Science-Based Approach to Harmonize Contraception Recommendations in Clinical Trials and Pharmaceutical Labels.

This review presents a European Federation of Pharmaceutical Industries and Association/PreClinical Development Expert Group (EFPIA-PDEG) topic group consensus on a data-driven approach to harmonized contraception recommendations for clinical trial protocols and product labeling. There is no international agreement in pharmaceutical clinical trial protocols or product labeling on when/if female and/or male contraception is warranted and for how long after the last dose. This absence of consensus has resulted in different recommendations among regions. For most pharmaceuticals, contraception recommendations are generally based exclusively on nonclinical data and/or mechanism. For clinical trials, contraception is the default position and is maintained for women throughout clinical development, whereas appropriate information can justify removing male contraception. Conversely, contraception is only recommended in product labeling when warranted. A base case rationale is proposed for whether or not female and/or male contraception is/are warranted, using available genotoxicity and developmental toxicity data. Contraception is generally warranted for both male and female subjects treated with mutagenic pharmaceuticals. We propose as a starting point that contraception is not typically warranted when the margin is 10-fold or greater between clinical exposure at the maximum recommended human dose and exposure at the no observed adverse effect level (NOAEL) for purely aneugenic pharmaceuticals and for pharmaceuticals that induce fetal malformations or embryo-fetal lethality. Other factors are discussed, including contraception methods, pregnancy testing, drug clearance, options for managing the absence of a developmental toxicity NOAEL, drug-drug interactions, radiopharmaceuticals, and other drug modalities. Overall, we present a data-driven rationale that can serve as a basis for consistent contraception recommendations in clinical trials and in product labeling across regions.

The Dog as a Second Species for Toxicology Testing Provides Value to Drug Development.

The objective of the pharmaceutical industry is to develop new drugs that are safe for human use. In many cases, the accepted approach codified in guidance from regulatory authorities to assess the nonclinical safety profile of potential pharmaceuticals is to perform toxicity testing in two species. However, the use of a second species to establish the safety of new pharmaceuticals has been the subject of much scrutiny in recent years and the industry has been repeatedly challenged to reduce, refine, or replace some or all of the animals used to establish the safety of these pharmaceutical candidates. Specifically, the value of the dog in this testing paradigm has been questioned. Publications reviewing available data for marketed drugs suggest that for many drugs, the dog does not identify unique toxicities critical to human safety. The weakness of this approach, however, is that many of the cases where the dog (or any other species) has the greatest impact on drug development are cases for which development decisions based on safety concerns are not shared publicly. The European Federation of Pharmaceutical Industries and Associations (EFPIA) Preclinical Development Expert Group (PDEG) decided to share case studies collected from its membership and the literature to illustrate the value of the dog in drug development decision-making and clinical monitoring practices to protect the safety of trial subjects.

Integration of Consortia Recommendations for Justification of Animal Use Within Current and Future Drug Development Paradigms.

The pharmaceutical and biotechnology industries continually review the requirements for, and relevance of, safety assessment strategies. Various industry consortia are currently discussing and reviewing data on a range of topics with respect to regulatory toxicology programs. These consortia are charged with critical evaluation of data and the identification of opportunities to promote best practice and to introduce improved approaches to safety assessment. Such improvements may include enhanced predictivity, more efficient ways of working, and opportunities for promoting and implementing the 3Rs (replacement, refinement, or reduction). As each consortium is considering a distinct question, individual outputs and recommendations could be perceived to be conflicting. However, a common theme embraced by the consortia represented here is exploration of the most appropriate use of animals for the safety assessment of new medicinal products. This short review summarizes presentations and discussions from a symposium describing the work of four industry consortia and considers whether their recommendations can be aligned into realistic approaches to improve future toxicology testing strategies, highlighting justification for the appropriate use of different animal species and opportunities for reductions in animal use without compromising patient safety.

Histomorphology and vascular lesions in dorsal rat skin used as injection sites for a subcutaneous toxicity study.

Subcutaneous injection of pharmaceutical compounds into the dorsal skin of rats is common in preclinical and nonclinical studies. However, no detailed histologic description of this anatomic location has been published to date. Following the observation of vascular lesions in the dorsum of rats in a thirteen-week toxicity study, a complementary study was performed on untreated Sprague-Dawley rats to evaluate the normal histology of the skin and subcutis, the potential effect of chronic subcutaneous injection on the morphology of the skin and its vasculature, and the spontaneous vascular pathology in the areas used as injection sites in the principal study. This study showed that saline injection did not fundamentally alter the morphology of the injection sites used for the principal study. Skin thickness was greater in males than in females. Although acellular intimal thickening occurred spontaneously in the dorsal skin of untreated males and females, only males had a spontaneous incidence of intimal hyperplasia. No site predilection for intimal lesions was apparent for either sex. Saline injection, or the physical trauma of injection, may induce intimal hyperplasia; males appear more likely to develop the lesion than do females. It is possible that acellular intimal thickening can progress to intimal hyperplasia under appropriate conditions.

Intimal hyperplasia in rats after subcutaneous injection of a somatostatin analog.

The somatostatin analog octreotide was administered to male and female Sprague-Dawley rats by subcutaneous injection for thirteen weeks at 0 (saline control), 0 (placebo control [mannitol and lactic acid; pH 4.2]), 1.25 mg/kg/day and 2.5 mg/kg/day to explore its potential effect on cutaneous vascular morphology. The placebo caused an increase in the incidence of intimal hyperplasia compared to saline controls in female rats; octreotide increased the incidence and severity of intimal hyperplasia in males and females. Intimal hyperplasia consisted of increased numbers of cells located between the endothelial cell layer and the internal elastic lamina. Severity was based on the degree of compromise of the vascular lumen (regardless of vessel size and number), with severely affected vessels having no visible lumen. Intimal hyperplasia in rats treated with octreotide was considered to be an unexpected and adverse finding, given that this compound and other somatostatin analogs have been investigated as reducers of intimal proliferation or restenosis after angioplasty in humans and that no such lesion has been reported in the literature for this class of compound to date. The induction of intimal hyperplasia by the placebo is also a notable finding; this may be because of the low pH of the formulation.