FDA issues in-effect interim rule
Additional safeguards published April 24, 2001
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The U.S. Food and Drug Administration (FDA) issued an interim rule last spring to amend regulations for clinical investigations of FDA-regulated products that involve children. The FDA estimates the rule will result in a total annual cost of reviewing ongoing and future pediatric clinical trials of $33,000 for this year and $23,550 per year in years 2002 through 2009. In addition to these costs, each impacted IRB will need to conduct a one-time review and update of standard operating procedure documents to include the requirements of the rule.
New duties to include
Now in effect, the interim rule includes some new duties for IRBs, including the following:
• IRBs must conduct a review of research to determine compliance in cases when children are the subjects of ongoing research. Criteria to be satisfied if an IRB is to approve the research include:
- risks to subjects are minimized;
- risks to subjects are reasonable in relation to anticipated benefits;
- selection of subjects is equitable;
- informed consent is adequate and appropriately documented;
- where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects;
- where appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data;
- appropriate safeguards have been included to protect vulnerable subjects.
• IRBs should conduct continuing review of research at intervals appropriate to the degree of the research, but not less than once per year.
• IRBs may approve a clinical investigation in which no greater than minimal risk is presented only if the IRB finds and documents that adequate provisions are made for soliciting the assent of the children involved and the permission of their parents or guardians.
• The FDA modified regulations to include all FDA-regulated products in which there is no greater than minimal risk to children. Previously this referred to research that is funded or conducted by the U.S. Department of Health and Human Services (HHS).
• The types of procedures that might be used in a clinical investigation that would present no more than minimal risk to children would include the following:
- clean-catch urinalysis;
- obtaining stool samples;
- administrating electroencephalograms;
- requiring minimal changes in diet or daily routine;
- the use of psychological tests.
• The types of clinical investigations that would present no more than minimal risk include these examples:
- a taste test of an excipient;
- tests of devices involving temperature readings orally or in the ear.
• When an investigation involves a new drug application or an investigational device exemption and the IRB does not know the level of risk the subject may be exposed to, the IRB should make such a judgment on a case-by-case basis.
• IRBs should use appropriate strategies to mitigate risks that may change during a clinical study. These strategies include:
- exit strategies in the case of adverse events or lack of efficacy;
- establishing a data monitoring committee to review ongoing data collection and recommend study changes, including stopping a trial on the basis of safety information.
• Placebo-controlled clinical investigations may be conducted in accordance with FDA regulations because there is evidence of direct benefit to subjects, including increased monitoring and care of subjects even when the subject may not actually receive the test product.
• An IRB may make a judgment as to whether children are capable of providing assent by taking into account the ages, maturity, and psychological state of the children involved. Assent is not a necessary condition if the IRB determines:
- that the capability of some or all of the children is so limited that they cannot reasonably be consulted;
- that the investigation or procedure involved in the clinical investigations presents a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the clinical investigation.
• Even where an IRB determines children are capable of assenting, the IRB may waive the assent requirement if:
- the clinical investigation involves no more than minimal risk to the subjects;
- the waiver will not adversely affect the rights and welfare of the subjects;
- the clinical investigation could not practicably be carried out without the waiver;
- and, when appropriate, the children will be provided with additional pertinent information after participation.
• Wards of the state may be included in clinical investigations only if such research is related to their status as wards or conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards.
For more information about the interim rule, visit the FDA’s web site at www.fda.gov\ohrms\dockets\98fr\042401a.htm.
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