Non‐clinical considerations for supporting accelerated inclusion of pregnant women in pre‐licensure clinical trials with anti‐HIV agents

Abstract

Introduction:To allow the continued participation of women enrolled in pre-licensure clinical trials who become pregnant, and to potentially enrol pregnant women in clinical trials, non-clinical developmental and reproductive toxicology studies (DART) are essential. Generally during pharmaceutical development, DART studies are conducted late during clinical development, leading to the exclusion of pregnant women from enrolment and withdrawal of women becoming pregnant during pre-licensure trials. Discussion: Completing all DART studies prior to or early during the conduct of phase 3 trials (i.e. earlier than current common practice) can accelerate and facilitate the inclusion of women who become pregnant during pre-licensure trials to remain on study drug and to potentially enrol pregnant women more rapidly. Promoting complementary strategies, such as alternative combinations of DART study designs and physiologically based pharmacokinetic modelling, could better inform drug dosing and safety in pregnancy at an earlier stage in drug development. The interpretation of the results of non-clinical DART studies is often complex. Institutional review boards/ethics committees should have access to relevant expertise for interpretation and application of results of non-clinical developmental and reproductive toxicity studies. Clear communication and thorough understanding of non-clinical findings and the overall benefit-risk profile of the product are critical to review protocols and determine if women who become pregnant during a clinical trial could continue on study drug and/or to enrol pregnant women in the trial. The informed consent document should be well written so that participants can make an informed decision to stay on study drug or participate in a trial during pregnancy. Ultimately, the decision to allow women who become pregnant during pre-licensure trials to remain on study will depend on the totality of the evidence and benefit-risk considerations. Conclusions: We propose that industry completes non-clinical reproductive toxicity studies prior to or early during the conduct of phase 3 trials in HIV drug development, especially for priority agents, and potentially uses alternative DART study design strategies to achieve this goal.

Approaches to accelerating the study of new antiretrovirals in pregnancy

“…In almost all cases, PK and short‐term safety studies in pregnancy are completed well after licensure. Preclinical developmental and reproductive toxicology should be completed earlier in the drug development cycle [2]. More specifically, non‐clinical studies (fertility and early embryonic development and embryo‐foetal development) should be completed during or no later than the end of the phase 2 registrational trial; pre‐ and postnatal development studies should be completed at or near the beginning of the phase 3 registrational trials.…”

“…More specifically, non-clinical studies (fertility and early embryonic development and embryo-foetal development) should be completed during or no later than the end of the phase 2 registrational trial; pre-and postnatal development studies should be completed at or near the beginning of the phase 3 registrational trials. Approaches to facilitate more rapid completion of these studies are discussed in other papers in this supplement [2,12], but this accelerated timeline would enable short-term safety and PK pregnancy data to be available by the end of the phase 3 registrational trial and thus included in the regulatory submission for licensure. It will not be feasible to complete a dedicated study of composite key foetal/pregnancy/neonatal outcomes by the time of licensure but having that evaluation underway at the time of licensure would expedite the availability of this critical information.…”

“…Delayed completion of pre-clinical reproductive toxicology studies leads to the exclusion of pregnant women (or women who could become pregnant) from pre-licensure studies and as justification in pre-licensure trials for requiring contraception for women of reproductive potential and discontinuing study drug among women participants who become preg-nant. The reluctance-fuelled by liability concerns-of sponsors, institutional review boards, investigators, research and regulatory agencies to conduct studies in pregnant women further contributes to the exclusion of this important population and results in delays in obtaining critical PK and safety data [2][3][4].…”

Disrupting the status quo to achieve early inclusion of pregnant women in studies of new agents for prevention and treatment of HIV infection

“…More work needs to be done to better interpret and apply findings from the non-clinical studies. Greupink et al discuss the optimal timing for these studies, their complex interpretation and the need to improve communication of the results and their implications [24].…”

“…Innovation will be key to achieving greater equity and more timely inclusion of pregnant women in pre-licensure studies. Greupink et al propose alternative combinations of DART study designs and physiologically based PK modelling as complementary approaches to determine drug dosing and safety in pregnancy [24]. Similarly, Brummel et al provide a compelling rationale for the importance of randomized clinical trials (RCTs) to study safety in pregnancy for all high-priority agents, specifically safety outcomes uniquely important to the mother and infant [27].…”