# Presentation: 923038

## The Ethical Conduct of Clinical Research Involving ChildrenInstitute of Medicine, National Academy of Sciences, 2004

- Robert M. Nelson, M.D., Ph.D.
- Associate Professor of Anesthesia and Pediatrics
- The Children’s Hospital of Philadelphia
- University of Pennsylvania

- FDA Pediatric Advisory Subcommittee, June 9, 2004

## Study CommitteeRichard Behrman, JD, MD, Chair

- Arthur Beaudet, MD
- Russell Chesney, MD
- F. Sessions Cole, III, MD
- Deborah Dokken, MPA
- Celia Fisher, PhD
- Angela Holder, JD, LLM
- Marilyn Field, PhD
- 	Study Director

- Loretta Kopelman, PhD
- Susan Kornetsky, MPH, CIP
- Robert Nelson, MD, PhD
- David Poplack, MD
- Bonnie Ramsey, MD
- Diane Scott-Jones, PhD
- Stephen Spielberg, MD, PhD
- Alan Fleischman, MD
- 	Expert Adviser

- June 9, 2004

**Notes:**
	We had a very distinguished committee of experts to prepare this report. Their affiliations are listed in the materials we handed out.

## Study Process

- 5 Committee meetings between January 2003 and November 2003
- Public meetings with professional societies, advocacy groups, and parents and adolescents
- Outside review: Dec 2003 - Feb 2004
-  Public release: March 25, 2004

- June 9, 2004

**Notes:**
	Briefly, the study process involved five meetings between January and November 2003. Public meetings included government, professional, and advocacy groups, and also parents and adolescents who had experience with child health research.
	The report underwent intensive review from December to February and will be publicly released tomorrow.	 

## Facing a Dilemma

- “Those who care about and for children currently face a dilemma. We _want children to benefit_ from the dramatic and accelerating rate of progress in medical care that is fueled by scientific research. At the same time, we _do not want to place any children at risk of being harmed_ by participating in such research, even though their very involvement may be essential to improving the overall medical care of children. ...The concern is how best to balance these potentially conflicting objectives.”

- Preface, Ethical Conduct of Clinical Research Involving Children (IOM 2004)

- June 9, 2004

**Notes:**
Those who care about and for children currently face a dilemma. We want children to benefit from the dramatic and accelerating rate of progress in medical care that is fueled by scientific research. At the same time, we do not want to place any children at risk of being harmed by participating in such research, even though their very involvement may be essential to improving the overall medical care of children. We also want to discourage research that is of minimal value. The concern is how best to balance these potentially conflicting objectives. Five important considerations should guide us as we seek to resolve our dilemma. 

## The Charge to the IOM

- Review regulations, reports, research; recommend desirable practices in _clinical research_ with children
- Specific topics were:
- appropriateness of regulations for children of various ages
- interpretation of regulatory criteria for approving research
- processes for securing parents' and children's agreement to child's participation in research
- expectations and comprehension of children and parents about participating in research
- appropriateness of payment for child's research participation
- compliance with and enforcement of federal regulations
- unique roles and responsibilities of IRBs

- Best Pharmaceuticals for Children Act of 2002 (P.L. 107-109)

- June 9, 2004

**Notes:**
Concerns about the adequacy of the system for protecting child participants in research, combined with the public commitment to expanding clinical research involving children, provided the impetus for this Institute of Medicine (IOM) report, which was requested in the Best Pharmaceuticals for Children Act of 2002 (P.L. 107-109). The legislation charged the IOM with preparing a report that reviewed federal regulations, reports, and research and that made recommendations about desirable practices in clinical research involving children. Specifically designated topics were (1) the appropriateness of the regulations for children of various ages, (2) the interpretation of regulatory criteria for approving research, (3) the processes for securing parents' and children's agreement to a child's participation in research,
the expectations and comprehension of children and parents about participating in research,
the appropriateness of payments related to the child's participation in research, (6) compliance with and enforcement of federal regulations, and (7) the unique roles and responsibilities of institutional review boards (IRBs). 

## Three Broad Themes - 1

- Well-designed and well-executed clinical research involving children is essential to improve the health of future children-and future adults-in the United States and worldwide.

- Ethical Conduct of Clinical Research Involving Children (IOM 2004)

- June 9, 2004

**Notes:**
Well-designed and well-executed clinical research involving children is essential to improve the health of future children-and future adults-in the United States and worldwide. Children should not be routinely excluded from clinical studies. No subgroups of children should be either unduly burdened as research participants or unduly excluded from involvement.
A robust system for protecting human research participants in general is a necessary foundation for protecting child research participants in particular. An efficiently administered, effectively performing system with adequate resources must, however, commit additional resources and attention to meet ethical and legal standards for protecting infants, children, and adolescents who participate in research.
Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research. This expertise includes knowledge of infant, child, and adolescent physiology and development as well as awareness of the unique scientific, psychosocial, and ethical requirements and challenges of pediatric clinical care and research.

## Three Broad Themes - 2

- A robust system for protecting human research participants in general is a necessary foundation for protecting child research participants in particular.

- Ethical Conduct of Clinical Research Involving Children (IOM 2004)

- June 9, 2004

**Notes:**
Well-designed and well-executed clinical research involving children is essential to improve the health of future children-and future adults-in the United States and worldwide. Children should not be routinely excluded from clinical studies. No subgroups of children should be either unduly burdened as research participants or unduly excluded from involvement.
A robust system for protecting human research participants in general is a necessary foundation for protecting child research participants in particular. An efficiently administered, effectively performing system with adequate resources must, however, commit additional resources and attention to meet ethical and legal standards for protecting infants, children, and adolescents who participate in research.
Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research. This expertise includes knowledge of infant, child, and adolescent physiology and development as well as awareness of the unique scientific, psychosocial, and ethical requirements and challenges of pediatric clinical care and research.

## Three Broad Themes - 3

- Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research.

- Ethical Conduct of Clinical Research Involving Children (IOM 2004)

- June 9, 2004

**Notes:**
Well-designed and well-executed clinical research involving children is essential to improve the health of future children-and future adults-in the United States and worldwide. Children should not be routinely excluded from clinical studies. No subgroups of children should be either unduly burdened as research participants or unduly excluded from involvement.
A robust system for protecting human research participants in general is a necessary foundation for protecting child research participants in particular. An efficiently administered, effectively performing system with adequate resources must, however, commit additional resources and attention to meet ethical and legal standards for protecting infants, children, and adolescents who participate in research.
Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research. This expertise includes knowledge of infant, child, and adolescent physiology and development as well as awareness of the unique scientific, psychosocial, and ethical requirements and challenges of pediatric clinical care and research.

## Summary Statement

- The federal regulations...for child participants are, in general, appropriate for children of different ages.
- The problems with the regulations relate to
- insufficient government guidance about their interpretation and implementation
- shortfalls in data about implementation and compliance
- variability in investigator and IRB interpretations of the criteria for approving research involving children.
- Some criteria include inherently subjective elements that would not be substantially and predictably clarified by revising the regulations.

- Ethical Conduct of Clinical Research Involving Children (IOM 2004)

- June 9, 2004

**Notes:**
The committee concluded that the federal regulations providing special protections for child participants are, in general, appropriate for children of different ages. They reasonably defer to state laws that define both the age at which individuals become entitled to make medical care decisions and the special circumstances under which minors may make such decisions in their own right (e.g., for care related to sexually transmitted diseases).
For the most part, the problems with the regulations relate to insufficient government guidance about their interpretation and implementation, shortfalls in data about implementation and compliance, and variability in investigator and IRB interpretations of the criteria for approving research involving children. Some of these criteria include inherently subjective elements that the committee doubts would be substantially and predictably clarified by revising the regulations. 

## Selected Recommendations

- Interpretation and Application of Regulations (Subpart D)
- Parental Permission and Child Assent
- Payments (subjects, investigators)
- Regulatory Compliance
- Responsible Conduct of Research (i.e., System Improvements

- June 9, 2004

## Definition: Minimal Risk

- the probability and magnitude of harm or discomfort anticipated in the research are not greater ... than those ordinarily encountered in daily life or ... [in]  routine physical or psychological examinations or tests.
- 					45 CFR §46.102(i)

- June 9, 2004

**Notes:**
	Evaluating and categorizing risks in research are among the most challenging tasks for IRBs.
	Federal regulations interpret minimal risk—which applies to all human research—to mean that the
[[Read the definition]]

## Interpretation of Minimal Risk

- In evaluating potential harms or discomfort posed by a research protocol that includes children...
- interpret *minimal risk *in relation to the _normal experiences of average, healthy, normal children_
- focus on _equivalence_ of potential harms or discomfort anticipated in research with harms or discomfort that average, healthy, normal children may encounter in daily lives *or *experience in routine physical or psychological examinations or tests
- consider risk of harms or discomfort in relation to _ages_ of children to be studied
- assess _duration_, probability and magnitude of potential harms or discomfort in determining level of risk

- Recommendation 4.1 (IOM, 2004)

- June 9, 2004

## Minor Increase Over Minimal Risk

- 	In evaluating risks of research involving children with a disorder or condition but no prospect of direct benefit
- Interpret *minor increase over minimal risk* to mean *slight* increase in potential for harm beyond minimal risk (as defined in relation to normal, healthy children)

- Recomendation 4.2 (IOM, 2004)

- June 9, 2004

**Notes:**
And further
In evaluating the potential harms or discomfort posed by a research protocol that includes children who have a disorder or condition but no prospect of benefiting from participation, investigators and reviewers of research protocols should
--interpret minor increase over minimal risk to mean a slight increase in the potential for harms or discomfort beyond minimal risk (as defined in relation to the normal experiences of average, healthy, normal children);
--assess whether the research procedures or interventions present experiences that are commensurate with, that is, reasonably comparable to experiences already familiar to the children being studied on the basis of  their past tests or treatments or their knowledge and understanding of the treatments that they might undergo in the future;
--consider risks of harms or discomfort in relation to the ages of the children to be studied; and
--assess the duration as well as the probability and magnitude of potential harms or discomfort in determining the level of risk.

## Interpretation of Condition

- The term *condition *should be interpreted as referring to a specific (or a set of specific) physical, psychological, neurodevelopmental, or social characteristic(s) that an established body of scientific _evidence_ or clinical knowledge has shown to _negatively affect_ children's health and well-being or to increase their _risk_ of developing a health problem in the future.

- Recommendation 4.3 (IOM, 2004)

- June 9, 2004

## FDA Ethics Working Group Consensus Statement

- “In general, pediatric studies should be conducted in subjects who may _benefit_ from participation in the trial. Usually this implies the subject has or is _susceptible_ to the disease under study. The Advisory Subcommittee utilized a broad definition of potential benefit. For example, any child has the potential to benefit from a treatment for otitis media.”

- FDA Pediatric Advisory Subcommittee, September 15, 1999

- June 9, 2004

## Need for Federal Guidance

- SACHRP should... develop additional consensus descriptions of interventions that present minimal risk or no more than a minor increase over minimal risk
- OHRP and FDA should cooperate to develop and disseminate guidance and examples... to clarify important regulatory concepts and definitions (including minimal risk, minor increase over minimal risk, condition, and prospect of direct benefit)

- Recommendation 4.5 (IOM, 2004)

- June 9, 2004

## Component Analysis of Risk

- IRBs should assess the potential harms and benefits of _each_ intervention or procedure in a pediatric protocol to determine whether each conforms to the regulatory criteria for approving research involving children. When some procedures present the prospect of direct benefit and others do not, the potential benefits from one component of the research should _not_ be held to offset or justify the risks presented by another.

- Recommendation 4.6 (IOM, 2004)

- June 9, 2004

## Choice of Control Group

- “For research involving children and a placebo control group to be approved by an IRB under federal regulations, either
- (1) the balance of potential harms and benefits for children in the placebo control arm must be as favorable as those for children receiving the active, standard treatment or
- (2) the potential harms to which children in the placebo control arm would be exposed are no more than minimal or involve only a minor increase over minimal risk.”

- Ethical Conduct of Clinical Research Involving Children (IOM 2004)

- June 9, 2004

## ICH: Choice of Control Group

- Placebo controls may be used if...
- No serious harm of withholding effective treatment (or) ...
- Serious harm: “death or irreversible morbidity”
- Effective treatment has severe toxicity
- Voluntary and informed consent required
- Noncoercive setting and patients fully informed

- ICH E-10 Section 2.1.3 Ethical Issues (July 2000)

**Notes:**
ICH HARMONISED TRIPARTITE GUIDELINE CHOICE OF CONTROL GROUP AND RELATED ISSUES IN CLINICAL TRIALS (Recommended for Adoption at Step 4 of the ICH Process on 20 July 2000 by the ICH Steering Committee) 2.1.3 Ethical Issues
     When a new treatment is tested for a condition for which no effective treatment is known, there is usually no ethical problem with a study comparing the new treatment to placebo. Use of a placebo control may raise problems of ethics, acceptability, and feasibility, however, when an effective treatment is available for the condition under study in a proposed trial. In cases where an available treatment is known to prevent serious harm, such as death or irreversible morbidity in the study population, it is generally inappropriate to use a placebo control. There are occasional exceptions, however, such as cases in which standard therapy has toxicity so severe that many patients have refused to receive it.
     In other situations, when there is no serious harm, it is generally considered ethical to ask patients to participate in a placebo-controlled trial, even if they may experience discomfort as a result, provided the setting is noncoercive and patients are fully informed about available therapies and the consequences of delaying treatment. Such trials, however, even if ethical, may pose important practical problems. For example, deferred treatment of pain or other symptoms may be unacceptable to patients or physicians and they may not want to participate in a trial that requires this. Whether a particular placebo controlled trial of a new agent will be acceptable to subjects and investigators when there is known effective therapy is a matter of investigator, patient, and institutional review board (IRB)/independent ethics committee (IEC) judgment, and acceptability may differ among ICH regions. Acceptability could depend on the specific design of the trial and the patient population chosen, as will be discussed below (see section 2.1.5).
     Whether a particular placebo-controlled trial is ethical may, in some cases, depend on what is believed to have been clinically demonstrated and on the particular circumstances of the trial. For example, a short term placebo-controlled trial of a new antihypertensive agent in patients with mild essential hypertension and no end-organ disease might be considered generally acceptable, while a longer trial, or one that included sicker patients, probably would not be.

## Selected Recommendations

- Interpretation and Application of Regulations (Subpart D)
- Parental Permission and Child Assent
- Payments (subjects, investigators)
- Regulatory Compliance
- Responsible Conduct of Research (i.e., System Improvements

- June 9, 2004

## Waiving Parental Permission

- IRBs should consider waiving parental permission for adolescent research participation when research...
- is important to adolescent health and well-being and cannot reasonably or practically be carried out without waiver _or_
- involves treatments that state laws permit adolescents to receive without parental permission and evidence exists that adolescents capable of understanding _and_
- appropriate safeguards included to protect interests of adolescent consistent with risk presented by research

- Recommendation 5.4 (IOM, 2004)

- June 9, 2004

## Harmonization of FDA and HHS Regulations

- FDA should adopt policies consistent with federal regulations at 45 CFR 46.408(c) that allow IRBs with appropriate expertise to waive requirements for parental permission in research, provided that additional, appropriate safeguards are in place to protect the child's or the adolescent's welfare.

- Recommendation 5.5 (IOM, 2004)

- June 9, 2004

## Selected Recommendations

- Interpretation and Application of Regulations (Subpart D)
- Parental Permission and Child Assent
- Payments (subjects, investigators)
- Regulatory Compliance
- Responsible Conduct of Research (i.e., System Improvements

- June 9, 2004

## Compensation for Injury

- Research organizations and sponsors should pay the medical and rehabilitation costs for children injured as a direct result of research participation, without regard to fault. Consent and permission documents should disclose to parents (and adolescents, if appropriate) the child's right to compensation and the mechanisms for seeking such compensation.

- Recommendation 6.3 (IOM, 2004)

- June 9, 2004

## Investigator Payments

- Investigators and their staffs may appropriately be reimbursed for the costs associated with conducting research. Payments in the form of finder's fees or bonuses for enrolling a specific number of children or adolescents are unethical and should not be permitted.

- Recommendation 6.4 (IOM, 2004)

- June 9, 2004

## Payment to Investigators

- Payment to clinical investigators or their institutions should be reasonable and based on work performed by the investigator and the investigator’s staff, not on any other considerations.
- When enrollment is particularly challenging, reasonable additional payments may be made to compensate the clinical investigator or institution for time and effort spent on extra recruiting efforts to enroll appropriate research participants.

- Pharma: Principles For Conduct Of Clinical Trials (2002)

- June 9, 2004

**Notes:**
Payment to Clinical Investigators. Payment to clinical investigators or their institutions should be reasonable and based on work performed by the investigator and the investigator’s staff, not on any other considerations.
A written contract or budgetary agreement should be in place, specifying the nature of the research services to be provided and the basis for payment for those services.
◗ Payments or compensation of any sort should not be tied to the outcome of clinical trials. 
◗ Clinical investigators or their immediate family should not have a direct ownership interest in the specific pharmaceutical product being studied.
Clinical investigators and institutions should not be compensated in company stock or stock options for work performed on individual clinical trials.
When enrollment is particularly challenging, reasonable additional payments may be made to compensate the clinical investigator or institution for time and effort spent on extra recruiting efforts to enroll appropriate research participants.

## Investigator Payments

- Secret payments to treating physicians and principal investigators for recruitment...[is] illegal conduct.
- No law prohibits payments to doctors for recruiting study subjects, but jury would find practice wrong.
- "Even in the absence of an express statutory prohibition on finders' fees, they're problematic."
- Sponsors should be able to explain the process they used in deciding how much to pay an investigator, based on anticipated expenses and overhead.

- James G. Sheehan, Assoc U.S. Attorney, Eastern District PA, 12-11-2003

- June 9, 2004

## Selected Recommendations

- Interpretation and Application of Regulations (Subpart D)
- Parental Permission and Child Assent
- Payments (subjects, investigators)
- Regulatory Compliance
- Responsible Conduct of Research (i.e., System Improvements

- June 9, 2004

## Need for Data

- To identify what guidance, education, or other steps are needed to protect child participants in research, DHHS should develop and implement plan for gathering and reporting data on
- research involving children, with categorization of studies by relevant section of regulations, and
- implementation of regulations governing research involving children, including OHRP and FDA data on inquiries, investigations, and sanctions

- Recommendation 7.1 (IOM, 2004)

- June 9, 2004

## Selected Recommendations

- Interpretation and Application of Regulations (Subpart D)
- Parental Permission and Child Assent
- Payments (subjects, investigators)
- Regulatory Compliance
- Responsible Conduct of Research (i.e., System Improvements

- June 9, 2004

## Closing the Gaps

- Federal law should require that all clinical research involving infants, children and adolescents be conducted under the oversight of a formal program for protecting human participants in research.

- Recommendation 8.1 (IOM, 2004)

- June 9, 2004

## Research Revitalization Act of 2004

- Provides statutory authority and requires OHRP to issue unified rule by Jan. 1, 2007
- If OHRP misses Jan 2007 deadline, the “Common Rule“ would apply to all research involving human participants, regardless of the funding source.
- Require all “greater than minimal risk” research with human participants gain approval from an accredited IRB, effective Jan. 1, 2008.

- Sen. Edward M. Kennedy (D-Mass.)

- June 9, 2004

**Notes:**
Draft of Kennedy Human Subject Bill Proffers Federal Research Standards  
Planned legislation by Sen. Edward M. Kennedy (D-Mass.) aims to create a unified, comprehensive set of requirements and protections for both privately funded and government-funded research involving human participants, according to a draft of the bill. 
Kennedy's draft bill would require that all research involving human participants "involving greater than minimal risk" gain approval from an accredited institutional review board. The legislation would provide lead time for researchers to come into compliance by making the requirement effective beginning on Jan. 1, 2008. The draft also would establish standards for research involving humans that involves "minimal risk." 
A Kennedy spokesman did not address the details of the draft bill directly, but said that the senator plans to offer his legislation soon. The senator has floated legislation in this area in the past. The bill is known as "The Research Revitalization Act of 2004." 
Republicans and Democrats in both chambers have offered previous bills aimed at protecting human participants in research, but so far the issue has failed to gain legislative momentum in Congress. 
Kennedy's draft legislation would provide statutory authority for the already existing Office for Human Research Protections in the Department of Health and Human Services and would require the director of OHRP to issue a unified rule by Jan. 1, 2007, safeguarding the rights of human participants in research. 
If the OHRP director misses the January 2007 deadline for issuing unified rules on human research subject protections, the legislation stipulates that "the Common Rule"--which guarantees certain protections for patients enrolled in federally funded medical experiments (45 C.F.R. Part 46)--would apply to all research involving human participants, regardless of the funding source. The draft bill also provides for the scenario in which the OHRP director issues rules, but does so after the January 2007 deadline. If this occurs, then those rules would not become effective until one year after the date of issuance of final rules, according to the draft.
Rule Would Supersede Prior Federal Rules, Laws
Beginning on Jan. 1, 2008, the unified rules required under the draft bill would supersede all prior federal laws and rules relating to protecting human research participants. 
Kennedy also stipulates in the draft that failure to meet the January 2007 deadline would constitute grounds for firing the OHRP director. 
Also in the draft bill are principles for OHRP to use in the development of accreditation standards for IRBs. The draft states that OHRP must establish standards within one year of the bill's enactment into law. 
The draft bill also includes provisions that would:
 require the HHS secretary to establish an advisory committee to offer counsel to the secretary on issues associated with protecting human research subjects; 
 require the Department of Homeland Security and the Environmental Protection Agency to ensure that all agency-sponsored research conforms to the Common Rule, and after Jan. 1, 2008, conforms to the unified rules to be issued by OHRP; 
 establish procedures for accrediting IRBs; 
 require investigators who submit a proposal for research involving human subjects to an IRB to disclose it if another IRB has rejected the proposal and to disclose whether any investigators involved with the proposal have been "disqualified or restricted by any federal entity in their ability to conduct covered research within the preceding 10 years"; 
 stipulate requirements to protect against financial conflicts of interest in research involving humans, including disclosure standards; 
 require the OHRP director, within a year of the bill's enactment, to establish guidelines for IRBs to use in determining whether financial compensation for the recruitment of research participants is acceptable; and 
 require the OHRP director to issue rules within a year regarding the use of placebos or nontreatment in research involving humans. Placebo research would be deemed unlawful if another available treatment had been shown effective and if there is "a risk of significant harm" to a human participant in the absence of treatment. 
Disclosure Requirements
Kennedy's draft bill also would require the HHS secretary--within one year--to issue rules requiring any applicant for HHS-administered research grants, contracts, or cooperative agreements to assure that he or she will disclose in published research findings whether the applicant holds "a significant investment interest in any financially interested entity that is, in whole or in part," the sponsor of the research. The applicant also would be required to disclose to editors or publishers of the publication whether he or she has received "significant income from any financially interested entity that is in whole or in part the sponsor of such research." 
The draft includes language recommending that medical journals publish this information. One year after the bill's enactment the recommendation effectively would become a requirement, since the bill stipulates that publications that do not comply by then would be deemed ineligible for federal funds

## Need for IRB Expertise

- IRBs reviewing pediatric protocols should have adequate expertise in child health care and research.
- at least three individuals with such expertise present (and voting) when pediatric research protocol is reviewed
- among them, these individuals should have expertise in
- pediatric clinical care and research
- psychosocial aspects of child and adolescent health care and research
- ethics of research involving children.
- When appropriate, IRBs should consult with other child health experts and with parents, children, adolescents, and community members who can provide relevant family or community perspectives

- Recommendation 8.3 (IOM, 2004)

- June 9, 2004

## Need for Expertise (cont.)

- “This committee...advises that standing pediatric advisory committees and pediatric IRBs include at least one nonscientist, unaffiliated member who can represent *explicitly* the perspectives of parents and children.”

- Ethical Conduct of Clinical Research Involving Children (IOM 2004)

- June 9, 2004

**Notes:**
[[continue from preceding slide]]
	“As appropriate for specific studies, IRBs should consult with other child health experts and with parents, children, adolescents, and community members who can provide relevant family or community perspectives.”

	Further, following the spirit of the earlier IOM report, Responsible Research, pediatric IRBs and advisory panels should have at least 1 nonscientist, unaffiliated member to represent explicitly the perspectives of families. 

## Multicenter Studies

- The federal government, research institutions, research sponsors, and groups of institutional review boards should continue to test and evaluate means to improve the efficiency as well as the quality and consistency of reviews of multicenter studies, including those involving infants, children, and adolescents.

- Recommendation 8.5 (IOM, 2004)

- June 9, 2004

## Guidance

- OHRP, FDA, NIH, and other agencies with relevant responsibilities that include research involving children should each provide comprehensive, consistent, periodically updated guidance to investigators, IRBs, and others on the interpretation and application of federal regulations for the protection of child participants in research.

- Recommendation 8.6 (IOM, 2004)

- June 9, 2004

## 21 CFR 50.54; 45 CFR 46.407

- OHRP and FDA should
- establish an _open and publicly accessible process_ for reviewing research protocols referred by IRBs under 45 CFR 46.407 and 21 CFR 50.54
- create a _standing panel_ that would meet as needed to consider such proposals
- provide _detailed guidance_ on interpretation of federal regulations governing research involving children to reduce unnecessary referrals of protocols

- Recommendation 8.7 (IOM, 2004)

- June 9, 2004

## Selected Recommendations

- Interpretation and Application of Regulations (Subpart D)
- Parental Permission and Child Assent
- Payments (subjects, investigators)
- Regulatory Compliance
- Responsible Conduct of Research (i.e., System Improvements

- June 9, 2004

## Three Broad Themes

- _Clinical research is essential_ to improve the health of future children.
- _Robust system is necessary_ for protecting child research participants.
- _Effective protection requires expertise _in child health at all stages in the design, review, and conduct of such research.

- June 9, 2004

**Notes:**
Well-designed and well-executed clinical research involving children is essential to improve the health of future children-and future adults-in the United States and worldwide. Children should not be routinely excluded from clinical studies. No subgroups of children should be either unduly burdened as research participants or unduly excluded from involvement.
A robust system for protecting human research participants in general is a necessary foundation for protecting child research participants in particular. An efficiently administered, effectively performing system with adequate resources must, however, commit additional resources and attention to meet ethical and legal standards for protecting infants, children, and adolescents who participate in research.
Effective implementation of policies to protect child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research. This expertise includes knowledge of infant, child, and adolescent physiology and development as well as awareness of the unique scientific, psychosocial, and ethical requirements and challenges of pediatric clinical care and research.