The Children's Hospital of Philadelphia

**Department of Anesthesiology and Critical Care Medicine**

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| **Robert M. Nelson, M.D.,        | 34^th^ Street & Civic Center      |
| Ph.D.**                          | Boulevard, Rm. 1513               |
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| ##  Chair, Committees for        | Philadelphia, Pennsylvania        |
| the Protection of Human Subjects | 19104-4399                        |
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| *Associate Professor of          | \(215\) 590-9180 Office           |
| Anesthesia and Pediatrics*       |                                   |
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|                                  | \(267\) 426-5035 Fax              |
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|                                  | nelsonro@email.chop.edu           |
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November 25, 2002

Dockets Management Branch (HFA--305)

Docket Number 02N--0466

Food and Drug Administration

5630 Fishers Lane, Room 1061

#### Rockville, MD 20852

Re: A Multi-center, Randomized Dose Response Study of the Safety,
Clinical and Immune Response of Dryvax^®^ Administered to Children 2 to
5 Years of Age

Dear Drs. Crawford and Slater:

We write in response to the solicitation of public review and comment on
the above-named research protocol, as announced on October 31, 2002 in
the Federal Register, Vol. 67, No. 211, pages 26403-04. [Our comments
will ask and answer the following four questions]{.underline}.

(1) Can the research study be approved by an IRB under one or more of
    the categories 45 CFR 46.404/21 CFR 50.51, 45 CFR 46.405/21 CFR
    50.52 or 45 CFR 46.406/21 CFR 50.53? Our answer is [no]{.underline}.

(2) Will the research be conducted in accord with the primary "sound
    ethical principle" of research involving children, which holds that
    children should only be involved if the research question cannot be
    answered using adults? [Absent significant
    modifications]{.underline} to the research design, our answer is
    [no]{.underline}.

(3) Will the research be conducted in accord with a number of secondary
    "sound ethical principles", assuming that the use of children in the
    research is necessary? [Absent significant
    modifications]{.underline} to the research design and consent form,
    our answer is [no]{.underline}.

(4) Is the process of consultation being used to determine whether or
    not the research could be approved under 45 CFR 46.407/21 CFR 50.54
    appropriate and ethical? Our answer is [no]{.underline}.

We conclude that [the proposed research should not be
approved]{.underline} absent further public discussion of the need for
using children to achieve the study objectives, and significant
modifications of both the research design and consent documentation and
process.

**[Question One]{.underline}: Can the research study be approved by an
IRB under one or more of the categories 45 CFR 46.404/21 CFR 50.51, 45
CFR 46.405/21 CFR 50.52 or 45 CFR 46.406/21 CFR 50.53? Our answer is
[no]{.underline}.**

With the exception of Dr. Fulginiti, who felt that the study should be
approved yet failed to discuss the level of risk exposure, all of the
consultants agreed that [administration of the smallpox vaccine presents
greater than a minor increase over minimal risk]{.underline} and thus
could not be approved under sections 45 CFR 46.404/21 CFR 50.51 or 45
CFR 46.406/21 CFR 50.53. In effect, all of the consultants agreed that
the study either must offer the prospect of direct benefit to the
children enrolled in the trial (45 CFR 46.405/21 CFR 50.52), or meet the
requirements for approval under 45 CFR 46.407/21 CFR 50.54. We agree
with this assessment.

continued

In addition to the assessment of risk, the children to be enrolled in
this study do not to have a "disorder or

condition" as a requirement for approval under sections 45 CFR 46.406/21
CFR 50.53. This specific point was discussed by a minority of the
consultants since the risk determination alone disqualified the study
from consideration under this category.

Administration of the smallpox vaccine [does not offer the prospect of
direct benefit]{.underline} to the children to be enrolled in this
research study. Only 2 of the 10 consultants (Daum, Baltimore) thought
that the research offers the prospect of direct benefit to the children
enrolled in the research. Although Dr. Fulginiti did not discuss the
Subpart D categories, he clearly states that the research offers "no
direct, immediate benefit to the children". Dr. Daum argues for the
prospect of direct benefit based on an analogy to the use of oral polio
vaccine in spite of the known but small risk of vaccine-associated
polio. However, this analogy is not useful. The oral polio vaccine was
(and is) administered to children at the same time that polio disease
occurs in many areas of the world. The benefits of that vaccine are,
therefore, not theoretical. Dr. Baltimore argues that being immune from
smallpox is a direct benefit even in the absence of a known
bioterrorism-related risk for smallpox dissemination. Turning ethical
concern for the "therapeutic misconception" on its head, Baltimore
argues that parental perception of direct benefit based on the fear of
smallpox dissemination is sufficient justification for an IRB to
determinate that the prospect of direct benefit, in fact, exists.
Contrary to Baltimore's claim, Quigley appropriately asserts that the
"parental instinct to protect a child should not be played upon as an
impetus to enroll in this trial." We do not know whether a conversation
between consultants would have resulted in agreement on this point, as
an the opportunity for such a panel discussion was never provided.

We agree with the majority of consultants that the research could
[not]{.underline} be approved by an IRB under categories 45 CFR
46.404/21 CFR 50.51, 45 CFR 46.405/21 CFR 50.52 or 45 CFR 46.406/21 CFR
50.53.

**Approval under category 45 CFR 46.407/21 CFR 50.54 requires that "the
research will be conducted in accordance with sound ethical
principles."**

Although all of the consultants recommended that the research could be
approved under section 45 CFR 46.407 and 21 CFR 50.54, there was little
discussion of the "sound ethical principles" according to which the
research must be conducted (apart from three of the four consultants
with ethical and/or legal expertise). These "sound ethical principles"
can be considered under two general categories: (1) the ethical
principles that must be met for the research to be conducted in children
at all, and (2) the ethical principles that must be met for the proper
and ethical conduct of the research, assuming the use of children is
ethically appropriate. Although the consultant's discussion focused
primarily on the second category, we must first ask and answer the first
question of whether the research should be conducted in children at all.

**[Question Two]{.underline}: Will the research be conducted in accord
with the primary "sound ethical principle" of research involving
children, which holds that children should only be involved if the
research question cannot be answered using adults? [Absent significant
modifications]{.underline} to the research design, our answer is
[no]{.underline}.**

The primary ethical principle in conducting research involving children
is that the scientific question(s) cannot be answered by using adults
who are capable of consent. Assuming that consenting adults cannot be
used, a secondary ethical principle in conducting research involving
young children is that the scientific question(s) cannot be answered by
using children who are capable of assent.

As stated in the protocol, the primary objective is to evaluate the
cutaneous responses (take rates) after vaccination in children given
undiluted and diluted (1:5 dilution) vaccine. Among the secondary
objectives are the following: (a) to evaluate the immunological
responses in children given undiluted and diluted (1:5 dilution)
vaccine; (b) to ascertain the clinical and immunological responses and
safety of 5 intradermal punctures with a bifurcated needle; and (c) to
assess the safety profile in the vaccinated individual and assess the
risk to contacts.

continued

The rationale for the study clarifies that a major concern is the risk
of autoinoculation and secondary transmission from young vaccinees to
contacts, with evaluation of the use of a semi-occlusive dressing to
prevent such spread. The primary study endpoint is the clinical
formation of a vesicle/pustule at the site of primary vaccination, and
thus assumes efficacy based on this surrogate endpoint. The protocol
states that the study is under-powered to examine differences between
the groups receiving the undiluted and diluted (1:5 dilution) vaccine.
In addition, the study is also too small to provide any meaningful
safety data.

In examining whether children should be included in a study of smallpox
vaccine, we ask the following five questions: (1) Is there a need to
test diluted vaccine? (2) Is there a need to test the five-insertion
scarification method? (3) Is there a need to evaluate a new
semi-occlusive dressing applied to the site, in order to prevent
secondary viral spread? (4) Is there a need to test children based on
the possibility of a different immune response? Can one expect a
different immunological response from children ages 2-5 years? Thus (5)
are children as research subjects required to answer the research
objectives?

[Is there a need to test diluted vaccine?]{.underline} The need to test
diluted vaccine is based on the public health concern to have an
adequate supply of vaccine in the event of a terrorist attack. Whether
the vaccine supply will remain scarce for the foreseeable future is a
question of fact that could not be answered from the information
provided. One of the consultants, Dr. Ebert, points out: "A newer
version of smallpox vaccine is in development. I believe more useful
information would be gained by delaying further testing in children
until the new product is available." It is thus difficult to assess the
need for this study absent facts concerning the reality of a terrorist
attack, and the timeline for alternative vaccine development. Even so,
unless one assumes that children would respond differently to the
smallpox vaccine (addressed below), there would be no need to test the
diluted vaccine on children.

[Is there a need to test the five-insertion scarification method (i.e.,
5 intradermal punctures with a bifurcated needle)?]{.underline} Although
there is no discussion in the protocol as to why the 5 prick (as opposed
to the 15 prick) method was being tested, one may assume that the
shorter method has been selected for ease of administration and time
efficiency. If so, there is no discussion of using intradermal jet
injection as one possible method to be evaluated in the study. To the
inexperienced observer, one would assume that this method would be even
faster.

If the speed and efficiency of the 5 prick versus the 15 prick (or other
method) is why the 5 prick method was selected, this hypothesis can be
tested without introducing the risks of smallpox vaccine. It is possible
that parents would not volunteer his or her child to be simply "stuck"
without the presence of the vaccine; however, this hesitation
illustrates the ethical problem with the parental perception of benefit
from the vaccine. Testing the 5 prick method alone would make clear the
public health benefit of the intervention without the prospect of direct
benefit to the child. Furthermore, the comparative effectiveness of the
5 prick method in producing a vesicular response with either undiluted
or diluted vaccine can be answered using adult subjects.

[Is there a need to evaluate a new semi-occlusive dressing applied to
the site, in order to prevent secondary viral spread?]{.underline} The
previous adult study (n = 740) did not show an increase in adverse viral
reactions or bacterial superinfection with the use of the semi-occlusive
dressing. One would not expect there to be a difference between adults
and children in the frequency of dressing-related adverse events, nor is
the proposed pediatric trial powered (n = 40) to detect a rise in such
adverse events. In addition, previous studies in adults demonstrated
that two layers of the semi-occlusive dressing are required to obtain
negative cultures from the top of the dressing. There is no reason to
assume that viral penetration of the semi-occlusive dressing would vary
between adults and children.

Thus the main reason to study the semi-occlusive dressing in children is
to see if the behavioral differences results in a higher rate of
autoinoculation and contact transmission. The rate of contact
transmission will not be studied directly, as the children are being
isolated in a way that will minimize such contacts when compared to

the "real world" situation. The question then would be whether children
of varying ages would be able to keep

continued

the semi-occlusive dressing in place during the 30-60 day period of
post-vaccination viral shedding. Answering this question may not require
vaccination with an active smallpox vaccine, unless one postulates that
the presence of the vesicle would cause sufficient skin irritation to
increase the likelihood that the child would remove the dressing. There
is no discussion of whether there are alternative methods for mimicking
a vesicle in order to reproduce the appropriate trial conditions without
administering active smallpox vaccine.

Is there a need to test children based on the possibility of a different
immune response? Can one expect a different immunological response from
children ages 2-5 years? Three of the six infectious disease experts
appear to disagree. Absent a panel discussion among them, it is unclear
if they would have reached consensus on this point. However, the weight
of opinion appears to favor the view that children have the same
immunological response as adults, leaving the only difference that is
then being tested as the 5 prick method (versus the 15 used on the adult
studies).

Dr. Daum asserts that children's "immune responses may be different from
those documented in adults. There are other vaccines where it is already
known that the responses in adults do not mimic those in children, for
example in the cases of diptheria toxoid and pneumococcal conjugate
vaccines." However, Dr. Halsey claims that "there is no biologically
plausible reason to expect children 2-5 years of age to respond less
well to this or any other live viral vaccine than adults if the vaccine
virus and administration methods were the same." He asserts that "above
two years of age there is no impairment of the immune response to any
other live viral vaccine as compared to adults and children often
respond better than adults." Halsey cites as evidence the fact that
"there is no impairment in the immune response to measles vaccine, oral
polio vaccine, yellow fever vaccine, mumps, or rubella vaccine in
children ages 2-5 as compared to adults." Drs. Baltimore ("nearly all
will respond to the undiluted and it is likely some or many will respond
to the 1:5 based upon the adult data") and Ebert ("A recent study showed
that old preparations of Dryvax^®^ are still quite immunogenic in young
adults. By inference, I would expect that the product would still be
effective in young children, and that his study is unnecessary.") agree
with Dr. Halsey's assessment. We do not know whether a conversation
between consultants would have resulted in agreement on this point, as
an the opportunity for such a panel discussion was never provided.

[Thus, are children as research subjects required to answer the research
objectives?]{.underline} Apart from the question of maintaining the
intactness of the semi-occlusive dressing, there does not appear to be a
reason that children are necessary to answer the other study objectives.
This assumes that the immune response of a 2-5 year old child to a live
smallpox vaccine is similar to that of an adult. Since there may be
alternative methods for assessing the ability to maintain the intactness
of the semi-occlusive barrier, it is unclear whether the administration
of smallpox vaccine to children is necessary.

**[Question Three]{.underline}: Will the research be conducted in accord
with a number of secondary "sound ethical principles", assuming that the
use of children in the research is necessary? [Absent significant
modifications]{.underline} to the research design and consent form, our
answer is [no]{.underline}.**

The research must be conducted in accord with at least the following
four ethical principles: (1) the research design must minimize risk; (2)
there must be adequate provisions for parental permission and child
assent; (3) there should be adequate provisions for the treatment of
research-related injury; and (4) the research subjects should control
the disposition and use of biological specimens collected in the
research.

[The research design must minimize risk]{.underline}. Although a number
of features have been put into place within the research protocol that
minimize risk, several consultants point to additional questions that
need to be addressed. Is there the need for a control group using
undiluted vaccine? Is the response of the children to the undiluted
vaccine predictable enough to eliminate the need for a concurrent
control group? According to Dr. Baltimore,

continued

"nearly all \[the children\] will respond to the undiluted \[vaccine\]."
Dr. Halsey asserts that "the fact that all children will respond to the
undiluted vaccine renders the control group unnecessary." In our view,
if the main research question is the effectiveness of the 5 pin prick
method, the two groups should be given the diluted vaccine with one
group receiving 5 and the other group 15 pin pricks. Does the research
require young children? In answer to Dr. Halsey's question about the
need to restrict school attendance, and thus study a population that is
not attending school, the apparent answer is the unpredictability of
children keeping the semi-occlusive dressing in place. Otherwise one
could study older children and still allow for school attendance.

[There must be adequate provisions for parental permission and child
assent]{.underline}. We agree that there should be a two tiered process
of parental permission, with a separate screening consent document. All
language that suggests any prospect of direct benefit (such as
references to "treatment"), or plays upon parental fear or desire to be
a "good parent" by enrolling a child in the research, must be removed
from the consent documents and process. The documents should contain a
more appropriate description of the smallpox vaccine-related risks,
including that they are more common than other vaccines. Finally, the
process should optimize voluntary and informed parental permission.
Among the more creative suggestions is to optimize the quality of
parental permission through preferentially recruiting children of the
adults who were enrolled in the adult trials. If an adult would not be
willing to be exposed to the risks of smallpox vaccination, that same
adult should not be exposing his or her child to those same (or greater)
risks.

[There should be adequate provisions for the treatment of
research-related injury]{.underline}. Coverage for the costs any
research-related injury must be provided, as these children are making a
sacrifice for the public good in the absence of direct personal benefit.
Any language that suggests the sponsor or institution is not responsible
for any research-related injury should be removed.

[The research subjects should control the disposition and use of
biological specimens collected in the research]{.underline}. The testing
of biological specimens should be limited to the purposes outlined in
the research (and disclosed in the consent document). Explicit and
additional consent should be required for any other testing, with
provisions for the subject removing the specimen from the specimen
repository at any point in the future.

**[Question Four]{.underline}: Is the process of consultation being used
to determine whether or not the research could be approved under 45 CFR
46.407/21 CFR 50.54 appropriate and ethical? Our answer is
[no.]{.underline}**

The federal regulations require both "consultation with a panel of
experts in pertinent disciplines (for example: science, medicine,
education, ethics, law)" and the "opportunity for public review and
comment" (45 CFR 46.407/21 CFR 50.54). For this consultation, the
documents were mailed to the individual consultants who then delivered
their reports. Although we understand that the individual consultants
were permitted to contact each other, we suspect that this process did
not allow for substantive exchange between panel members, either on
points of scientific disagreement or for clarification of ethical
arguments and/or claims. We have indicated in our analysis above where a
substantive exchange on key scientific and ethical issues would have
allowed for a more informed judgment about the research.

From the current documents, one cannot conclude that a concern raised by
one consultant would not have been a concern for one or more of the
other nine consultants. By way of analogy, the use of a focus group (of
which a convened panel is a specific instance) is often recommended for
qualitative research so that ideas raised by one panel member can be
considered and developed further by the other panel members. This same
approach informs the review of a research protocol by a convened meeting
of an institutional review board (IRB) made up of members with different
perspectives. Frequently only one member of an IRB expresses a concern
which is then supported by the majority or a consensus of the IRB
membership. It would be a serious error to conclude that a
recommendation made by only one or two panel members reflects the
opinion of only a minority of the panel.

continued

The lack of public discussion among panel members renders it impossible
to determine whether the apparent differences of opinion would have been
resolved, or to assess the relative merits of arguments for or against
the divergent opinions. The scientific question of whether children ages
2-5 years have a different immune response from adults is absolutely
essential in determining whether the research should be performed in
children. The ethical and legal consultants did not have the benefit of
hearing these different perspectives, nor did any of the panel members
benefit from hearing a discussion among those with different views of
the issue. In effect, it leaves the FDA and DHHS in the position of
picking and choosing among the individual consultant's advice in order
to support conclusions drawn by unnamed experts within either
Department, thereby undercutting the moral justification of research
conducted under 45 CFR 46.407/21 CFR 50.54.

The irony is that this consultative process may have been selected to
avoid violating the Federal Advisory Committee Act (FACA). FACA is
founded on the important principles of open government and public
participation, especially when panel deliberations will have an impact
on governmental policy. Although the public has adequate opportunity and
access to the source documents in order to comment on this research, the
manner in which the expert panel was conducted undercuts the moral
legitimacy of the overall process.

The FDA has considerable experience in the use of public advisory panels
to provide a forum for deliberation and advice on issues concerning
FDA-regulated products. Such a process should be established and used
for research falling under sections 45 CFR 46.407 and 21 CFR 50.54. As
is done now, existing advisory panels could be supplemented by
appropriate subject-specific expertise. As schedules may conflict and
prevent the participation of appropriate experts, written comments could
be solicited ahead of time for consideration by the panel, with the
ability to establish an audio-conference link with individuals whose
schedules do not permit personal attendance. It is unclear why the
existing FDA Advisory Panel structure, supplemented by individuals with
appropriate subject-specific expertise, was not used for this panel. In
fact, a meeting of the FDA Pediatric Advisory Subcommittee of the FDA
Infectious Disease Advisory Committee was already scheduled for early
November 2002 and cancelled due to lack of an agenda.

**[In summary]{.underline}**, we conclude that [the proposed research
testing existing smallpox vaccine in young children should not go
forward]{.underline} absent further public discussion of the need for
using children to achieve the study objectives, and significant
modifications of both the research design and consent documentation and
process.

Sincerely,

Robert M. Nelson, M.D. Ph.D. Paul A. Offit, M.D.

Associate Professor of Anesthesia & Pediatrics Henle Professor of
Immunologic and

The Children's Hospital of Philadelphia Infectious Diseases

University of Pennsylvania The Children's Hospital of Philadelphia

> Professor of Pediatrics
>
> University of Pennsylvania