Food And Drug Administration Amendments Act Research Articles

Reporting Compliance and Factors Influencing Timeliness of Stroke-Related Trial Results on ClinicalTrials.gov.

Since 2007, research groups are mandated by the Food and Drug Administration Amendments Act (FDAAA) to report clinical trial findings to ClinicalTrials.gov within 12months of trial completion. This observational study aims to analyze compliance data of stroke-related randomized controlled trials subject to these mandates. Using a previously published algorithm, we identified clinical trials likely to be required to adhere to FDAAA mandates (highly likely applicable clinical trials, or HLACTs) from January 2008 to February 2023. We assessed the proportion of studies that reported results within 12months of trial completion, as well as those that reported at any point within 5years. Additionally, we utilized Kaplan-Meier and regression analysis to explore factors associated with on-time reporting. Among 357 stroke-related HLACTs on ClinicalTrials.gov that were terminated or completed between January 1, 2008, and February 1, 2023, 59 (16.5%) reported results within 12months, while 320 (89.6%) reported results within 5years. Median reporting times for industry funded, other government or academic institution funded, and National Institute of Health (NIH) funded studies were 18.5months, 22months, and 22.5months, respectively. Open-label studies were less likely to report results by 12months compared to double-blinded studies (p = 0.002). Biological trials exhibited a lower probability of reporting within 5years compared to device and/or drug trials (p = 0.007). Clinical trial registries and FDAAA mandates aim to promote accountability and transparency in health sciences research. However, regardless of their funding source, only a minority of stroke-related randomized controlled trials comply with FDAAA's 12-month result reporting mandate.

Characterization of the US Food and Drug Administration Post-Marketing Commitments and Requirements for Pregnancy and Lactation.

Enactment of the US Food and Drug Administration Amendments Act (FDAAA) in 2007 and the Pregnancy and Lactation Labeling Rule (PLLR) in 2015 are important milestones giving the FDA the authority to request studies in pregnant and lactating women. Our objective was to characterize trends of pregnancy and lactation-related postmarketing commitments (PMCs) and postmarketing requirements (PMRs) for new molecular entities approved by the FDA between 2000 and 2022. Approval letters of original New Drug Applications (NDAs, N = 488) for new molecular entities were obtained from the FDA website. NDAs with pregnancy and lactation-based PMCs/PMRs were identified, and data extracted. Data included: PMC/PMR timelines and attributes of requested study(ies) (type, design elements, and outcomes) when available. Fifty-nine NDAs included 92 PMCs/PMRs related to pregnancy and lactation. Forty-one NDAs had pregnancy-related PMRs/PMCs, 4 had lactation-related PMRs, and 14 had both. Most PMRs/PMCs were for nervous system medications (N = 33). Forty-seven NDAs specified safety data collection in infants in at least the first year of life. All pregnancy-related PMRs were issued after 2008, most PMCs (N = 8) were issued before 2008. Only one PMC requested a pharmacokinetic study in pregnant women. All lactation-related PMRs (N = 18) requested measurement of drug concentrations in breast milk with one also requiring measurement of maternal blood concentrations. Eighty-nine percent of lactation-related PMRs were requested after 2015. There was a steady increase in pregnancy and lactation-related PMRs following enactment of FDAAA and PLLR. Additions involved information collection pertaining to safety of the medication in pregnant and lactating women and children exposed to medications during pregnancy and breastfeeding.

Evaluating publication bias for clinical trials supporting new dermatologic drug approvals from 2003 to 2018.

The degree of publication bias and impact of the Food and Drug Administration Amendments Act (FDAAA) of 2007, which aimed to improve clinical trial transparency, has yet to be examined for recent dermatologic drugs. The objective of our study was to estimate the degree of publication bias for clinical trials supporting FDA approval of new dermatologic drugs. This retrospective cohort study examined all phase II and III efficacy trials supporting approval of new dermatologic drugs from 2003 to 2018. FDA drug approval documents were reviewed for supportive clinical trial information, and publications were matched using PubMed and Google Scholar searches. Ratios of relative risks (RRR) comparing positive versus non-positive trials before and after FDAAA enactment served to estimate publication bias. We found that the likelihood of publishing positive versus non-positive drug trials in dermatology was unchanged before and after FDAAA enactment (RRR 0.87, 95% CI 0.37-2.08), as was the likelihood of publishing without misleading interpretation (RRR 1.51, 95% CI 0.22-10.50). There was no measurable publication bias for efficacy trials supporting new drug approvals in dermatology over the past 15years. Fewer pre-FDAAA trials (n = 21) compared to post-FDAAA trials (n = 106) met inclusion criteria. Though not analyzed in this study, safety and secondary efficacy results are other potential sources for publication bias.

"Extensive Proof-of-Concept Studies in TNF-Alpha Antagonists might be Responsible for A Delay of Patient Access in Pediatric Rheumatology"

In order to improve the route to market for approved pediatric therapeutics, the current Pediatric Regulation in the EU and the Food and Drug Administration (FDA) Amendments Act (FDAAA) were both adopted in 2007..

Clinical trial transparency and data sharing among biopharmaceutical companies and the role of company size, location and product type: a cross-sectional descriptive analysis

ObjectivesTo examine company characteristics associated with better transparency and to apply a tool used to measure and improve clinical trial transparency among large companies and drugs, to smaller companies and...

Transparency in Biomedical Research and the Human Right to Health: An Empirical Evaluation of Registered Protocols and Published Clinical Trials

The relationship between clinical research and the pharmaceutical industry has placed clinical trials in jeopardy. According to the medical literature, more than 70% of new drug trials are industry funded. Many of these trials remain unpublished or have methodological flaws that distort the results. The United States was the first country to respond. In 2007, the White House signed into law the Food and Drug Administration Amendments Act (FDAAA), aiming to provide universal access to a broad range of biomedical research information to be made available on the online platform “ClinicalTrials.gov.” In our paper, we accessed ClinicalTrials.gov and evaluated the compliance of researchers and sponsors with the FDAAA. We also assessed the proportion of industry-funded and independently funded trials and the relationship between funding and methodological flaws in clinical trials. Our analysis reveals that the FDAAA has positively affected transparency patterns in clinical research. Poorly designed trials, however, remain a challenge to be overcome These flaws negatively affect the quality of information available, breaching ethical duties of sponsors and researchers and the human right to health enshrined in Article 12 of the International Covenant on Economic, Social, and Cultural Rights (ICESCR).

Consequences of Disclosing Clinical Trial Results: Evidence from the Food and Drug Administration Amendments Act

We examine how the U.S. Food and Drug Administration Amendments Act (FDAAA) of 2007, which requires additional disclosures regarding clinical trial results, impacts information asymmetry between the disclosing pharmaceutical firm and capital market participants, the general public, academics, and practitioners. We document a reduction in information asymmetry in capital markets. We also document an increase in adverse event and product problem complaint reports filed against the pharmaceutical firms to the FDA and a higher number of drug and medical device recalls for affected firms after the FDAAA enactment. Finally, cross-sectional analyses suggest that the increase in FDA complaint reports and recalls after the FDAAA enactment was more prominent in firms with a higher bid-ask spread decrease. Taken together, our results suggest that the FDAAA has some benefits for both investors and consumers.

Compliance with legal requirement to report clinical trial results on ClinicalTrials.gov: a cohort study

Failure to report the results of a clinical trial can distort the evidence base for clinical practice, breaches researchers' ethical obligations to participants, and represents an important source of research waste. The Food and Drug Administration Amendments Act (FDAAA) of 2007 now requires sponsors of applicable trials to report their results directly onto ClinicalTrials.gov within 1 year of completion. The first trials covered by the Final Rule of this act became due to report results in January, 2018. In this cohort study, we set out to assess compliance. We downloaded data for all registered trials on ClinicalTrials.gov each month from March, 2018, to September, 2019. All cross-sectional analyses in this manuscript were performed on data extracted from ClinicalTrials.gov on Sept 16, 2019; monthly trends analysis used archived data closest to the 15th day of each month from March, 2018, to September, 2019. Our study cohort included all applicable trials due to report results under FDAAA. We excluded all non-applicable trials, those not yet due to report, and those given a certificate allowing for delayed reporting. A trial was considered reported if results had been submitted and were either publicly available, or undergoing quality control review at ClinicalTrials.gov. A trial was considered compliant if these results were submitted within 1 year of the primary completion date, as required by the legislation. We described compliance with the FDAAA 2007 Final Rule, assessed trial characteristics associated with results reporting using logistic regression models, described sponsor-level reporting, examined trends in reporting, and described time-to-report using the Kaplan-Meier method. 4209 trials were due to report results; 1722 (40·9%; 95% CI 39·4-42·2) did so within the 1-year deadline. 2686 (63·8%; 62·4-65·3) trials had results submitted at any time. Compliance has not improved since July, 2018. Industry sponsors were significantly more likely to be compliant than non-industry, non-US Government sponsors (odds ratio [OR] 3·08 [95% CI 2·52-3·77]), and sponsors running large numbers of trials were significantly more likely to be compliant than smaller sponsors (OR 11·84 [9·36-14·99]). The median delay from primary completion date to submission date was 424 days (95% CI 412-435), 59 days higher than the legal reporting requirement of 1 year. Compliance with the FDAAA 2007 is poor, and not improving. To our knowledge, this is the first study to fully assess compliance with the Final Rule of the FDAAA 2007. Poor compliance is likely to reflect lack of enforcement by regulators. Effective enforcement and action from sponsors is needed; until then, open public audit of compliance for each individual sponsor may help. We will maintain updated compliance data for each individual sponsor and trial at fdaaa.trialstracker.net. Laura and John Arnold Foundation.

Do Mandatory Disclosure Requirements for Private Firms Increase the Propensity of Going Public?

This paper investigates the effect of mandatory disclosure requirements for private firms on their decision to go public. Using detailed project-level data for biopharmaceutical firms, we explore the effects of a legal reform---the Food and Drug Administration Amendments Act (FDAAA)---which exogenously required that firms publicly disclose information regarding clinical trials. Exploiting cross-sectional heterogeneity in firms' exposure to the regulation based on their internal development portfolios, we find that affected firms are significantly more likely to transition to public equity markets following the reform. We also find that firms that go public due to the increased disclosure requirements subsequently reduce the size of their project portfolios while shifting to safer investments acquired externally. The results suggest that private firms' general information environment and disclosure requirements influence the propensity of going public, and the nature of their subsequent project decisions.

Registration, results reporting, and publication bias of clinical trials supporting FDA approval of neuropsychiatric drugs before and after FDAAA: a retrospective cohort study

BackgroundMandatory trial registration, and later results reporting, were proposed to mitigate selective clinical trial publication and outcome reporting. The Food and Drug Administration (FDA) Amendments Act (FDAAA) was enacted by Congress on September 27, 2007, requiring the registration of all non-phase I clinical trials involving FDA-regulated medical interventions and results reporting for approved drugs. The association between FDAAA enactment and the registration, results reporting, and publication bias of neuropsychiatric trials has not been studied.MethodsWe conducted a retrospective cohort study of all efficacy trials supporting FDA new drug approvals between 2005 to 2014 for neuropsychiatric indications. Trials were categorized as pre- or post-FDAAA based on initiation and/or completion dates. The main outcomes were the proportions of trials registered and reporting results in ClinicalTrials.gov, and the degree of publication bias, estimated using the relative risks pre- and post-FDAAA of both the publication of positive vs non-positive trials, as well as of publication of positive vs non-positive trials without misleading interpretations. Registration and results reporting proportions were compared pre- and post-FDAAA using the two-tailed Fisher exact test, and the degrees of publication bias were compared by calculating the ratio of relative risks (RRR) for each period.ResultsThe FDA approved 37 new drugs for neuropsychiatric indications between 2005 and 2014 on the basis of 142 efficacy trials, of which 101 were pre-FDAAA and 41 post-FDAAA. Post-FDAAA trials were significantly more likely to be registered (100% vs 64%; p < 0.001) and report results (100% vs 10%; p < 0.001) than pre-FDAAA trials. Pre-FDAAA, positive trials were more likely to be published (relative risk [RR] = 1.52; 95% confidence interval [CI] = 1.17–1.99; p = 0.002) and published without misleading interpretations (RR = 2.47; CI = 1.57–3.73; p < 0.001) than those with non-positive results. In contrast, post-FDAAA positive trials were equally likely to have been published (RR = 1; CI = 1–1, p = NA) and published without misleading interpretations (RR = 1.20; CI = 0.84–1.72; p = 0.30). The likelihood of publication bias pre-FDAAA vs post-FDAAA was greater for positive vs non-positive trials (RRR = 1.52; CI = 1.16–1.99; p = 0.002) and for publication without misleading interpretations (RRR = 2.06, CI = 1.17–3.61, p = 0.01).ConclusionsThe enactment of FDAAA was followed by significantly higher proportions of trials that were registered and reporting results on ClinicalTrials.gov and significantly lower degrees of publication bias among trials supporting recent FDA approval of drugs for neuropsychiatric indications.

Reporting bias in completed epilepsy intervention trials: A cross-sectional analysis

ObjectiveTo explore the evidence of reporting bias among completed epilepsy intervention trials (EITs) and compliance of applicable EITs to Food and Drug Administration Amendments Act (FDAAA). MethodsWe included consecutive EITs registered as completed on ClinicalTrials.gov from 2008 to 2015. Descriptive data was collected including study type, study phase, funding source, primary completion date, and result reporting date. Time to result reporting was analyzed using Kaplan-Meier estimates for two time periods (2008–2011 and 2012–2015). PubMed, Web of Science, and Google scholar databases were manually searched for publication details. ResultsOverall, 95/126 EITs (75%) reported, while remaining 31/126 (25%) did not report their results. Time to reporting was significantly lower for trials completed during 2012–2015 (16.5 months; 95% CI: 13.60–19.40; p = .002; Cohen’s d = 0.68) as compared to the trials completed during 2008–2011 (25.9 months; 95% CI: 21.56–30.22). 72/126 trials were conducted in at least one U.S. center. 56/72 (78%) of the trials met the FDAAA criteria, while only 19/56 (34%) reported within the mandated one-year time frame. ConclusionThe lack of reporting of nearly one-quarter of completed epilepsy intervention trials suggests existence of reporting bias. As such, it should be considered an important criterion for determining risk of bias in epilepsy systematic reviews.

Clinical trial transparency: a reassessment of industry compliance with clinical trial registration and reporting requirements in the United States

ObjectiveTo evaluate the accuracy of a 2015 cross-sectional analysis published in the BMJ Open which reported that pharmaceutical industry compliance with clinical trial registration and results reporting requirements under US...

Impact of study outcome on submission and acceptance metrics for peer reviewed medical journals: six year retrospective review of all completed GlaxoSmithKline human drug research studies

Objectives To determine whether the outcome of drug studies influenced submission and/or acceptance rates for publication in peer reviewed medical journals.Design A six year retrospective review of publication status by...

FDAAA legislation is working, but methodological flaws undermine the reliability of clinical trials: a cross-sectional study.

The relationship between clinical research and the pharmaceutical industry has placed clinical trials in jeopardy. According to the medical literature, more than 70% of clinical trials are industry-funded. Many of these trials remain unpublished or have methodological flaws that distort their results. In 2007, it was signed into law the Food and Drug Administration Amendments Act (FDAAA), aiming to provide publicly access to a broad range of biomedical information to be made available on the platform ClinicalTrials (available at https://www.clinicaltrials.gov). We accessed ClinicalTrials.gov and evaluated the compliance of researchers and sponsors with the FDAAA. Our sample comprised 243 protocols of clinical trials of biological monoclonal antibodies (mAb) adalimumab, bevacizumab, infliximab, rituximab, and trastuzumab. We demonstrate that the new legislation has positively affected transparency patterns in clinical research, through a significant increase in publication and online reporting rates after the enactment of the law. Poorly designed trials, however, remain a challenge to be overcome, due to a high prevalence of methodological flaws. These flaws affect the quality of clinical information available, breaching ethical duties of sponsors and researchers, as well as the human right to health.

Compliance with Results Reporting at ClinicalTrials.gov

BackgroundThe Food and Drug Administration Amendments Act (FDAAA) mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results.MethodsUsing an algorithm based on input from the National Library of Medicine, we identified trials that were likely to be subject to FDAAA provisions (highly likely applicable clinical trials, or HLACTs) from 2008 through 2013. We determined the proportion of HLACTs that reported results within the 12-month interval mandated by the FDAAA or at any time during the 5-year study period. We used regression models to examine characteristics associated with reporting at 12 months and throughout the 5-year study period.ResultsFrom all the trials at ClinicalTrials.gov, we identified 13,327 HLACTs that were terminated or completed from January 1, 2008, through August 31, 2012. Of these trials, 77.4% were classified as drug trials. A total of 36.9% of the trials were phase 2 studies, and 23.4% were phase 3 studies; 65.6% were funded by industry. Only 13.4% of trials reported summary results within 12 months after trial completion, whereas 38.3% reported results at any time up to September 27, 2013. Timely reporting was independently associated with factors such as FDA oversight, a later trial phase, and industry funding. A sample review suggested that 45% of industry-funded trials were not required to report results, as compared with 6% of trials funded by the National Institutes of Health (NIH) and 9% of trials that were funded by other government or academic institutions.ConclusionsDespite ethical and legal obligations to disclose findings promptly, most HLACTs did not report results to ClinicalTrials.gov in a timely fashion during the study period. Industry-funded trials adhered to legal obligations more often than did trials funded by the NIH or other government or academic institutions. (Funded by the Clinical Trials Transformation Initiative and the NIH.)

Pediatric Exclusivity

To review the successes and omissions of the Food and Drug Administration (FDA) pediatric exclusivity incentive. Pediatric drug development receives less attention and funding than drug development targeting adults resulting in fewer appropriately labeled pediatric drugs. Newly introduced legislation aims to correct this deficit using market exclusivity incentives. Under the Food and Drug Administration Modernization Act (FDAMA, 1997), the FDA established the exclusivity principle. This legislation was renewed and amended in 2007 under Food and Drug Administration Amendments Act (FDAAA) allowing drug companies to receive a 6-month patent extension for initiating clinical investigation in pediatric populations. Fostering improved knowledge in pediatric indications and dosing is the motivating force behind this program. We examined drugs granted exclusivity through FDA published database as well as relevant drug labeling and postmarket safety studies. Our examination shows that studies conducted in support of patent protection are often not designed to meet current pediatric needs. Amendments to FDAAA are needed to ensure that studies approved for exclusivity strive to meet the following requirements: relevant pediatric clinical indication ; disease addressed should represent a significant disease burden to the appropriate population; important age ranges should be covered; studies should not be allowed when a safety signal is identified prior to initiation of the study; and trials where endpoints are successfully achieved providing considerable contribution to pediatric dosing knowledge or result in labeling changes may gain an additional incentive.

Finishing the Picture: Problems With Public Reporting of Clinical Trials

When the Food and Drug Administration Amendments Act (FDAAA) was signed into law in September 2007, the legislation mandated registration and reporting of primary and secondary outcomes of all non–phase I trials of US Food and Drug Administration-regulated drugs to the ClinicalTrials.gov Web site for public review regardless of publication status. This mandate was in response to ethical and scientific concerns regarding socalled incomplete pictures of drugs that follow from selective reporting of study results. The consequences of selective reporting are significant; only after litigation was filed against Merck in 2004 were phase III clinical trial data disseminated that revealed an association with rofecoxib (Vioxx, Merck, Whitehouse Station, NJ) and increased cardiovascular risk. This is far from the exceptional case of underreporting (references 9 and 15-18 in the article by Nguyen et al). Nguyen et al in the article that accompanies this editorial describe an incomplete picture of cancer drug reporting that has potentially profound effects on patient management and counseling, as timely and complete dissemination of results can refine patient treatments, outcomes, and safety. They found that almost one half of trials had no publically available results at 3 years after completion. In addition, compliance with the FDAAA requirement of outcome reporting within 12 months of study completion was even poorer, with only 13% of trials posting results within the legislated timeframe. Contrary to the notion that the pharmaceutical industry might have the most to lose from clinical studies which did report negative results, compliance with the FDAAA legislation was highest in trials with industry primary funding. This parallels the unexpected finding reported previously; namely, that pharmacoeconomic findings reported in pharmaceutical industry–funded reports were of higher quality than those findings reported by researchers who lacked pharmaceutical industry support. While issues around publication review and revision may delay availability of study results, no such barrier exists around publication of data on ClinicalTrials.gov. It is not known if the selective incomplete reporting reflected differentials in studies with statistically nonsignificant primary or secondary outcomes or if the delayed studies were those where US Food and Drug Administration registration was being pursued and corporate interests mitigated against early dissemination. The consequences of nonreporting study results—in particular, those from clinical trials with statistically nonsignificant findings or where significant toxicities are identified which are more likely to remain unpublished—have far reaching effects. Meta-analyses of both safety and efficacy outcomes may produce biased results due to publication bias, as nonpublication of studies with nonsignificant findings typically leads to overestimation of treatment effect by the inclusion of published (and therefore more likely positive) studies and underestimation of safety effects by omission of nonpublished safety findings. As over two thirds of cancer trials included in this study were not randomized controlled trials, their inclusion or exclusion in metaanalyses likely make up the highest-quality evidence provided on that particular agent. Limitations of the study are inherent in its design. Nguyen et al chose to use publication in PubMed as an indication of journal publication; while this index is an extremely comprehensive biomedical bibliographic database, it does not index 1,800 journals found in Embase, which generally focuses more on the pharmacologic literature. In addition, the authors elected to search PubMed by the Number Clinical Trial identification to link study to publication. Although Medline began to attempt indexing publications to Number Clinical Trial numbers in 2005, the process was not uniformly adopted for several years. For the older studies registered before the passage of the FDAAA, this may potentially have created difficulty in identifying associated publications. In addition, using MEDLINE search methodology, as the authors did, has been demonstrated to miss many randomized clinical trials due to errors in indexing. How do we improve the likelihood that the complete picture of a drug will be disseminated in the future? First, while nonreporting of trial results is currently punishable by penalty under the FDAAA, individuals who conduct studies supported by federal funds should be required to report trial results to ClinicalTrials.gov as required by FDAAA as a condition of receiving continued grant support. Similarly, the US Food and Drug Administration should monitor reporting rates of studies supported by pharmaceutical manufacturers to ClinicalTrials.gov and consider regulatory actions if these trial results are not submitted to the ClinicalTrials.gov Web site. Thirdly, the proposed creation of an independent, external organization that provides independent and impartial data analysis may be helpful here. Finally, study investigators must JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 24 AUGUST 2

Public Availability of Results of Trials Assessing Cancer Drugs in the United States

To evaluate to what extent results of completed trials of cancer drugs conducted in the United States are publicly available at ClinicalTrials.gov, as required by the Food and Drug Administration Amendments Act (FDAAA), or are published in journals. We searched ClinicalTrials.gov for cancer trials governed by the FDAAA: phase II to IV trials assessing drugs in the United States with a primary completion date between December 26, 2007, and May 31, 2010. For each trial, we also searched PubMed to identify the publication of results. We assessed the cumulative percentages of posted or published results over time by using the Kaplan-Meier method. We identified 646 trials, including 209 randomized controlled trials (RCTs). At 12 months after completion of the trials, the cumulative percentages of trials with results posted at ClinicalTrials.gov, published in journals, and available either at ClinicalTrials.gov or in journals were 9% (95% CI, 7% to 11%), 12% (95% CI, 10% to 15%), and 20% (95% CI, 17% to 23%), respectively, and for RCTs, the percentages were 12% (95% CI, 8% to 16%), 5% (95% CI, 2% to 8%), and 17% (95% CI, 12% to 22%), respectively. At 36 months, these percentages were 31% (95% CI, 28% to 35%), 35% (95% CI, 31% to 39%), and 55% (95% CI, 51% to 59%), respectively, and for RCTs, they were 38% (95% CI, 31% to 45%), 32% (95% CI, 25% to 39%), and 56% (95% CI, 48% to 62%), respectively. Public availability of phase III trials was 15% (95% CI, 7% to 23%) at 12 months, 39% (95% CI, 27% to 49%) at 24 months, and 64% (95% CI, 50% to 73%) at 36 months. Despite the FDAAA, results for nearly half the trials of cancer drugs in the United States were not publicly available 3 years after completion of the trials.

Development of a federally mandated risk evaluation and mitigation strategy (REMS) for transmucosal immediate-release fentanyl products

Opioid analgesics, including transmucosal immediate-release fentanyl (TIRF) products, are associated with serious risks of abuse, addiction, and overdose. In 2007, Congress passed the Food and Drug Administration Amendments Act (FDAAA), requiring manufacturers to implement a Risk Evaluation and Mitigation Strategy (REMS) for opioid distribution. In 2009, recommendations for “Elements to Assure Safe Use” (ETASU) were released. In March 2012, a shared TIRF-REMS program (http://www.tirfremsaccess.com) was implemented; the shared TIRF-REMS was modeled in part on a separate REMS program for sublingual TIRF tablets. The goals of the shared TIRF-REMS program are to “mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors.” These goals were designed to limit dispensing to appropriate patients, prevent inappropriate conversion between fentanyl products, avoid accidental exposure, and educate about risks. The shared TIRF-REMS program is controlled by a limited-access distribution system that mandates enrollment and certification of prescribers, pharmacies, distributors, and patients. Clinicians who prescribe TIRF products to outpatients must meet several ETASU requirements, including reviewing educational materials and completing a Prescriber Knowledge Assessment (https://www.tirfremsaccess.com/TirfUI/rems/education.action) and Prescriber Enrollment Form (https://www.tirfremsaccess.com/TirfUI/rems/pdf/prescriber-enrollment-form.pdf). A Patient-Prescriber Agreement Form (https://www.tirfremsaccess.com/TirfUI/rems/pdf/ppaf-form.pdf) must be submitted within 10 days from prescription processing; only 3 prescriptions can be written until the form is received. Form renewals are required every 2 years. Pharmacies distributing TIRF products must meet specific guidelines, including designating a pharmacist to be responsible for a pharmacy management system that supports communication with the TIRF-REMS program; however, pharmacies dispensing TIRF products solely to inpatients only need to be certified. Although the shared TIRF-REMS program is an important step toward the FDAAA goals, it is likely that additional measures will be needed, including procedures to control non-prescription opioid misuse and abuse. Supported by ProStrakan. Opioid analgesics, including transmucosal immediate-release fentanyl (TIRF) products, are associated with serious risks of abuse, addiction, and overdose. In 2007, Congress passed the Food and Drug Administration Amendments Act (FDAAA), requiring manufacturers to implement a Risk Evaluation and Mitigation Strategy (REMS) for opioid distribution. In 2009, recommendations for “Elements to Assure Safe Use” (ETASU) were released. In March 2012, a shared TIRF-REMS program (http://www.tirfremsaccess.com) was implemented; the shared TIRF-REMS was modeled in part on a separate REMS program for sublingual TIRF tablets. The goals of the shared TIRF-REMS program are to “mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors.” These goals were designed to limit dispensing to appropriate patients, prevent inappropriate conversion between fentanyl products, avoid accidental exposure, and educate about risks. The shared TIRF-REMS program is controlled by a limited-access distribution system that mandates enrollment and certification of prescribers, pharmacies, distributors, and patients. Clinicians who prescribe TIRF products to outpatients must meet several ETASU requirements, including reviewing educational materials and completing a Prescriber Knowledge Assessment (https://www.tirfremsaccess.com/TirfUI/rems/education.action) and Prescriber Enrollment Form (https://www.tirfremsaccess.com/TirfUI/rems/pdf/prescriber-enrollment-form.pdf). A Patient-Prescriber Agreement Form (https://www.tirfremsaccess.com/TirfUI/rems/pdf/ppaf-form.pdf) must be submitted within 10 days from prescription processing; only 3 prescriptions can be written until the form is received. Form renewals are required every 2 years. Pharmacies distributing TIRF products must meet specific guidelines, including designating a pharmacist to be responsible for a pharmacy management system that supports communication with the TIRF-REMS program; however, pharmacies dispensing TIRF products solely to inpatients only need to be certified. Although the shared TIRF-REMS program is an important step toward the FDAAA goals, it is likely that additional measures will be needed, including procedures to control non-prescription opioid misuse and abuse. Supported by ProStrakan.

The Drug Safety and Risk Management Advisory Committee

The Food and Drug Administration Amendments Act (FDAAA) of 2007 granted FDA-expanded drug safety authority. We hypothesized that meetings involving the FDA Drug Safety and Risk Management (DSaRM) Advisory Committee might serve as a barometer for the impact of FDAAA on drug safety regulatory decision making. We conducted a case study analysis of 42 DSaRM advisory committee meetings held between 2002 and 2011. Publicly available sources (FDA meeting minutes and materials, safety alerts, and drug manufacturer Web sites) were reviewed to describe and compare DSaRM meeting frequency, content and outcomes between the pre-FDAAA (2002-2007) and post-FDAAA (2008-2011) periods. DSaRM meeting frequency increased after FDAAA (from 2.7 to 6.5 meetings per year). DSaRM meetings were more likely to be held jointly with other drug advisory committees after FDAAA (from 68% to 92% of meetings). DSaRM members were invited participants in 35 additional meetings of other drug advisory committees (2007-2011). DSaRM meetings were more likely to review issues of approvability (eg, new drugs, new indications, and new product formulations) after FDAAA. FDA questions to the committee were more likely to request an explicit drug safety assessment after FDAAA (from 31% to 76% of meetings). Content analysis of meeting outcomes and subsequent FDA regulatory decisions did not suggest a more or less risk aversive climate after FDAAA. Increased DSaRM advisory committee activity indicates its advice was being sought more broadly for drug regulatory decision making and at earlier stages of drug development after FDAAA was enacted.