Wednesday, March 16, 2011

Vaccinated vs. Unvaccinated Part 3 - Ethical Evaluation

In part 1 of this series, I went over the general description of a prospective randomized, placebo-controlled clinical trial (RCT) to study vaccinated vs. unvaccinated children. In part 2, I reviewed some of the history of medical research ethics, including three foundational documents that have helped to shape the current human research landscape: the Nuremberg Code, the Declaration of Helsinki and the Belmont Report. If you have not yet read those posts, I strongly encourage you to do so now. They should provide a decent basis for understanding part 3. The full series of posts can be found here.

Just to recap certain aspects of the design of a prospective vaccinated vs. unvaccinated RCT to determine whether or not vaccines cause or contribute to autism, we would need to follow the subjects from birth through at least 4 or 5 years of age. In order for the results to be clear and show a definite cause, several thousand children would need to be enrolled in both the group receiving vaccines and the group not receiving any vaccines (who would get a saline shot instead, to keep it blinded). Subjects in the vaccinated group would need to be matched to the placebo group as closely as possible on a range of factors, such as parental age, ethnicity, birth order/# siblings and so on - in short, any factors which may play a confounding role in the analysis and outcomes of the study.

In the remainder of this post, I will apply the ethical considerations and regulations introduced in part 2 to some of the specifics of the type of study discussed in part 1. Since I am most familiar with U.S. regulations, when discussing legalities, I will be referring in large part to 45 CFR 46, the set of regulations that govern research involving human subjects. This is probably going to be pretty long, so bear with me.

The regulations make some distinctions regarding the type of research and how much review by an ethics committee is required. So, the first question to ask is, is this study minimal risk or greater than minimal risk? As far as the law is concerned, minimal risk is defined as follows:

46.102(i) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

We need to think about what we know for certain. In our study, we do not know with any level of certainty whether vaccines contribute to an increased risk of autism. If we did, we wouldn't be doing the study, so that factor is out. Based on existing scientific literature, we know the general safety profiles of childhood vaccines with quite a bit of detail. We know who can get the vaccines safely. We know the common side effects. We even know many of the really rare side effects. We know, based on extensive study, that vaccines are very effective at preventing disease. We also know, with even more detail, the common course of the diseases that the vaccines prevent: duration from exposure to onset of symptoms, typical symptoms and the order they usually appear, period of infectivity, treatment options and the complications (and usual rate) that can occur. For many of the diseases that are prevented by vaccines, death or other serious or permanent injury is not uncommon (e.g., 1-2 per 1,000 cases of measles [PDF]).

In the United States, thanks in large part to our vaccination program and herd immunity, the normal course of daily life involves little exposure to infectious diseases and, even if exposed, the vaccines enable the body to fight off the disease before it can cause any problems. Routine care of newborns and small children involves the administration of vaccines according to the recommended, science-based schedule. As far as giving vaccines in this study, we meet the definition of minimal risk. How about not giving the vaccines?

In ordinary daily life, again, because of the vaccination program and effectiveness of vaccines, childhood diseases are uncommon. Purposefully withholding vaccines would not only directly put the infants in this study at increased risk of contracting a disease (no vaccine = no primed immune system ready to wipe out an infectious agent before it causes problems), but it also indirectly increases risk by lowering herd immunity (fewer people vaccinated = increased chance of a disease spreading). There is, therefore, increased risk as compared to ordinary daily life. That means that the unvaccinated group would be put at greater than minimal risk, according to the regulations.

So we have established that a prospective, randomized vaccinated vs. unvaccinated study involves greater than minimal risk. That does not mean, however, that we cannot do the study. It does, however, mean that other provisions must be met before it can move forward.

Before I dive into further regulations, let's think for a moment about those ethical documents from part 2. We'll start with the Nuremberg Code and Declaration of Helsinki, since the latter mainly expands on the former. What are the elements from the Nuremberg Code?

1) Voluntary informed consent - The infants cannot give consent, but the Declaration of Helsinki expanded this to allow parental consent. As long as there is no coercion or undue influence, we're fine here.
2) Benefit to society that cannot be obtained any other way - We could conceivably figure out the question as to whether vaccines increase the risk of autism through an epidemiological study, but not as firmly and confidently as in this study. This one could go either way.
3) It is based on prior animal research or history of the disease/problem - There is, to my knowledge, no quality science in animals or humans showing that vaccines play a role. There are, of course, studies of poor quality. Again, this one is shaky, though a strong argument could be made that the study would violate this point.
4) Avoid unnecessary harm or injury - Since we're deliberately exposing one group to increased risk, including the risk of death, the study would not meet this point. I'll discuss this more when we consider the Belmont Report.
5) Death or disabling injury should not be a suspect outcome of the experiment - As with #4, we do know that there is an increased risk of death or disabling injury from withholding vaccines. Again, I'll touch on this below. Alternatively, those who argue against vaccines would suspect the disabling injury of autism as an outcome of this study. So, whichever side you're on, this point is violated.
6) Risk shouldn't outweigh benefit to humanity - There is a known risk of death or serious injury to the control subjects. I would argue that such a risk is worse than knowing with reasonable certainty whether vaccines contribute to autism, but then, I think that death is worse than autism. This point would probably be violated by the study.
7) Subject should be protected against the possibility of injury, disability or death - All subjects should receive the best possible medical care to minimize the likelihood of injury. As long as such care is provided, this point is fine.
8) Conducted by scientifically qualified persons - The study must be conducted by researchers trained in the appropriate disciplines (e.g., vaccinology, immunology, neurological disorders, etc.). As long as such is the case, we're okay on this point.
9) Subject can end participation at any time - As long as parents/guardians have the option to withdraw consent and cease study participation whenever they feel like it, without coercion or undue influence to stay in, then this point is satisfied.
10) Researcher in charge can end subject participation for the well-being of the subject - As with #9, we should be okay on this point, too.

Out of 10 ethical points to consider, we're okay on five, shaky on two and violate three. Those three are, in my opinion, pretty serious ones, too, since they directly involve the health and well-being of the subjects. What about the Belmont Report?

Recall that we must treat the subjects with respect (autonomy), beneficence (do no harm) and justice (equal share of benefits and burdens). The first is not really an issue here, as long as the parents are neither coerced nor unduly influenced to enroll their child in the study nor to keep the child in the study once it has begun. As regards beneficence, we must maximize the benefits for the subjects while minimizing the harms. Based on what we know, one group receives decreased benefits along with increased harm, so we've violated that principle. Finally, we need to look at justice. No group should receive greater benefits than another, nor should one group bear a greater burden than another. We know that one group receives the known benefit of protection from infectious diseases, while the other group is denied that protection. We also know that one group has a greater burden (increased risk of disease) than the other group. Based on that knowledge, the third principle is also violated.

Thus, we have two out of three ethical concepts from the Belmont Report that are violated by this study. Even if all legal requirements are satisfied, we can see that this study would not be ethical. The only way in which one could argue that ethics are not violated, would be to argue that the hypothetical idea that vaccines cause autism is a greater risk than the known and well-established risk of death or permanent injury from disease, that autism is worse than disease-caused brain damage, worse than death.

From an ethical perspective, a prospective, randomized study of vaccinated vs. unvaccinated children would be unethical. However, we'll still take a look at the legalities of such a study, coming up.
Related Posts:
Vaccinated vs. Unvaccinated Part 1 - An RCT Overview
Vaccinated vs. Unvaccinated Part 2 - A History of Medical Research Ethics
Vaccinated vs. Unvaccinated Part 4 - The Legal Perspective
Complete Vaccinated vs. Unvaccinated Series

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