Understanding the Biology of Sex and Gender Differences: Using Subgroup Analysis and Statistical Design to Detect Sex Differences in Clinical Trials

Sarah K. Keitt, MPH, Catherine R. Wagner, BS, Sherry A. Marts, PhD

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In This Article

From Sex Differences to Individual Differences: Where the Science is Taking Us

Detecting sex differences in drug trials is a step toward an era of personalized medicine. Penelope Manasco, MD, Vice President of Clinical Genetics at GlaxoSmithKline, Research Triangle Park, North Carolina, identified the future of personalized therapy as resulting in the right drug given at the right dose to the individual patient. She predicted an increase in the use of genetic subtypes in diagnosis rather than relying solely on phenotypes (such as male/female).

Currently, single nucleotide polymorphism (SNP) technology is leading the movement toward individualized therapy. The human genome is made of 3 billion base pairs, and for every thousand base pairs there is a variable base pair that gives rise to an SNP, resulting in 3 million SNPs in the human genome. SNPs serve as markers for mapping the genome. Ten pharmaceutical companies and the Wellcome Trust Research Laboratory have worked with 5 academic centers through the SNP Consortium to develop and disseminate an SNP map of the human genome.

Currently, SNPs are being used at GlaxoSmithKline to look for a difference in allele frequency between cases of a particular disease (for example, migraine headache, which affects 18% of women and 6% of men) and healthy controls. Using SNPs, scientists were able to identify the insulin receptor gene as a susceptibility gene for migraine. This is borne out by the higher incidence of migraine in patients with noninsulin-dependent diabetes. This information gives scientists a platform to work from in developing a therapy and information about what genes and systems to target.

Pharmacogenetics, according to Dr. Manasco, is the future for research. Pharmacogenomics is the use of genetic information to predict the safety, toxicity, and/or efficacy of drugs in individual patients or groups of patients.[42] Pharmacogenetics analysis can be used to develop a medicine response profile (MRP) for individual patients. For example, patients with Alzheimer's disease who have an ApoE4 allele were found to benefit from an Alzheimer's therapy that was ineffective in those who lacked ApoE4. Similarly, in the treatment of asthma with 5-lipoxigenase inhibitors, Jeff Drazen of Harvard University (Boston, Massachusetts) found that subjects with the normal size of the promoter region for the 5-lipoxigenase gene responded to a 5-lipoxigenase inhibitor, whereas those with an abnormal size of the promoter region did not respond.[43]

One example of a pharmacogenomic therapy currently in use is trastuzumab (Herceptin), a drug used to treat breast cancer. Trastuzumab targets the production of protein from the HER2 gene, which is overexpressed in 20% to 25% of breast cancers. These "HER2-positive" tumors are associated with more rapid metastasis, decreased survival, and increased tumor recurrence. Trastuzumab blocks overexpression of HER2. Patients who had overexpression of the HER 2 genes responded to herceptin, whereas those without HER2 overexpression did not.

Currently, a goal for pharmacogenomics research is to make the technology affordable and more widely available. Additionally, changes may be needed in the regulation and oversight of drug development. Genetic analysis raises ethical issues of privacy and potential discrimination that must be addressed when performing clinical studies of gene-specific therapies.

This report presents some facets of the current debate regarding the design of clinical trials and the analysis of resulting data to accurately and efficiently detect sex differences. As is evident from the presentations at this conference, greater attention must be given to the design of early-phase clinical trials. Further, novel statistical approaches should be explored to better analyze data from these trials. Detecting sex differences in clinical trials and translating those findings into appropriate dosing regimens will serve to promote safer and more effective drugs for both men and women. As the field of pharmacogenomics advances, clinical trial design and statistical analysis will become even more important as we move into an era of personalized medicine.

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