Regulatory strategies for early device development and approval.

The development of new technology to treat unmet clinical needs is an important component of modern cardiovascular disease. The need for this has been emphasized in the past several years beginning with the Food and Drug Administration (FDA) guidance document on Early Feasibility Studies in 2012 and then the 21st Century Cures legislation. A number of steps need to be considered in this process by the stakeholders involved including physician innovators and scientists, professional societies such as Society for Cardiovascular Angiography & Interventions, regulatory agencies, and medical device companies. This article focuses on the early iterative steps required to optimize the process and achieve the goal of timely efficient innovation and device development in cardiovascular disease.

Identification of hepatitis B virus genotype I in Thailand.

The rare hepatitis B virus genotype I (HBV-I) classification includes complex A/G/C/U recombinants identified amongst the individuals from China, India, Laos, and Vietnam. Herein we report the first HBV-I specimen from Thailand, with detectable HBsAg despite a 10-amino-acid truncation. This HBV-I genome has a similar recombinant pattern to reference strains, including a C region that branches basal to references, suggesting a premodern era recombination event gave rise to HBV-I. With an average sequence divergence from other genotypes ranging from 7.66% (standard deviation [SD], 0.42%; C) to 14.27% (SD, 0.31%; H), this new genome supports the HBV-I classification as a unique genotype.

Preexposure chemoprophylaxis for HIV prevention in men who have sex with men.

BACKGROUND: Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. METHODS: We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. RESULTS: The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57). CONCLUSIONS: Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).

Early Feasibility Studies for Cardiovascular Devices in the United States: JACC State-of-the-Art Review.

The development of technology to treat unmet clinical patient needs in the United States has been an important focus for the U.S. Food and Drug Administration and the 2016 Congressional 21st Century Cures Act. In response, a program of early feasibility studies (EFS) has been developed. One of the important issues has been the outmigration of the development and testing of medical devices from the United States. The EFS committee has developed and implemented processes to address issues to develop strategies for early treatment of these patient groups. Initial implementation of the U.S. Food and Drug Administration EFS program has been successful, but residual significant problems have hindered the opportunity to take full advantage of the program. These include delays in gaining Institutional Review Board approval, timeliness of budget and contractual negotiations, and lack of access to and enrollment of study subjects. This paper reviews improvements that have been made to the U.S. EFS ecosystem and outlines potential approaches to address remaining impediments to program success.

The 21st Century Cures Act and Early Feasibility Studies for Cardiovascular Devices: What Have We Learned, Where Do We Need to Go?

Performance of early feasibility studies in the United States can advance the goal of evaluating the safety and effectiveness of new devices aimed at unmet clinical needs and facilitating earlier access for U.S. patients to new technology. Early feasibility studies are an important component of the 21st Century Cures Act, enacted by Congress in 2016. Although regulatory processes have improved since the introduction of the Early Feasibility Studies Program, impediments at the hospital and clinical site level remain. In this paper, the authors review these issues and outline the structure and function of a clinical site consortium designed to address the problems and improve the U.S. clinical trial ecosystem.

Skating on thin ice: stimulant use and sub-optimal adherence to HIV pre-exposure prophylaxis.

INTRODUCTION: Stimulant and heavy alcohol use are prevalent and associated with elevated risk for HIV seroconversion among men who have sex with men (MSM) and transgender women. In addition, each can pose difficulties for antiretroviral adherence among people living with HIV. Scant research has examined the associations of stimulant and heavy alcohol use with adherence to daily oral pre-exposure prophylaxis (PrEP) among MSM and transgender women. To address this gap in the literature, we evaluated the hypothesis that stimulant use and binge drinking are prospectively associated with sub-optimal PrEP adherence. METHODS: We analysed data from participants in a nested case-cohort in the iPrEx open label extension. Stimulant use (i.e. powder cocaine, crack-cocaine, cocaine paste, methamphetamine, cathinone) and binge drinking (i.e. ≥5 drinks in a single day) in the last 30 days were assessed. Baseline urine was tested for stimulants using immunoassays to reduce misclassification. Sub-optimal adherence was defined as tenofovir drug concentrations in dried blood spots less than 700 fmol per punch, indicative of less than four doses per week. We tested the prospective association of stimulant use and binge drinking with sub-optimal adherence at the 4-week follow-up visit. RESULTS AND DISCUSSION: Data from 330 participants were analysed. The majority of the participants were MSM (89%) with a median age at baseline of 29 years (interquartile range 24 to 39). Approximately 16% (52/330) used stimulants and 22% (72/330) reported binge drinking in the last 30 days. Stimulant users had fivefold greater odds of sub-optimal PrEP adherence compared to non-users in adjusted analysis (adjusted odds ratio [aOR] 5.04; [95% CI 1.35 to 18.78]). Self-reported binge drinking was not significantly associated with sub-optimal adherence after adjusting for stimulant use and baseline confounders (aOR 1.16 [0.49 to 2.73]). Depressive symptoms, being transgender, and number of sex partners were also not significantly associated with sub-optimal PrEP adherence (p > 0.05). CONCLUSIONS: Stimulant use is a risk factor for sub-optimal PrEP adherence in the month following PrEP initiation. Comprehensive prevention approaches that reduce stimulant use may optimize PrEP adherence. Creating adherence plans that specifically address PrEP dosing in the context of ongoing stimulant use should also be considered.

The Safety of Tenofovir-Emtricitabine for HIV Pre-Exposure Prophylaxis (PrEP) in Individuals With Active Hepatitis B.

BACKGROUND: Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) prevents HIV infection. The safety and feasibility of HIV PrEP in the setting of hepatitis B virus (HBV) infection were evaluated. METHODS: The Iniciativa Profilaxis Pre-Exposición study randomized 2499 HIV-negative men and transgender women who have sex with men to once-daily oral FTC/TDF versus placebo. Hepatitis serologies and transaminases were obtained at screening and at the time PrEP was discontinued. HBV DNA was assessed by polymerase chain reaction, and drug resistance was assessed by population sequencing. Vaccination was offered to individuals susceptible to HBV infection. RESULTS: Of the 2499 participants, 12 (0.5%; including 6 randomized to FTC/TDF) had chronic HBV infection. After stopping FTC/TDF, 5 of the 6 participants in the active arm had liver function tests performed at follow-up. Liver function tests remained within normal limits at post-stop visits except for a grade 1 elevation in 1 participant at post-stop week 12 (alanine aminotransferase = 90, aspartate aminotransferase = 61). There was no evidence of hepatic flares. Polymerase chain reaction of stored samples showed that 2 participants in the active arm had evidence of acute HBV infection at enrollment. Both had evidence of grade 4 transaminase elevations with subsequent resolution. Overall, there was no evidence of TDF or FTC resistance among tested genotypes. Of 1633 eligible for vaccination, 1587 (97.2%) received at least 1 vaccine; 1383 (84.7%) completed the series. CONCLUSIONS: PrEP can be safely provided to individuals with HBV infection if there is no evidence of cirrhosis or substantial transaminase elevation. HBV vaccination rates at screening were low globally, despite recommendations for its use, yet uptake and efficacy were high when offered.