Much information on adverse events in clinical trials remains unpublished — and the number of adverse events is higher in unpublished than published versions of the same study, according to a recent review.1

“We have been studying adverse effects for many years,” says study author Yoon K. Loke, MD, professor of medicine and pharmacology at Norwich Medical School at United Kingdom’s University of East Anglia. The researchers conducted the study because they noticed it was very difficult to find information on adverse effects in scientific journals.

“We wanted to find out if we were the only people having this difficulty, or if there were other people who had uncovered similar problems of missing or hidden data,” says Loke. “The scale of the problem was surprising.” The researchers found reports of similar issues occurring in the U.S., Canada, Germany, and the U.K. The median percentage of published documents with adverse events information was 46%, compared to 95% in the corresponding unpublished documents. “This is a very serious ethical problem that I would like to see institutional review boards and ethics committees take action on,” says Loke.

Efforts campaigning for full disclosure and full transparency of research data include the international AllTrials initiative. “I fervently believe that ethics committees should bite the bullet and lend their voice to these calls,” says Loke. “After all, their role is to protect research participants.”

Individuals participate in research in good faith, usually for altruistic reasons, notes Loke. Often, participants face significant risk of harm from the research and no clear prospect of personal gain. “If you were a patient, would you give up your time to volunteer for an experimental research study, if you knew that the results would never be made publicly available?” asks Loke.

Loke argues it’s clearly unethical to have human beings volunteering to be experimented on, with results never released. “What could be worse than for someone to let their body be used for research, yet the information or findings are never made available?” he asks.

Sunita Vohra, MD, MSc, FRCPC, FCAHS, professor at University of Alberta’s Faculty of Medicine and School of Public Health, says, “Research confirms that clinical trials do an inadequate job of reporting adverse events.” This creates the false impression that the therapy being studied is safe. “The problem is compounded when systematic reviews of clinical trials fail to identify or report adverse events,” says Vohra.

Franklin G. Miller, PhD, professor of medical ethics in medicine at Weill Cornell Medical College in New York City, sees two problematic scenarios:

  • investigators fail to publish the results of a clinical trial for various reasons, such as disappointing outcomes for the drug under investigation, and
  • the results are published, but adverse events are not reported accurately.

In either case, if the drug under investigation produces adverse events and these are not published or described accurately, the same problem exists: Clinicians can’t get information on adverse events that could be important for patient care.

“There are potential problems here of harm to patients from withholding clinically valuable information — and deficiencies in informed consent if patients are not told about side effects or complications that might be important for them,” says Miller.

Patients, healthcare providers, and health policymakers require accurate knowledge of both potential benefits and potential harms for informed decision-making. “If harms are not measured or not reported, patient safety is put at risk. To knowingly suppress reporting of adverse events is not ethical,” Vohra says.

Kay Dickersin, PhD, director of the Center for Clinical Trials and Evidence Synthesis at Johns Hopkins Bloomberg School of Public Health in Baltimore, says lack of publication of adverse events is getting more attention because researchers are paying more attention to patients’ views.

“Ten years ago, there was emphasis on the patient view. But committees were made up of doctors who said what the patient view was,” says Dickersin.

Now, patients are consulted directly by investigators. In some cases, they’re even part of the research team. As a result, the lens of investigators’ focus has shifted somewhat.

“What we’ve found is that patients really want to know not just whether there is a beneficial effect, but about adverse events,” says Dickersin.

In particular, patients want enough specific information to allow them to make a decision as to whether the benefits versus risks are worth the trade-off to them in particular. The fact that a painkiller is known to cause dizziness might be of great importance to a 90-year-old patient with a fall history, for instance. “Information about adverse events can be lost in several ways,” says Dickersin.

There may be no formal way of collecting data on adverse events. To address this, researchers can ask participants specific questions such as, “Have you experienced dizziness?” instead of open-ended questions such as, “Have you experienced anything you’d consider an adverse event since we last talked?”

“It may not be reported by the patient if the patient doesn’t know it’s important,” says Dickersin. If the percentage of people experiencing an adverse event doesn’t meet a specified threshold, such as 5%, it may never become known to the public.

“That’s not necessarily the way we should be doing things. We had space constraints with paper journals, so I can see how that evolved,” says Dickerson. “But now with online supplements, we may not need to use thresholds.”

Information on adverse events can be lost if a clinical trial goes unpublished. Dickersin co-authored a paper arguing that “invisible” and abandoned trials should be restored, with findings including adverse events made publicly available.2

Patients typically get information on adverse events from labels. However, these lack enough specificity for a truly informed decision. “The label needs to be made better,” Dickersin says. Patients might want to know more about a particular adverse event, such as whether dizziness reported by participants was severe or mild.

“Ethically, I think we should be paying attention to adverse events because it matters to patients,” says Dickersin. “It’s part of the whole picture of the intervention.”

REFERENCES

  1. Golder S, Loke YK, Wright K, et al. Reporting of adverse events in published and unpublished studies of health care interventions: A systematic review. PLoS Med 2016; 13(9):e1002127.
  2. Doshi P, Dickersin K, Healy D, et al. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013; 346:f2865.

SOURCES

  • Kay Dickersin, PhD, Director, Center for Clinical Trials and Evidence Synthesis, Johns Hopkins Bloomberg School of Public Health, Baltimore. Phone: (410) 502-4421. Email: kdicker3@jhu.edu.
  • Yoon K. Loke, MD, Professor of Medicine and Pharmacology, Norwich Medical School, University of East Anglia, United Kingdom. Email: Y.Loke@uea.ac.uk.
  • Franklin G. Miller, PhD, Professor of Medical Ethics in Medicine, Weill Cornell Medical College, New York City. Phone: (301) 656-8757. Email: FMiller@cc.nih.gov.
  • Sunita Vohra, MD, MSc, FRCPC, FCAHS, Professor, Faculty of Medicine and School of Public Health, University of Alberta, Canada. Phone: (780) 492-6445. Fax: (780) 492-5883. Email: svohra@ualberta.ca.