Women and Health Research Ethical and Legal Issues of Including Women in Clinical Studies, Volume 1 (1994) / Chapter Skim
Currently Skimming:
4 Scientific Considerations
4 Scientific Considerations
Pages 84-107
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 84... ...
Important examples include hormonal differences, particularly the variation in drug response by women during different stages of the menstrual cycle, and pharmacokinetic effects such as differential rates of drug absorption and excretion. Other differences are psychosocial in origin or are mediated by tendencies of men and women to act differently with respect to health care.
|
From page 85... ...
, they will usually respond in much the same way to treatment and experience a similar evolution of the disease. The underlying reasons for this belief are rooted in several observations regarding health problems relevant to both men and women: for the majority of drug treatments, efficacy and safety do not depend on such factors as body mass, adipose tissue, hormones, or other factors associated with gender.
|
From page 86... ...
Significant gender differences in drug response have not been detected in the majority of cases, but where they are detected they can be important. Therefore, it becomes important for clinical investigators to ascertain under what conditions such gender differences are likely to occur and to design clinical studies accordingly.
|
From page 88... ...
They may also modify the pharmacokinetics and pharmacodynamics of selected drugs. Gender differences may also be found in other commonly measured laboratory tests such as serum iron, uric acid, creatinine phosphokinase, and gamma glutamyl transpeptidase, all of which are important in distinguishing the normal from the abnormal in selected disease states (Table 4-31.
|
From page 89... ...
Although older men and women both experience decreases in lean body mass and increases in fat tissue as a fraction of body weight, these changes may be more pronounced in women, who tend to have more body fat than males in youth and middle age. As a result, drugs such as lithium may have a more immediate toxic effect in older women (Everitt and Avorn, 19861.
|
From page 90... ...
Just as sources of morbidity differ between men and women over 65, so too do causes of mortality. Older men die from heart disease and malignant neoplasms more frequently than do older women, who die more often from cerebrovascular disease (National Center for Health Statistics, 19931.
|
From page 91... ...
Endogenous hormonal changes in menstruating women can affect drug disposition, but few studies have examined the impact of changing hormonal concentrations on drug metabolism across the different phases of the menstrual cycle (GAO, 1992; NRC, 19934. One recent report noted the importance of varying the dose of an antidepressant over the menstrual cycle to achieve optimal benefit and minimal side effects (Jensvold et al., 19924.
|
From page 92... ...
Table 4-4 lists some of these physiological changes and their pharmacokinetic effects. Some of the changes that occur during pregnancy, such as increased plasma volume, body weight, and body fat, can decrease the concentration TABLE 4-4 Changes During Pregnancy that May Alter Pharmacokinetics Pharmacokinetic Parameter Change Pharmacokinetic Impact Absorption Gastric emptying time Increased Increased absorption and/or metabolism Intestinal motility Decreased Increased absorption Pulmonary function Increased Increased absorption and/or elimination Cardiac output Increased Increased distribution rate Blood flow to the skin Increased Increased transdermal absorption Distribution Plasma volume Total body water Plasma proteins Body fat Metabolism Hepatic metabolism +/ Extra-hepatic metabolism Plasma proteins Excretion Increased Increased Decreased Increased +1 Decreased Increased volume of distribution Increased volume of distribution Decreased volume of distribution, decreased binding capacity Increased volume of distribution, increased reservoir for lipid-soluble xenobiotics +/- Metabolic alteration and elimination +/- Metabolic alteration and elimination Increased metabolic alteration and ..
|
From page 93... ...
For example, OCs have been found to increase the risk of coronary heart disease, particularly acute myocardial infarction, a risk that is compounded in smokers. Most of the studies linking OCs to heart disease, however, are based on women who took pills containing much higher doses of estrogen
|
From page 94... ...
and lowering levels of low-density lipoprotein cholesterol (Matthews et al., 1989; Stampfer et al., 1991; NIH Consensus Development Panel on Triglyceride, High Density Lipoprotein, and Coronary Heart Disease, 1993~. Combination hormonal therapy (estrogen and progestin together)
|
From page 95... ...
. For the remainder of this chapter, however, we focus on clinical trials, and particularly treatment trials, as an important subset of clinical studies.
|
From page 96... ...
The discussion that follows focuses on fixed sample size designs. External and Internal Validity Some of the methodological concerns raised about gender equity in clinical trials (and clinical studies more generally)
|
From page 97... ...
This kind of design focuses instead on achieving internal validity that is, how consistently and how well the treatment works. In this sense clinical trials, as a design, cannot truly speak to external validity issues; nevertheless, they can speak to gender differences in treatment effect, and in that sense can contribute to the knowledge and understanding of whether women and men differ in their responses to treatment.
|
From page 98... ...
The list should be pared by an active process of review and challenge prior to the start of the trial, and the list should be periodically reviewed during the trial for possible further trimming. Typical reasons for excluding patients from clinical trials include any or all of the following: · Disease stage (the disease Is too advanced or not advanced enough for the treatment being studied; prognosis inconsistent with treatment)
|
From page 99... ...
Gender-based exclusions More germane to this report are the rationales underlying the exclusion of women from two large preventive clinical trials: the Physicians' Health Study and MRFIT. The primary reason for excluding women from the Physicians' Health Study was the gender mix of the physician cohort approached for study (approximately 90 percent male)
|
From page 100... ...
Another possible argument for excluding women from clinical trials is that of efficiency: is the increase in information gained proportionate to the increased costs of including women? If including women would have resulted in a 10 percent increase in person-years of follow-up information, for example, then to justify excluding them it would have been necessary to show that adding women would have increased costs by more than 10 percent.
|
From page 101... ...
, the committee believes that examination of subgroups where feasible given the number of people enrolled in each subgroup is to be encouraged. Alternatives to Clinical Trials Strategies other than clinical trials are available to help devise hypotheses about the differential response of men and women to medical interventions.
|
From page 102... ...
Where calculated rates of adverse events among users tend to unreliable, largely as a result of underreporting and differential reporting, a structured epidemiologic study can be a powerful tool for quantitatively studying unexpected adverse events. Although pharmacoepidemiologic studies are generally less costly than clinical trials, these studies can also be complex and expensive, particularly if the risk of an adverse event is small (and the population needed to detect events therefore large)
|
From page 103... ...
For these reasons we focus our concluding remarks on clinical trials of treatment effects for diseases that affect both women and men namely treatment trials. The committee finds that the weight of scientific evidence, as well as practical considerations, supports the inclusion of both genders and indeed all kinds of demographic subgroups- wherever possible.
|
From page 104... ...
And if they do have convincing hypotheses about qualitative gender-specific differences, then this too argues for including both genders, but in sufficient numbers to test for gender-specific results. When there are no anticipated treatment effects by gender, however, a policy that requires scientists to include sufficient representation of both genders to permit subgroup analyses would require, at a minimum, that clinical trials significantly increase their size (to detect the main effect in each group)
|
From page 105... ...
are available to help devise hypotheses about the differential response of men and women to medical interventions. These strategies may be significantly less costly than large-scale clinical trials that include sufficient numbers of men and women to detect gender differences in response.
|
From page 106... ...
1989. Menopause and risk factors for coronary heart disease.
|
From page 107... ...
In: Clinical Trials and Statistics: Proceedings of a Symposium. Washington, D.C.: National Academy Press.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.