Thomas J. Hwang

Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: analysis of published guidance and meta-analysis of cohort studies

Objectives Given the spread of multidrug-resistant tuberculosis (MDR-TB), new therapies are urgently needed, including the repurposing of existing drugs. We aimed to assess key considerations for the clinical and programmatic use of clofazimine (Cfz), a riminophenazine with antimycobacterial activity currently used to treat leprosy. Design Fixed and random effects meta-analysis of cohort studies and systematic review. Setting Electronic and manual searches were combined. Inclusion criteria Observational studies on treatment of multidrug-resistant and extremely drug-resistant tuberculosis with Cfz or a Cfz-containing regimen, and published guidance and documents relating to cost and availability were eligible. Results 5 observational studies enrolled 861 patients, of which 602 received Cfz. The pooled proportion of adverse drug reactions requiring discontinuation of Cfz treatment was 0.1% (95% CI (0.0 to 0.6%)), and the median frequency of all adverse events was 5.1%. Cfz showed in vitro efficacy against Mycobacterium tuberculosis, and Cfz-containing regimens may have had a useful role in the treatment of patients with drug-resistant strains and who had limited alternative treatment options. However, Cfz uptake remains insufficient to meet global needs; there is only one internationally quality-assured manufacturer, which produces a limited quantity of the drug prioritised for treatment of leprosy, the only indication for which the drug is registered. Conclusions While the data were limited, Cfz was associated with a risk for adverse drug reactions comparable to that of first-line TB treatment, which could be reasonably managed under programmatic conditions. However, low market availability and high cost are important barriers to access to Cfz for patients with MDR-TB.

Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results.

Importance Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research. Objective To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results. Design, Setting, and Participants Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product. Main Outcomes and Measures For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval. Results Among 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved. Conclusions and Relevance Roughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.

Two decades of new drug development for central nervous system disorders

This article analyses the characteristics of the pipeline for experimental drugs for central nervous system disorders and how they have fared in the clinical phases prior to FDA approval over the past two decades.

Postmarketing Trials and Pediatric Device Approvals

BACKGROUND: Medical devices can be useful in a variety of diseases, but few devices have been specifically approved for use in children. The 2007 Pediatric Medical Device Safety and Improvement Act was passed to stimulate pediatric device development. The current state of trial evidence underpinning the approval of pediatric devices remains poorly described. METHODS: We identified all high-risk (ie, class III) devices approved through the premarket approval or humanitarian device exemption pathways for therapeutic use in children between 2008 and 2011. We collected key information on clinical trial design (randomization, blinding, controls, and types of end points) as well as age distribution of trial participants. We also identified US Food and Drug Administration (FDA)–mandated postmarketing trials. RESULTS: Twenty-two devices were approved for use in children via the premarket approval pathway and 3 via the humanitarian device exemption pathway. Twenty-two (88%) qualified as pediatric despite minimum approval ages of ≥18 years (the FDA Center for Devices and Radiologic Health considers patients 18–21 years old as pediatric). Most devices were approved on the basis of nonrandomized (59%), open-label (68%) studies with surrogate effectiveness end points (86%). Overall, 21 (84%) devices were not studied in any patients <18 years of age. Postmarketing studies were mandated by the FDA for 19 (76%) devices, although only 3 (18%) required enrollment of pediatric patients. CONCLUSIONS: Most high-risk pediatric devices are approved on the basis of trials in patients ≥18 years old, with few pediatric patients exposed to the devices before market availability. Few postmarketing studies require additional study in pediatric patients.

Comparison of rates of safety issues and reporting of trial outcomes for medical devices approved in the European Union and United States: cohort study

Objective To evaluate safety alerts and recalls, publication of key trial outcomes, and subsequent US approval of high profile medical devices introduced in the European Union. Design Cohort study. Setting Novel cardiovascular, orthopedic, and neurologic devices approved in the EU through Conformité Européenne marking between 2005 and 2010. Data sources Public and commercial databases searched up to January 2016 for press releases and announcements of approvals; public Food and Drug Administration and European regulatory authority databases for US approvals and safety alerts and recalls; and Medline, Embase, and Web of Science for peer reviewed publications. Main outcome measures We categorized the novelty of the devices in the study sample as a “major innovation” or an “other change,” and extracted descriptive data about the devices and information on any safety alerts and withdrawals. Linear regression models examined factors associated with differential EU and US approvals. Cox proportional hazards regression models were used to evaluate factors associated with safety alerts and recalls and the publication of trial outcomes for devices categorized as major innovations. Models controlled for time, therapeutic category, regulatory pathway, size of sponsoring company, and indicator variables for devices approved first in the EU and devices approved only in the EU. Results 67% (206/309) of devices identified were approved in both the US and the EU, of which 63% (129/206) were approved first in the EU. The unadjusted rate of safety alerts and recalls for devices approved first in the EU was 27% (62/232) compared with 14% (11/77) for devices approved first in the US. The adjusted hazard ratio for safety alerts and recalls was 2.9 (95% confidence interval 1.4 to 6.2) for devices approved first in the EU. The results of pivotal trials were published for 49% (37/75) of devices categorized as major innovations, with an overall publication rate of 37% five years after approval. Conclusions Devices approved first in the EU are associated with an increased risk of post-marketing safety alerts and recalls. Poor trial publication rates mean that patients and clinicians need greater regulatory transparency to make informed decisions about treatment.

Assessment of US pathway for approving medical devices for rare conditions.

An FDA program established in the 1990s made it easier for manufacturers to get devices for rare diseases into use. Thomas J Hwang and colleagues examine how the program has been used and what can be learnt for US and European device regulation

Temporal Trends and Factors Associated With Cardiovascular Drug Development, 1990 to 2012

Summary Cardiovascular disease remains a leading cause of death, but stakeholders have recently raised concerns about the pace of innovation and investment in developing new therapeutics. Here, the authors characterized temporal trends in cardiovascular research and development over the past 2 decades and the likelihood of successful completion of pre-approval clinical trials. The authors also evaluated the reasons for discontinuation, novelty, and rates of trial results publication for cardiovascular therapies in late-stage development. Between 1990 and 2012, the number of new cardiovascular drugs entering clinical trials declined across all stages of development (p < 0.001 for linear trends). There was no evidence for a difference in probability of successful progression to the next stage of development between cardiovascular and noncardiovascular drugs. Small and medium-sized companies sponsored 43%, 38%, and 31% of new Phase 1, Phase 2, and Phase 3 trials, respectively. Roughly one-half of the drugs in Phase 3 trials were categorized as targeting a novel biological pathway. The number of cardiovascular trials sponsored by small and medium-sized companies and the number of novel drugs entering Phase 3 trials increased over time. Most drugs were discontinued in Phase 3 due to inadequate efficacy (44%) or safety issues (24%), but the Phase 3 trial results for only one-half of the discontinued drugs were published in peer-reviewed journals. These results shed light on important shifts in research and development activity and confirm the perceived challenges in cardiovascular translational research.

Drug Safety in the Digital Age

Wikipedia is reportedly the most frequently consulted online health care resource globally, but it is not reliably updated after the FDA issues safety warnings on drugs. The FDA and others can take some steps to improve the dissemination of essential drug information.

Target small firms for antibiotic innovation

Once in clinical trials, antibiotics are more likely to survive than drugs in other classes Antibiotics are an indispensable part of modern medicine. Yet, since the first β-lactam, aminoglycoside, macrolide, tetracycline, and fluoroquinolone classes of antibiotics were discovered and approved from 1940 to 1980, few antibiotics with novel mechanisms of action have been developed (1). At the same time, antibiotic resistance has been on the rise (see photo). Ensuring appropriate use, or stewardship, of antibiotics is critical to ensure that antibiotics retain their effectiveness against pathogens. In addition, the need for new classes of antibiotics has seen increasing international attention. To inform ongoing policy debates, we characterize trends in antibiotic research and development (R&D) over the past two decades.

The Pediatric Research Equity Act Moves Into Adolescence

Children continue to be underrepresented as participants in clinical trials, limiting the evidence available to guide treatment decisions. Among new interventional trials registered on ClinicalTrials.gov in 2015, only 6% of 19 239 trials focused on children from birth to 17 years of age, even though this age group comprises about a quarter of the US population. As a result, clinicians frequently use medications tested in adults for the treatment of children and adolescents. In one study, rates of off-label prescribing were estimated to involve 85% of 57 000 hospitalized children nationally.1 Without adequate evidence to support these interventions, children may be exposed to serious unintended harms. Notable examples include the off-label use of verapamil to treat children with supraventricular tachycardia (associated with hypotension and death) and the antimicrobial chloramphenicol administered to infants (leading to fatal circulatory collapse). To improve the clinical study of medications in children, Congress passed in 2002 the Best Pharmaceuticals for Children Act, which grants sponsors an additional 6 months of market exclusivity in return for voluntarily performing US Food and Drug Administration (FDA)– requested studies in children. The Pediatric Research Equity Act (PREA), passed in 2003, is a complementary, mandatoryprogramthatauthorizestheFDAtorequirethe studyofanewdrugorbiologic inpediatricpopulations(defined as <17 years of age). Under PREA, sponsors must submit data that assess the safety and effectiveness of a product in children or that justify the extrapolation of adult data to relevant pediatric subpopulations for the indications under review in adults. The act’s requirements apply to new drug applications and biologics license applications, as well assupplementstothese, includingnewindicationsandformulations. Although these studies are ordinarily required before approval, sponsors can request that the FDA deferorwaivetheirPREArequirementsincertaincases(Box). The Pediatric Research Equity Act has the potential to provide pediatric labeling data at the time of entry of a new product to the market, thereby helping to prevent non– evidence-based use of new therapeutics in children. However, several reports, including from the Institute of Medicine (now the National Academy of Medicine),2 have suggested that the goals of the program have been diluted by exemptions, frequent study delays, and inadequate results reporting. Since its last reauthorization in 2012 through the end of 2015, 53 of the 137 novel drugs approved by the FDA required pediatric studies under the act.3 Only 7 of these 53 products had completed pediatric studies at the time of approval and entered the market with pediatric-specific labeling information.3 Policy makers are currently negotiating the reauthorization of the Prescription Drug User Fee Act, due to expire in September 2017, which governs the FDA’s drug approval process as well as the PREA program. As the program marks its 13th anniversary and with as many as half of drug labels still lacking any pediatric information, the PREA program should be updated to better generate and communicate evidence used in clinical practice.