It's been more than three years since the University of Pennsylvania was sued for its involvement in the death of one of its gene therapy research subjects, but the lessons learned from that incident still apply: It's incumbent upon researchers to be open with their subjects about all aspects of the treatment being studied.

Even though any studies of ophthalmic agents you might perform may seem to be a far cry from the stakes involved in gene therapy, adverse events can happen in any study, so it pays to be sure that your rights and those of your research subjects are protected. In this article, we'll review the protections in place for human subjects and the steps you should take to make sure you are protected, as well.

The Gelsinger Case
In the fall of 1999, Jesse Gelsinger enrolled in a gene therapy clinical trial at the University of Pennsylvania aimed at treating ornithine transcarbamoylase (OTC) deficiency, a genetic liver disorder that affects 1 in 40,000 newborns by impeding the elimination of ammonia. Even though Jesse's OTC was effectively controlled with medication and diet, he volunteered to participate in the study with the desire to help the researchers find a cure. Four days after the initial drug infusion, he had an adverse reaction that caused liver, kidney and brain failure, killing him. The case was ultimately settled out of court.

During the trial, evidence was revealed that the university had, unfortunately, failed to disclose to the U.S. Food and Drug Administration that previous study participants had experienced toxic reactions, and that monkeys given drug injections had either died or had serious adverse reactions. This information was never included on any informed consent form. A closer look at Jesse's medical records revealed more flaws: Even though he had blood ammonia levels higher than allowed in the inclusion criteria, he was still permitted to participate.

Although the Gelsinger incident was the first well-publicized case of clinical research misconduct, others followed. Families of participants in a study of the prevention of graft-versus-host disease in bone marrow transplants filed a class-action lawsuit against the Fred Hutchinson Cancer Center in Seattle. The families alleged that the study, which was conducted from 1981 to 1993, failed to adequately warn subjects of the risks. According to the claim, 80 of the 82 subjects participating in the study died from graft failures and/or leukemic relapse attributable to the treatment. The families' complaint alleged that the Cancer Center failed to follow ethical standards, misrepresented the risks of participating in the trial and failed to disclose its financial interests.

Laws Protecting Subjects
One of the first, and more high-profile, cases against medical research came in 1949 when Karl Brandt, Adolph Hitler's personal physician, and 22 others were charged with war crimes and crimes against humanity for conducting cruel and unusual experiments on Jews and other minorities. As a result of the case, the Nuremberg Code was adopted, and remains in effect today, protecting us from crimes against humanity and the unethical treatment of research subjects. The code specifically addresses the research study requirements appearing in Table 1.

More recently, in 1974, the National Research Act was signed into law, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The National Commission's role was to evaluate the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine, the role of risk-benefit criteria in the determination of the appropriateness of research involving human subjects, appropriate guidelines for the selection of human subjects for research and the nature and definition of informed consent in the various research settings.

Table 1. The Nuremberg Code1

• The subject has free choice and is under no element of force or fraud.  • The study is for the good of society and is designed based on previous experiments on the drug or disease.  • The research avoids unnecessary physical or mental injury.  • Risks of the study should not exceed the humanitarian importance of the study.  • All precautions should be made to avoid injury or death.  • The study is conducted only by scientifically qualified persons.  • The subject has the liberty to withdraw his participation at any time.  • The scientist in charge of the experiment should stop the study if he believes it may result in injury or death.

In 1979, the National Commission published a summary of these deliberations, known as The Belmont Report.² Institutional Review Boards are responsible for determining the appropriateness of research, guidelines for subject selection and approving an appropriate informed consent process.

The determination of the difference between research and the general practice of medicine is important, not only in the protection of subjects' rights, but also in determining how you are protected by medical malpractice insurance.

The Belmont Report states that, "the term 'practice' refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventative treatment or therapy to particular individuals." The report defines research as, "an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach it."

The distinction between "practice" and "research" becomes increasingly relevant when reviewing the adequacy of your insurance coverage.

Professional Liability Insurance
Chances are that your medical malpractice insurance policy will only protect you in your research activities if you receive a statement of indemnification from the sponsor of the clinical study. At some academic institutions where research is a primary part of the physician's workday, research is clearly covered by the policy. Other policies may not cover your research regardless of indemnification.

It's likely that an insurance policy will cover your work as long as you are performing "professional services." Therefore, obtain a clear understanding of the definitions in your policy and whether or not your research requires an indemnification.

The intent of the indemnification is to provide protection from claims as long as the study has been conducted per the IRB's protocol. The indemnification is often invalid if claims arise out of malpractice, negligence or willful misconduct. Be sure to consult with your medical malpractice policy provider about its requirements prior to beginning your next clinical study.

Additional Tips
 • Properly trained personnel. As the principal investigator of the clinical study, you are ultimately responsible for all subjects involved. A study coordinator can be extremely helpful in assisting with study organization, logistics and as a technician, but never require the coordinator to run the study without your supervision.

 • Institutional Review Boards. IRBs can provide a great deal of useful information regarding the protection of subjects' rights. If your institution doesn't have its own IRB, many private IRBs exist to aid your research.

 • Benefits to the subject. Never promise your study participants any medical benefits. The purpose of the trial is to investigate the effectiveness and safety of a therapy, so you can't promise a cure. Based on the results of a study, the FDA will approve proper claims and labeling of medications.

 • Informed consent. The subject has the right to be fully informed of all risks of participating in the study. Make sure subjects are able to read and fully understand the informed consent: The integrity of your study rests on the completeness of the information you give to patients. You must try to make patients as knowledgeable as possible about the study—reveal all that is known about the drugs involved and their possible risks. If you don't disclose any information, or even give the appearance of hiding information, you lose the respect and trust of your subjects.

Based on the University of Pennsylvania case, we've seen that withholding information can hurt not only the patients but also the integrity and reputation of the medical community, the study's doctors and the clinical research system.

 • Reporting adverse events. Serious and unexpected adverse events should be reported to the IRB and the study's sponsor. Proper submission of these events allows the sponsor and IRB to determine if the risks of the study exceed the study's humanitarian importance.

Though most bacterial conjunctivitis, allergy, dry-eye or glaucoma studies may not seem like serious threats to subjects, you should always conduct studies in strict accordance with all laws, regulations and Good Clinical Practice guidelines. Review all study-related materials, including investigator brochures, protocols and informed consents, with care. Constantly communicate with the study's sponsor and your IRB about any protocol deviations or serious adverse events. If you find any data troublesome, don't hesitate to address it. Lastly, always consult with your insurance provider to ensure your policy will cover the research you plan to conduct. 

Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Mr. Shapiro is a research associate at Ophthalmic Research Associates in North Andover.

1. Office of Human Subjects Research website: http://ohsr.od.nih.gov/nuremberg.php3.
2. Office for Human Research Protections website: http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm.