45 CFR 46.111(a)
Criteria for IRB Approval of research
(1) Risks to subjects are minimized: (i.) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii.) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
The IRB is not only required to assess the risks and benefits of the research, it must also ensure that the risks of the research have been minimized. Even when the research is only minimal risk, the risks may not have been minimized. For example, the data management proposal might include identifiers in the database when they aren't required or blood tests might be unnecessarily require extra blood draws. Careful planning is the key to minimizing risk.
Sound Scientific Design
Scientifically unsound research design, exposes subjects to risk without any possibility for achieving useful results. Under the federal regulations an IRB cannot approve research where the proposed research does not have an achievable, meaningful objective or where the research design is inadequate to to answer the proposed objectives. The IRB is therefore required to assess the design of the research and assess its ability produce something of scientific and social value.
Why does the IRB's review the validity of the study design?
WHO Standards and Operational Guidance for Ethics Review of Health-Related Research with Human Participants
Standard 7: Ethical basis for decision-making in research ethics committees
1. Scientific design and conduct of the study
Research is ethically acceptable only if it relies on valid scientific methods. Research that is not scientifically valid exposes research participants or their communities to risks of harm without any possibility of benefit. RECs* should have documentation from a prior scientific review, or should themselves determine that the research methods are scientifically sound, and should examine the ethical implications of the chosen research design or strategy. Unless already determined by a prior scientific review, RECs should also assess how the study will be conducted, the qualifications of the researcher(s), the adequacy of provisions made for monitoring and auditing, as well as the adequacy of the study site (e.g. availability of qualified staff and appropriate infrastructures).
*research ethics committees, a term used instead of IRBs in many international statements
Many investigators do not believe that the IRB should comment on scientific design. However, Emanual et al. make clear in their paper What Makes Clinical Research Ethical? that sound scientific design - one that can lead to results that will be of social and scientific value - stands as the first principle for ethical human subjects research. The World Health Organization Standards and Operational Guidance for Ethics Review of Health-Related Research with Human Participants describes the role of the IRB (REC) in scientific review. (see box at right)
Who else besides the IRB assesses the soundness of the scientific design?
- Expert Scientific Review
- When a study has undergone external scientific peer review by a federal or national foundations or a pharmaceutical company (which have internal protocol review procedures) the IRB may defer some but not all of its responsibility.
- Prospective studies at CHOP must be approved by a Scientific Review Committee
- Review by one or more IRB members knowledgeable in the field;
- When the IRB lacks sufficient expertise, the IRB calls upon Consultant reviewers
What other factors contribute to sound study design?
- Evidence that a thorough review of the literature is essential. This includes can include the grant or Investigator's Brochure, a summary of the literature in the protocol, and a listing of key references;
- Evidence that the investigator, co-investigators and collaborators are qualified by virtue of training and experience to conduct the research;
- A clear, well-written protocol that adheres to established principles of epidemiology and biostatistical analysis helps establish the qualifications of the investigators and ensures that the operational aspects of the research have been thought through. A poorly written protocol that ignores sound scientific design principles cannot be approved. Poorly designed studies and badly written protocols are the most common reasons for delay in IRB approval.
Minimizing Risk of Procedures
Minimizing the risks of procedures incorporates several complementary concepts.
Eliminating all unnecessary procedures
The protocol analysis section should provided sufficient detail to demonstrate how each data element will contribute to the analysis plan. Performing procedures and tests without a clear plan for their analysis violates the obligation to minimize risk. Even procedures that in and of themselves are not greater than minimal risk are not worth doing if not scientifically justified. Some examples:
- Collecting the minimum data necessary for the research
- Collecting the minimum number of identifiers necessary (overlaps with HIPAA requirements)
- Performing only procedures that are necessary to achieve the study objectives.
- Collecting the fewest specimens with the least volume of blood necessary (for example, the fewest PK specimens necessary using the smallest blood volume).
Minimizing the risk of procedures
There are often opportunities to decrease the risk, pain, discomfort, burden or other untoward impact of the research on subjects. Some examples:
- Use of a blood-drawing IV instead of separate venipunctures for a PK study;
- Use of topical anesthetic, analgesics or sedation to minimize pain;
- Obtaining a certificate of Confidentiality to minimize the likely of forced disclosure of sensitive materials;
- Coding data and samples to conceal identifiers; and
- Securing the stored data/specimens so that the confidentiality of the subjects is preserved.
Combining research procedures with clinical care
If procedures can be timed to take place at the same time as a clinically indicated procedure or if clinical test results can be used instead of repeating the measurements, the risks are often greatly reduced.
- Timing research blood draws, X-rays or other procedures to occur at the same time as clinical procedures;
- Limiting research MRI, PET, CT or other scans, to those having a clinically indicated study, particularly when sedation or general anesthesia is required.