A clinical trial (also clinical research) is a research study in human volunteers to answer specific health questions. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and ways to improve health. Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments. Observational trials address health issues in large.
Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions.
In phase 1 trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. In phase 2 trials, the experimental study drug or treatment is given to a large group of people (100-300) to see if it is effective and to further evaluvate its safety. In phase 3 trials, the experimental study drug or treatment is given to large groups of people (1000-3000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. In phase 4 study, post marketing studies delineate additional information including the drug's risks, benefits and optimal use.
There continues to be a perception that women are under represented in clinical trials of new drugs, few data are available from formal evaluations of approved new drug applications. Until 1998, clinical trials of new drugs by the US FDA were routinely conducted predominantly on men, even though women consume approximately 80 per cent of pharmaceuticals in the United States. The results of male-only clinical trials have led to the development of diagnoses, preventive measures, and treatments that are commonly extrapolated to women, yet the reverse is rare.
A consequence of extrapolating the results of male-only clinical data to female consumers is that women were (and still are) typically prescribed dosages devised for men's average weights and metabolisms. For example, it is now known that acetaminophen, an ingredient in many pain relievers, is eliminated by the female body at approximatelty 60 per cent the rate of elimination documented in men. The administration of drugs to women at dosages designed for men can place women at risk for overdose.
FDA's 1977 "general considerations for the clinical evaluation of drugs" restricted participation by most women of childbearing potential in phase 1 and early phase 2 trials for non-serious diseases. The FDAs policies regarding the participation of women in clinical investigations have evolved over time. The agency now believes it is important to codify its policies regarding the participation of women with reproductive potential in clinical investigation of drug products intended to treat life-threatening diseases. The Food and Drug Modernization Act (FDMA) of 1997 prompted FDA to examine issues related to the inclusion of women in clinical trials.
Task force recommendations
On January 19, 1995, the AIDS task force made a series of recommendations related to women's participation in the drug development process, including the recommendation that women with reproductive potential not be excluded from studies of drugs being tested for use again life-threatening diseases, particularly HIV/AIDS related diseases.
The discussion about women as subjects in clinical research, however, is not new; in contrast, it has a more than four-decade history, particularly in the United States. Several medical tragedies during the 1960s and 1970s prompted public interest in protecting women and consecutively influenced worldwide regulatory authorities. The two most meaningful events are briefly mentioned here:
" More than 10,000 birth defects between 1959 and 1962 followed the use of the sedative thalidomide in early pregnancy. The thalidomide event was the result of both generally insufficient research standards and a relative uncritical use of the drug. The thalidomide disaster finally had a major impact on the worldwide intensification of drug laws in particular on the role of women of childbearing age in drug research.
" The synthetic estrogen diethylstilbestrol (DES) caused vaginal and cervical clear cell adenocarcinoma in 0 to 34 years old daughters of women who received the drug during pregnancy. The DES was taken by many women since 1940s in the belief that it would prevent a miscarriage. When the correlation of mothers, the DES use and the daughters cancer in the 1970s became known, public trust in research and medicine was shaken once again after the thalidomide disaster, particularly because the drug was continuously prescribed for another 20 years, although two studies in the 1950s could not demonstrate any clinical benefit. Protect in women's health in the 1970s and 1980s although these unfortunate medical events mainly occurred in the context of medical practice rather than in the context of research, clinical research was widely perceived as risky and of minor benefit to research participants. Investigators were reluctant to include women in clinical trials, mainly due to safety and legal liability concerns.
Women have been shown in general sufficiently represented in clinical research aiming at drug approval. Drugs are developed globally today, and the United States guidelines have demonstrated a worldwide impact, sponsors of clinical research studies are aware of the need to look for adequate women's enrollment. Although inclusion of women in early development phase studies can still be improved. It is of higher importance that the number of women enrolled is sufficient to derive gender specific differences in development of early studies are important to measure how women and men absorb, metabolize, eliminate a drug and to get dose-related safety and efficacy information. As long as enough women are enrolled in these studies to set a rationale basis for the dosage amounts in subsequent confirmatory studies - and this seems to be the case today - a relative lower number of women as compared to men should not be relevant. Still, existing exclusion or under enrollment of women in the area outside the drug development regulations may be due to a variety of reasons such as legal liability concerns, higher complexity of the informed consent process, additional efforts with pregnancy testing and adequate birth control during the study, and generally more difficulties in recruiting women.
General clinical significance of gender differences
Already in the 1980s, gender related differences in Pharmacokinetics (PKs) were identified for some drugs, including theophylline, several benzodiazepines, and lidocaine. In the 1990s, a wave of research activities on the impact of gender differences on drug therapy began.
One needs to realize that both general and specific gender differences exist: apart from female specific issues such as variations in hormone levels throughout the menstrual cycle or menopause, there are also basic physiological differences between women and men that also influence reactions to drugs. The lower glomerular filtration rates of certain dugs in women, for instance, may be merely a body weight effect, and the gender differences in the Pharmacokinetics of lipophilic drugs or alcohol are effects of different body composition, ie, of the higher percentage of body fat in women than in men and thus a different volume of distribution. There are various examples of drugs with differences in Pharmacokinetics related to general gender differences, such as body weight, organ size or body composition, eg, diazepam, vancomycin, ofloxacin, and cefotaxime. In general, except for extreme cases of obesity, differences in body weight and composition have only minor or moderate effects on the Pharmacokinetics profile of drugs.
The differences in Pharmacokinetics with respect to drug transporters, metabolizing enzymes protein binding or gastrointestinal physiology (absorption and bioavailability), however, have been shown to be generally only subtle and their overall clinical relevance remains questionable. There will be again limited examples in which a different metabolism, eg, increased CYP3A4 activity or reduced p-glycoprotein activity in females, becomes clinically significant. Verapamil and erythromycin, for instance, appear to be more effective in women than in men. And gender related differences in liver enzyme activities and p-glycoprotein MDRI expression may be an important reason for different responses to antidepressants, eg, selective serotonin reuptake inhibitors (SSRI).
With respect to gender differences in renal elimination, a well known example is that of digoxin: The body weight adjusted glomerular filtration rate and the renal clearance are around 10 per cent lower in women; The lower clearance and consecutively higher digoxin concentrations might be the reason for a slightly increased death rate in women with heart failure. Nevertheless, impressive examples like that of tirilazad, which directly demonstrate a high clinical significance of a Pharmacokinetic gender difference are rare approval of tirilazad, a drug that was designed to improve patients with ruptured aneurysms was at first denied by the FDA as efficacy was shown only in men, probably due to a much higher clearance of the drug in women.
Another question concerns the general clinical relevance of gender related differences in Pharmacodynamics are women have a 1.5 to 1.7 greater risk for adverse drug reactions than men. It is, however, difficult to separate a dosing effect (as women generally receive a higher dose related to body weight) or a true Pharmacokinetics effect from a Pharmacodynamic effect. There are some examples of gender related differences in Pharmacodynamics, eg, it is known that premenopausal women respond better to SSRI than men, whereas men respond better to tricyclic antidepressants. Furthermore, women have a lower response to some analgesics and a higher risk for developing drug-induced cardiac arrhythmia. Women show less benefit than men from oral anticoagulants and thrombolytic agents (with respect to mortality), but the later cause more bleeding episodes in women. Randomized trials have shown in the past that low-dose aspirin is effective in the primary prevention of myocardial infarction in men, with little effect on the risk of ischemic stroke. Data in the women were rare. In a recently published primay prevention study designed to address this question in nearly 40,000 women, aspirin significantly lowered the risk of ischemic stroke without affecting the risk of myocardial infarction. Surprisingly, aspirin may affect women and men differently - the reason remains unclear. This example demonstrates the necessity of addressing gender effects in large outcome studies too. Gender dependent differences in Pharmacodynamics may become clinically important, but overall they are not frequent. Differences between individual patients, eg, in body weight, body fat distribution, training status or organ functions, are at least as important as gender specific issues.
It is important that women are sufficiently enrolled in clinical studies so that clinically significant gender differences can be detected and labelled. At least in the United States, the majority of product labelling today contains references to gender assessment in most cases there are no gender related differences in the labelling or just minor ones ie, clinically insignificant Pharmacokinetics differences (with a less than 15 per cent difference in Cmax or AUC).
Women are today sufficiently represented in clinical drug studies aimed at drug approval. Inclusion of women in early drug development studies may be improved in academically driven studies, there is still an under representation of women. In individual cases where clinically significant gender related differences exist, appropriate women enrollment rates in clinical drug studies and subsequent adequate analyses for potential gender effects are important. As shown, women are at higher risk for drug induced life-threatening ventricular arrhythmia and may benefit differently from drugs, eg, from aspirin in primary prevetion of cardiovascular diseases. In particular, large outcome studies need to look for potential gender differences. In general, however, gender differences should not be over estimated for the vast majority of drugs, no significant gender effects exist. Differences between individual patients seem to be in general more important than gender specific differences.
(The author is Medical Director, Quest Life Sciences Pvt Ltd, SDF III, MEPZ, Tambaram, Chennai - 600 045).