Determining whether a particular occurrence during a clinical trial constitutes an adverse event can lead to honest differences of opinion. There are those who feel that too many unexpected, yet very ordinary, occurrences are reported as adverse events, adding to the paperwork burden and driving up the cost of studies. Others contend that any unexpected or unintended occurrence should be classified as an adverse event and quickly reported. Who’s right?
The reporting of adverse events during clinical trials was not always required. In 1932, a study of syphilis was begun in Tuskegee, Alabama. The study participants were not fully informed about the study, instead being told that they were being treated for “bad blood.” For the “benefit” of science, many with syphilis were not treated during their participation. The study originally was planned for completion within six months. It continued for 40 years.
In 1972, a government advisory panel reviewed the Tuskegee Study, deemed it ethically flawed, and ordered it stopped. A class-action lawsuit, filed on behalf of the study participants the following year, prompted Congress to pass the National Research Act in 1974 to regulate clinical research.1 This Act established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. It also led to the creation of institutional review boards charged with overseeing study protocols, ensuring that study investigators understand research regulations, and monitoring adverse events. These boards became, and remain, active in both the human and veterinary arenas.
Today, Good Clinical Practice guidelines (GCPs) set the standards for adverse event reporting in both human and veterinary clinical trials. GCPs define a veterinary adverse event as “any observation in animals that is unfavorable and unintended and occurs after the use of a(n)…investigational veterinary product, whether or not considered to be product related (emphasis added).”2 Pretty clear, no? Quiz time.
A Texas cat, subject #PRO- 035, is napping on the back yard deck. It’s August, and it hasn’t rained for more than a month. Awakened by a sound, the cat is bitten by a snake. Adverse event? When it’s very dry, snakes come out of their normal abodes to look for water. Was the snake threatened by the startled cat? Or was the snake attracted by the cat’s strange odor caused by the test article?
How about a dog, subject #MAS-011, that gets loose, runs into the street, and collides with a passing car. This is a dog that never ventures far from the living room couch, let alone runs into the street. Had the test article excited the dog, affected its cognitive ability, or limited its peripheral vision?
What about the owner who notes in her study diary that her cat is “just not right today, and she usually is always all right.” Does it surprise you that the investigator did not report this as an adverse event? Would you have reported it?
In a New England Journal of Medicine article (March 2010), Dr. Ethan Basch cited evidence that “clinicians systematically downgrade the severity of patients’ symptoms, that patients’ self-reports frequently capture side effects that clinicians miss, and that clinicians’ failure to note these symptoms results in the occurrence of preventable adverse events.”3
According to Dr. Basch, “direct reports from patients are rarely used during drug approval or in clinical trials.”3 All of us would like to believe that every unfavorable and unintended side effect observed after a test article is administered is properly documented, including the relative timing, perceived causal relationship, and severity of the event.
Because owner observations often form the basis of an adverse event report, it is essential that investigators instruct each owner on how to observe their pet, what constitutes an unfavorable or unintended event, and how and when to communicate them to the study investigator.
1http://ohsr.od.nih.gov/guidelines/belmont.html, National Institutes of Health, Office of Human Subjects Research.
2CVM Guidelines and Guidance Documents, No. 85 (VICH GL9), Good Clinical Practice; U. S. Department of Health and Human Services, Food and Drug Administration, Center for Veterinary Medicine; May 9, 2001.
3Basch E. The Missing Voice of Patients in Drug-Safety Reporting. New England Journal of Medicine, 362; 10:865-869, March 11, 2010.