Trends in Bone Morphogenetic Protein Usage since the U.S. Food and Drug Administration Advisory in 2008: What Happens to Physician Practices When the Food and Drug Administration Issues an Advisory?
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ABSTRACT: Study Design Retrospective cross-sectional study of spinal procedures from 2002 to 2010 using the Nationwide Inpatient Sample database. Objective To determine the patterns of bone morphogenetic protein (BMP) usage in fusion surgery before and after the U.S. Food and Drug Administration (FDA) 2008 advisory for the anterior cervical spine to understand how advisories affect U.S. physician practices. Methods Procedures were identified through International Classification of Diseases, Ninth Revision procedure codes and were plotted over time based on fusion procedure type, site, and area of fusion. U.S. national trends were approximated by polynomial regression analysis. Results The majority of the data trends of BMP usage reflect a second-order polynomial model. BMP usage in anterior cervical spine fusion procedures plateaued during the fourth quarter of 2007. The most apparent change in trend was noted in BMP usage pre- and postadvisory in the analysis of anterior cervical spine fusions. BMP percentage of use decreased in this area by 5% from the time of the FDA advisory to the fourth quarter of 2010. Conclusions The decrease in BMP usage in anterior cervical spinal fusion procedures coincided with the timing of the FDA advisory. The fact that BMP continued to be used in cervical spine fusion procedures, even at lower rates, despite the advisory, may reflect the availability of new clinical information that could lessen complications (i.e., lower BMP dose, perioperative steroids, BMP containment). Furthermore, factors like the natural ceiling effect of use or demand for new technology, complications, prohibitive institutional costs, access to information, and insurance compensation may have all contributed to the BMP usage trends observed.
Project description:Policy Points Food and Drug Administration (FDA) advisory committee recommendations and the agency's final actions exhibit high rates of agreement, with cases of disagreement tending to reflect the proposed action type and degree of advisory committee consensus. In the case of disagreements, the FDA tended to be less likely than its advisory committees to approve new products, approve new supplemental indications, or enact new safety changes. These findings raise important issues regarding the factors that differentially shape decision making by advisory committees and the FDA as an agency, including institutional or reputational concerns.ContextThe Food and Drug Administration (FDA) convenes advisory committees to provide external scientific counsel on potential agency actions and to inform regulatory decision making. The degree to which advisory committees and their respective agency divisions disagree on recommendations has not been well characterized across product and action types.MethodsWe examined public documents from FDA advisory committee meetings and medical product databases for all FDA advisory committee meetings from 2008 through 2015. We classified the 376 voting meetings in that period by medical product, regulatory, and advisory committee meeting characteristics. We used multivariable logistic regression to determine the associations between these characteristics and discordance between the advisory committee's recommendations and the FDA's final actions.FindingsTwenty-two percent of the FDA's final actions were discordant with the advisory committee's recommendations. Of these, 75% resulted in the FDA making more restrictive decisions after favorable committee recommendations, and 25% resulted in the agency making less restrictive decisions after unfavorable committee recommendations. Discordance was associated with lower degrees of advisory committee consensus and was more likely for agency actions focused on medical product safety than for novel approvals or supplemental indications. Statements by public speakers, advisory committee conflicts of interest, and media coverage were not associated with discordance between the committee and the agency.ConclusionsThe FDA disagrees with the recommendation of its advisory committees a minority of the time, and in these cases it tends to be less likely to approve new products or supplemental indications and take safety actions. Deviations from recommendations thus offer an opportunity to understand the factors influencing decisions made by both the agency and its expert advisory groups.
Project description:IntroductionThe United States Food and Drug Administration (FDA) Gastrointestinal Drug Advisory Committee (GIDAC) is involved in gastrointestinal drug application reviews. Characteristics and conflicts of interest (COI) in GIDAC meetings are not well described. This study analyzed FDA GIDAC meetings and characteristics that predict recommendations.MethodsIn this cross-sectional study, all publicly available GIDAC meetings where proposed medications were voted on were included. Data were collected regarding indications, medication sponsor, primary efficacy studies, and voting member characteristics (e.g. committee membership, COI). Univariate analyses were conducted at per-meeting and per-vote levels to assess for predictors of committee recommendation and individual votes respectively.ResultsThirty-four meetings with 476 individual votes from 1998-2018 were included. Twenty-three (68%) proposals were recommended for approval and 25 (74%) received FDA approval. Most proposals involved >1 primary study (n = 27, 79%). At least one voting member had a COI in 24 (71%) of 34 meetings. Twelve (35%) meetings had at least one sponsor COI. Among 476 individual votes, 74 (15.5%) involved a COI, with 33 (6.9%) sponsor COI. COI decreased significantly over time, with fewer COI in 2006-2010, 2011-2015, and 2016-2020 compared to 1996-2000 and 2001-2005 (p<0.01). There were no significant associations between pre-defined predictors, including COI, and committee level recommendations or individual votes (p>0.05 for all univariate analyses).ConclusionsThe GIDAC reviewed 34 proposals from 1998-2018. The majority were recommended for approval and later approved by the FDA, highlighting the GIDAC's prominence in the regulatory process. COI are present among GIDAC panelists but decreasing over time and not associated with recommendations.
Project description:In an age of biomedicalization, medical devices have become more common and more technologically complicated, and adverse events associated with medical devices have increased. The U.S. Food and Drug Administration (FDA) relies on advisory panels to assist in regulatory decision making regarding medical devices. Public meetings held by these advisory panels allow stakeholders to testify, presenting evidence and recommendations, according to careful procedural standards. This research examines the participation of six stakeholder groups (patients, advocates, physicians, researchers, industry representatives and FDA representatives) in FDA panel meetings focused on the safety of implantable medical devices between 2010-2020. We use qualitative and quantitative methods to analyze speakers' opportunities for participation, bases of evidence, and recommendations, applying the concept of 'scripting' to understand how this participation is shaped by regulatory structures. Regression analysis demonstrates statistically significant differences in speaking time, where researchers, industry, and FDA representatives had longer opening remarks and more exchanges with FDA panelists than patients. Patients, advocates and physicians shared the least amount of speaking time, and were the parties most likely to leverage patients' embodied knowledge and recommend the most stringent regulatory actions like recalls. Meanwhile, researchers, FDA, and industry representatives rely on scientific evidence and, with physicians, recommend actions that preserve medical technology access and clinical autonomy. This research highlights the scripted nature of public participation and the types of knowledge considered in medical device policymaking.
Project description:UnlabelledRegenerative medicine (RM) is a popular term for a field of scientific and medical research. There is not one universally accepted definition of RM, but it is generally taken to mean the translation of multidisciplinary biology and engineering science into therapeutic approaches to regenerate, replace, or repair tissues and organs. RM products have the potential to provide treatments for a number of unmet needs but have substantial scientific and regulatory challenges that need to be addressed for this potential to be fully realized. FDA has established formal regulatory definitions for biologics, medical devices, and combination products, as well as human cells and tissues. Regenerative medicine products regulated by FDA are classified on the basis of these definitions, and the classification forms the basis for determining the regulatory requirements to each specific product. FDA regulations are generally written to allow the agency flexibility to accommodate new scientific questions raised by novel and evolving technologies. FDA efforts to facilitate product development in this novel and promising area include working with individual sponsors, interacting with the scientific and industry communities, participating in standards development, and developing policy and guidance.SignificanceRegenerative medicine is generally taken to mean the translation of multidisciplinary biology and engineering science into therapeutic approaches to regenerate, replace, or repair tissues and organs. This article provides an overview of the efforts of the U.S. Food and Drug Administration (FDA) to facilitate product development in the field commonly known was regenerative medicine. It provides an introduction to the processes by which FDA works with individual sponsors, interacts with the scientific and industry communities, participates in standards development, and develops formal FDA policy and guidance.
Project description:A 2003 Food and Drug Administration advisory warned of increased hyperlipidemia and diabetes risk for patients taking second-generation antipsychotics (SGAs). After the advisory, a professional society consensus statement provided treatment recommendations and stratified SGAs into high, intermediate, and low metabolic risk. We examine subsequent changes in incident and prevalent SGA use among individuals with severe mental illness.We created a retrospective cohort using Florida Medicaid's claims from 2001 to 2006. We included non-Medicare eligible adults with bipolar disorder or schizophrenia who filled an SGA prescription. We assessed changes in overall and agent-specific use, discontinuations, interruptions, and therapeutic alternative use among prevalent users and agent-specific use among incident users. Pre-advisory utilization was compared with utilization initially after the advisory and two subsequent periods.Among prevalent users, overall SGA use decreased slightly, and no increases in treatment interruptions or discontinuations were observed after the advisory and consensus statement publication. Compared with the pre-advisory period, in the months immediately after the advisory, the use of the highest metabolic-risk agent, olanzapine, decreased by 34% among prevalent users with bipolar disorder (adjusted risk ratio [aRR]?=?0.66, 95%CI?=?0.59-0.74) and 26% among prevalent users with schizophrenia (aRR?=?0.74, 95%CI?=?0.72-0.76). A greater decrease was estimated among incident users with bipolar disorder (aRR?=?0.37, 95%CI?=?0.29-0.47) and schizophrenia (aRR?=?0.42, 95%CI?=?0.35-0.51) during this period. During each subsequent post-advisory period, olanzapine use continued to decrease whereas quetiapine, ziprasidone, and aripiprazole use increased.The metabolic risk advisory and the published consensus statement were associated with a selective reduction in olanzapine use without evidence of treatment disruptions among this population.
Project description:ImportanceThe US Food and Drug Administration (FDA) often relies on independent advisory committees when making decisions about the approval of prescription drugs or their withdrawal from the market. These committees provide the FDA with valuable insight and an opportunity to build public trust through transparent deliberation, but recent controversies have raised questions about the optimal use of FDA advisory committees.ObjectiveTo assess the frequency, purposes, and voting outcomes of human drug advisory committees convened from 2010 to 2021 and the FDA's corresponding actions.Design, setting, and participantsThis qualitative study used a manual review of meeting summaries prepared by FDA staff for the 18 human drug advisory committees active at any time from January 1, 2010, to December 31, 2021, as well as FDA announcements and press releases, drug labels and approval data, industry publications, and company press releases.Main outcomes and measuresOutcomes of votes on regulatory questions were recorded using meeting minutes. Alignment of FDA action with advisory votes for new drugs and indications was judged as of 1 year after the vote was held and as of November 30, 2022.ResultsThe FDA held 409 human drug advisory committee meetings from 2010 to 2021. Committees were convened less frequently over time, from a high of 50 in 2012 to a low of 18 in 2020 and 2021. Much of this decrease occurred at committee meetings involving votes on initial approvals, which declined from a high of 26 in 2012 to a low of 8 in 2021. Overall, FDA regulatory actions aligned with 262 of 298 advisory committee votes on initial approvals, supplemental approvals, withdrawals of approval, and safety actions (88%). Approval followed 142 of 147 positive votes for initial approvals (97%) and 33 of 36 positive votes for supplemental indications (92%), while nonapproval followed 40 of 60 negative votes on initial approvals (67%) and 18 of 21 negative votes on supplemental indications (86%).Conclusions and relevanceIn this qualitative study, there was consistent alignment between advisory votes and FDA action across years and subject areas, but the number of meetings decreased over time. Discordance between FDA actions and advisory committee votes was most frequently an approval after a negative vote. This study demonstrated that these committees have played a key role in the FDA's decision-making process but that the FDA sought independent expert advice less frequently over time even as it continued to follow it. The role of advisory committees in the current regulatory landscape should be more clearly and publicly defined.
Project description:BackgroundRegulatory approval of oncology drugs is the cornerstone of the development process and approval characteristics shape eventual utilization. Approval trends and characteristics provide valuable information for drug developers and regulators and ultimately affect clinicians and patients.MethodsIndication characteristics were tabulated for drugs approved by the U.S. Food and Drug Administration (FDA) for systemic therapy of malignancies from 1949 through October 2011. Variables included time to approval, initial/supplemental indication, tumor type, stage of disease, specification of protein expression or genetic information, drug class, trial design, concomitant agent, trial size, and endpoint.ResultsA total of 121 unique anticancer agents, including 242 unique indications, were approved. The number of trials for each indication has decreased; however, trial size has increased and more randomized controlled trials have been performed. Trial designs have increasingly used time-to-event endpoints and rarely have used symptom-based primary endpoints. Approvals have been primarily single agent, with less emphasis on palliative treatments and increasing emphasis on advanced disease stages and requirements for prior therapy. Molecular specifications in labels have increased, but they are present in less than 30% of recent indications and are not associated with shorter approval times.ConclusionApproval of oncology agents is occurring in increasingly more challenging settings, suggesting gaps between eventual practice and development in potentially suboptimal indications. Molecular specifications promise to enhance development, yet widespread use in label indications has not yet been achieved.
Project description:Seven FDA-certified food dyes have been investigated as organocatalysts. As a result, Fast Green FCF and Brilliant Blue FCF have been discovered as catalysts for the chlorination of a wide range of arenes and heteroarenes in moderate to excellent yields and high regioselectivity. Mechanistic investigations of the separate systems indicate that different modes of activation are in operation, with Fast Green FCF being a light-promoted photoredox catalyst that is facilitating a one-electron oxidation of N-chlorosuccinimide (NCS) and Brilliant Blue FCF serving as a chlorine-transfer catalyst in its sulfonphthalein form with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) as stoichiometric chlorine source. Dearomatization of naphthol and indole substrates was observed in some examples using the Brilliant Blue/DCDMH system.
Project description:Introduction: Tobacco control policies have helped to reduce the health, social, and economic burden of commercial tobacco use worldwide. Little is known about the long-term impact of regulatory policies and functioning bodies that make recommendations to inform policies. The Tobacco Products Scientific Advisory Committee (TPSAC) of the U.S. Food and Drug Administration (FDA) was formed in 2009 to evaluate the safety, health, and dependence of tobacco products and provide related advice and recommendations to the FDA and the Secretary of Health and Human Services. This article describes the first 10 years of the TPSAC activities and reflects on the impact of their service on regulatory actions.Methods: We reviewed public documents from the 2010-2019 TPSAC meetings to examine the purposes, TPSAC decisions, public health participation in meetings, and concordance of the TPSAC recommendations with regulatory actions. Meeting agendas, transcripts, public testimony, and presentations were reviewed to obtain this information.Results: Since 2010, the TPSAC held 25 public meetings with 178 speakers who provided oral public testimony. Sixty-four percent of meetings were held from 2010 to 2012, when three congressionally mandated reports were due on the topics of menthol cigarettes, harmful and potentially harmful constituents in tobacco products, and dissolvable tobacco products. Forty-four percent of meetings focused on menthol cigarettes, 32% on modified risk tobacco products, 16% on harmful and potentially harmful constituents, 12% on dissolvable tobacco, and 4% on tobacco addiction/dependence. FDA regulatory actions were largely nonconcordant with voting decisions by TPSAC.Conclusions: The TPSAC has evaluated an enormous amount of science during the first 10 years, but their influence on regulatory policies has been limited. The TPSAC roles and functioning should be reevaluated to determine how TPSAC can better fulfill its mandate to inform the FDA's regulatory decision making, which could ultimately reduce the burden of tobacco use in the United States.
Project description:The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naïve mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60-0.84). The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamide arm (HR, 0.17; 95% CI, 0.14-0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30-0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide.