the FDA MAUDE database since 2015 reveals over 25 000 complaints of CGM sensor inaccuracy, with instances directly leading to serious outcomes. These new data were not considered at a recent FDA Advisory Panel meeting that voted to approve Dexcom G5 relabeling for nonadjunctive use. Social media is another source of surveillance data providing evidence of large CGM inaccuracies in real-world use. We need to improve safety procedures, not remove them. CGMs offer unique information and alerts for managing diabetes, but the issue is not whether they are better than other approaches to monitoring glucose, but how they can be best used in conjunction with devices that offer the confirmatory readings needed for patient safety.

Commentary: confidentiality of interim trial data-the emerging crisis.

Randomized controlled clinical trials (RCTs) represent the pinnacle of evidence used by clinicians and regulators to determine the effectiveness of therapeutic interventions. The importance of RCTs is so universally accepted that clinical practice guidelines for many fields of medicine assign the highest rating for quality of evidence (Class 1A) to recommendations supported by data derived from multiple RCTs. Similarly, regulators have generally required evidence derived from RCTs for approval of pharmacological interventions. These policies ensure that the therapies approved by regulatory agencies and endorsed by professional societies actually deliver the benefits promised to patients. Now, after decades of application, this paradigm is threatened by a looming crisis related to the ability to conduct cardiovascular safety trials of diabetes drugs using the highest standards of scientific integrity. As described by Fleming in this edition of Clinical Trials, maintaining the confidentiality of data for interim results from ongoing clinical trials is essential to maintaining the feasibility and reliability of these crucial studies. The current threat to clinical trial integrity arises from a regulatory crisis that emerged during the past decade. The US Food and Drug Administration (FDA) and global regulatory authorities traditionally approved diabetes drugs based primarily upon the ability of these agents to lower blood sugar in the absence of any apparent toxicity. Diabetes drugs were typically evaluated based upon short-term trials (6–12 months) showing a reduction in glycohemoglobin levels, a measure of average blood glucose values over the previous 3 months. In actual practice, most sponsors, to mitigate the risk of demonstrating toxicity, conducted relatively small trials (total sample size about 3000 patients) in populations with a predicted low likelihood of adverse clinical outcomes. However, like most surrogate outcomes, the use of average blood glucose values to approve diabetes drugs carried considerable theoretical risks. A therapeutic intervention could lower blood glucose, but worsen other important outcome measures, which would go undetected in the small, short-term trials conducted with glycemic endpoints. That’s exactly what happened. In 2005, the diabetes drug muraglitazar was presented to an FDA Advisory Panel, and a recommendation for approval received nearly unanimous support. A few weeks later, we published a meta-analysis of the clinical data presented to the FDA Panel, which showed an approximate doubling of the risk of major adverse cardiovascular events (MACE) in patients treated with muraglitazar compared with placebo or other glucoselowering therapies. Then, 2 years later, we published a meta-analysis of cardiovascular outcome data for an approved and widely prescribed drug, rosiglitazone, showing evidence for increased MACE. This latter publication resulted in considerable controversy with alarming newspaper headlines, Congressional inquiries, and public outcry. A consensus emerged that approval of diabetes drugs primarily on the basis of glucose lowering (without additional cardiovascular outcome data) was no longer tenable. Accordingly, the FDA assembled an advisory panel in 2008 to consider what changes in regulatory policy, if any, were needed. Two participants in that advisory committee meeting, Dr Fleming as a panel member and me as an invited speaker, proposed a new paradigm for diabetes drug approval. The approach we advocated was carefully designed to balance the need to approve new drugs for diabetes in a timely fashion with the compelling societal interest in making certain such drugs did not increase adverse cardiovascular outcomes. We weighed the risks and benefits of several approaches, including requiring a large-scale RCT prior to approval, but ultimately proposed a strategy that would require sponsors to rule out an upper 95% confidence interval (CI) for the hazard ratio (HR) for MACE of 1.8 prior to approval and an

The Food and Drug Administration advisory committees and panels: how they are applied to the drug regulatory process.

Food and Drug Administration (FDA) advisory panels and committees play a critical role in advising the FDA on the safety and efficacy of medical devices and drugs marketed in the US. Advisory panel recommendations are used by the FDA to make decisions regarding medical products. Currently, the FDA utilizes over 50 advisory panels that serve the three major FDA centers, including the Centers for Biologics, Drugs and Device Products. Members of an advisory panel typically include academicians, clinicians, consumers, patients, and industry representatives. The FDA establishes the schedules for advisory panel meetings on an annual basis and a panel usually meets several times a year for two consecutive days in Washington, DC. Typically, the advisory panel discusses issues highlighted by the FDA and is then asked to vote a response to the questions posed in advance by the FDA. Advisory panel recommendations have a strong influence on FDA's decision to approve a product, as evidenced by the 214 Advisory Panels FDA convened between January 2008 to November 2012, during which advisory panel members voted to approve the product (or use of the product) ∼74% of the time, with FDA ultimately approving the medical product (or use of the product) ∼79% of the time. The ACG membership are encouraged to consider serving the public's interest by participating in an FDA advisory panel utilizing their expertise for the evaluation of a new drug or medical device, and providing advice about whether the product should be sold in the US.

FDA Advisory Panel Recommends Approval of Drug for Preoperative Treatment of Breast Cancer

In a nearly unanimous vote, an advisory panel for the US Food and Drug Administration (FDA) voiced its support on September 12 for the approval of the drug pertuzumab for use in the neoadjuvant (preoperative) treatment of breast cancer. Pertuzumab, a monoclonal antibody targeting the HER2/neu receptor, was approved by the FDA in 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who had not received prior anti-HER2 therapy or chemotherapy. If the FDA takes its advisory panel�s advice, pertuzumab would also be approved for use as neoadjuvant treatment in early HER2-positive breast cancers.

Study Finds Anti-NGF Factor Effective for Hip Arthritis

Treatment with the anti–nerve growth factor (NGF) tanezumab was associated with significant improvements over placebo in pain, physical function, and Patient's Global Assessment of osteoarthritis (OA) results, after 16 weeks in a phase III study of patients with OA of the hip. In the randomized, double-blind, placebo-controlled study of 621 patients with painful hip OA, treatment with tanezumab (an “anti-NGF”) was also well tolerated, according to Dr. Mark Brown and his associates. The study was funded by Pfizer, the manufacturer of tanezumab, and Dr. Brown and three of the five other authors are full-time employees of the company. Tanezumab “may eventually be useful in OA patients who are intolerant of or nonresponsive to nonopioid treatment,” the authors concluded. The study was published in Arthritis & Rheumatism (Arthritis Rheum. 2013;65[7];1795-1803). Anti-NGFs are monoclonal antibodies directed against nerve growth factor, which is associated with injury, inflammation, and chronic pain, according to the authors. Tanezumab is one of several anti-NGFs being studied for OA and other chronic pain conditions and is the furthest along in development. In 2010, the Food and Drug Administration (FDA) placed a partial hold on anti-NGF clinical trials after cases of osteonecrosis and avascular necrosis were reported in patients treated with tanezumab and in those treated with another anti-NGF. After an FDA advisory panel said that the anti-NGFs showed promise as analgesics, the clinical hold on tanezumab trials was lifted in August 2012, Dr. Brown's team noted. The development of the anti-NGFs “is an exciting potential addition to our present inadequate control of pain,” and research is resuming with a careful review of the risk of bone and joint changes, Dr. Roy Altman said in an interview. In his view, “the known risks would be acceptable to many people with poorly controlled pain.” Dr. Altman, professor of medicine, rheumatology, at the University of California, Los Angeles, was not an investigator in the study. The Pfizer study compared three tanezumab doses (2.5 mg, 5 mg, and 10 mg) administered intravenously at baseline, 8 weeks, and 16 weeks, with placebo, in 621 people with OA of the hip (mean age, 62-63 years) who could not or did not want to take nonopiate pain medications, did not get enough relief from these medications, or were candidates for hip surgery or other invasive treatments. Almost half were candidates for invasive treatment. At 16 weeks, tanezumab, at all three doses, “produced greater, clinically meaningful, and statistically significant improvements,” compared with placebo, in pain, physical function, and patient assessment of OA. Differences between placebo and treatment were greatest for the two higher doses. About two-thirds of the patients on treatment remained in the study through week 24 (considered the end of the study because of tanezumab's long half-life), compared with 38% of those on placebo. Overall, more patients on tanezumab reported adverse effects (55%-58% vs. 44% on placebo). Serious adverse events occurred in 3%-4.5% of patients in the treatment groups. The rate of total hip replacement was similar in the treatment and placebo groups, with a total of eight patients who had the operation (three in the placebo group, two each in the 2.5-mg and 5-mg groups, and one in the 10-mg group). These included two patients on tanezumab who had osteonecrosis thought to be related to tanezumab. The authors pointed out that an outside adjudication committee, however, did not confirm osteonecrosis in either of these patients and concluded that the reasons for joint replacements in the eight patients were inflammatory arthropathy, end-stage OA, rapidly progressive OA, or worsening OA. Dr. Altman said that he has consulted with Abbott and its now discontinued program on anti-NGF drugs.

Betadine and Breast Implants

In the spring of 2000, the US Food and Drug Administration (FDA) issued a ban on the use of Betadine (Purdue Frederick, Stamford, Connecticut) with breast implants due to concern about an adverse effect on shell integrity that could lead to implant deflation or rupture. The ban was enacted primarily on the basis of 2 studies, the first of which was presented to the FDA by Mentor Corporation (Santa Barbara, California). This study tested Mentor saline implants with long-term intraluminal Betadine fill, and subsequent valve patch delamination was reported.1 This was the first published instance of Betadine being used intraluminally rather than as pocket irrigation, which may have contributed to negative results. The second study evaluated the effect of Betadine on silicone elastomer. Changes in elastomer strength and color were demonstrated, but this was the result of soaking the fill tube in Betadine and not the implant shell, which is manufactured differently.2 At that time, the FDA advisory panel did not recommend a prohibition on the use of Betadine with breast implants, however the FDA chairman went against the panel's recommendation and the prohibition was put in place.3 In my own practice, I utilize Betadine irrigation because it offers ease of use, minimized medication error potential, decreased allergic risk (for patients who are allergic to Betadine, I use Adams's triple antibiotic irrigation4), and cost-effectiveness. Furthermore, studies—including my own5 and those of Adams et al,4 Burkhardt and Eades,6 and many others—have shown not only no deleterious effect of Betadine on breast implants but also a significant decrease in the incidence of capsular contracture (CC). In fact, CC rates can be reduced to 1% or less with the use of Betadine,4–6 a significant finding considering that CC can result in significant patient …

Electroconvulsive Therapy Device Classification: Response to FDA Advisory Panel Hearing and Recommendations

Electroconvulsive therapy (ECT) is a safe and highly effective treatment for management of acute episodes of a variety of serious mental disorders, particularly for major depressive episodes that are resistant to multiple interventions with treatment alternatives. As such, the National Network of Depression Centers (NNDC), a consortium of major academic centers with interest and expertise in this area, believes there is an important public health need for ECT to remain available for clinical use. As with all medical devices, ECT is regulated by the US Food and Drug Administration (FDA), which is presently involved in formulating a proposed rule as to how such devices should be classified. Since such classification may have substantial effects on the availability of ECT to patients for whom it is clinically indicated, the NNDC has reviewed the information provided by the FDA to its Advisory Panel, as well as the subsequent deliberations of the Panel itself at a January 2011 public hearing. This review indicates that the FDA may have substantially underestimated the efficacy of ECT as a means to produce large clinical improvements for individuals suffering from severe major depressive disorders and that such an underestimate likely affected the Panel's willingness to recommend reclassification of ECT devices to a less restrictive category. In addition, the NNDC's review generates support for a variety of methods by which the safety of ECT can be ensured, which is an essential requirement for such reclassification.

Benefit-risk paradigm for clinical trial design of obesity devices: FDA proposal

Diet and exercise, except in controlled circumstances, have not been shown to provide effective and prolonged weight loss for the majority of those who are obese. Several older drugs intended to reduce weight have been withdrawn from the market, and the new drugs show only modest weight loss. Surgical intervention, specifically procedures that alter the normal gastrointestinal anatomy, does provide prolonged periods of sustained weight loss, with rebound weight gain over time. A variety of medical devices to assist in weight reduction have been studied, but only two are legally marketed devices for obesity. The authors propose a new paradigm for devices intended to treat obesity, based on a benefit-risk determination, with the hope to provide sponsors an a priori tool for systematic assessment of the risks associated with the devices intended for treatment of obesity and to suggest appropriate levels of benefit for devices with different risk levels. The paradigm is not intended to determine the class of a device from a regulatory perspective. This approach was conceived at a Food and Drug Administration (FDA) co-sponsored workshop in October, 2011 and formally presented to an FDA advisory panel for discussion in May 2012.

US FDA advisory panel rejects early denosumab therapy

US Food and Drug Administration (FDA) experts have decided against expanding denosumab’s indications to include prophylaxis against bone metastasis in high-risk castrationresistant prostate cancer. Marketed as Xgeva by Amgen, denosumab inhibits bone loss and fractures, and is already approved for patients with metastatic bone tumours. Amgen’s phase 3 clinical trial of denosumab administration before bone metastasis in patients with castration-resistant prostate cancer found denosumab slowed metastasis to bone. But early denosumab administration did not improve survival rates, and had a signifi cant 5% risk of osteonecrosis of the jaw. That troubled members of the FDA Oncologic Drugs Advisory Committee, who voted 12 to 1 against recommending the agency approve the expanded indication, noting that without clear evidence of clinical benefi ts, denosumab administration before metastasis only imposes on patients “the increased risks of the drug”. What bone-metastasis-free survival— Amgen’s primary endpoint, based on bone imaging—really means for patient survival or quality of life is unclear, the panel decided. “Unfortunately, there wasn’t an endpoint directly measuring clinical benefi ts like symptomatic bone metastasis or skeletal events”, Brent Logan (Medical College of Wisconsin, Milwaukee, WI, USA) told The Lancet Oncology. A few patients might benefi t from early treatment, but most wouldn’t— and many would have osteonecrosis, cautioned Maha Hussain (University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA). “The rate of osteonecrosis is likely to go higher the longer you treat patients”, said David Quinn (Norris Comprehensive Cancer Centre, University of Southern California, CA, USA). “This was a relatively early snapshot of these patients. There’s a concern that these patients are likely to be living longer, thanks to the other drugs we’ve got—and that we’ll see a major issue with osteonecrosis or other unanticipated side eff ects.” Agents to prevent metastasis in these patients are not available, Hussain said. “But there has to be good reason to treat”, Hussain said. “Unmet need does not justify suboptimal treatment. We need to go back to the drawing board and look at agents and endpoints, and whether we should be adding more drugs.”

Medical Device Regulatory Landscape

The past 60 years have witnessed fundamental advances in our understanding and treatment of cardiovascular disease, prolonging and improving patients' lives. Central to these improvements has been the introduction of medical devices, including mechanical and biological heart valves, heart rhythm devices, and balloon angioplasty and stents. The introduction of these technologies has been dependent on an entrepreneurial medical device sector, coupled with an equally robust infrastructure to clinically develop and evaluate these new technologies. After approval and commercialization, continued study of device performance under “real world” conditions is crucial to ensure that the clinical potential is being realized. Central to a healthy medial device “ecosystem” is a robust regulatory system. Regulators must ensure that a device performs reliably and is adequately characterized, allowing physicians and patients to use it appropriately. Determining if/when a device is appropriate for approval is difficult and challenging and requires balancing its safety-efficacy profile. The technical sophistication required to make these determinations has grown as device complexity has grown. The stakes are very high, as illustrated by the recent Fidelis AICD lead recall, affecting 268 000 patients worldwide.1 These safety concerns must be balanced by the harm inflicted by withholding beneficial technology from patients. There is wide variation in how devices are regulated among countries with well-developed health care delivery systems, for example, the United States and Europe as well as Japan and Canada. The recent Food and Drug Administration (FDA) approval of the Sapien Transcatheter Heart Valve has brought these differences into sharp focus. In this commentary, we review the differences between the US and European Regulatory systems and how they have affected the investigational and approval process. ### Sapien Transcatheter Heart Valve: A Case Study On November 2, 2011, the Sapien Transcatheter Heart Valve (TAVR), manufactured by Edwards Lifesciences, was approved by the US FDA.2 The approval of the Sapien …

New Study Answers Questions About Cardiac Risk of ADHD Drugs

New Study Answers Questions About Cardiac Risk of ADHD Drugs

Immunization 2011: Expanding Coverage, Enhancing Protection

Annually, the ACIP of the Centers for Disease Control and Prevention issues a revised Adult Immunization Schedule that is approved by the major specialty societies representing physicians who care ...

Pharmaceutical news and updates for renal care providers

Pharmaceutical news and updates for renal care providers

Thiazolidinedione Drugs and Cardiovascular Risks

The purpose of this science advisory is to summarize the currently available data concerning thiazolidinediones and cardiovascular risk, with a focus on ischemic heart disease (IHD) events, and to provide practical recommendations to healthcare workers seeking to minimize the burden of cardiovascular disease (CVD) and other complications in their patients with type 2 diabetes mellitus. On May 21, 2007, the US Food and Drug Administration (FDA) released a safety alert concerning a possible increased risk of ischemic cardiovascular events in patients prescribed the thiazolidinedione rosiglitazone. This safety alert was prompted by the results of a large meta-analysis that reported that treatment with rosiglitazone resulted in a 43% increase in risk for myocardial infarction (MI) and a possible increase in risk for cardiovascular death.1 These data were particularly alarming because the metabolic effects of thiazolidinediones were widely presumed, although not proven, to reduce the risk for IHD. Subsequently, a number of additional reports using alternative meta-analytic techniques,2,3 new meta-analyses,4–10 recently published results of new clinical trials,11–15 and observational studies of both rosiglitazone and pioglitazone16–24 have provided variable evidence regarding an adverse cardiovascular effect of these agents. On November 14, 2007, after a specially convened FDA Advisory Panel meeting on July 30, 2007, the FDA decided not to withdraw rosiglitazone from the market. They issued new prescribing information that included a new boxed warning regarding the potential risk for myocardial ischemia, particularly in patients with heart disease taking nitrates, and in patients for whom rosiglitazone was added to established insulin therapy.25 Diabetes mellitus is increasing in prevalence in the United States and worldwide. An estimated 23.6 million people in the United States, 7.8% of the population, had diabetes in 2007, with more than 90% of cases being type 2 diabetes mellitus. Diabetes increases the risk of …

Rx Report

Rx Report