Value of Data Sharing to Advance Drug Development: A Regulatory Perspective.

New tools are needed to evaluate and predict the efficacy and safety of medical products. However, the development of such tools requires collaboration and effective data sharing. In this issue of Therapeutic Innovation & Regulatory Science, scientists from the Critical Path Institute (C-Path) discuss their experiences using patient-level data to facilitate innovation in drug development. We share our perspective on the issues discussed in the C-Path paper and offer suggestions on future efforts.

Public-private partnerships in transplant drug development.

The Transplant Therapeutics Consortium (TTC), a public-private partnership (PPP) led by the Critical Path Institute (C-Path), recently published a whitepaper titled "The Importance of Drug Safety and Tolerability in the Development of New Immunosuppressive Therapy for Transplant Recipients" by Stegall et al in the American Journal of Transplantation. As staff members of the Food and Drug Administration's (FDA), Center for Drug Evaluation and Research (CDER), Office of New Drugs and Office of Translational Science, and the Oncology Center of Excellence, we would like to provide our perspective on the TTCs efforts and the whitepaper.

Participation of women and sex analyses in late-phase clinical trials of new molecular entity drugs and biologics approved by the FDA in 2007-2009.

BACKGROUND: Biological sex differences may contribute to differential treatment outcomes for therapeutic products. This study tracks women's participation in late-phase clinical trials (LPCTs), where efficacy and safety of drugs and biologics are evaluated, of new molecular entity (NME) drugs and biologics approved by the U.S. Food and Drug Administration (FDA) in 2007-2009. Furthermore, presentations of sex-based analyses were assessed from the FDA reviews. METHODS: New drug applications (NDAs) and biologics license applications (BLAs) were accessed from the U.S. FDA database and evaluated for women's participation in LPCTs. Sex-based analyses for efficacy and safety contained in FDA reviews were surveyed. Ratios for women's LPCT participation (PROPORTION OF STUDY SUBJECTS) to their proportion in the disease population were calculated for each approved therapeutic product and grouped into therapeutic categories. RESULTS: Sex-specific (n=5) and pediatric (n=3) drug applications were excluded. Women's participation in LPCTs was 39%, 48%, and 42% in NDAs (n=50) and 49%, 62%, and 58% in BLAs (n=11) for 2007, 2008, and 2009, respectively. Sixty-four percent of NDAs and 91% of BLAs had participation to proportion ratios of ≥0.80. Seventy-four percent of NDA reviews and 64% of BLA reviews included safety and efficacy sex analysis. Ninety-six percent of NDA reviews and 100% of BLA reviews included efficacy sex analysis. CONCLUSION: Women's participation in LPCTs averaged 43% for NDAs and 57% for BLAs in 2007-2009 and varied widely by indication. As a comparison, the 2001 U.S. Government Accountability Office (GAO) reported 52% of women's participation for drug clinical trials in1998-2000 and an FDA study reported 45% for BLAs approved from 1995 to 1999. This study showed that sex-analysis of both safety and efficacy in NDA has increased to 74% since the GAO report of 72%, while those for BLAs increased to 64% from 37% reported for therapeutic biologics approved in 1995-1999. Knowledge of disease prevalence and participation in clinical trials provides an understanding of recruitment and retention patterns of patients in these trials.

Sex differences and genomics in autoimmune diseases.

Autoimmune diseases (AIDs) are believed to be multifactorial diseases that commonly involve multiple organ systems. About three fourth of the patients afflicted with AIDs are women suggesting that sex differences impact the incidence of AID. However, the proportion of females to males suffering from AID varies depending on the disease. The response to some AID therapeutics also differs in females versus males, suggesting that enrollment of adequate numbers of women and men is important in clinical trials for development of AID drugs. It is known for a long time that genetic factors are important contributors to AID susceptibility. Currently available information suggests that multiple genes with modest association to AID contribute to susceptibility to AID. Also, the associations may differ for the various ethnicities. The major histocompatibility (MHC) locus appears to be a major genetic factor that confers susceptibility to multiple AIDs, even though the locus is complex and has the highest density of genes in the human genome. Thus, the association of different AIDs could be with different genes in the MHC locus. Among the non-MHC genes, some of the risk alleles are shared between different AIDs, but may not be common to all AIDs. For example, genetic polymorphisms in the Protein Tyrosine Phosphatase-22 (PTPN22) gene have reproducibly shown to have association with systemic lupus erythematosus (SLE), Graves' disease (GD), rheumatoid arthritis (RA) and multiple sclerosis (MS), but not with psoriasis. Identification of factors responsible for risk for developing AID and the of the pathways underlying these diseases are likely to help understand subsets of disease, identify responders to a specific treatment and develop better therapeutics for AID.

Adverse effects in women: implications for drug development and regulatory policies.

The requirement to establish safety of drugs prior to marketing has been in place since 1938 by the US Food, Drug and Cosmetic Act and is by no means a new concept. The efficacy regulations were enacted in 1962 via the Kefauver-Harris Amendment and the drug approval process has evolved thereafter. The assessment of safety and efficacy of drug products is made by pharmaceutical companies during drug development, which then goes through a regulatory review by the US FDA for the determination of market approval or nonapproval. The drug development and regulatory approval processes have endured close ongoing scrutiny by regulatory bodies, the public, US Congress and academic and private organizations and, as a result, have ensured continual refinement. Over the years, evidence has been emerging on varied drug responses in subgroup populations, and the underlying biology associated with age, race and sex as demographic variables have been examined. The resulting growing knowledge of disease burden, treatment response and disparate outcomes has generated opportunities to streamline and improve treatment outcomes in these populations. This article discusses the historical context of women's participation in clinical drug trials submitted to the FDA for regulatory review and approval purposes. The inadvertent consequences of women's exclusion or inadequate representation in past clinical trials and the evidentiary basis for understanding sex differences are also evaluated. Advances in the US regulatory processes to address treatment outcomes that are tied to the topic of this paper, specifically, adverse drug effects in women, are also discussed.

Population pharmacokinetic and concentration--QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies.

To increase our understanding of important subject characteristics and design variables affecting the performance of oral moxifloxacin in thorough QT studies, population pharmacokinetic and concentration-QTc models were developed by pooling data from 20 studies. A 1-compartment model with first-order elimination described the pharmacokinetics. Absorption delay was modeled using 8 transit compartments. Mean (95% confidence interval) values for oral clearance, apparent volume of distribution, the first-order absorption rate constant, and mean transit time were 11.7 (11.5-11.9) L/h, 147 (144-150) L, 1.9 (1.7-2.1) 1/h, and 0.3 (0.28-0.34) hours, respectively. Overencapsulating the moxifloxacin tablet increased mean transit time by 138% and delayed time to maximum concentration by 0.5 hours but had a minimal effect on overall exposure. Administration with food decreased absorption rate constant by 27%. Women had higher moxifloxacin exposure compared with men, which was explained by lower body weights. A linear model described the concentration-QTc relationship with a mean slope of 3.1 (2.8-3.3) milliseconds per µg/mL moxifloxacin. Mean slopes for individual studies ranged from 1.6 to 4.8 milliseconds per µg/mL. Hysteresis between moxifloxacin plasma concentrations and QTc was modest, and incorporating this delay did not result in a different slope (3.3 milliseconds per µg/mL). There were no differences in slope estimates between men and women or among race categories.

Increasing participation of women in early phase clinical trials approved by the FDA.

BACKGROUND: Historically women were excluded from participation in phase 1 clinical trials. The goal of this study was to determine the participation of women and evaluate if participation has increased over time. METHODS: Clinical trial data submitted to the FDA for New Molecular Entities (NMEs) for adult, non-sex specific indications between January 2006 and December 2007 were reviewed. Electronic data available on phase 1 trial were evaluated for proposed indications, sex of participants, and doses tested. Therapeutic doses were obtained from the approved labeling. RESULTS: FDA approved 34 NMEs in 2006-2007. Data for 352 phase 1 trial of 30 NMEs were obtained. Data for 1 NME was not available electronically , 2 did not include new phase 1 data, and 1 provided only summary demographic data. All NMEs reviewed were for drugs used to treat conditions occurring in both men and women. Overall 120 (34.1%) trials had only male participants while 232 (65.9%) trials also enrolled female participants. 30.6% (3106/10,134) of participants were women. 149/352 (42.3%) of trials included safety and tolerability testing above the highest approved dose. In those trials, 32.5% (1628/5011) of the participants were women. An evaluation of trial start date illustrated the number of trials that enrolled women (p = 0.01) and the number of female participants (p < 0.001) has increased over time. CONCLUSION: Females subjects have traditionally been underrepresented in phase 1 trials. The number trials enrolling women and the number of women participating in phase 1 trials has increased since 2001, however, women are still underrepresented.

The effect of food on the relative bioavailability of rapidly dissolving immediate-release solid oral products containing highly soluble drugs.

The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of Cmax and AUC(inf) were 98-118% and 92-115%, respectively. For propranolol, the 90% confidence intervals of Cmax and AUC(inf) were 91-121% and 89-117%, and for hydrochlorothiazide, the 90% confidence intervals for Cmax and AUC(inf) were 96-107% and 97-106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions.