December 1, 2002

Dr. Leslie K. Ball

Office for Human Research Protection

The Tower Building

1101 Wootton Parkway, Suite 200

Rockville, MD 20852

Re: Docket No. 02N--0466

Dear Dr. Ball:

I am submitting these comments in reference to the announcement
published in the Federal Register, Vol. 67, No. 211, Thursday, October
31, 2002 regarding the Solicitation of Public Review and Comment on
Research Protocol: A Multicenter, Randomized Dose Response Study of the
Safety, Clinical and Immune Response of Dryvax Administered to Children
2 to 5 Years of Age.

These comments have been submitted electronically on December 1 and
again on December 2, 2002 to http://www.fda.gov/dockets/ecomments. A
copy was also emailed to you at <LBall@osophs.dhhs.gov> on December 1,
2002.

OVERVIEW

This study proposes to test the immunogenicity of undiluted and a 1:5
dilution of Dryvax in pre-school children between the ages of 2 and 5. I
believe the study is seriously flawed. There is nothing to suggest that
the immune response of children is different now than it was 30 years
ago. All children in the study would be exposed to a very small but
finite risk of death or severe permanent disability from Post-Vaccinal
Encephalitis (PVE), a vaccine side effect with no known treatment. And,
given the supply of other vaccines and the likely uses of existing
stocks of Dryvax, there is no compelling need to know if the 1:5
dilution is immunogenic. Notwithstanding the approvals of other IRBs, I
find the risks exceed the benefits. The study should not be approved by
the Department of Health and Human Services.

QUALIFICATIONS

I am a member of the Boston Medical Center Institutional Review Board, a
former Commissioner of Public Health in Massachusetts and a faculty
member at the Schools of Medicine and Public Health at Boston
University. I am very familiar with the published literature regarding
smallpox vaccine and its complications. Although I am opposed to
approval of this protocol, I am not at all opposed to selective
pre-exposure, voluntary vaccination of adults or, in a post-exposure
scenario, of children.

RELEVANT CONTEXT & MAJOR CONCERNS

I will not review the protocol or the informed consent form in detail.
Rather I will limit my remarks to those few points which I feel are of
vital importance in considering whether or not to approve this protocol.

A -- We know Dryvax is potent in adults from the recent studies
published in the New England Journal of Medicine (NEJM) April 25, 2002.

B -- We also know from the protocol that the vaccine has been tested in
children in the 60s and 70s. Further, I have seen nothing to question
the immunogenicity of Dryvax administered to children prior to 1972.

C -- We know from the 1968 data published in the NEJM in 1969 that a
very small number of children under ten will develop Post Vaccinal
Encephalitis (PVE). PVE has an overall mortality rate of 30% for which
there is NO KNOWN TREATMENT.

5 of 16 cases of PVE reported in the 1968 data were in children between
the ages of 2 and 5 with the following outcomes: possible seizure
disorder, possible psychiatric disturbance, quadriplegia, recovery and
death. (Lane JM, Ruben FL, Neff JM, Millar JD, Complications of
smallpox, national surveillance in the United States 1968. *N Engl J
Med*, 1969; 281, 1201-1208, November 27.)

D -- To the best of my knowledge there is nothing to suggest that the
immune response of children between 2 and 5 has changed since the 1960s
and 1970s.

E - The only remaining possible justification centers around learning
more about the immunogenicity of a 1:5 dilution of Dryvax in children.
We know that the responses to 1:5 and 1:10 dilutions in adults are not
significantly different from undiluted vaccine (Frey SE, Couch RB,
Tacket CO, et al. Clinical response to undiluted and diluted smallpox
vaccine. N Engl J Med 2002;346, April 25, 2002). The protocol points out
that 1:10 dilutions in tests carried out in children in the 60s and 70s
resulted in takes of between 74% and 90%. Thus, there is some
uncertainty about the effectiveness of a 1:5 dilution. Does this
uncertainty justify the proposed research? The question is only relevant
if we are likely to dilute Dryvax.

What is the current situation? The justification for testing the 1:5
dilution is based on the limited availability of vaccine and the
requirement to dilute existing stocks in the case of an attack. It
appears the nation is on a course to vaccinate many in the military and
according to press reports (not yet officially confirmed by the
Government) up to 10 million first responders with existing stocks of
Dryvax. Therefore, with planned military and possible/probable civilian
first responders use of from 6 million to up to 11 million doses of
undiluted Dryvax, no amount of dilution will be sufficient to protect
children or adults in case of an attack. If there is an attack and a
dilute vaccine is required it will have to be the 70 to 90 million doses
of the Aventis Pasteur vaccine that came to light earlier this year. Far
more likely, existing stocks of the new Acambis vaccine, still in
clinical trials but reported to be on a fast track for licensure, will
be used instead. In any case this protocol is NOT proposing to test the
old Aventis Pasteur product or the Acambis product. With every passing
day the availability of substantial stocks of Dryvax for the general
population and the need to dilute Dryvax decreases. Thus, there is no
meaningful dilution argument in support of the proposed research.

Conclusion: The protocol proposes to put 40 children, including 20
controls, at a very small but finite risk of death or permanent major
disability from a known vaccine complication (PVE) for which there is no
known treatment. As it is not plausible that the immune response of
children has changed in the past several decades, we can reasonably
expect no significant new knowledge from this research while exposing
children to the risk of death and permanent severe disability. Further,
the stated need to determine the efficacy of the 1:5 dilution in
children, if it ever existed, no longer exists. Modifications to the
consent form cannot be sufficient to justify or allow the research as
the benefits, essentially none, cannot outweigh the remote but real
risks of death and permanent severe disability. In brief, the risks
outweigh the benefits and the protocol should be DISAPPROVED.

THE CONSENT FORM

The consent form, in part, states:

"More serious reactions may also occur, but they are rare and occur most
often in small infants, people with eczema and people who take
medicines, such as steroids, or have problems with their immune system.
More serious reactions may include signs and symptoms of brain and
nervous system infection such as 1) convulsions or seizures, 2) muscle
weakness, 3) paralysis, and/or 4) stiff neck."

and later

"The risk of death from smallpox vaccination for children in this age
group was estimated to be 2 for every 1,000,000 first vaccinations.
Complications occurred less often in children who received a second
vaccine (revaccination). In rare cases, vaccinia immune globulin (a
substance which provides antibodies or substances that fight infection
against vaccinia) is needed to prevent or treat complications."

THE CONSENT FORM NEVER STATES THE CHILD IS AT RISK OF DEATH OR SERIOUS
DISABILITY FOR WHICH THERE IS NO KNOWN TREATMENT.

Other reviewers have commented on other deficiencies in the consent
form.

COMMENTS ON THE RATIONALE

Please see my comments within parentheses (**in bold face type**)

The following is from section 2.3 Rationale for the current study:

Given the limited amount of smallpox vaccine currently available, (**The
vaccine supply is no longer limited**) there is a public health need to
specify an optimal minimal dose and optimal vaccination strategy to
protect the maximum number of people in the event of a terrorist release
of the smallpox virus. The current adult trials summarized above have
focused on the immunogenicity and take rate of Dryvax vaccine in varying
dilutions. However, in a pediatric population, the safety assessment is
particularly important. (**Two groups of 20 can hardly assess or predict
safety**) Even though Dryvax was a licensed vaccine with prior
widespread use in millions of children, the Food and Drug Administration
(FDA) currently regards it as an investigational new drug (IND). (**It
is my understanding that the IND status either has been removed or is
about to be removed**) The US population is no longer immune to smallpox
(**substantially non-immune would be more accurate but this is not
relevant to the issue**) and there are other reasons (**such as?)** for
concern about the use of this stockpiled vaccine.

This is a non-sterile bovine product proposed for use at a time when
standards of vaccine safety are much more stringent than they were 30
years ago. (**Relevance to argument?**) Our population must now be
considered essentially non-immune (**to vaccinia?**) and there is (**may
be is probably more accurate**) greater potential for secondary
transmission of virus to susceptible children and adults, and to those
with immunologic deficiency states who have greater potential for
serious complications **(Relevance to argument?)**. There is little
information available concerning the risk of secondary transmission of
vaccinia in a largely nonimmune population. (**This protocol with two
groups of 20 each using the specified dressing will not be able to
address this question**) Control of possible autoinoculation and
transmission from vaccinees to contacts is more problematic for infants
or young children than adults (**correct**). The effectiveness of
placing a semi-occlusive dressing over the vaccination site, to minimize
risk of transmission has never been adequately studied (**Would it not
be far safer and easier to do this in adults who have far fewer risks of
vaccination and will we not be able to do this almost automatically as
we move to vaccinating 500,000 or many more in the next few months?**)
Finally, fewer intra-dermal punctures (3-5 punctures) have been used to
administer the vaccine to children than in adults (10-15 punctures).
(**And what does this have to do with the argument?**)

MINOR CONSIDERATIONS

The number of punctures proposed by the protocol is 5. The protocol
suggests that this is less than usual and needs to be validated.
However, the Dryvax product brochure suggests 2 to 3 punctures with the
bifurcated needle in primary vaccinees without regard to age. Thus,
depending on whether the baseline is two or three, the proposed research
more or less doubles the manufacturers suggested dose, in effect
increasing the amount of virus inoculated and reducing the effect of
dilution.

The protocol is slightly inconsistent with regard to whether or not the
semi-occlusive dressing will be used on the dilution group. For example,
section 3.5.1, page 19, has group 2 with no mention of the dressing
while the in section 3.5.3 on page 21 the box describing Stage 1
specifies using the semi-occlusive dressing.

SUMMARY

The proposal to vaccinate 40 children with dilute and full-strength
Dryvax should not be approved. Modifications of the consent form cannot
be sufficient to allow approval as, even if parents are fully informed
of the risks, the risks outweigh the benefits.

I appreciate the opportunity to comment on this protocol and compliment
your office and the Department for soliciting wide public comment.

Please feel free to contact me if you have any questions..

With best regards,

Bill Bicknell

William J. Bicknell, MD, MPH

Professor of International Health, Socio-Medical Sciences, and Community
Medicine

Department of International Health

Boston University School of Public Health

715 Albany Street, T4W

Boston, MA 02118-2526

USA

Please try this first: Cell Phone: (1) 617-283-5775 (with voice mail)

Email: \<wbicknel@bu.edu\>

Main Office Phone: (1) 617-638-5234

Fax: (1) 617-812-5834

Home Phone: (1) 781-837-4101