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Clinical Trials and Investigative Procedures

Advisory Opinion of the Code of Ethics

Issues Raised:

(1) How is it determined what constitutes a "clinical trial" or an "investigative procedure?"

(2) What are "adequate review mechanisms" for such procedures?

(3) What constitutes "appropriate informed consent" for such procedures?

Applicable Rules:

Rule 2. Informed Consent
Rule 3. Clinical Trials and Investigative Procedures
Rule 14. Interrelationships between Ophthalmologists

Background

The purpose of Rule 3 of the Code of Ethics is to protect patients from being subjected to inappropriate or ill‑considered trials or investigational procedures. This rule advances Principle 2 of the Code of Ethics, that "Ophthalmological services must be provided with ... respect for human dignity...," and Principle 7, that an ophthalmologist must "act in the best interest of the patient." Rule 3 defines trials or investigational procedures as those that are undertaken in circumstances where "insufficient information exists," and therefore procedures "are conducted to develop adequate information on which to base prognostic or therapeutic decisions or to determine etiology or pathogenesis...."

Ophthalmologists Dr. S and Dr. J wish to know the applicability of the Code of Ethics to their conduct.

It seems clear from the facts presented that both Dr. S and Dr. J are contemplating activities that constitute "clinical trials or investigative procedures." Such activities are proper only when the potential risks to the patient are reasonable in relation to the potential benefits to the patient and the importance of the knowledge that reasonably may be gained.

First Inquiry
Facts - Dr. S, an ophthalmologist and Fellow of the Academy, proposes to perform non-emergency retinal surgery on a few patients using an innovative technique. The procedure would be different from any that Dr. S has employed previously, and based on his general awareness of the literature, Dr. S does not know of any clinical research by others on the proposed surgical technique or on similar techniques. Dr. S desires to perform the innovative procedure because he believes it might prove to be as effective as or better than, conventional techniques for the type of patients he plans to select, and he hopes to publish his results. He intends to perform the surgery on a few adult inpatients in a hospital at which he has privileges and also on some patients at a freestanding ambulatory surgery center.

Resolution - Dr. S reasonably believes the new technique may prove to be better for his patient as well as other patients. Dr. S's desire to publish the results of his research does not vitiate this patient‑oriented motivation, but it must not be the primary motivation for undertaking innovative treatments.

A physician undertaking clinical trials or investigation involving human subjects also has an obligation to consider the research literature concerning the proposed procedures. In this case, Dr. S does not know of any reported research, but he should also ask colleagues or check the literature. His proposal is clearly a trial or investigative.

Rule 3 may not apply to minor refinements or alterations of prevailing surgical techniques, especially where they pose little or no added risk of harm to the patient. However, Dr. S is contemplating use of substantially novel procedures, with potentially significant consequences for his patient. Accordingly, these procedures are clearly a trial or investigative and must therefore be subject to "adequate review mechanisms."

Dr. S intends to conduct some procedures in a hospital. In an individual case, if the new procedure is considered a modification of an earlier operation or a pilot procedure, it is usually not necessary to obtain prior approval from the hospital's Institutional Review Board (IRB). Further, in an individual case, if a drug is used for an indication or in a manner other than that for which it was approved, and is being used in a compassionate sense, then it is also usually not necessary to have prior approval from the IRB. However, if the procedure or the drug is used in several cases or an attempt is made to determine the merits of the drug or procedure by conducting a research project, it is necessary to obtain approval from the IRB before proceeding. Some hospitals also have surgical review committees, and submission to such a committee may be necessary. "Adequate review mechanisms" should ensure that the research is competently designed and has some reasonable prospect of producing helpful results. Such mechanisms should also ensure that there is informed consent, that the rights of the research subjects are respected, and that research subjects are treated with the same concern and devotion as other patients.

Dr. S also proposes to perform certain of these procedures in a freestanding ambulatory surgery center. Before undertaking such surgery, his proposed research protocol should be reviewed by an appropriate professional review body, either a hospital IRB, or some colleagues with whom such consultation is appropriately documented. Such a review mechanism should include professional surgical review and human subject (ethical) review. If Dr. S cannot arrange for such review, or if his protocol is not approved by such reviewing bodies, he should not proceed with such surgery. Repeated application to successive IRBs or similar bodies should be avoided, unless the physician has a good faith basis for believing that a different decision will be made and is justified. If a professional review body has approved a course of research on certain types of patients as described above, new review ordinarily does not need to be sought for the same procedures on subsequent patients of the same type.

After performing several procedures, Dr. S concludes that his innovation works. At this point, he has an obligation to share his findings with his colleagues (see Rule 14).

Second Inquiry
Facts - Dr. J is an ophthalmologist and a Fellow of the Academy. She has a patient with severe glaucoma who has not responded to conventional treatments either with drugs or with prior surgery. Dr. J has reason to believe that the patient may respond favorably to a particular drug because she has observed some lessening of intraocular pressure in her patients who happen to be on the medication. However, the labeling and instructions for use of the drug do not include glaucoma, and the drug has possible moderate, but not insignificant, side effects. Dr. J has asked colleagues, and neither she nor they are aware of any research on use of the drug for glaucoma. In addition, an on-line computer search reveals no information about the use of the drug for glaucoma. Dr. J proposes to administer the drug to the patient initially in her office, then prescribe it, and periodically review the patient's condition.

Resolution - Dr. J's case is also clearly a trial or investigative, since she too lacks adequate information concerning the safety and therapeutic value of the proposed pharmacological agent.

Like Dr. S, Dr. J is contemplating use of substantially novel procedures, with potentially significant consequences for her patients. These procedures are also clearly a trial or investigative and must therefore be subject to “adequate review mechanisms.”

Dr. J's case presents special problems, since her patient requires prompt treatment. Formal application to and review by an IRB is probably not feasible. Trials or investigative therapies should be applied in such emergency cases only rarely, where the case has proven refractory to conventional treatments. However, in such a case, it may be appropriate to proceed with the therapy, but only after undertaking that degree of independent review by knowledgeable colleague(s) that is feasible under the circumstances (and that is later appropriately documented). For example, Dr. J should at least seek a telephone consultation with a knowledgeable colleague or conduct an on-line computer search concerning the possible benefits and risks of the therapy. It is also significant that Dr. J has a reasoned clinical basis for trying the new drug, and that she plans to monitor the patient's response carefully. The provision of Rule 3 requiring "adequate review mechanisms" is intended to advance, and not obstruct, patient care. It is intended to be flexible and not to mandate one type of review in all circumstances. Accordingly, varying levels of review may be appropriate in light of the seriousness, irreversibility, alternatives, side effects, risks, and other features of the proposed trial or investigative therapy.

Rule 2 of the Code of Ethics establishes a general requirement that "the performance of medical or surgical procedures shall be preceded by appropriate informed consent." In addition, Rule 3 states that where clinical trials or investigative procedures are contemplated, "Appropriate informed consent for these procedures must recognize their special nature and ramifications." Informed consent to clinical trials is a complex medical and legal concept, which has at least several basic elements.

First, the physician must inform the patient concerning the proposed treatment, its likely effects on the patient, and the purposes of the research. Legal decisions in the states are split as to how much information must be disclosed, some requiring such information as most physicians in like circumstances would disclose, and others requiring all information that the patient would be likely to regard as significant in deciding whether or not to participate in the research and undergo the treatment. In addition, federal regulations may also govern informed consent to clinical trials and investigative procedures in certain contexts. Ophthalmologists should provide at least that degree of information required by applicable federal and state law (and they may wish to consult with their legal counsel to ensure that they do so). Except in exceptional cases where the therapeutic privilege might apply, this will include data on the investigational character, purposes, effects, side effects, alternatives, and appreciable risks of the proposed therapy, and the method, purpose, conditions of participation, and likely results of the research.

Second, the patient's consent must be based on comprehension; that is, the patient must have understood the basic information and have engaged in a rational decision‑making process concerning participation in the research. Third, the patient must clearly indicate his/her voluntary consent to the treatment proposed. Enthusiastic description of the project, patient reimbursement, and suggestions of major advantages to the patient are examples of incentives that encourage the patient to participate in a research project and that may unfairly influence the informed consent. The patient's consent should be reasonably free of undue or overbearing influences, such as the fear of loss of medical care or benefits if he/she declines to participate in the research.

Substituted consent to treatment on behalf of a patient may be accepted by an ophthalmologist in conformity with law and good medical practice. This may be permissible, for example, where the patient is unconscious or lacks the capacity to make an informed decision concerning treatment. Ordinarily, in nonemergencies, the informed consent of the patient (or a surrogate) to trials or investigative procedures should be recorded in advance and in writing.

Based on the facts presented, both Dr. S and Dr. J should obtain appropriate informed consent of their patients. The procedure may be streamlined in Dr. J's case in light of the nature of the emergency facing the patient and related circumstances, as long as the patient's interests are always held paramount.

Applicable Rules:

"Rule 2. Informed Consent. The performance of medical or surgical procedures shall be preceded by appropriate informed consent."

"Rule 3. Clinical Trials and Investigative Procedures. Use of clinical trials or investigative procedures shall be approved by adequate review mechanisms. Clinical trials and investigative procedures are those conducted to develop adequate information on which to base prognostic or therapeutic decisions or to determine etiology or pathogenesis, in circumstances in which insufficient information exists. Appropriate informed consent for these procedures must recognize their special nature and ramifications."

"Rule 14. Interrelationships Between Ophthalmologists. Interrelationships between ophthalmologists must be conducted in a manner that advances the best interests of the patient, including the sharing of relevant information."

Other References

"Principle 2. Providing Ophthalmological Services. Ophthalmological Services must be provided with compassion, respect for human dignity, honesty and integrity."

"Principle 7. An Ophthalmologist's Responsibility. It is the responsibility of an ophthalmologist to act in the best interest of the patient."

Food and Drug Administration statement, January 1988, titled, "Advertising for Study Subjects"

American Academy of Ophthalmology Advisory Opinion of the Code of Ethics, Informed Consent.


Approved by: Board of Directors, June 1984
Revised and Approved by: Board of Directors, October 1992
Revised and Approved by: Board of Directors, October 1996
Reaffirmed by: Board of Trustees, February 2003
Reaffirmed and Approved by: Board of Trustees, June 2006