Clinical trial sponsors must step up their efforts to address underrepresentation of women among trial subjects, FDA Commissioner Scott Gottlieb said Wednesday during a meeting in White Oak, Maryland, to commemorate National Women’s Health Week. He cited the FDA-led Decadal Review that studied clinical trial efficacy and safety by sex for 34 drugs and five cardiovascular disease indications over a 10-year period from 2005 to 2015. The study analyzed the inclusion and exclusion criteria for five of the trials to get a clearer picture of whether such criteria affected subject enrollment. The results, Gottlieb said, indicated there were minimal gender differences in drug profiles, and that while women were well-represented in trials for hypertension and atrial fibrillation drugs and overrepresented for pulmonary arterial hypertension (PAH) drugs, they were underrepresented in trials for heart failure, acute coronary syndrome and coronary artery disease drugs. “These findings support the need for the FDA to issue a call to action to clinical investigators. In this case, the bottom line was that more work is needed to identify factors leading to under-participation of women in cardiovascular clinical trials in certain areas, notably heart failure, coronary artery disease and acute coronary syndrome,” Gottlieb said. One possible reason for under-enrollment of woman subjects may be of advanced age at disease onset, Gottlieb said, indicating sponsors should look into prevalence-adjusted representation of women in cardiovascular trials across relevant age categories. On the other end of the spectrum, sponsors are often hesitant to expose new or expectant mothers, who tend to be younger women, to experimental drugs, which can be a major barrier to developing drugs for conditions that are prevalent in younger women. To correct this, the FDA is using the Medication Exposure in Pregnancy Risk Evaluation Program to model pregnant women’s responses to drugs at reduced risk, he said. Other agency efforts to remedy gender parity issues include the agency’s Diverse Women in Clinical Trials Initiative consumer awareness campaign and a planned series of webinars on recruitment and retention of women in clinical trials. The agency is also conducting several research initiatives to aid in its regulatory decision-making with regard to sex differences, he said.
A clinical trial has been launched for children’s bionic arms produced on 3D printers, the first of its kind in the U.S., headed by researchers at the Oregon Health & Science University and Limbitless Solutions, a non-profit bionic arm manufacturer affiliated with the University of Central Florida. The clinical trial will accept 20 children to be fitted with bionic arms, who will be trained to use the implants over the span of a year. The study will test the functionality of the arms in children ages 6 to 17, evaluate its impact on their quality of life and assess how they use the arms for specialized tasks. The study will help determine the devices’ eligibility for insurance coverage, which hinges on whether or not the FDA would clear the arm for marketing.
A study by Swansea University in the U.K. demonstrated the possibilities of using anonymous, regularly collected electronic health records (EHRs) for electronic follow-up of clinical trials. With patients’ consent, data analysts can match patients to their EHRs, such as those linked in the Secure Anonymized Information Linkage (SAIL) database and access data quickly. Results showed that SAIL can help track trial participants, with long term monitoring of medical interventions and health outcomes, and new insights into population health. As a result, the cost of follow-up using routine data is potentially relatively small and does not increase with the number of participants. The original randomized controlled trial researched the effect of probiotics taken during pregnancy on asthma and eczema in a group of children at six months and then two years of age. The study’s key findings showed that the retention of children in lower socio-economic groups was improved through the use of SAIL and the electronic follow-up results were more reliable because of a reduction in bias, unreliability or inaccuracy in participants’ recollections. The electronic five year follow-up also produced new insights, particularly for asthma, which usually appears after two years of age.
The FDA issued an alert to clinical investigators, doctors and consumers about safety issues associated with use of Keytruda or Tecentriq as a monotherapy in oncology clinical trials. Early reviews by the FDA’s Data Monitoring Committee found patients in the monotherapy arms of two clinical trials had decreased survival compared to those receiving cisplatin- or carboplatin-based chemotherapy. All of the patients in question had low expression of the protein programmed death ligand 1 (PD-L1). Overall, neither drug’s adverse event profile was changed, and Merck, which manufactures Keytruda, and Genentech, which manufactures Tecentriq, have both halted enrollment of patients with low PD-L1 to both trials’ monotherapy arms. The combination arms and chemotherapy arms of both trials will remain open, while the monotherapy arms will remain open to patients with higher PD-L1. “The data informing this decision has not been shared with Genentech and we continue to be blinded to study results. No changes to other ongoing studies have been made at this time,” Austine Graff, senior manager of corporate relations at Genentech, told CWWeekly. “We continue to believe in the efficacy and safety of Tecentriq monotherapy in people with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy.” Both drugs received the agency’s accelerated-approval designation for treatment of locally advanced or metastatic urothelial carcinoma patients who do not meet the requirements for cisplatin-containing chemotherapy. According to the notice, any patients taking the drugs for other approved uses should continue taking it as directed by their doctor.
The FDA final guidance outlining clinical trial designs for hypogonadotropic hypogonadism treatments, recommending efficacy endpoints and enrollment criteria. The guidance, which was unchanged from the agency’s January draft guidance, recommends that sponsors have clinical and laboratory evidence of the condition of trial subjects, including normal thyroid function, low testosterone amounts in the morning on at least two occasions and symptoms or signs the drug aims to target. Patients should have an undamaged hypothalamus, pituitary glands and testes and the population should be specifically defined by their underlying symptoms, signs and conditions. The trials should show that the drug increases serum testosterone and contributes clinically meaningful improvement in at least one symptom or sign of hypogonadism. “A responder would be a patient who has normalized testosterone concentrations (based on pharmacokinetic sampling) and also has clinically meaningful improvement in the specific symptoms or signs,” the guidance advises. The agency is open to evaluating existing or modified patient-reported outcome (PRO) instruments for use in assessing disease-related symptoms or signs in men with hypogonadism but is unaware of any that are adequate for regulatory use to assess improvement in hypogonadal symptoms or signs. Improvement in biomarkers, such as changes in muscle mass, that are not established surrogate endpoints for how patients feel, function or survive, are not considered sufficient evidence of clinical benefit. For drugs that improve spermatogenesis, sponsors could establish efficacy by showing improved fertility outcomes, such as pregnancy in the patient’s partner. Changes in semen parameters—such as sperm count—are not sufficient by themselves for establishing efficacy because the intent of the drug is to improve male fertility. In addition, improved semen parameters does not ensure fertility and sperm count is only one measure of normal spermatogenesis. Drugs that worsen or do not affect spermatogenesis could still be considered effective if the sponsors show improvement in other hypogonadal signs or symptoms. The guidance does not address development programs for testosterones or testosterone esters seeking the traditional replacement therapy indication in adult males with a condition associated with endogenous testosterone deficiency or absence.
Sponsors of trials for drugs to prevent cytomegalovirus (CMV) infection in transplantation should use incidence of disease within 6 to 12 months post-transplantation as their primary endpoint, according to new draft guidance from the FDA. The guidance distinguishes between CMV prophylaxis trials in patients who have undergone solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). In the case of SOT patients, the recommended primary endpoint is a clinical endpoint of both CMV syndrome and tissue-invasive CMV disease at 6 or 12 months post-transplantation, depending on the duration of prophylaxis. For HSCT patients, the recommended primary endpoint is incidence of infection or disease within six months post-transplantation.In enrolling patients in prophylaxis trials, sponsors should ensure that patients have no detectable CMV infection post-transplantation within five days before the beginning of therapy. To be enrolled in a CMV treatment trial, meanwhile, transplant recipients should have virological evidence of CMV replication. Sponsors can generally include pediatric patients in clinical trials after ensuring sufficient safety, pharmacokinetic and efficacy data are available from adults. If adult clinical trials do not give rise to any safety concerns that would preclude children from study inclusion, sponsors are encouraged to evaluate adolescents using the adult dosage. “Depending on results of the adult clinical trials, and on whether efficacy in adults can be extrapolated to pediatric patients (i.e., if the course of disease and the effect of the drug are sufficiently similar in adults and pediatric patients), either comparative or single-arm trials may be appropriate in pediatric subjects,” the guidance states. “The sponsor’s pediatric study plan should include information to support pediatric extrapolation, as needed.” Sponsors have the option to choose from a range of doses and treatment durations for phase III trials if they are unsure about the optimal regimen, or if their models indicate different doses and durations work better for different subpopulations.