| Comment Record|
Ms. Patricia Stinchfield, NP ||
2002-11-29 12:48:38 |
Children's Hospitals and Clinics, Minnesota |
Health Professional |
| Comments for FDA General |
1. General Comments
November 29, 2002
To: Department of Health and Human Services
Offices of Public Health and Science and Food and Drug Administration
Office for Human Research Protection
From: Multidisciplinary Working Group
Childrenís Hospitals and Clinics of Minneapolis and St Paul
Re: Docket No. 02N-0466
Our working group is writing in response to the request for public review and comment regarding the research proposal entitled ďA Multicenter, Randomized Dose Response Study of the Safety, Clinical, and Immune Response to Dryvax [reg] Administered to Children 2 to 5 Years of Age.Ē Our group reached the conclusion that the benefits of additional knowledge potentially gained from this study do not outweigh the risks to the subjects, and therefore that the research as currently proposed should not be approved. The reasoning leading to this conclusion is presented below.
Our working group included professionals from Children's Hospitals and Clinics of Minneapolis and St Paul with expertise in many disciplines. The participants included three physicians in the area of pediatric infectious disease (including our hospital epidemiologist), an infectious disease pediatric nurse practitioner and director of infection control, two infection control practitioners, our hospital safety officer responsible for bioterrorism preparation, a media relations specialist, and our hospital bioethicist, a psychologist who chairs the IRB. In addition a representative from the Minnesota Department of Health working in the area of bioterrorism preparation attended. The conclusions reached were unanimous.
We want to clarify our working groupís and our organizationís strong commitment to immunization of children. We are community leaders and active nationally in advocating for vaccination programs. Our comments should in no way be interpreted as critique of the vaccinations recommended by the CDCís Advisory Committee on Immunization Practices, the American Academy of Pediatrics and other organizations. We are strong supporters of routine, regular, and complete vaccination of children.
We also want to emphatically state that if a smallpox event occurs we strongly support the vaccination of children with Dryvax [reg] in appropriate dilution and with already known and demonstrated technique (5 insertions of a bifurcated needle).
Furthermore, we are, as individuals and an institution, strongly committed to pediatric research and appropriate inclusion of children in clinical trials when the knowledge gained justifies the risks of the study. We recognize the additional protections needed for individuals, such as children, who cannot consent for themselves. The research endeavor in general is best served by careful examination of the factors which overcome the presumption of voluntary participation of subjects. We take seriously the general presumption of voluntary informed consent for all medical research as described in the Declaration of Helsinki and the Common Rule. We believe this research is not approvable under 45CFR46 Subpart D 46.404, 405 or 406. If it is approvable at all, and we believe it is not, it would be approvable only under Subpart D 46.407.
Our conclusions relate specifically to the proposed research project in light of potential benefits and harms of the study as proposed. We will discuss the issues within the framework of the specific questions published for comment.
What are the potential benefits, if any, to the subjects and children in general?
The potential benefits of the research must be analyzed in light of current knowledge of the Dryvax vaccine in adults and children and the potential risk of smallpox exposure. We, in detail, addressed the question of benefits in terms of direct benefit to the subjects, indirect benefits to the subjects and their families, and benefits to society in terms of other children.
Regarding the potential risk of smallpox exposure we clearly are unable to fully evaluate actual current risks, so can comment only from discussions regarding bioterrorism at professional meetings and in the media. Based on those sources we evaluate the risk as extremely small due not only to the limited availability of the agent but also due to the technological difficulty of using the agent. We felt any potential direct benefit to subjects is best described as a hypothetical benefit, and therefore cannot be considered a direct benefit to the subjects. If the government has information of plausible immediate threats this calculation of direct benefit is likely to change (although we concluded that existing knowledge is sufficient to know how to use the existing vaccine supplies, as discussed below).
There may be potential indirect benefits to parents worried about smallpox who gain peace of mind by having their child vaccinated in this study. However, these indirect benefits are small in comparison to the risks to the subjects and household and community contacts of the preschool-aged subjects. These indirect benefits to subjects and families do not justify the proposed research project. In fact, the current public state of anxiety may induce worried parents to expose their children to irrational risk to achieve some peace of mind when actual risks outweigh potential benefits.
The question of benefit to society and children in general does not justify approving the proposed research. We believe the current state of knowledge regarding the Dryvax vaccine and dilution of current stocks is sufficient to guide if a smallpox outbreak occurs, and therefore the benefits of the proposed research are minimal. Specifically, our group discussed in detail the following issues which are noted as potential benefits to children in general:
A. Knowledge of Pediatric Immune Response To Undiluted (1:1) and Diluted (1:5) Vaccine (Primary Objective and Secondary Objectives 1 and 4)
We recognize that in some sense the 1:5 dilution is a different vaccine than the 1:1 form. Recent trials of diluted vaccine in adults (Frey et al, N Engl J Med. 2002 Apr 25;346(17):1265-74.)
have demonstrated sufficient take rate with 1:5 diluted vaccine to justify use in diluted form. There is little or no reason to believe children ages 2-5 will show an immunologically lower response. Also, previous studies (cited in the protocol) in children from the vaccination era demonstrate the effectiveness of the 1:5 dilution in children. Therefore, there is little or no benefit to the knowledge gained in the proposed study.
B. Knowledge of Effectiveness of 5 v. 15 Insertions (Secondary Objective 2)
The proposed study differs from the adult studies in using 5 vs. 15 insertions of a bifurcated needle. We concluded that knowledge of the effectiveness of this technique from the past when children were routinely inoculated is sufficient to justify this technique if mass vaccination is needed. Therefore there is little or no benefit to the knowledge, which will be gained, in the proposed study.
C. Knowledge of the Safety Profile of the Vaccine to Vaccinees and Contacts (Secondary Objective 3
The sample size is insufficient to gain meaningful knowledge, and significant knowledge already exists from the previous vaccination era. Furthermore risks in todayís population of more frequently immunosuppressed individuals will not be gained because such families are specifically excluded from the study. Therefore, there is little or no benefit to the knowledge gained in the proposed study.
D. Knowledge of Revaccination of Nonresponders (Secondary Objective 5)
Our review of the existing studies and knowledge still extant from the vaccination era indicate sufficient knowledge of take rates in initial nonresponders exists. Furthermore, since there is no reason to believe these children will react differently than adults, any further studies can be carried out in adults. Therefore, there is little or no benefit to the knowledge gained in the proposed study.
It is also important to note that the U.S. Government has contracted for the development of a new, presumably safer vaccine to be produced for the entire U.S. population (Acambis). This vaccine will require full clinical trials to establish its safety and effectiveness, apparently some time in the next 12-18 months. Therefore any knowledge of the dilution of the Dryvax vaccine will be obsolete when the new vaccine is available. This small window of the usefulness of any knowledge gained in the proposed study is also relevant and indicates further that the benefits from the proposed study are extremely limited. We conclude that there are only hypothetical benefits to the subjects themselves, little or no benefit to children in general. Therefore the proposed study does not present a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.
1. What are the types and degrees of risk that this research presents (to subjects)?
The risks of the Dryvax vaccine are well-known and documented, including autoinnoculation, eczema vaccinatum, erythema multiforme, generalized vaccinia progressive vaccinia, vaccinia keratitis, and in rare instances death from some of the complications already listed. The best knowledge of the frequency of these risks emerges from the 1968 ten-state survey, which demonstrates adverse event rates, which are significant and clearly are beyond minimal risk or a minor increase over minimal risk.
In the proposed population the possibilities of such risks may be higher due to issues of cooperation in a preschool population. While the proposed study does have a recommended method of using occlusive dressings to limit risk, our group of pediatric infectious disease specialists noted that it is extremely difficult to achieve cooperation with occlusive dressings with toddlers and preschoolers. Children do not understand the need for the dressing, but will feel the itch and because of their ability to remove the dressing, will try to do so. There is also insufficient understanding of effectiveness of the proposed occlusive dressing. The study is not optimally configured to gather this information regarding the usefulness of the dressing, nor is it a primary or secondary objective of the study.
We also believe that the study as proposed does not take potential steps to establish normal immune function of the children. It was also noted that in the recent adult study additional consent safeguards included presentation and discussion with potential subjects and a 24 hour waiting period before consent could be documented. We are not aware of such provisions in the proposed study and if the study is approved (which we do not recommend) strongly endorse such additional protections.
It has been pointed out that treatment with VIG is potentially available if side effects of the vaccine arise. While this is a consideration, the protocol as currently written does not guarantee subjects no cost availability of treatment. While we do not know the cost of VIG, if the costs are similar to current similar products, depending on dosage, it could be significant such as $1,000/dose. Also the stockpiles of VIG are small and the study patients are not guaranteed access. Parents are not fully informed in current documents of these factors.
We therefore conclude that significant risks exist in spite of the planned use of occlusive dressing. This risk includes significant risk to contacts such as siblings, relatives and playmates, pregnant women and the immunocompromised.
2. Are the risks to the subjects reasonable in relation to the anticipated benefits, if any, to the subjects, and the importance of the knowledge the may be expected as a result?
As described in the answer to question 1, we believe there are only hypothetical direct benefits to subjects, little or no benefit of the knowledge gained in the proposed study to the general population. Given the limited current benefits, the short window during which Dryvax would be utilized when the new vaccine becomes available we conclude the benefits of the proposed study are extremely small. As described in our answer to question 2, there are significant risks to the subjects.
Therefore we conclude that the risks to the subjects are not reasonable in relation to the anticipated benefits and the study should not be approved.
3. Does this present a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children?
We believe it is clear, given our answers to the previous questions, that we believe this study does not present a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children because the information currently available is sufficient to answer the study questions and the risks to children and contacts is significant.
In conclusion we recommend against approving the current study.
If the study is approved we strongly recommend the FDA takes into account the review comments from Mary Faith Marshall Ph.D. and Rosemary Quigley, JD, MPH regarding inadequacies in the current consent process and documents and in the study design regarding payment for treatment of any injury associated with the study.
We wish to reiterate that our comments are directed specifically to disapproval of the current study. We remain strong supporters of immunization of children according to recommended guidelines, of the use of the vaccine if a smallpox outbreak were to occur, and of the need for research into the conditions and treatments of children.
The Children's Hospitals and Clinics Minneapolis and St Paul Working Group:
Donald Brunnquell, Ph.D., Director of the Office of Ethics, IRB Chair
Patricia Stinchfield, RN, MS, CPNP Director of Infectious Disease/Infection Control
James E. Levin, MD, Ph.D. Pediatric Infectious Disease, Medical Director of Informatics
Michelle Hulse, Pediatric Infectious Disease, Hospital Epidemiologist
Richard D. Andersen, MD Pediatric Infectious Disease, Associate Director, Medical Education
Kathy Gray, RN Infection Control Practitioner
Ann Endy, RN, CIC, Infection Control Practitioner
James Leste, Safety Officer, Chair of Biosecurity Preparedness Team
Allison Sandve, Media Relations Specialist, Marketing and Communications
Lynn Bahta, RN, PHN Immunization Section, Minnesota Department of Health