Docket Management
Docket: 02N-0466 - Randomized Dose Response Study of Dryvax in Children Ages 2 to 5
Comment Number: EC -468

Accepted - Volume 4

Comment Record
Commentor Dr. Kenneth Carter Date/Time 2002-12-02 16:09:52
Organization Truman State University
Category Academic

Comments for FDA General
1. General Comments [Docket No 02N-0466] Public Review and Comment on Research Protocol: A Multicenter, Randomized Dose Response Study of the Safety, Clinical and Immune Response of Dryvax(R) Administered to Children 2 to 5 Years of Age. I offer my comments as a scientifically trained layman (Ph.D., physical chemistry) and the father of a child in the proposed age group. In my current position as an associate professor, I mentor several undergraduate students in research on scientific and ethical aspects of vaccination policy. We have reviewed the proposed protocol and associated documents, including the solicited expert opinions. I agree substantially with the suggestions and caveats of those experts who stated that the research could be approved, though only after appropriate modifications, under 45 CRF 46.407. If there is, indeed, inadequate Dryvax(R) for use at full strength for the entire population,* and if sufficient quantities of the acellular vaccine will not be available until well after the conclusion of the crucial first month of the study, then this study has the potential for enormous savings of life in the presently incalculable event of a large-scale smallpox attack. However, I wish to underscore strongly the following concerns: The word “Safety” should be removed from the title, as suggested in the by Steven Ebert, Pharm.D. in his expert report. The small size of the study ensures that it cannot reject the null hypothesis that rates of serious and life threatening side effects are similar to, or even an order of magnitude greater than, those reported in the ten-state study of 1968. The small size lowers the likelihood of any participant being seriously injured or killed, and is therefore a virtue in light of the ethical problems attendant upon uncertain odds of personal benefit and young child subjects. Care in planning to exclude from the study those with conditions predisposing to adverse affects is commendable and appropriate. Such exclusions might lower the risk of serious complications below the approximately one per thousand previously reported, but this study cannot so demonstrate. Furthermore, these careful exclusions are unlikely to obtain in a mandatory ring vaccination strategy. Removing the word “safety” from the title may help guard against later misconstrual of findings. Modifications to the consent form are in order, as detailed by consultant Mary Faith Marshall, Ph.D. and others. It is essential that the cost of medical care be guaranteed covered for any recognized side effects of the vaccination, whether mild or severe. Without such provision, in my view the proposal fails the tests of beneficence and justice as prescribed by the Belmont Report. Even with this change, it is highly questionable whether participation in the study is free of cost (even though there is no direct charge for participation). But, without coverage, the cost could, in the case of major complications, be large, even crushingly exorbitant! To be sure, the odds are long, but they should be borne by the taxpayers of America, not the participating families. As one expert pointed out, uncertainty about expense might lead some families to delay in seeking timely aid, which could have devastating consequences. Great care must be taken to ensure that informed consent is well and accurately informed. Immunity to smallpox is only a direct benefit in the event of an attack, and that fact needs to be made explicit. The quantitative risk of an attack and the subsequent risk to a particular child cannot be estimated rationally based on information presently available to the public. However, with news of President Bush’s decision to authorize vaccination of health care workers, it has become clear that at least some high ranking officials consider the threat of attack sufficiently plausible to justify the almost certain loss of life that sufficiently widespread vaccination with Dryvax(R) would entail. In light of such well publicized preparation for potential attack, one other health benefit that might accrue to the child vaccinated in this study, regardless of attack, is increased peace of mind. Therefore, while it would not be ethical to attract subjects by exacerbating fears of attack, it would seem acceptable to offer the opportunity to parents who, being informed of the risks, still consider vaccination to be in their child’s best interest. Given the vigorously promulgated official public heath line that vaccines are “safe and effective,” pains need to be taken to insure and ascertain that parents of prospective subjects are aware that Dryvax(R) is emphatically not safe by currently applied standards! “Better safe than sorry” doesn’t decide the issue, since the relative risk of participation versus non-participation cannot be known with confidence. In this regard, parents and guardians who want more information about potential side effects should have access to fuller descriptions of the conditions, including pictures such as the ones available on the CDC website. A mere listing of technical names for conditions may not convey much to the non-specialist. (Some countervailing perspective could be gained from comparison with pictures of variola itself; and pictures of chicken pox could make the point that pictures, too, do not tell the whole story.) I am most emphatically not suggesting that participating children be shown these pictures! This is a case where the principles of respect and beneficence must be held in balance. The social situation of the child matters. Dislocation from usual routine could be a significant consideration. The most appropriate subject would be a child with a full-time stay-at-home medically astute parent who was convinced of the reasonable likelihood of smallpox attack. Children of parents who discount the risk of participation or, at the other extreme, consider themselves to be motivated purely by sacrificial altruism, should not be enrolled. Just as there is medical screening, there should be a screening for attitude and comprehension. As Dr. Hammerschmidt noted, humane measures such as the use of EMLA to reduce the discomfort of drawing blood would seem to make a lot of sense. Whether participation in the study proves to be of objective medical benefit to the child is ultimately out of the investigator’s hands, but there is much opportunity for treating the subjects with consideration. Whether participation is a positive experience for most may depend significantly on factors that cannot be guaranteed by a protocol: the kindness and good humor of the staff and clinicians (Patch Adams is far from being the only fun person in medicine!), the wisdom of the parents or guardians in their explanations and support, and the temperaments of the individual children. With the changes advocated in the expert testimony, I believe this investigation can meet the criteria of respect, beneficence, and justice. I wish much wisdom for those who will make the decision. Sincerely, Kenneth N. Carter, Jr. (Ph.D., Physical Chemistry) Associate Professor of Chemistry, Truman State University Footnote: *In a news article announcing anticipated plans to vaccinate health care workers, an unnamed official was quoted as saying, We have enough vaccine for every man, woman and child right now, with some to spare. I hope that those making the final decision on this research know the actual truth regarding this claim!

EC -468