# Presentation: 099270

## Pediatric Studies and RDRC

- Sara F. Goldkind, M.D., M.A.
- Bioethicist
- Office of Pediatric Therapeutics
- Office of the Commissioner
- 11/16/04

## Outline

- Adult Studies
- Pediatric Studies
- Children’s Health Act
- 21 CFR 50 Subpart D
- Current understanding of risk levels
- NHRPAC REPORT
- IOM REPORT
- Additional risks

## The research subjects shall be at least 18 years of age and legally competent

- 21 CFR 361.1(d)(5)

## ADULT STUDIES

**Meets **
**21 CFR 361.1**

**Yes**

**No**

**IND Required**

**No IND required**

## Some Conditions For Approval Under 21 CFR 361.1

- RDRC Approval
- Limit pharmacological dose: known not to cause any clinically detectable pharmacological effect in human beings *based on available data from published literature or from other valid human studies*
- Limit radiation dose:
- smallest radiation dose with which it is practical to perform the study
- Single dose and cumulative dose limits
- Approval of IRB
- Compliance with 21 CFR 56 IRB regulations
-    require compliance with 21 CFR 50, Informed Consent and Additional Safeguards for Child

## Pediatric Studies

## Exceptions are permitted only in those special situations when it can be demonstrated to the committee that the study presents a unique opportunity to gain information not currently available, requires the use of research subjects less than 18 years of age, and is without significant risk to the subject.

- 21 CFR 361.1(d)(5)

## Pediatric Research: Historical Perspective 

- 1975, 21 CFR 361.1
- “Without significant risk to the subject” which is not defined
- Pediatric protection-little pediatric research
- 1990’s growing awareness that children are treated on the basis of sparse data
- 1997 F and D Modernization Act, Pediatric Exclusivity-increasing pediatric research
- 2000, Children’s Health Act: all HHS-funded and **regulated **research must comply with these additional protections for children
- 2001, FDA Adoption of 21 CFR 50 Subpart D
- “Minimal risk”
- “Greater than minimal risk”

## Application of Subpart D to Research Conducted Under 21 CFR 361.1

- 21 CFR 361.1(d)(5): each investigator shall obtain an IRB review that conforms to 21 CFR 56
- 21 CFR 56.109(h) states: When some or all of the subjects in a study are children, an IRB must determine that the research study is in compliance with part 50, subpart D

## 21 CFR 50 Subpart DAdditional Safeguard for Children in Clinical Investigations

- 50.51: Not involving greater than minimal risk
- 50.52: Involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects
- Radiation exposure prohibit classification under 50.51
- Basic research under 361.1, cannot be classified under 50.52

## 21 CFR 50 Subpart DAdditional Safeguard for Children in Clinical Investigations

- 50.53: Involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition
- 50.54: Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children

## Likely Approval Categories 

- 21 CFR 50.53, IRB is authorized to approve
- 21 CFR 50.54
- The IRB finds and comments that clinical investigation presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
- Requires FDA referral (and HHS referral if the research is also federally funded or conducted)
- Requires review by an expert panel with findings by the Commissioner (and Secretary)

## PEDIATRIC STUDIES

**IRB finds that study meets 21 CFR 50 Subpart D**

**Yes**

**No**

**Cannot  Do Study**

**Meets rest of **
**21 CFR 361.1**

**Referral to Expert Panel.  If Commissioner finds study can proceed, then meet rest of 21 CFR 361.1?**

**Yes**

**No**

**IND Required**

**No IND Required **
**But . . .**

**Qualified  Yes, 50.54?**

**List of Conditions**

## Minimal Risk

- The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests
- 21 CFR 50.3(k)

## Minimal Risk

- Preamble to Subpart D Regulations: clean-catch urinalysis, stool samples, EEG, minimal diet or daily routine changes, standard psychological test, taste tests, device test of oral temperature readings
- NHRPAC: venipuncture*, chest x-ray, bone density test,  oral glucose tolerance test, MRI without sedation
- *quantity and frequency dependent

## Greater Than Minimal Risk

- Not defined in the regulations
- NHRPAC: urine collection via catheter, lumbar puncture, skin punch biopsy with topical anesthesia, bone marrow aspirate with topical anesthesia, nasogastric tube insertion
- IOM: interpret to mean a slight increase in the potential for harms and discomfort

## Risk Assessment

- Magnitude
- Probability
- Duration
- Age-graded
- Cumulative analysis
- Component analysis
- Special population

## Component Risk Analysis

- radioactive drug
- concomitant medications
- radiation risk of the imaging machine
- venipuncture (frequency and total blood volume)
- use of enclosed or confining equipment
- prolonged immobilization
- use of sedation
- any additional protocol interventions

## PEDIATRIC STUDIES

**IRB finds that study meets 21 CFR 50 Subpart D**

**Yes**

**No**

**Cannot  Do Study**

**Meets rest of **
**21 CFR 361.1**

**Referral to Expert Panel.  If Commissioner finds study can proceed, then meet rest of 21 CFR 361.1?**

**Yes**

**No**

**IND Required**

**No IND Required **
**But . . .**

**Qualified Yes, 50.54?**

**List of Conditions**

## Additional Concerns

-    The amount of active ingredient or combination of active ingredients to be administered shall be known not to cause any clinically detectable pharmacological effect
-    Pharmacological dose calculations based on  data available from published literature of from other valid human studies
- Limited amount of pediatric data
- Experience with pediatric exclusivity has demonstrated difficulties in extrapolation from adults to children (growth, development, absorption, distribution, metabolism, hormonal factors)

## Advantages of IND

- Discussed by Lynn Panholzer

## Pediatric Studies

- Additional research risks  in a vulnerable population warrant additional safeguards.  Recommend pediatric research be conducted under IND.