Jenner
On Trial
Tom
Kerns
Chapter 4
Ethics Review Committee Application
Form
Date of application:
April in the year of Our Lord 1796.
I. Principal Investigator:
Mr Edward Jenner, MD, FRS, &c,
physician and surgeon in private practice.
II. Title of activity:
An experiment to test the prevention of the Small-pox by inoculation
with the Cow-pox.
III. Time period for involvement
of human subjects:
Beginning May 14, 1796 and for approximately six months following.
One subject, James Phipps (age 8), may be monitored and challenged
with Small-pox for a number of years following, perhaps as many
as 20 to 25 years, in order to test for continuing safety and
efficacy
IV. Funding information:
My own private funds.
Type of proposal:
Independent private medical research.
New application or renewal:
New.
V. Signatures:
Investigator:
Date
VI. Summary of activity:
A. Background and purpose of research:
Purpose:
To test whether inoculation with the Cow-pox is a safe and effective
prophylactic measure for protection against the Small-pox.
Importance:
The Small-pox has already killed approximately 25% of the British
population in the present century (18th) alone. Almost every British
subject is exposed to it at some time in his or her life, and
those who are not killed by it are often blinded, deafened, or
grotesquely scarred by it for the remainder of their lives. It
is a scourge of humanity more devastating than the Black Death.
Background:
i. It is common knowledge through all England that inoculation
with a mild case of the Small-pox will, if one survives it, immunize
a person against subsequent infection with the Small-pox. The
question is whether inoculation with the Cow-pox will do the same.
ii. Substantial anecdotal evidence and local folk wisdom has it
that anyone who has caught the Cow-pox will never take the Small-pox.
I have numerous oral testimonies of this directly from dairymen
and their families here in Gloucestershire.
iii. I have, furthermore, attempted direct challenge with the
Small-pox inoculation of several adult persons who had reputedly
already had naturally occurring Cow-pox disease, and who also
reported that they had never had the Small-pox. This attempt to
infect with the Small-pox had no effect whatsoever on these persons,
thus demonstrating that naturally occurring Cow-pox infection
does protect persons against infection with the Small-pox.
iv. My immunization experiment with my (then) ten-month old son
Edward, Jr in 1789 was successful. I inoculated him with the Swine-pox
pus during a Swine-pox epidemic. After waiting for some weeks
I then challenged him with inoculation of purulent matter from
a Small-pox pustule. He showed no reaction whatsoever. I tried
to infect him four more times, all with no unfavorable reaction.
Two years after that I inoculated him with the Small-pox again.
Unfortunately, this time he became very sick following that inoculation,
but that was only because the Small-pox matter was apparently
contaminated with another disease-causing agent. Young Edward
did satisfactorily heal from this condition, however. One year
following this episode I inoculated him again with the Small-pox,
and again there was no untoward reaction. The Swine-pox did appear
to protect him against subsequent infection with the Small-pox.
v. There may be some question about the ethical justification
of challenging my subjects with virulent Small-pox (which is an
often lethal disease). I do own that if there were no evidence
to the contrary, the practice of deliberately challenging a subject
with a lethal disease would be seriously ethically suspect. However,
I wish to offer two pieces of evidence which clearly argue that
the practice of challenging subjects with virulent Small-pox pus
is within the bounds of reasonable safety:
a) The Newgate gaol experiment in 1721, in which six prisoners
were inoculated with Small-pox in the presence of numerous observers,
is sound evidence of the safety of the practice. None of those
subjects died from the experiment. This argues that the practice
of inoculation with the Small-pox is at least reasonably safe.
b) Furthermore, the experience of variolation in all England in
the intervening seven decades has been an experience of relatively
low lethality (1 - 4%) from the practice of the Small-pox inoculation.
This is further evidence of the safety of the practice (relative
to the risk of naturally occurring Small-pox infection, which
has a lethality of approximately 25 - 40%).
If the Small-pox inoculation had a relatively low lethality with
immunoinnocent subjects (to introduce a 20th century term), there
should be even less risk of lethality in my subjects who will
instead be inoculated with a much milder disease (viz., the Cow-pox),
and who will almost certainly be protected from infection with
the Small-pox by this inoculation with the Cow-pox.
Therefore, the risks involved in challenging my subjects with
the Small-pox are no greater than, and are almost certainly less
than, the risks in the practice of variolation.
B. Research procedures involved:
1. Description of the study design,
sequence and timing:
I have explained my proposal to young James Phipps (age 8) and
to his parents and they have all, considering the alternatives,
given permission for me to proceed. On May 14th, 1796 I intend
to scarify young James' arm with a lancet that has just gathered
some purulent matter from the sores of a person infected with
the Cow-pox. He will probably develop a mild case of the disease
(with attendant axillary discomfort, headache, nausea, loss of
appetite for two or three days, perhaps even a few small pustules)
and will then heal. Severe morbidity or mortality from infection
with the Cow-pox is virtually unheard of.
On or about July first, I will in the same manner attempt to infect
Master Phipps with purulent matter directly from the pustules
of a person sick with the Small-pox. We will then wait to see
if Master Phipps develops the Small-pox or any of its symptoms.
If he does take sick, I will then cease this round of experiments.
If he does not take sick, i.e., if the Cow-pox inoculation does
evidently protect him from infection with the Small-pox, then
some few months later I will again attempt to infect him with
the Small-pox. If that attempt continues to evidence protection,
I will consider the experiment a success and will attempt the
identical procedures on another eight or nine subjects in succession.
If these experiments are also successful, I will continue to attempt
infection of Master Phipps with the Small-pox approximately once
per year for the next several years.
Results of my studies will be written up and presented publicly
to the Royal Society.
2. How study procedures differ from
standard care or procedures:
The present standard of care for
prevention of the Small-pox is simply to minimize contact between
healthy persons and those sick with the Small-pox.
In addition to this precaution, some persons also attempt immunization
against the Small-pox by the practice of variolation. This procedure
entails inoculating children or adults with purulent matter directly
from a Small-pox pustule on the skin of an actively sick person,
in the hopes that the child will then develop a mild case of the
Small-pox, will heal from it with only minor scarring, and will
then be immune from future Small-pox infection for the rest of
their lives. Unfortunately some variolated persons do become very
sick in the process, some do die, some are blinded or made deaf,
and some are severely scarred. All variolated persons, during
the course of even a mild infection, of course, are fully contagious
to all other persons in their vicinity.
My own experience of variolation, including the period of preparation,
at the age of eight years has been described as follows:
"He [Edward Jenner] was bled
until pale, then purged and fasted repeatedly, until he wasted
to a skeleton. He was denied solid food in favor of a vegetable
drink that was supposed to sweeten the blood; after the inoculation
itself - the least traumatic event of the entire experience -
he was removed to an "inoculation stable," and, according
to an early biographer, "haltered up with others in a terrible
state of disease, although none died." His recovery, amidst
the moaning and crying of other inoculated children, took another
three weeks, and he was sickly for some time thereafter."
Variolation as a standard of preventive
care is highly unpleasant. There is also a 1 - 4% possibility
that the patient who suffers the procedure will not even live
to enjoy the benefits of it. Moreover, the threat of contagion
to others in the household is high. The practice of variolation
has probably in fact even contributed to the spread of the Small-pox
epidemics, and furthermore has probably made the disease even
more virulent now than it was originally.
C. Deception:
There will be no deception of any
sort in this experiment as that would be most ungentlemanly.
D. Subjects:
1. Number, ages and representation
of subjects:
There will at first be one subject,
Mr James Phipps, age 8. If that experiment is successful, there
will then be approximately eight more subjects, almost all of
whom will be minors ranging from five to eight years of age. In
addition, my own eleven month old son will be tested, and one
adult, Mr Barge, has consented to participate. All except one
child are males, and all are British subjects.
My reasons for using primarily children as subjects are the following:
i) Children are the ones most at risk of contracting the Small-pox.
Most British children have had a bout of the Small-pox before
they are seven years old. Our children, consequently are the ones
most threatened by the disease, and hence are the ones most in
need of a preventive measure. If the preventive measure is to
be used on them, it must first be tested on them. ii) Furthermore,
it is more difficult to find adults who have not yet already had
a case of the Small-pox. Most adults have already had the disease,
and therefore are already immune to future Small-pox infection.
My preventive procedure would have no effect on them at all. iii)
Finally, as everyone is no doubt aware, there is precious little
time to waste, given that there is presently an epidemic of the
Small-pox occurring in London, just one day's journey hence, and
if there is anyone we wish to protect from its scourges, it is
our children.
2. Criteria for selection:
Subjects should live nearby in Gloucestershire.
They should be in general good health.
They must never have had the Small-pox or the Cow-pox.
They and their parents must be willing to try the experiment.
3. Criteria for exclusion:
If they have had a bout with the Small-pox or the Cow-pox.
4. Source of subjects:
Families in the county.
5. Approaching subjects (avoiding
coercion and protecting privacy):
I will approach the subjects and
their families individually in the normal course of my medical
affairs. I will put no undue pressure on anyone. All will be free
to participate or not.
6. Payments or free services to
subjects:
I will look after my subjects during
the course of the experiments, and will provide them medical care
without charge during the course of the experiment.
I will continue to look after my subjects without charge for so
long as they may need me, in gratitude for their offering to participate
in my experiments.
7. Location of study:
The inoculation procedures will
be carried out either in the family homes of the subjects or in
my medical offices.
E. Risks and Benefits:
1. Nature and amount of risk:
The general uncertainty of the experiment.
The discomfort of a Cow-pox infection (axillary discomfort, headache,
nausea, loss of appetite for two or three days, perhaps even a
few small pustules). Fatalities from Cow-pox infection are virtually
unknown.
The unlikely possibility of subsequent sickliness and possible
mild mental retardation as experienced by my son Edward after
being inoculated with the Swine-pox and challenged with the Small-pox.
Some of my less informed antagonists have expressed concern that
inoculation with the Cow-pox would lead to "new and foul
diseases," that children inoculated with the Cow-pox would
grow horns, would develop "bestial, cattle-like characteristics,"
and that "human character would undergo transformation." There has,
of course, been not one shred of evidence to support
these preposterous claims.
Possible infection with the Small-pox (if the prevention treatment
is not effective). If this occurs, then all the dangers attendant
upon contracting Small-pox become immediate risks, including blindness,
mild to severe scarring, pneumonia, heart failure, brain damage,
insanity, paralysis, deafness and neuritis. There is also approximately
a 1-4% possibility of mortality from challenge with the Small-pox
infection.
Probable contagion of the Small-pox (if the prevention treatment
is not effective) to other third parties in the vicinity.
Other possible unanticipated side effects than those mentioned
above.
In any case, all these risks together should add up to much less
risk than the risk entailed in undergoing normal variolation.
2. Expected benefits for individual
and/or society:
For individual subjects: Lifelong
immunity from infection with the Small-pox, with fewer risks than
with the process of variolation, and with much smaller risk of
the Small-pox contagion to others. My Cow-pox inoculation process
will also be much simpler and much less expensive, since it will
require no period of isolation (as is required for variolation)
of the inoculees away from other persons susceptible to the Small-pox
infection.
For society: Large scale lifelong immunity from infection with
the Small-pox, with a consequently greatly reduced risk of the
Small-pox contagion to the community.
Complete eradication of the Small-pox from the entire earth is
even conceptually possible.
F. Adverse effects:
1. How will adverse effects be handled?
I will care for my subjects in my
own quarters in the event that any sickness or harm may come to
them. This will present no danger to my own person as I am myself
already immune to the Small-pox, and would therefore not be at
any risk.
2. Are facilities adequate to handle
adverse effects?
Yes, my facilities are as able as
any in the area to handle potential adverse effects.
3. Financial responsibility for
adverse effects:
I will personally be financially
responsible for any adverse effects of my experiments. If a subject
who is a family breadwinner dies and leaves the family without
any means of financial support, I will personally take financial
responsibility for the care of the family.
G. Confidentiality:
Will data be anonymous? No.
Will identifiable data be coded and kept separate? No.
Will other agencies have access to data? Yes.
I will compile the results of my
study, complete with names of the subjects, and will deliver it
to the Royal Society when the experiment is completed.
How will data be protected?
It will be kept safe in my offices,
by God's good Providence.
H. Additional information:
I will employ an artist to make
drawings of the physical effects of the inoculations, if there
are any effects.
The only instrument to be used will be a small lancet for collecting
purulent material from the sores, and for effecting scarification
of the skin in order to introduce the purulent matter.
I will personally test the cleanliness and sharpness of the lancet
myself.
I. Consent forms:
See attached consent form.
Oral consent will be obtained, as most of my subjects will not
be literate and will probably not be well schooled in the art
of writing.
J. Drugs, substances and devices:
1. List drugs or substances:
Cow-pox pus, collected from pustules
on the hand or wrist of an infected milkmaid. The infectious doses
will be moderate. They will be administered by scarification of
the skin on the arm with a lancet.
Small-pox pus, collected from pustules
on the skin of a person sick with fulminant Small-pox. The infectious
doses will be of average amount, or perhaps a bit larger than
normal, in order to insure that efficacy has been established.
They will be administered by scarification of the skin on the
arm with a lancet.
2. Toxicity data:
The Cow-pox causes moderate (almost
never severe) morbidity. Mortality from Cow-pox infection is virtually
unheard of.
Small-pox morbidity ranges from moderate to severe, with a 1 -
4% chance of mortality from the variola inoculation.
No animal studies have been done. The Small-pox is not a disease
of animals.
No study such as this has ever been performed on human beings
before now, though a similar study using a Swine-pox inoculation
was performed seven years ago on my (then) ten-month old son,
Edward Jenner, Jr. That experiment was successful, as described
above, and did protect him from infection with the Small-pox.
This completed application form
would probably also have required that a proposed informed consent
form be developed by the applicant. Jenner's consent form would
probably have looked something like the following:
Consent Form
Title of Experiment
An experiment to test the prevention
of the Small-pox by inoculation with the Cow-pox
Conducted by Mr Edward Jenner, MD,
FRS, &c
Purpose and Benefits
This is a research activity to determine
whether inoculation with the Cow-pox will be a safe and effective
prophylactic measure for the prevention of future infection with
the Small-pox. If the procedure is successful, then all subjects
will be forever immune from taking the Small-pox.
Procedures
Subjects will receive a small scratch
on the arm with a lancet that has just gathered a measure of pus
from the sores of a person infected with the Cow-pox. Inoculated
subjects will probably develop a mild case of the Cow-pox (moderate
discomfort in the armpit, headache, nausea, loss of appetite for
two or three days, perhaps a few small sores) but will then heal.
Within six or eight weeks of that first inoculation, I will attempt
to infect subjects with the Small-pox. That is, subjects will
be inoculated in the same manner described above, but with pus
taken directly from the pustules of a person sick with the Small-pox
(just as is done in the practice of variolation). We will then
wait to see if subjects develop the Small-pox or any of its symptoms.
If any of them do develop the Small-pox, then this round of experiments
will cease.
If subjects do not develop any symptoms of the Small-pox and do
not have any other adverse reactions, i.e., if the Cow-pox inoculation
does evidently protect the subject from infection with the Small-pox,
then a few months later I will again attempt to infect the subjects
with the Small-pox. If that attempt continues to evidence protection,
then the experiment will be considered a success.
If the experiment is successful, then I will continue to attempt
infection of one or two subjects with the Small-pox approximately
once per year for the next several years.
Risks, Stress or Discomfort
Potential risks and discomforts
to subjects include the following:
The discomfort of a Cow-pox infection (moderate discomfort in
the armpit, headache, nausea, loss of appetite for two or three
days, perhaps a few small sores). Death from the Cow-pox infection
is exceedingly rare, and is therefore an extremely unlikely possibility.
The unlikely possibility of subsequent sickliness and possible
mild mental retardation as experienced by my son Edward after
being inoculated with the Swine-pox and challenged with the Small-pox.
Possible infection with the actual Small-pox if the Cow-pox inoculation
does not prevent the Small-pox, and possible consequent blindness,
deafness, or scarring (mild to severe). There would then also
be a 1% to 4% chance of death from the Small-pox inoculation.
Probable contagion of the Small-pox infection (if the Cow-pox
inoculation is not effective in preventing the Small-pox) to other
third parties in the household or vicinity.
There may also be some unanticipated side effects other than those
mentioned above, since this procedure has not been performed on
any human beings before now.
Other information
The standard of preventive care:
The present standard of care for prevention of the Small-pox is
simply to prohibit contact between healthy persons and those sick
with the Small-pox.
In addition to that measure, some persons also attempt to effect
immunization by the practice of variolation. Variolation is a
procedure which entails inoculating children or adults with pus
taken from a Small-pox sore, in hopes that the inoculee will then
develop a mild case of the Small-pox, will heal from it with only
minor scarring, and will then be immune from any future Small-pox
infection for the rest of their lives. Unfortunately some variolated
persons do die in the process, some are severely scarred, and
all, during the course of even a mild sickness, are fully contagious
to all other persons around them.
Following is a brief account of one person's experience of variolation.
He was bled until pale, then
purged and fasted repeatedly, until he wasted to a skeleton. He was
denied solid food in favor of a vegetable drink that was supposed
to sweeten the blood; after the inoculation itself - the least
traumatic event of the entire experience - he was removed to
an "inoculation stable," and, according to an early
biographer, "haltered up with others in a terrible state
of disease, although none died." His recovery, amidst the
moaning and crying of other inoculated children, took another
three weeks, and he was sickly for some time thereafter.
Variolation as a standard of preventive
care is not pleasant and has no guarantee that the patient will
even live to enjoy the benefits. Moreover, the threat of contagion
to others in the household is high. The practice of variolation
has probably even contributed to the spread, and increased virulence,
of the Small-pox.
Privacy:
Subjects who participate in this experiment will proudly have
their names included in my report to the Royal Society.
Quitting:
Subjects are free to decide to quit their participation in this
study at any time they wish with no penalty or loss of any benefits
to which they would otherwise be entitled.
Free care:
Subjects will receive free medical care from me during the course
of their participation in the experiments, whether the experiment
is successful or not, and will continue to receive free medical
care from me, in so far as I am able to give it, for the rest
of my natural life (as long as they continue to live in the region
of Gloucestershire). I will personally bear all costs of any such
medical treatments.
Compensation:
If a subject who has been the financial support of his family
dies, I will personally make every attempt to support his family
from my own financial resources.
Signature of the investigator
Date
Subject's statement:
The study described above has been
explained to me. I voluntarily consent to participate (or have
my child participate) in this experiment. I have had an opportunity
to ask questions. I understand that future questions I may have
about my rights as a subject will be answered by the investigator
listed above.
Signature of the subject Date
[Include when subject is a minor
or incompetent to provide informed consent.]
Signature of parent or legal guardian
Date
Signature of subject's advocate
Date
[Include when subject is legally
competent, but subject is vulnerable. Subjects may waive the right
to an advocate by initialing in this space.]
Relationship of advocate to subject (spouse, relative, friend,
or someone who knows subject well)
Signature of subject's legally authorized representative
Date
[Include when subject is not legally
competent to provide consent and Committee as authorized use of
a legally authorized representative.]
Relationship of representative to subject
Date
Now consider:
If Dr Jenner had submitted these materials to the Ethics Review
Committee on which you sat as a member, what would be your response
to the proposal? What questions would you have for him? Would
you vote to approve his protocol as proposed? Would you suggest
modifications to his protocol so that you could, if he was willing
to make such changes, then approve it? Or would you reject his
proposal outright as clearly unethical?
If you would reject his proposal as unethical, what do you think
should be done with research data garnered from medical experiments
that were done in an unethical manner? Should data from such experiments
be available for use, even though the methods of collecting the
data have been judged to be unethical? Or should the data be discarded,
or in some other way be rendered unavailable for general use?
Jenner
homepage and Table of Contents
preface | Introduction | chp
1 | chp
2 | chp
3 | chp
4
cchp 5 | chp
6 | chp
7 | chp 8 |
App I | App
II
Ethical
Issues in HIV Vaccine Trials