Cultural diversity in subject selection is strongly encouraged.  Clinical studies should be inclusionary, designed in such a way that the subject pool is representative in gender, race, ethnicity, age and hormonal status of the local population affected by the condition being studied.  Exclusion of particular subgroups may be justified in the following cases:

1. A specific scientific question is more appropriately addressed with a more targeted group,
2. Specific known risks of intervention (or other participation) warrant exclusion of specific groups,
3. Gender- or racial-neutrality has been previously demonstrated,
4. Redress of gaps in medical knowledge about specific groups,
5. Multicenter studies may achieve overall balance by choosing centers with complementary minority representation.

Subject enrollment need not be sufficient to provide high statistical power for calculating effects of gender and minority status on intervention effect in all cases.  Investigators planning “phase 3 clinical trials” (see definition below) in which prior studies suggest a clinically “significant difference” (see definition below) in effect among subgroups or those in which differential effects are uncertain are encouraged to design the subject pool in sufficient numbers so as to provide a “valid analysis” (see definition below) in each subgroup.

Subject recruitment

Clinical studies should be advertised to and made accessible to an equitable group of individuals.  In cases in which recruitment and/or retention of women or minority subjects may be difficult, a proactive program may be employed.  Cultural sensitivity in approaching potential subjects is to be encouraged (e.g., respectful of language and custom).  Barriers to participation in underrepresented groups should be anticipated and overcome prospectively (e.g., compensation for child care, lost wages or transportation; waiving of residency requirements; translation of advertising or educational literature and informed consent for non-English speakers).  The extent of compensation will be reviewed critically by CPHS to ensure that it is appropriate to the context of the study and not potentially coercive to vulnerable subgroups.  In order to ensure a diverse study population with sufficient statistical power to examine major gender and ethnic effects, large studies may consider the use of quota systems to manage enrollment.

To overcome lingering distrust of the medical and scientific establishment in minority populations, outreach programs may be used to inform local minority groups about the individual and collective benefits of participation in biomedical research.  Follow-up in these groups with modest advertising of individual projects and discussion of results may be employed.

CPHS will monitor subject enrollment to ensure equitable distribution.  To that end, investigators will be asked to describe the demographic characteristics of the subject population expected in the request for approval.  It shall be the responsibility of the investigator to describe the results of prior studies with regard to effects of gender and ethnic/minority status on intervention.  The CPHS letter of approval shall include a statement of the CPHS expectations in that regard. Furthermore, annual renewal request forms shall reiterate that statement and inquire about the demographics of the study population to date.

Definitions 

• “Phase 3 Clinical Trial” – a broadly based prospective clinical investigation, usually involving several hundred human subjects, designed to evaluate an experimental intervention in comparison to a control intervention or to compare two or more interventions.
• “Valid analysis”  - an unbiased assessment of the difference in outcome between two or more groups, specifically requiring:
  
1. allocation of participants of both genders and from different racial/ethnic groups to each intervention and/or control group by an unbiased process such as randomization,
2. unbiased evaluation of outcome, and
3. use of unbiased statistical analyses and proper methods of inference to estimate and compare intervention effect among the gender and racial/ethnic groups.

Valid analysis does not require a high statistical power for detecting a stated effect. 

• “Significant difference” – a difference between subgroups of clinical or public health importance.  This term does not imply statistical significance.
• “Minority groups” – an identifiable subgroup of the U.S. population distinguished by either racial, ethnic, and/or cultural heritage.  The minimum standard of categories, defined by the Office of Management and Budget Directive No. 15, includes American Indian or Alaskan natives, Asian or Pacific Islander, Black or African-American, and Hispanic.  Assignment to subpopulations depends upon self-reporting of specific racial and ethnic origin by the subject.
• “Childbearing or reproductive potential” – Individuals biologically capable of being or becoming pregnant, lactating or fathering children in the present or at some time in the future, including those employing reversible forms of contraception.

Risk/benefit analysis:

Both potential risk and potential benefit shall be considered when constructing study populations.  In early clinical trials of new drugs, devices and procedures, risk assessment must be based solely on animal toxicity data or known risk from similar interventions.  Reevaluation of the risk/benefit ratio should be an ongoing process as investigation proceeds.  Investigators and pharmaceutical and device manufacturers sponsoring clinical trials shall be responsible for providing CPHS reviewers with detailed, current reports on toxicology and adverse effects.

Potential benefit must be viewed with compassion from the standpoint of both the individual subject and the community at large, which may ultimately profit from the results of the study.  A higher potential risk may be acceptable if offset by potential benefit in the setting of life-threatening, incapacitating or otherwise hopeless illnesses.  Is the current standard of care unsatisfactory?  Does the proposed study offer a potential improvement over the other procedures currently available to the subject?  Would patients similar to the subjects be considered potential candidates for the proposed intervention after commercial release?  Will society at large benefit measurably from the results of the study?

The autonomy of potential subjects approached for enrollment into clinical trials should be respected.  Decisions about the welfare of future or potential children should, wherever possible, be left to the discretion of the respective potential parents.  After fully informed consent about any potential risk and benefit to the individual and to existing or future offspring, the individual subject should be allowed to accept or decline according to the dictates of his/her own conscience.

The following scales for evaluating potential benefit and risk (in ascending order) are offered to standardize deliberations involving subjects in their reproductive years:

Potential Benefit:

1. No foreseeable benefit to either individual subject or to future patients
2. No foreseeable benefit to individual subject, but potentially beneficial to society
3. Alternative to current medical practice standards for the individual subject
4. Advantage over current medical practice standards for the individual subject
5. Alternative to current medical practice standards for a serious or life-threatening condition (typically requiring treatment even during conception, pregnancy or lactation)
6. Advantage over current medical practice standards for a serious or life-threatening condition (typically requiring treatment even during conception, pregnancy or lactation)

Potential Risk:

1. No male or female reproductive risk identified in completed animal toxicology package and previous clinical trials
2. Incomplete animal toxicology package, but negative to date
3. Potential fertility or general reproductive risk (male or female) identified in pre-clinical studies
4. Potential teratogen or embryotoxic risk identified in pre-clinical studies
5. Potential perinatal or postnatal (lactation) risk identified in pre-clinical studies or in trials of a similar class of drug
6. Potential human reproductive and/or teratologic risk identified in previous clinical trials

Benefit/risk combination I-F is unacceptable for approval.  Combinations I-B to I-E and II-B to II –F shall be scrutinized with a particularly critical eye and are likely to be approved only with appropriate precautions for subject and fetal protection.

Precautions for protection of existing or potential offspring:

Whenever a known or potential risk to future offspring exists in association with a clinical trial, the investigators shall minimize that risk to the best of their ability by the use of any or all of the following measures which seem appropriate:

• Informed consent briefly explaining the results of previous pre-clinical and clinical testing (In the instance of a pregnant subject, paternal consent is also encouraged).
• Protocol design (e.g., administration of the intervention during least vulnerable segments of the menstrual cycle, etc.).
• Subject education on avoidance of pregnancy and referral to contraceptive clinic, when appropriate.
• Pre-enrollment HCG screening.
• Ongoing HCG screening, especially in the case of ongoing risk.
• Relaxed enrollment for sexually inactive subjects, those involved in monogamous relationships with sterilized or homosexual partners, and others in whom the likelihood of pregnancy is extremely small.
• Secondary written informed consent for continued study participation in the event of pregnancy and/or lactation occurring during the course of the study.

Educational materials (sensitive to multiple cultures, languages and reading abilities) and referral sources for contraception shall be made readily available to subjects of childbearing or reproductive potential.