Dr Tom Kerns
North Seattle Community College

 

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.

 

 

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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

 

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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