Aw Warner

Prospective–retrospective biomarker analysis for regulatory consideration: white paper from the industry pharmacogenomics working group

One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective-retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provides robust scientific evidence for decision-making in situations where it is not necessary, nor practical or ethical to conduct a new prospective clinical study.

Global Requirements for DNA Sample Collections: Results of a Survey of 204 Ethics Committees in 40 Countries

The Industry Pharmacogenomics Working Group has an interest in attaining a better understanding of global requirements for sample collections intended for pharmacogenetics research. To have adequately powered pharmacogenetics studies representative of the clinical trial population, it is important to collect DNA samples from a majority of consenting study participants under many institutional review board/ethics committee (IRB/EC) jurisdictions. A survey was distributed to gather information from local and central IRBs/ECs. The survey included questions related to the approval of pharmacogenetics studies, collection and banking of samples, and return of data to subjects. A total of 204 responses were received from global IRBs/ECs with pharmacogenetic experience. The data show that requirements for approval of pharmacogenetic research differ between IRBs/ECs within and between countries but not between regions of the United States. A better understanding of differing requirements should facilitate global sample collection of DNA for pharmacogenetics research and may provide the basis for harmonized regulations for collection of genetic samples in the future.

Current Practices for DNA Sample Collection and Storage in the Pharmaceutical Industry, and Potential Areas for Harmonization: Perspective of the I‐PWG

Collection and storage of DNA samples in clinical drug development programs are an important investment for the pharmaceutical industry to allow efficient evaluation of observed variability in drug response. To enable collection and future use of samples, individual companies must define (i) processes to collect specimens worldwide, (ii) whether collection is optional or mandatory, (iii) conditions and duration of sample storage, (iv) whether research data can be returned to subjects, and (v) other logistical aspects. To determine current industry practices for collection and storage of these samples, the Industry Pharmacogenomics Working Group (I‐PWG) conducted a survey of the industry (21 respondents) to identify areas of commonality and divergence. On the basis of the survey results, the I‐PWG details areas of focus for harmonization of the industrys sample collection practices. A more unified approach would facilitate DNA sample collection, thereby contributing to the advancement of personalized medicine and more efficient development of safe and effective drugs.

PhRMA survey of pharmacogenomic and pharmacodynamic evaluations: what next?

Interindividual variation in pharmacodynamic (PD) response to drugs is an ongoing area of research for drugs in clinical development, pre‐ and postapproval. To characterize how pharmacogenomic (PG) variations can serve as a predictor of differences in PD outcomes, the pharmaceutical industry has incorporated PG/PD analysis into clinical drug development. The Pharmaceutical Research and Manufacturers of America (PhRMA) and the Industry Pharmacogenomics Working Group (I‐PWG) conducted a survey of 16 pharmaceutical companies to ascertain to what extent PG/PD research is being incorporated into drug development. The survey results showed that, while the industry has made some attempt to incorporate PG/PD studies into drug development, application has been inconsistent. Nevertheless, several valid PG/PD markers have since emerged in drug labels. The I‐PWG considers PG/PD research an important approach to improving success rates in drug development. This article reports the results of the survey and proposes steps toward increasing the use of PG/PD research by the industry.

Coding of DNA Samples and Data in the Pharmaceutical Industry: Current Practices and Future Directions—Perspective of the I‐PWG

DNA samples collected in clinical trials and stored for future research are valuable to pharmaceutical drug development. Given the perceived higher risk associated with genetic research, industry has implemented complex coding methods for DNA. Following years of experience with these methods and with addressing questions from institutional review boards (IRBs), ethics committees (ECs) and health authorities, the industry has started reexamining the extent of the added value offered by these methods. With the goal of harmonization, the Industry Pharmacogenomics Working Group (I‐PWG) conducted a survey to gain an understanding of company practices for DNA coding and to solicit opinions on their effectiveness at protecting privacy. The results of the survey and the limitations of the coding methods are described. The I‐PWG recommends dialogue with key stakeholders regarding coding practices such that equal standards are applied to DNA and non‐DNA samples. The I‐PWG believes that industry standards for privacy protection should provide adequate safeguards for DNA and non‐DNA samples/data and suggests a need for more universal standards for samples stored for future research.

Improving clinical trial sampling for future research – an international approach: outcomes and next steps from the DIA future use sampling workshop 2011

Clinical trial samples collected for pharmacogenomic and future research are vital resources for the development of safe and effective drugs, yet collecting adequate, representative sample sets in global trials is challenging. The Drug Information Association (DIA) sponsored a workshop on future use sampling in September 2011, bringing together experts from regulatory agencies, academia and industry to discuss challenges to future use sample collection and identify actions to improve collection. Several common themes and associated action items emerged, including the need for international guidance on the collection of samples for future research; additional discussion related to coding, scope of research, and return of research results; and additional education about pharmacogenomic/future research and the importance of long-term storage of specimens.

Mobilizing pharmacogenomic analyses during clinical trials in drug development

The utilization of pharmacogenomics (PGx) in drug development is increasing as pharmaceutical companies and regulatory agencies work to understand variation in response to medications. The implementation of PGx in clinical trials requires a number of considerations that begin early at the point of program development for a compound. This article will discuss the issues involved in mobilizing a PGx study during the conduct of a clinical trial, including the development of a PGx hypothesis, the identification of genetic markers for analysis, PGx platform selection and assay development, as well as challenges that arise in relation to global laws and regulations related to genetic research and logistical/timeline concerns in the execution of a PGx analysis.

A question-based approach to adopting pharmacogenetics to understand risk for clinical variability in pharmacokinetics in early drug development.

Understanding genetic variations that influence pharmacokinetics (PK) in humans is important for optimal clinical use of drugs. Guidances for making decisions on when to conduct pharmacogenetic research during drug development have been proposed by regulatory agencies, but their uniform adoption presents problems due to an inherent lack of flexibility. A questions‐based approach (QBA) was developed to enable drug development teams at Merck to iteratively and flexibly evaluate the potential impact of pharmacogenetics (PGx) on clinical pharmacokinetic variability.

Harmonizing Global Biospecimen Consent Practices to Advance Translational Research: A Call to Action.

One of the many challenges of translational medicine is working with research participants to donate biospecimens through an ethical informed consent framework. The increasingly complex ethical and regulatory differences across jurisdictions translates into limitations on use and potential value of biological specimens and their associated data in clinical research. We introduce a call to action for more uniform global standards for collection of biological specimen informed consent data to enable greater advancements in medical research.