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If the activity is a significant risk device study, surgeons must first obtain FDA and IRB approval.
It is axiomatic, because we work in clinical research, that we think we know what clinical research is. It's too fundamental an issue, too basic a concept, to give it much thought. However, there are compounds administered to patients (not subjects), as well as procedures performed on patients that are unapproved, untested, and could in no way be considered the generally accepted standard of care. These therapies, albeit well intentioned, are largely unreviewed for scientific merit. For example, a physician hears from a colleague that off-label use of a drug might be helpful in treating a patient's clinical condition and so prescribes the drug for this off-label indication. There are no statutory prohibitions on this approach, and the physician feels that he or she is in the best position to make this determination. Regulatory agencies are loath to interfere with these kinds of clinical approaches, lest innovative care be stifled.
Photography: Eyewire Artwork: Paul Belci
Innovation and experimentation are part of the daily life of some physicians and dentists. They may inadvertently cross the line from innovative care to clinical research. Both medical and dental activities are regulated by state law regarding their practice, but clinical research has additional GCP requirements, including FDA and IRB oversight. Individual patients may benefit from innovative care, but society also benefits from innovative clinical research; individual patients must be protected from substandard care and research subjects must additionally be protected from substandard research. So there are significant differences in processes and procedures applied to specific clinical situations depending upon a regulatory agency, sponsor, or IRB determination of whether it is innovative care or clinical research.
This short paper explores current thinking/best practices regarding distinctions between routine care, innovative care, and clinical research including research that may represent innovative care. It begins with three scenarios that approach, and possibly cross, an unmarked, "fuzzy" border into clinical research, describes how regulatory agencies and IRBs look at these scenarios, and finally adds dimension and perspective to the discussion.
A pulmonologist decides he would like to experiment with a compound that has been previously studied 30 years ago in the treatment of asthma. He obtains IRB approval to try this compound on a few subjects, but like the surgeon below, he "innovates" and makes changes as his series of patients expands; he varies the dosing conditions and he changes the premedication treatment.
Scenario #2: For a certain kind of benign tumor that's usually found in the femur, the standard treatment is to remove the tumor, curette the area, then fill the hole in the bone with cement, or cement plus some hardware, to strengthen the bone and hopefully avert a later fracture.
An orthopedic surgeon thinks this last step might be accomplished better with cement and a slight modification of the hardware that is usually applied, or by adding hardware specially designed by the surgeon. He has a patient he thinks might benefit from this innovative approach and he will decide which hardware to install once his patient's bone is exposed. He expects he'll probably use this surgical approach for more than just this one patient, and if he does, he'll probably do a retrospective chart review and publish his results. However, his description of this activity is that he's just going to do what he thinks is best for each individual patient, and he is being an innovator in his surgical practice.
Scenario #3: An infectious disease consultant has just read a paper describing the use of an old generic antibiotic for staphylococcal skin abscesses. Coincidently, she is called to the ER that weekend to see such an abscess. With the results of the study fresh in her mind, she uses the old and cheaper, but non-standard of care—antibiotic—on this patient.
None of these physicians seeks FDA approval of their activities, and neither consents patients with a consent that describes the treatment as experimental. Are these approaches research that fall under GCP rules and regulations or are they simply innovative care? Can treatment of a single patient constitute "research?"
An examination of this question begins with another question: what is the FDA's expectation regarding these clinical activities? A March 31, 2003 FDA warning letter issued to Johns Hopkins asthma specialist Albis Togias is informative (Reference: 02-HFD-0303) regarding Scenario #1. First, Togias is specifically cited for violation of the Federal Food, Drug, and Cosmetic Act (USC 331(d)) by engaging in a prohibited act by causing the introduction or delivery of an unapproved new drug in interstate commerce. Second, Dr. Togias failed to submit an IND for the conduct of a clinical investigation with an investigational new drug as required by 21 CFR 312.20(a). The warning letter states that a clinical investigation is defined as "any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects — except for the use of a marketed drug in the course of medical practice" (21 CFR 312.3). These statements make it clear that participation of even one subject is a regulated activity. Dr. Togias should have submitted an investigator IND to the FDA. On the other hand, had he been using a marketed product, the case would have been less clear cut. The case is also clouded by the fact that this study was similar to a Phase I study because the subjects were healthy volunteers and were not being "treated" for a specific disease.
Regarding the surgeon's activities in Scenario #2, FDA regulations (21 CFR Part 812) define two types of device studies—"significant risk" and "nonsignificant risk" studies. A significant risk device study is a study that presents potential for serious risk to the health, safety, or welfare of a subject and 1) is intended as an implant; 2) is used in supporting or sustaining human life; 3) is of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise prevents impairment of human health; or 4) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. A nonsignificant risk device study is one that does not meet the definition for a significant risk study.
If the activity is a significant risk device study, then the surgeon must obtain approval from both the FDA and the IRB before the surgeries are initiated. The surgical procedures described in Scenario #2 above would fall under the significant risk category, and since it would appear as though this procedure has elements of research, such as modified and/or unapproved hardware, it requires FDA and IRB oversight.
So in the first two cases, unauthorized research has been undertaken. In the third case, despite the fact that a nonstandard therapeutic intervention has been initiated, this is not research because it involves a drug marketed for an approved indication.
The Office of Human Research Protection (OHRP) has provided yet another way to address the care versus research question. In February 1998 it published a chart that describes when a patient becomes a subject. The chart begins by asking, "Is there an intervention or an interaction with a living person that would not be occurring or would be occurring in some other fashion, but for this research?" A "yes" answer means that human subjects are involved and 45 CFR 46 applies. In other words, if the care provider's intervention is proceeding differently from normal practice, then the patient is a subject and the activity is considered research. The OHRP definition calls into question the conclusion that Scenario #3 is not research.
Secondarily, from a less regulatory perspective, the following questions might be asked about these clinical procedures:
Answers of "yes" to some or all of these questions would suggest that the innovative approach is actually clinical research, which must undergo IRB scrutiny and be conducted under an IND. A more subtle question might be: Was the decision to use the hardware, and or other treatment approaches, made on a case-by-case basis, after diagnostic "discovery" began?
In other words, is every single case treated differently, or has the potential for being treated differently? An answer of "yes" to this question would tend to suggest that the approach is less likely to be research. However, one would still expect that this decision-making process was explained to the patient before the surgery or treatment started.
A third consideration is the locus of authority within an institution to make decisions about innovative procedures. Is there a hospital oversight committee, such as an innovative care committee, in place to review such approaches, and does the committee work closely with the hospital IRB? An oversight committee of this type protects the hospital from legal and regulatory risks but also encourages innovation in treatment modalities.
Lastly, there may be a medico-legal duty to create research records and perform contemporaneous chart review on early patients receiving innovative care as a way to adequately protect their safety. To do less might be considered, for a procedure that is sufficiently different from the standard of care, malpractice.
While the innovative physician's intentions regarding use of his or her findings may incrementally change over time, rather than change for one treatment, it would probably be best to switch to a research project and IRB approval earlier rather than later for a series of similar treatments.
There have been previous attempts at drawing a distinction between research and practice. The Belmont Report, in its introduction, addresses the boundaries between practice and research:
"It is important to distinguish between biomedical and behavioral research, on the one hand, and the practice of accepted therapy on the other, in order to know what activities ought to undergo review for the protection of human subjects of research. The distinction between research and practice is blurred partly because both often occur together (as in research designed to evaluate a therapy) and partly because notable departures from standard practice are often called 'experimental' when the terms 'experimental' and 'research' are not carefully defined.
"For the most part, 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, preventive treatment or therapy to particular individuals. By contrast, the term 'research' designates an activity designed to test an 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 that objective. "When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is 'experimental,' in the sense of new, untested or different, does not automatically place it in the category of research. Radically new procedures of this description should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project.
"Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. This need not cause any confusion regarding whether or not the activity requires review; the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects."
The Belmont Report makes it clear that if there is an "element of research" in the treatment, then the GCP rules of research apply: the FDA should be notified, IRB approval is required, and the consent should have all the mandated research sections and explain that the treatment is experimental.
One classic clinical trial text is Curtis Meinert's Clinical Trials: Design, Conduct, and Analyses.1 Meinert defines a clinical trial as:
"A research activity that involves administration of a test treatment (e.g., a drug, surgical procedure, diagnostic test, or medical device) to some experimental unit in order to evaluate the treatment. The term is subject to wide variation in usage. In some cases it may refer to the first use of a new treatment in man without any control treatment. In other cases it may refer to a rigorously designed and executed experiment involving a test and control treatment and randomization. The experimental unit in most cases is man (or a larger unit involving man, such as a hospital ward), but can be some other experimental animal."
Meinert goes on to state that his use of the term involves human beings. He also appears to support the notion that "first use" constitutes research. His caution that the term "clinical trial" is subject to wide variation in usage is a good one. In fact, the terms "clinical trial," "clinical study," "clinical investigation," and "clinical research" are generally used in an interchangeable manner, but there is no universal or regulatory agreement marking a sharp distinction between innovative treatment and these terms.
Reading through a recently published text entitled
Abuse of Man: An Illustrative History of Dubious Medical Experimentation
one is struck by the long-term historical trends of inhumane and callous treatment of patients under the guise of improving the quality of care. These kinds of unregulated experiments continued well past World War II and may still be ongoing, only in less obvious forms and more secretive venues. Their legacy is one of public and professional outrage only after these treatments cause harm and are disclosed to a wider audience.
Better to err on the side of caution, particularly in light of recent clinical trials litigation,3 and fully protect patients by seeking FDA or EU approvals, IRB review, and administering appropriate consents. Until the FDA, which is reportedly studying this issue and other regulatory agencies, weighs in with more definitive guidance, care providers should consider submitting investigator INDs and abiding by GCP regulations, guidelines, and standards.
1. C. Meinert,
Clinical Trials: Design, Conduct, and Analysis
(New York: Oxford University Press, 1986).
2. W. Weyers, Abuse of Man: An Illustrative History of Dubious Medical Experimentation (New York: Ardor Scribendi, 2003).
3. J. Crongeyer and L. Owens, "Clinical Trials Litigation" in D. Mackintosh, V. Molloy, M. Mathieu (eds), Good Clinical Practice: A Question and Answer Reference Guide (Waltham, MA: Barnett, June 2004).
The authors would like to thank Steve DeCherney, MD, MPH, President, Clinical Development Services, North America, Quintiles Transnational, Inc., for his review and comments.
Douglas R. Mackintosh, DrPH, MBA, MS HYG and Vernette J. Molloy, MBA, RN, are president and vice president, respectively, of GCPA, Inc., 12208 Fairfax Station Road, Fairfax Station, VA 22039, (703) 988-9080, fax (703) 988-9082, email: GCPaudits@aol. com, http://members.aol.com.gcpaudits.