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Women and minorities in clinical trials
Posted on September 16th, 2016 by Jeffrey Paul, PhD in Pharma R&D
You are a female and/or a minority and concerned if you will respond to your medication. So you read the product label, asking yourself, “Do I see myself described as a patient in the drug testing trials?” Unfortunately, if you are a female/subgroup minority, the answer is usually “no.” If the clinical testing was conducted mostly in white males, there are unknowns about the drug’s efficacy and safety.
There is concern that drugs given to a diversified population may respond differently. The FDA also has concerns and has set up an Office of Women’s Health (ref 1) to encourage women to participate in drug trials and to address female health issues. Sex differences refers to the influence of sex hormones and chromosomes, whereas gender refers to socioeconomic, cultural and behavioral differences. A professor of Public Health recently remarked at a meeting I was attending that, “a zip code is better in predicting a drug trial outcome than a genetic code,” meaning socioeconomic realities had a large influence on a successful drug trial.
Clinical trials should include patients that represent the disease population who will use the product. Clearly, there has been an under-representation of women and racial minorities in trials. The FDA also has the Drug Trials Snapshot website (ref 2) to provide facts about the NDA, including the proportion of male/female and minority patients who participated in the studies. My experience with recruiting women has been that it is more difficult than males due to competing priorities, since women struggle with work, children, transportation, etc. Regardless, the FDA expects an analysis of data to determine if there are sex differences in the drug’s efficacy and safety.
So, how do drug companies test drugs and conclude that the drug has been adequately tested in subgroups, including females?
Preclinical – Toxicology and pharmacokinetic (PK) studies are performed in male and female animals. However, in vivo drug response studies are not routinely conducted in female animals, unless it is in a female-only disease experimental model.
PK variability in humans may lead to safety and efficacy differences between subgroups and sexes. PK variability refers to extrinsic (i.e. diet, smoking, drugs, etc.) and intrinsic (i.e. age, sex, race, weight) influences. A two-fold difference in PK is an alert to a plausible difference in drug safety or efficacy. Also, good predictions on drug performance, based on PK results in subgroups, can be made by quantitative modeling and simulation.
Pharmacodynamic (PD) variability, using biomarkers, is not routinely studied in subgroups because it is not required for drug approval. Here is where improvements can be made: more focus on understanding a plausible difference in PK/PD sensitivity in females and subgroups. In a recent workshop (ref 3) in which I participated, we recommended more exposure/response modeling with the use of PD biomarkers to provide initial signaling for females and subgroups. Late-phase statistical analyses, including meta-analyses, can be used to confirm the initial signals from small studies.
Zolpidem, a sleep aid, is a good example of a drug that has a steep PK/PD response and it may vary between men and women. Although there are only small differences in blood levels between men and women, the slightly higher morning blood level in women resulted in failed driving simulation test, an alert for a safety concern. Thus, the FDA decided to make a dose adjustment specifically for women.
Bidil, a therapeutic for cardiac failure is the first race-specific medication. The efficacy in blacks is much higher compared to non-blacks, leading to its approval. A possible reason is the higher vascular sensitivity in blacks. The original observation of the difference in efficacy between blacks and non-blacks came from a subgroup analysis of a large NIH-sponsored heart failure study.
Personalized medicine, with its growing utilization of pharmacogenomics, provides a basis for differences in PK and PD among subgroups and sexes. Inherited genomics is a surrogate for race and ethnicity and can be instrumental in predicting responsiveness in subgroup populations. In the near future, a simple gene test will be used to predict drug efficacy and safety. Much is known about predicting PK variation based on genetic polymorphisms of metabolism and transporter proteins. For example, Venlafaxine, an anti-depressant, is an example of a drug that can show 10-fold differences in blood level, based on CYP2D6 functional polymorphisms. CYP2D6 is responsible for the metabolism of venlafaxine. Furthermore, the polymorphisms of poor metabolizers tend to segregate with certain ethnic groups. Women of color (i.e. same race) can have a very different set of alleles based on their ancestry; a gene test can inform how venlafaxine will be metabolized and provide the correct dose. With Bidil, the race-specific medication that I mentioned above, its potent efficacy in blacks can be explained by the presence of specific G-protein genotype (GNB3).
In summary, differences in drug efficacy and safety between the sexes and subgroups is real for some drugs. More effort in including good representation of the users of the drug in clinical trials, better PK/PD modeling of subgroup responses and meta-analyses in late phase development to increase power of detection is needed to ensure drugs will be safe and efficacious in female and subgroup populations.
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All opinions shared in this post are the author’s own.
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Jeffrey Paul, PhD
Principal at JPharm Consulting
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