An Assessment of the NIH Women's Health Initiative (1993) / Chapter Skim
Currently Skimming:
Clinical Trial
Clinical Trial
Pages 25-76
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 25... ...
whether a low fat dietary pattern reduces the risks of breast and colorectal cancers; (2) whether hormone replacement therapy reduces the risk of coronary heart disease (CHD)
|
From page 26... ...
There are reasonably good rationales for some aspects of each of the three branches of the CI, although evidence for the central hypothesis for the DM branch that a change to a low fat dietary pattern by women over the age of 50 will reduce the incidence of breast cancer over the following nine years- isthe weakest and least consistent of the three. There are stronger rationales for expecting that there are effects of DM on colorectal cancer and various cardiovascular disease endpoints.
|
From page 27... ...
FIGURE 2-l Outcomes for the VVR! Clinical Trial.
|
From page 28... ...
For example, DM and HRT may affect coronary heart disease; DM and HRT may affect breast cancer; and HRT and CaD may affect fractures. Integration of the CT with Other Components of the WITT The goad of the WHT CT is to test whether the interventions being used will reduce the morbidity and mortality associated with breast cancer, cardiovascular disease, and osteoporotic fractures.
|
From page 29... ...
The partial factorial design is presented in Figure 2-2, which has been reprinted with NIH permission from the June 28, 1993 WHI Protocol, page 18. The committee feels
|
From page 30... ...
NIH also argued that it wall be more economical for the clinical centers to screen simultaneously for the two branches, DM and HRT, rather than to mount each one separately. As now planned, there are effectively two separate studies, HRT and DM, done within the same administrative structure.
|
From page 31... ...
and breast cancer incidence rates (Prentice et al., 1988) , the WHI Protocol assumes that the risk ratio decreases linearly from RR = 1.0 at baseline to RR = 0.5 at 10 years for fully adherent women.
|
From page 32... ...
may be critical in setting bounds on these estimates. Recruitment Because the sample size determines what recruitment efforts are required, it is necessary to assess recruitment assumptions.
|
From page 33... ...
criteria. bee Appenclx A tor more a detailed description of exclusion Participants will not be categorized by risk for breast cancer, colorectal cancer, or coronary heart disease.
|
From page 34... ...
The committee was told that the Clinical Coordinating Center wall present data on primary, subsidiary, and intermediate outcomes to the DSMB after Bonferroni adjustments for multiple comparisons are made. Each CT branch will be monitored for early stoppage based on summary measures of benefits and risks.
|
From page 35... ...
The committee suggests that the DSMB prespecif~r a number of outcomes and situations to monitor concerning stopping the trial. Ethics: Consent and Stopping Rules Any clinical trial must incorporate adequate protection for the well-being and selfdetermination of human participants.
|
From page 36... ...
The committee's concerns about informed consent were raised with representatives from the Clinical Coordinating Center (CCC) and Vanguard Clinical Centers at its meeting in July 1993.
|
From page 37... ...
Stopping Rules The Or involves interventions with effects that may occur within a few years (e.g., protection of estrogen against CHD) , after at least five years (e.g., protection of low fat diet against breast cancer)
|
From page 38... ...
· The DSMB should review the monitoring of the consent process, especially to confirm the propriety of proceeding in the face of an expected range of new findings with regard to estrogen and cardiovascular disease. · The DSMB should evaluate prespecified event rates for morbid and mortal potential outcomes, not only "al]
|
From page 39... ...
Although the intent of the CT is to generalize the data to the general population, it is not clear that there is a uniform effort to stratify the recruitment efforts by SES for the Minority Centers or at the other Vanguard Clinical Centers or additional centers. It is expected, but not necessarily correct, that many of the minority participants wall be at the
|
From page 40... ...
Specifying the Relationship of Intervention and Effect While the committee understood the constraints that gave rise to the specific design disadvantages, it pointed out several worthy of note so that expectations do not exceed the capabilities of the study design. If an association were to be demonstrated between the DM and decreased risks of CHD or breast cancer, the scientific and lay audience would want to know whether it was the low fat component or other changes in the diet that decreased risk.
|
From page 41... ...
Some Vanguard Clinical Centers have established a community
|
From page 42... ...
The investigators have organized a recruitment coordinators' group composed of the recruitment staff from the clinical centers. This group wild regularly share information about recruitment experiences by conference call, and wild report to the Recruitment and Retention Working Group, which includes representatives from the Clinical Coordinating Center, NTH, and six clinical centers.
|
From page 43... ...
This recent change in the protocol has implications for recruitment, since specialized The degree approaches may ne required to attract women ot this age group to the study. Of experience with this age group varies considerably among the investigators, and only a tew Vanguard Clinical Centers have developed approaches for this older group of women.
|
From page 44... ...
This 29-month study, carried out at three clinical centers, is designed to note the effect of a changer! diet on blood lipids, lipoproteins, and hormones, and to measure the influence of culture and economic status on the maintenance of a low fat diet.
|
From page 45... ...
The committee noted the considerable diffusion of low fat health messages to the population, due in part to dietary recommendations by the National Cancer Institute; National Heart, Lung and Blood Institute; the American Heart Association; other health organizations; and purveyors of low fat foods. In opposition to these messages are firmly ingrained food habits, advertising, and the availability of high-fat foods to most segments of the population.
|
From page 46... ...
Successful management is essential to ensure that protocols are successfully executed and that the primary hypotheses are tested. This depends in part on rapid and effective communication among clinical centers and between clinical centers and NTH staff NIH has developed a detailed subcommittee organization to address the different components of the study, a structure that incorporates many Vanguard Clinical Center investigators and staff (see Appendix G)
|
From page 47... ...
. Breast Cancer The low fat dietary pattern-breast cancer hypothesis is based largely on international comparisons: countries with diets of apparently lower fat content have lower rates of breast cancer.
|
From page 48... ...
There are other concerns with the low fat dietary pattern-breast cancer hypothesis; for example, factors early in life, such as diet during adolescence, may be more relevant to breast cancer risk. Alternatively, the number of years during which the woman ate a high fat diet may be more important in establishing breast cancer risk than intervention on dietary practices later in life.
|
From page 49... ...
The weight loss or maintenance of appropriate body weight associated with a change to a low fat dietary pattern could contribute to improved health as well. Decreased rates of obesity could relate to decreased risk of many chronic disorders, including hypertension and hyperlipidemia associated with coronary heart disease.
|
From page 50... ...
for possible adverse effects of a low fat dietary pattern. However, this attentiveness is not apparent in the written WHT Protocol, and the concern is not apparent in the consent process in which participants need to be informed of the need to maintain an adequate caloric intake.
|
From page 51... ...
Weighing Benefits and Uncertainties of the Breast Cancer Arm Some degree of uncertainty in the hypothesis and feasibility of the methods is inherent in any clinical trial; if one were certain about the outcome, one would not need to do a clinical trial. With uncertainty comes risk and potential benefits.
|
From page 52... ...
cancer, and was justifiable on those grounds. Therefore, despite disagreement among committee members over the strength of the scientific evidence supporting the low fat dietary pattern-breast cancer hypothesis, and the feasibility of testing that hypothesis, the committee agreed that the DM branch of the CT could proceed, with the recommendations specified.
|
From page 53... ...
Cyclical use of PERT prevents or greatly retards bone loss, although it is uncertain whether the beneficial effect of PERT is greater than that of ERT alone. Any effects of PERT on hip fracture and colorectal cancer risk have not been reported to date.
|
From page 54... ...
bone loss requires differential informing of these women and probably also subset analyses that focus upon this effect. Threats to Completion of the HRT Branch It is generally accepted that ERT increases the risk for endometrial cancer and decreases the risk for low bone mass.
|
From page 55... ...
It is reassuring that they will be followed more closely. Nonetheless, it is important for these women to be fully informed of the risks of HRT during the informed consent process.
|
From page 56... ...
Adverse events were not discussed. A dose of 0.625 mg of conjugated estrogens has been found to be effective in postmenopausal women for prevention or treatment of osteoporosis.
|
From page 57... ...
reported no beneficial effect on alI-cause mortality in estrogen users and an increased risk of cardiovascular events, including stroke and coronary heart disease, in estrogen users of all age groups. The risk was somewhat less in the age range of 70 to 83 but there were few subjects in that subgroup.
|
From page 58... ...
Summary Studies conclusively demonstrate that estrogen therapy has a positive effect on bone mineral density in younger postmenopausal women, and that this effect continues with continued use into the elderly age range. Data also strongly suggest a positive effect on cardiovascular disease in younger and older postmenopausal women.
|
From page 59... ...
Bone mineral density measurements will be made at only three Vanguard Clinical Centers (it is unclear how many of the additional clinical centers will measure bone mineral density)
|
From page 60... ...
Fewer studies have focused on the role that vitamin D plays in colorectal cancer risk, but a strong association has not been identified. It is of course not possible to separate the effects of calcium and vitamin D when they are issued together.
|
From page 61... ...
With the designed sample size there would be insufficient power to test this well. Therefore, the statisticians recommended not using a full factorial design for this component.
|
From page 62... ...
Data Available to Committee Deliberations The fact that this committee was formed after the funding of the Vanguard Clinical Centers should have been helpful to the budget evaluation, since, rather than mere plans for funding, negotiated contracts existed. However, the task of this committee was made difficult by the repeated failure of NTH to provide cost information in a usable format.
|
From page 63... ...
For studies that were initiated in the 1990s, this figure exceeds $3,000. Information on the cost of the CT was estimated by the Clinical Coordinating Center to be $586 million, consisting of approximately $168 million for the Vanguard Clinical Centers, $ 142 million for the Clinical Coordinating Center, and the remainder for the 29 additional clinical centers about to be selected.
|
From page 64... ...
Nonetheless, the committee felt that the costs budgeted for the Vanguard and additional clinical centers are low for the extensive effort necessary. NTH negotiated contract funding amounts with each Vanguard Clinical Center based on estimates of future costs, including an official inflation factor.
|
From page 65... ...
Second, but with more direct relevance to the WHT, the committee is concerned that when seeking additional centers, the NTH might not be able to identifier 29 institutions with both qualified investigators and the ability to provide substantial institutional support. The Vanguard Clinical Centers are very likely to be more sophisticated and experienced centers, which may enable them to be more efficient and have more resources with which to support the efforts of the trial.
|
From page 66... ...
and larder Participant Recruitment If participant recruitment were to lag, there is no money available for increased and usually more costly—staff time, clinic hours, or promotional materials. In response to questions by the committee regarding the ability to recruit minorities and older women and to monitor various demographic characteristics, such as SES and age level, during recruitment and enrollment, NTH pointed out repeatedly that the Vanguard Clinical Center investigators have signed contracts to produce specific recruitment results for the monies allocated.
|
From page 67... ...
Adherence Similar threats to the budget lie in attempts to achieve adequate adherence to the intervention regimens. If adherence to the DM or the medication schedule is weak, a clinical center could direct increased effort at education and incentives leading to increased adherence.
|
From page 68... ...
In terms of the total cost of the WHI, with the Clinical Coordinating Center at $142 million, if the Vanguard Clinical Centers are funded at $10.4 million each and if additional centers are funded at $S to $9 million each, this wait account for approximately $570 to 580 million of the $625 million that has been committed before consideration of the funding of the Community Prevention Study. If additional centers are funded at $10 million each, the tote]
|
From page 69... ...
The committee feels that the factorial design has major drawbacks. The overlap of 15.9 percent between the DM and HRT interventions is insufficient to provide adequate statistical power to assess interactions, and the difficulties of maintaining adherence to two or three interventions detracts from the attractiveness of a factorial design.
|
From page 70... ...
The obligation to inform potential and current research participants would require much more information at the outset, as well as a commitment to provide evolving information over the course of the project. · The committee suggested" that the counselors at the clinical centers be knowledgeable and have access to algorithms, guidelines, and printed material about known risks and benefit Is.
|
From page 71... ...
Specificity of Intervention and Effect The CT design does not distinguish which element of the low fat dietary pattern may be responsible for any observed outcome. Similarly, the design wall not allow analyses to distinguish whether calcium or calcium plus vitamin D is responsible for any observed outcome.
|
From page 72... ...
This is not adequately responsible. · The committee suggests that the clinical centers must continue to develop adequate links with reliable community providers to ensure that adequate follow-up care is available.
|
From page 73... ...
· The committee recommends that the dietary modification-breast cancer hypothesis be considered a subsidiary rather than a primely hypothesis, shifting the emphasis to the effect of dietary modification on coronary heart disease outcomes, making those the primely hypotheses.
|
From page 74... ...
This timeframe does not allow for adequate follow-up for the DM and breast cancer hypothesis, the DM and colorectal cancer hypothesis, or the HRT and breast cancer hypothesis. However, the committee feels that, as currently designed, the CT does not have a high probability of yielding statistically significant results for the DM and breast cancer hypothesis or the HRT and breast cancer hypothesis, even after more prolonged follow-up.
|
From page 75... ...
CLINICAL TRIAL 75 that an adequate test of a hypothesis would not be possible in any reasonable time frame, the Or or a branch of it could terminate. If, on the other hand, recruitment or adherence problems are discretely identifiable, the study could be redesigned for the remaining duration to compensate for these problems.
|
From page 76... ...
76 to to to no _ .
|
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.