Food and Drug Administration
Office of the Commissioner
PEDIATRIC ADVISORY COMMITTEE
Robert M. Nelson, M.D., Ph.D. (chair)
P. Joan Chesney, M.D.
Michael E. Fant, M.D., Ph.D.
Dianne Murphy, M.D.
Sara Goldkind, M.D., M.A.
Office for Human Research Protections Participants
Bernard A. Schwetz, D.V.M, Ph.D.
Kevin Prohaska, D.O.
Jan. N. Johannessen, Ph.D.
Jill Fisch (Patient-Family Representative
Alan Fleischman, M.D.
Angela Holder, LL.M.
Mark Hudak, M.D.
Paula Knudson (Acting Consumer Representative)
Mary Faith Marshall, Ph.D.
Ronald Rubenstein, M.D., Ph.D.
Kate Shafer, LICSW (Patient Family Representative)
Billie Lou Short, M.D.
Jeffery Whitsett, M.D.
Open Public Hearing Speakers:
Jeffery Whitsett, M.D., Ph.D.
FDA and OHRP Presentations:
Subpart D Expert Panel Process Sara Goldkind, M.D., M.A.
Bioethicist, Office of Pediatric Therapeutics, FDA
Bernard Schwetz, D.V.M, Ph.D.
Director, Office for Human Research Protections
Overview, Charge to Panel and Final Outcome Robert M. Nelson, M.D., Ph.D.
Chair, Pediatric Ethics Subcommittee
Summary of Submitted Public Comments Robert M. Nelson, M.D., Ph.D.
Chair, Pediatric Ethics Subcommittee
Overview on Surfactant Jeffery Whitsett, M.D., Ph.D.
Background on Protocol Aaron Hamvas, M.D.
IRB Questions Sarah Frankel, Ph.D.
Human Studies Committee
Questions to the Committee:
(1) What are the potential benefits of the research, if any, to the subjects and to children in general?
(2) What are the types and degrees of risk that this research presents to the subjects?
(3) Are the risks to the subjects reasonable in relation to the anticipated benefits, and is the research likely to result in generalizable knowledge about the subjects’ disorder or condition?
(4) Does the research present a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children?
For details of all presentations and discussions, please see the full transcript of this meeting.
The Subcommittee had a number of recommendations, which are
included in the Chair’s summary of the meeting.
This meeting summary was also presented to the Pediatric Advisory Committee
Prepared by Dr.
Chair, Pediatric Ethics Subcommittee
The Pediatric Ethics Subcommittee of
the Pediatric Advisory Committee met on
The proposed research involves the administration of a 24 hour infusion of palmitate and acetate labeled with the stable (non-radioactive) isotope carbon 13, followed by the measurement of labeled surfactant obtained by routine clinically indicated tracheal aspiration. In addition, two to five blood samples totaling a maximum cumulative volume of 2.5 mL will be drawn from either an indwelling catheter placed for clinical indications or in association with a clinically indicated blood sample. In other words, there will be no additional procedures performed as part of this research protocol other than the 24-hour infusion. All infants enrolled in the protocol will have been intubated for clinical indications. There will be no catheters placed for the research, nor additional venepunctures performed as part of the research. As such, the incremental risks of the research beyond the risks of routine clinical care include the rare (less than 2%) risk of infection from the infusion, the possibility of glucose and/or electrolyte disturbances, and the need for a blood transfusion given the additional blood volume taken for research testing. During the presentation and discussion, the subcommittee heard data from 53 previously studied infants showing no increase in these adverse events when compared to protocol eligible but not enrolled infants. The investigators have gone to great lengths to ensure the safety of the 24-hour infusion. The subcommittee determined (in agreement with the referring IRB) that the risks of the research procedures presented only a minor increase over minimal risk.
The protocol involves two different
populations of infants who are intubated for clinical indications. The first
population are infants born at a gestational age between 24 and 28 weeks who
are studied shortly after birth, at two weeks and four weeks after birth. As of
the Continuing Review Report dated
The second population are a comparison group of full-term infants who require endotracheal intubation and mechanical ventilation, along with the placement of intravascular catheters, as part of routine clinical care for non-pulmonary conditions. To be included, these infants would need to have a normal chest x-ray and gas exchange as reflected in an inspired oxygen concentration of less than 0.3. The investigators have proposed this population in order to explore the impact of gestational age versus the evolution of chronic lung disease on surfactant kinetics by studying a population of infants without lung disease. Although the ideal comparison group would be intubated and mechanically ventilated infants who are matched for both gestational and chronological age, such infants would be extremely rare. It is the inclusion of this comparison group that resulted in the referral for federal review under 21 CFR 50.54 and 45 CFR 46.407, for these infants lack the disorder that is the stated objective of study, i.e., surfactant kinetics in preterm infants with hyaline membrane disease. Although the Pediatric Ethics Subcommittee reviewed the amendment in the context of the entire protocol, it is the amendment to include this full-term comparison population that is the focus of discussion.
The subcommittee reviewed the appropriateness of the comparison group drawing on the scientific presentations and expertise of the panel members. Although the protocol as submitted focused on the use of a full-term population as a comparison group to shed light on the data from preterm infants, there are important questions of surfactant physiology and the respective impact of various disease processes and mechanical ventilation that could be usefully examined and would provide important information about this population of full-term infants. Nonetheless, the full-term infants in the comparison group lacked the condition as defined by the submitted protocol (i.e. disordered surfactant physiology as a result of prematurity). The decision to study the intubated full-term infants as a comparison group rather than the primary focus of investigation effectively defined this population as lacking the necessary condition under 45 CFR 46.406 and 21 CFR 50.53. However, the subcommittee believed that a protocol focused on describing surfactant kinetics in an intubated full-term population of infants could have been approvable under 45 CFR 46.406 and 21 CFR 50.53. The subcommittee agreed that referral under 45 CFR 46.407 and 21 CFR 50.54 was appropriate for this protocol as written. The subcommittee also agreed that such a referral may not have been necessary if understanding surfactant kinetics in full-term infants who are intubated and mechanically ventilated had been the focus of the investigation.
Following a full discussion of the issues as reflected in the above summary, the subcommittee voted unanimously (11 in favor, no objections or abstentions) in favor of the motion "approvable, with conditions" under the category 21 CFR 50.54 and 45 CFR 46.407. The subcommittee assessed that the proposed research presents a “reasonable opportunity” to further the understanding of a serious problem affecting children since premature births are increasing and have a high morbidity and mortality associated with them (e.g., an average hospitalization of 2-3 months, and potentially significant developmental and medical sequelae). The subcommittee voted in favor of requiring two conditions for the research to go forward, and of recommending but not requiring a third condition.
The first required condition (11 in favor, no objections or abstentions) focuses on the homogeneity of the comparison group in providing a meaningful comparison to the data generated from preterm infants. The subcommittee discussed a number of conditions that may impact on surfactant physiology in full-term infants, such as congenital abnormalities resulting in pulmonary hypoplasia and disorders in pulmonary blood flow associated with such conditions as congenital heart disease. The subcommittee recognized that the principal investigator had listed some exclusions in his presentation. As the focus of the proposed research was not on describing the heterogeneity of surfactant physiology in the various conditions affecting full-term infants, careful attention needs to be paid to make sure that this comparison group is relatively homogenous. As mentioned, although the ideal comparison group would be intubated and mechanically ventilated infants who are matched for both gestational and chronological age, the subcommittee felt the proposed research would in effect be a descriptive, hypothesis-generating study, and that inclusion of the comparison group would contribute to the overall knowledge potentially generated by the study. The subcommittee recognized that assuring homogeneity may involve a learning process as data about surfactant physiology in intubated full-term infants are obtained.
The second required condition (10 in favor, no objections, one abstention) involves a number of modifications to the parental permission documents reviewed by the subcommittee, particularly the document intended for use in the full-term population. The language needs to be simplified to an eighth grade reading level, including the required language about confidentiality and protected health information. The reference to there being no likely research related risks should be deleted. The discussion of alternatives should be framed from the perspective of research participants, and not from that of the investigators (i.e., the consent document should mention that one alternative is not to participate in the research). This discussion should also be highlighted under a section separate from the benefits of participation. The discussion of the purpose of the study should deemphasize any immediate connection between the data derived from full-term newborns and the understanding of surfactant physiology in preterm infants. The template language about not needing treatment found at the beginning of the document should be removed. Such language should not be included in a document describing a basic physiology study, as it may inadvertently reinforce a therapeutic misperception. Finally, there was considerable discussion about the importance of parents having an approachable and independent person to whom they can direct questions about the research. Parents may be intimidated by the inclusion of titles such as "chairman" and "privacy officer" in describing individuals who are available to answer questions about the research.
The third recommended but not required condition (11 in favor, no objections or abstentions) continued the discussion of the importance of parental understanding of the research with the recommendation for an independent advocate to be available during the parental permission process, i.e., someone who would be approachable, accessible, and available to discuss the research. Although the subcommittee came to no conclusion about who such a person should be, there was general agreement about the function of such a person. A key function of such a person would be to assure that the parents, before signing the parental permission document, understood that this was a basic physiology study that offered no therapeutic benefit for the individual infant. It should be noted that this recommendation was initially proposed as a mandatory condition, but rejected as such by a majority of the subcommittee (3 in favor, 8 against, no abstentions).
In summary, the Pediatric Ethics Subcommittee of the Pediatric Advisory Committee determined that the proposed research presents a reasonable opportunity to further the understanding of a serious problem affecting the health of children, will be conducted in accordance with sound ethical principles, and that adequate provisions are made for soliciting of the permission of parents or guardians as set forth in 45 CFR 46.408 and 21 CFR 50.55. As such, the Pediatric Ethics Subcommittee recommends that the Pediatric Advisory Committee recommend to the FDA Commissioner and the Secretary of HHS that the research be approved under 45 CFR 46.407 and 21 CFR 50.54 contingent on a satisfactory response to the two required conditions as discussed above.
I certify that I attended the
Jan N. Johannessen, Ph.D. Robert M. Nelson, M.D., Ph.D.
Executive Secretary Chair