Food And Drug Administration Reports Research Articles

Update: Reports of suicidality in patients taking diabetes/obesity medicines

The below is from a January 11 Drug Safety Communication from the U.S. Food and Drug Administration (FDA) evaluating reports of suicidal thoughts or actions in patients treated with a class of medicines called glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs). The initial evaluation found that there is no evidence of a link between these medicines and suicidality. Below is the FDA's report.

Implied Claims in Drug Advertising: A Review of Recent Literature and Regulatory Actions

ABSTRACT Federal agencies and self-regulatory bodies help to ensure prescription and nonprescription drug promotion contains accurate information; however, false or misleading claims may cause people to have inaccurate perceptions of a drug and inhibit their ability to make informed decisions. We conducted a systematic review assessing evidence from 2012–2021 on how consumers and healthcare providers (HCPs) interpret claims made indirectly or through inference (implied or implicit claims) as well as synthesizing prescription and nonprescription drug advertising claims that have been the subject of regulatory actions from 2017–2021. Our search identified 16 studies from the peer-reviewed literature and 26 letters or case reports issued by the Food and Drug Administration (FDA) or National Advertising Division (NAD). Results from peer-reviewed studies suggest that implied claims can result in inferences that may not be warranted by the material facts about the drug. Perceptions of a drug’s efficacy and, to a lesser extent, risk, are influenced by implied and explicitly false claims in prescription drug promotion. Claims related to implied superiority and overstatement of efficacy were the most prevalent claims flagged for review and examined in the literature. These types of claims were also the subject of many of the compliance actions by the FDA and case reports from the NAD. More research is needed to understand how people interpret varying types of implied claims and the impact of such claims on key outcomes. From a policy standpoint, understanding how people interpret implied claims can inform how the FDA approaches these claims in the marketplace.

A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives.

Liposomes have been considered promising and versatile drug vesicles. Compared with traditional drug delivery systems, liposomes exhibit better properties, including site-targeting, sustained or controlled release, protection of drugs from degradation and clearance, superior therapeutic effects, and lower toxic side effects. Given these merits, several liposomal drug products have been successfully approved and used in clinics over the last couple of decades. In this review, the liposomal drug products approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are discussed. Based on the published approval package in the FDA and European public assessment report (EPAR) in EMA, the critical chemistry information and mature pharmaceutical technologies applied in the marketed liposomal products, including the lipid excipient, manufacturing methods, nanosizing technique, drug loading methods, as well as critical quality attributions (CQAs) of products, are introduced. Additionally, the current regulatory guidance and future perspectives related to liposomal products are summarized. This knowledge can be used for research and development of the liposomal drug candidates under various pipelines, including the laboratory bench, pilot plant, and commercial manufacturing.

Recent Trends in Medicaid Spending and Use of Drugs With US Food and Drug Administration Accelerated Approval

State Medicaid programs have reported concerns about rising drug prices and spending, particularly regarding drugs entering the market through the accelerated approval program under the US Food and Drug Administration (FDA). The accelerated approval program enables the FDA to approve drugs on the basis of unverified surrogate end points, meaning that clinical benefits for these products are uncertain at the time of approval. However, state Medicaid programs are legally required to cover these drugs. Little is known about the set of products with accelerated approval over time, their use among Medicaid beneficiaries, or the magnitude of their financial influence on state Medicaid programs. To identify the number and class of drugs approved through the FDA's accelerated approval pathway and analyze state Medicaid programs' use and spending on these drugs from 2015 through 2019. In this cross-sectional study, biannual FDA reports were used to identify products granted accelerated approval and their associated indications approved between December 1992 and December 2020. State Medicaid Drug Utilization Data files available for 1992 through 2019 were used to estimate national totals for spending and use of outpatient drugs. National Medicaid use and gross and net spending on drugs with accelerated approval from 2015 through 2019. Since the inception of the FDA's accelerated approval pathway in 1992 through 2020, 216 product-indication pairs granted accelerated approval were identified, comprising 149 unique products. The composition of drugs approved through the pathway has changed over time, with 28 of 30 (93.3%) product-indication pairs receiving accelerated approval in 2020 being indicated for cancer. Relative to all outpatient prescription drugs paid for by Medicaid, products with accelerated approval ranged from 0.2% to 0.4% of use (1.3-2.4 million prescriptions annually). Despite their infrequent use, drugs with accelerated approval represented a minimum annual net spending on all drugs covered by Medicaid of 6.4% ($2.2 billion of $34.6 billion) in 2015 and a maximum of 9.1% ($2.5 billion of $27.6 billion) in 2018. Estimated annual gross spending on drugs with accelerated approval ranged from $4.2 billion to $4.9 billion over 2015 through 2019, and estimated net spending from $2.2 billion to $2.6 billion. In this cross-sectional study of 216 drugs granted accelerated approval, state spending on drugs approved through the FDA's growing accelerated approval program represented an outsized amount of spending relative to use. Because drugs with accelerated approval have come to market on the basis of trials using surrogate end points, considerable amounts of this spending may have been attributable to products with unproven clinical benefits.

Lamictal® and Hemophagocytic Lymphohistiocytosis (HLH)

Introduction: Hemophagocytic lymphohisticoytosis (HLH) is a life threatening disorder resulting from uncontrolled macrophage activation. HLH may be primary or associated with active infection, autoimmune disorder or neoplasia. In a recently reported national surveillance report from the Food and Drug Administration (FDA), HLH was observed shortly after the initiation of lamotrigine (Lamictal®) in eight patients. We report the development and treatment of HLH in an otherwise healthy young woman who was briefly treated with lamotrigine. Case: A 27 year-old female with a history of bipolar depression and anxiety began treatment with lamotrigine 25 mg daily. Six days later, she experienced cough and odynophagia progressing to nausea, vomiting, and diarrhea over one day. She was treated with cephalexin for presumptive streptococcal pharyngitis by her primary physician. The next morning she developed diffuse rash, along with lethargy, myalgia, dyspnea and headache, and presented to the emergency room. Vital signs revealed tachycardia, tachypnea, hypoxia, and fever. Her exam was significant for decreased alertness, and pulmonary rhonchi with wheezing. A lumbar puncture displayed cerebrospinal fluid pleocytosis. Liver function tests were abnormal with elevated transaminases and hyperbilirubinemia, and ferritin was markedly elevated. In addition, serum creatinine, C-reactive protein, triglycerides and prothrombin time were elevated [Table]. Rash and overall rapid decline without clear etiology prompted concern for HLH. Lamotrigine was discontinued and a bone marrow biopsy was obtained and revealed normocellular marrow with relative myeloid hyperplasia with erythroid hypoplasia and increased histiocytes without evident hemophagocytosis. Our patient was initially treated with several broad spectrum antibiotics, including vancomycin, meropenem, acyclovir, and clindamycin. Due to worsening oxygenation and respiratory failure, she was intubated. Low-grade disseminated intravascular coagulation developed requiring two units of cryoprecipitate. Intravenous immunoglobulin G (1 gm/kg daily) was administered on hospital days 3 and 4 along with five days of pulse dose steroids (30 mg/kg). On hospital day 9, as her respiratory status worsened she was placed on venous-venous extracorporeal membrane oxygenation (VV ECMO). Treatment with etoposide (300 mg twice weekly - dose adjusted to account for extracorporeal blood volume) and dexamethasone (10 mg/m2 daily) per HLH protocol was initiated. Neutropenia developed after two doses of etoposide, and was subsequently held. The patient remained on VV ECMO for eight days, and was able to be extubated on hospital day 18. Liver and renal function improved, and ferritin level progressively declined over the course of the admission, to near normal at discharge [Figure]. She was discharged on hospital day 32 and is currently living independently at home. Discussion: Our patient was admitted with overwhelming illness, requiring intensive management. She met diagnostic criteria for HLHand once stable, was treated per guidelines of HLH-94 protocol. The month prior to her presentation, a report from investigators at the FDA (Kim T, et al, Neurology 2019;92 e2401-5) using the Adverse Event Reporting System described eight cases of HLH associated with lamotrigine. In light of this report, we describe another patient with HLH developing in a temporal relationship with lamotrigine and in absence of other identifiable causes. The patient was diagnosed with HLH based on H score probability of 94%. Similar to those cases in the FDA report, the syndrome developed shortly after starting lamotrigine and improved after stopping therapy. Lamotrigine is a widely prescribed for bipolar disorder, and increasingly for depression. Other adverse reactions associated with lamotrigine include Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms. It should be stated that these conditions cannot be excluded in this case, as they represent a similar over activation of the immune system with manifestations that overlap with HLH. Early identification and intervention are critical for the successful treatment of HLH. In addition to stopping lamotrigine, immunosuppressive therapy may be beneficial. Presently, there are no guidelines that specifically address treatment for drug-induced HLH. Disclosures No relevant conflicts of interest to declare.

1174 Cases of Angiotensin Receptor Blocker (ARB) Related Sprue-Like Enteropathy (SE): A Review of the Food and Drug Administration Adverse Event Reporting System (FAERS)

INTRODUCTION: In 2002, olmesartan, an ARB, was introduced to the market as Benicar. In 2012, Rubio-Tapia et al. reported 22 cases of SE related to olmesartan. In 2013, the Food and Drug Administration (FDA) issued a safety warning about SE related to olmesartan. In August 2017, Benicar’s manufacturer paid $300 million to settle claims from about 2,300 plaintiffs in SE cases. The FAERS is a publicly available database for voluntary reporting of adverse drug events to the FDA. No study has summarized the reports of ARB-related SE to the FAERS. Our aim is to establish the timeline of FAERS reports of SE from ARBs and to further characterize reports of olmesartan and another ARB-related SE to the FAERS. METHODS: A total of 9,144,290 FAERS reports from January 2013 to December 2018 were downloaded. Data was first queried for all patients using an ARB for hypertension. All drugs were limited to those defined as “Primary Suspect”. Gastrointestinal adverse events (GIAE), including SE and control reactions were then obtained for all ARBs and searched by both generic and trade names. Information regarding the timeline of reports and demographics of reporters was collected. Reporters are categorized as physicians, pharmacists, other health care professionals, consumers, and attorneys. RESULTS: A total of 77,245 FAERS reports of people for ARBs were analyzed. SE was identified in 5,290 (6.8%) cases. With the exception of 6 cases, all were related to olmesartan. All olmesartan cases were filed under its trade name Benicar. In addition to the SE cases reported, there were 7,402 (9.6%) cases of GIAE related to ARB. These included drugs other than olmesartan. The number of reports filed by each category each year is shown in Table 1 and Figure 1. Cases of SE were followed, and their outcomes identified (Table 2). Hospitalization was reported in 52.7% and death in 0.9%. CONCLUSION: The FDA reports for olmesartan-related SE and ARB-related GIAE have increased dramatically. Unlike some high-profile cases with dramatically increased lawyer reporting, these reports originate from physicians and consumers. All reports were for Benicar, none for generics and a few reports for combinations. This can be explained by the minimum of 2 years of ARB use prior symptoms onset suggested in the literature. Other explanations include Benicar’s large market share or potential problems with the Benicar formulation.

Durability Data for Bioprosthetic Surgical Aortic Valve

Although several studies have reported data on surgical aortic valve durability, variability in study methodologies and definitions as well as inadequate follow-up make the interpretation of data from these studies difficult to interpret. To review available data on structural valve deterioration (SVD) of surgical bioprosthetic aortic valves by examining the published literature as well as data reported to the US Food and Drug Administration (FDA). A systematic review using Preferred Reporting Items for Systematic Review and Meta-Analysis reporting guidelines to obtain all available data from preexisting literature on the actuarial freedom from SVD and outcomes of SVD. Data were collected from database inception to November 2016. Additionally, data reported to the FDA were obtained. In total, 167 studies and 12 FDA reports including 101 650 patients and 17 different valve types were analyzed. There were 11 different definitions of SVD used in the studies. Core laboratory data were available for 11 studies. Mean follow-up ranged from less than 1 year to 14 years. Kaplan-Meier estimates were reported for up to 30 years of follow-up, with 0% to 37% of patients remaining at risk at maximum follow-up. Food and Drug Administration-reported data are similarly variable in duration (mean follow-up range, 1.2 to 7 years) and completeness of follow-up, with final follow-up of 0.1% to 95%. There is considerable variability in reporting SVD of surgical aortic valves, with different definitions and inadequate long-term systematically collected core laboratory data. Rigorously collected long-term data with standardized definitions for surgical valves are needed to provide a benchmark for the durability of rapidly evolving transcatheter valves.

Diversity in Medical Device Clinical Trials: Do We Know What Works for Which Patients?

Demographic differences can influence the safety and effectiveness of medical devices; however, clinical trials of devices for adults have historically underrepresented women, people of color, and patients over age 65. The US Food and Drug Administration (FDA) Safety and Innovation Act became law in 2012, encouraging greater diversity and subgroup analyses. In 2013, the FDA reported that there was diversity in clinical trials considered "pivotal" for approval decisions and that subgroup analyses were conducted for most applications for the highest-risk medical devices. However, the FDA's report did not specify whether analyses included sufficient numbers to be meaningful, whether analyses were conducted for most major subgroups, or whether analyses included safety, effectiveness, or accuracy. We examined publicly available documents for all 22medical devices that the FDA designated "highest risk" or "novel,"were reviewed through the premarket approval pathway, and were scrutinizedat FDA public meetings from 2014 to 2017. We evaluated patient demographics and subgroup analyses for all pivotal trials. Only 3 (14%) of the devices provided subgroup analyses for both effectiveness and safety or both sensitivity and selectivity for gender, race, and age. However, 55% of the devices reported both of those subgroup analyses for at least 1 of the 3 subgroups. Whether analyses were reported or not, the number of patients in most subgroups was too small to draw meaningful conclusions. Subgroup analyses were more likely to be reported to the FDA's Advisory Committees than in the FDA's public reviews or labeling. Despite a law encouraging more diversity and subgroup analyses in pivotal trials used as the basis for FDA approval, the results of our study indicate relatively few subgroup analyses are publicly available for the highest-risk and novel medical devices. The lack of subgroup analyses makes it impossible to inform patients or physicians as to whether many newly approved medical devices are safe and effective for specific demographic subgroups defined by gender, race, and age.

Postmarket studies required by the US Food and Drug Administration for new drugs and biologics approved between 2009 and 2012: cross sectional analysis

ObjectivesTo characterize postmarketing requirements for new drugs and biologics approved by the US Food and Drug Administration (FDA), and to examine rates and timeliness of registration, results reporting, and publication...

Tramadol, breast feeding and safety in the newborn

Tramadol has recently fallen under the same scrutiny as codeine because both drugs have an active metabolite formed by the hepatic liver enzyme cytochrome P450 (CYP)-2D6 that is subject to...

FDA Warns Against Unregulated Products.

Some drugs that aren't approved by the Food and Drug Administration (FDA) may still be legally sold in the United States. These include drugs compounded by licensed physicians, pharmacists, and pharmacies. However, drugs manufactured in other countries that do not come from reputable sources cannot be legally sold here, although these drugs can sometimes be purchased online.The FDA reports on adverse events from two unregulated products: a compounded subcutaneous drug (glutamine, arginine, and carnitine) and an overseas product, Balguti Kesaria Ayurvedic Medicine, which is adulterated and potentially lethal.The agency's BeSafeRX web page contains resources to help patients determine if an online pharmacy is reputable.

Predictive factors for the effect of acid-reducing agents on drug exposure.

Acid-reducing agents (ARAs) may affect drug exposure for orally-administered drugs exhibiting pH-dependent solubility. The aim of this research was to investigate factors predicting the effect of ARAs on drug exposure. Dose (mg)/250 mL/solubility at neutral pH and ratio of solubility at acidic pH to that at neutral pH were investigated as potential factors. Drug-drug interaction (DDI) study results with ARAs were selected based on PubMed search from 2007 to 2016 and novel drug approvals at the US Food and Drug Administration (FDA) from 2014 to 2016. For the selected drugs, solubility data at acidic and neutral pH were obtained from publications, FDA and European Medicines Agency (EMA) review report, and Japanese interview form. 32 DDI study results with ARAs from 27 drugs having solubility data were obtained. The effect of ARAs on the C_max or AUC ratio% (with/without ARAs) decreased with the increasing values of both factors, but the ratio of solubility showed higher values of squared correlation coefficient R2 (0.75-0.78) than the dose (mg)/250 mL/solubility at neutral pH (0.48 - 0.59). Ratio of solubility at acidic pH to that at neutral pH was a good predictor to estimate the effect of ARAs on drug exposure. Prediction of the effect of ARAs on drug exposure using solubility data would help to consider the necessity and timing for conducting a dedicated DDI study with ARAs and contribute to efficient drug development. .

No Increased Risk of Ketoconazole Toxicity in Drug-Drug Interaction Studies.

In July 2013 the U.S. Food and Drug Administration (FDA) released a safety announcement regarding the use of ketoconazole and its adverse drug reactions. The FDA report advised against the use ketoconazole tablets as a first-line treatment for any fungal infections because of the risk of potentially serious drug-drug interactions and liver and adrenal gland complications. The European Medicines Agency (EMA) also proposed to limit the use of oral ketoconazole in fungal infections because of the same risk of harmful effects and interactions. In addition, the FDA also advised against the use of oral ketoconazole in drug interaction studies, in which it has been extensively used as an index inhibitor of drug metabolism. The aim of this investigation was to evaluate the risks of ketoconazole-induced hepatotoxicity described by the FDA and EMA in published drug interaction studies with ketoconazole and compare these data with the toxicity reported for ketoconazole when used as antifungal treatment. In the drug interaction studies (2355 participants; healthy volunteers and patients; median treatment duration, 6 days), only 40 participants were reported to have increased liver transaminase activity (1.7%), and no deaths were reported or associated with ketoconazole. In studies investigating ketoconazole treatment, patients were treated for 276 days (median), and 5.6% of patients had elevated liver enzyme activity. Because of the short treatment period in drug interaction studies the risk of drug-induced hepatic injury is considered very low. As such, we recommend that ketoconazole remain a safe CYP3A index inhibitor for use in drug interaction studies with healthy volunteers.

Exposure Matching of Pediatric Anti-infective Drugs: Review of Drugs Submitted to the Food and Drug Administration for Pediatric Approval

PurposeOver the last decade, few new antibiotics have been approved by the Food and Drug Administration (FDA) for pediatric use. For most anti-infective agents, including antibiotics, extrapolation of efficacy from adults to children is possible if the disease and therapeutic exposures are similar between the 2 populations. This approach reduces the number of studies required in children, but relies heavily on exposure matching between children and adults. Failures in exposure matching can lead to delays in pediatric approvals of new anti-infective agents. We sought to determine the extent of exposure matching, defined by a comparison of area under the concentration-time curve, between children and adults, for anti-infective drug products submitted to the FDA for approval. MethodsWe reviewed anti-infective submissions to the FDA (2002–2014) for pediatric indication. We included drug products administered via oral, intravenous, or intramuscular administration routes, and those with AUC estimates for children in available FDA reports. Our main outcome of interest was the proportion of drugs with median (or mean) pediatric AUC within 20% of the median (or mean) reported adult value. FindingsWe identified 29 drug products that met inclusion criteria, 14 (48%) of which had mean (or median) AUCs of all submitted age groups within 20% of that in adults. Only route of administration and drug class were associated with pediatric AUC within 20% of adult AUC. ImplicationsFuture research is needed to define criteria for and predictors of successful exposure matching of anti-infectives between children and adults.

Evaluation of gemtuzumab ozogamycin associated sinusoidal obstructive syndrome: Findings from an academic pharmacovigilance program review and a pharmaceutical sponsored registry

BackgroundIn 2000, the Food and Drug Administration (FDA) approved gemtuzumab ozogamycin for monotherapy for older patients with relapsed AML. A 0.9% rate of hepatic sinusoidal obstructive syndrome (SOS) was noted in licensing trials. In 2001, FDA received reports of 14 GO-associated SOS cases from MD Anderson Cancer Center. A State of South Carolina/National Cancer Institute funded pharmacovigilance program and a manufacturer sponsored registry independently evaluated this concern. MethodsThe manufacturer’s registry and the academic program focused on risk factors and incidence of GO-associated SOS in routine clinical practice and clinical trial settings, respectively. Comparisons were made of findings and dissemination efforts from the two studies. ResultsRetrospective analysis of clinical trials by the academic initiative identified 99 cases of SOS among 221 GO-treated stem cell patients and 649 patients who did not undergo HSCTs. SOS rates were 3% when GO was administered at doses ≤6mg/m2 as monotherapy or with non-hepatotoxic agents; 28% when administered with 6-thioguanine, a hepatotoxic agent; 15% when administered as monotherapy at doses at a dose of 9mg/m2, and between 15% and 40% if a stem cell transplant (SCT) was performed within 3 months of GO administration. Death from SOS occurred in 33% of the cases. The manufacturer’s registry prospectively evaluated 482 GO-treated patients who received a mean dose of 7.8mg/m2. Overall, 41% received concomitant chemotherapy, 18% had undergone prior SCT, 9.1% developed SOS, and death from SOS occurred in 60% of the SOS cases. Findings from each initiative were disseminated at national conferences and in peer-reviewed manuscripts beginning in 2003. ConclusionRetrospective review of clinical trials, case series, and FDA reports and prospective registries can provide important information on safety signals initially identified in licensing trials.

Response to Forbes's comment.

We disagree with the comment of Forbes regarding our misinterpretation of data from the study of Catassi et al.1 and our statement that a safe daily limit is probably in the region of 10 mg/day. First, in the Catassi et al. study the authors reported that ‘some Celiac Disease patients showed a clear-cut worsening of the small-intestinal architecture after ingesting only 10 mg gluten/day’ and 1/13 patients challenged with 10 mg gluten/day developed a clinical relapse p.164. Therefore, with the limit of the small number of patients challenged with 10 mg gluten in this study (n = 13) some effects have been reported also for the quantity of 10 mg/day. The Food and Drug Administration (FDA) safety analysis2 concluded that <1 ppm of gluten in foods is required to protect the greatest number of patients. In the FDA report it is clearly specified that, in the gluten exposure studies examined, the results are not presented or interpreted within a toxicological risk assessment framework. Therefore, for the FDA hazard/safety analysis, the results were reinterpreted within the frame of reference of 1 ppm. The average no observable adverse effect level and the lowest observable adverse effect level associated with morphological effects were calculated utilising the appropriate uncertainty factor (that takes into account the variability among studies and data) and indicated as tolerable the acute intake level for gluten of 12.5 mg/day, and for the subchronic exposure 0.4 mg gluten/day and for chronic exposure 7.0 mg gluten/day. The FDA report, with the limitation of the available data, indicates as tolerable a quantity of gluten close to the one reported in our review. At the moment we do not have any reliable data for toxicity of gluten quantities in the range from 10–50 mg/day. Therefore, on the basis of the scanty data we have, according to the FDA safety assessment analysis and with the limit of personal sensitivity, the only conclusion is that 50 mg could be unsafe for most CD patients and 10 mg should be safe for most of the patients. Our final recommendation that the CD patients should be vigilant with their diet and avoid all sources of known gluten or contamination is the only reasonable conclusion.

Agreements and Discrepancies between FDA Reports and Journal Papers on Biologic Agents Approved for Rheumatoid Arthritis: A Meta-Research Project.

BackgroundSponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website.ObjectivesThis study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis.MethodsAvailable data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy.ResultsFDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The “signal” in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical.ConclusionThere was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias).

The Food and Drug Administration reports provided more data but were more difficult to use than the European Medicines Agency reports

ObjectivesTo compare the accessibility, comprehensiveness, and usefulness of data available from the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) drug reports. Study Design and SettingThis is a cross-sectional study. All new molecular drugs approved between January 1, 2011 and December 31, 2012 from the FDA and EMA Web sites were eligible. ResultsWe included 27 drug reports. Most were searchable, but the FDA table of contents did not match the file's page numbers. Several FDA documents must be searched compared with a single EMA document, but the FDA reports contain more summary data on harms. Detailed information about harms was reported for 93% of the FDA reports (25 of 27 reports) and 26% of the EMA reports (7 of 27 reports). The reports contained information about trial methodology but did not include trial registry IDs or investigator names. All reports but one contained sufficient information to be used in a meta-analysis. ConclusionDetailed data on efficacy and harms are available at the two agencies. The FDA has more summary data on harms, but the documents are harder to navigate.

What Can We Learn From Clinical Trials of Exon Skipping for DMD?

On 20 September 2013, GlaxoSmithKline (GSK) and Prosensa announced that GSK's Phase III clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT01254019","term_id":"NCT01254019"}}NCT01254019) of Drisapersen, an exon skipping drug for Duchenne muscular dystrophy (DMD), failed to meet the primary endpoint of a statistically significant improvement in the 6 Minute Walking Distance Test (6MWT) compared to placebo.1 On 12 November 2013, Sarepta Therapeutics announced that the US Food and Drug Administration (FDA) has considered its application for accelerated approval of Eteplirsen as a DMD drug to be premature.2 The news came as a great disappointment to the scientific community and more specifically to the families and foundations that had followed the trail of research articles and press announcements. Moreover, the clinical trial results and the FDA's view of the relationship between the dystrophin biomarker and functional endpoint of 6MWT in clinic will have a far reaching impact beyond exon skipping therapy in DMD.

Underreporting of Robotic Surgery Complications

Since its Food and Drug Administration (FDA) approval, robot-assisted laparoscopic surgery has grown with expanding indications. One factor used to expand indications is device-related complications. We designed a study to evaluate device-related robotic surgery complications reported to FDA. We searched the FDA device-related complication database, LexisNexis, and PACER (Public Access to Court Electronic Records) to identify robotic surgery-related complications over a 12-year period (January 1, 2000 to August 1, 2012). Cases from LexisNexis and PACER were cross-referenced with the FDA database to determine cases where an FDA report was inaccurate, filed late or not filed. A total of 245 events were reported to the FDA during the study period, including 71 deaths and 174 nonfatal injuries. Median time to report an event to the FDA was 30 days (range = 0-930 days). Eight cases were identified from the LexisNexis and PACER searches where FDA reports were improperly filed. In five of these, no report was filed with a mean follow-up of 4.1 years (range = 2.3-5.8 years). In the three cases where a report was filed, the mean time between the event and the FDA report was 20.4 months (611 days, range = 292-930 days). It is important that the true incidence of complications with robotic-assisted laparoscopic surgery be known to ensure continued safe innovation.