Current IRB Challenges and Practical Solutions

1. Current IRB Challenges andPractical Solutions Institutional Review BoardEducational Conference Columbia University New York City April 1, 2011

2. The Limits of Research with Human Beings: Definition or Boundaries? Alexander Morgan Capron University Professor Scott H. Bice Chair in Healthcare Law, Policy and Ethics University of Southern California Los Angeles, CA 90089-0071

3. Topic Addressed The fundamental issue for IRBs “Should we be reviewing this activity?” • Partly determined by institutional policy (such as “only federally funded” or “all research with human subjects”) • Basically determined by Common Rule My central contention: Answering the question is not just technical The answer arises from the core concept of research ethics

4. My Four Starting Premises • Research – the attempt to add to our understanding of the safety and efficacy of healthcare interventions – is a good (indeed, laudable & essential) activity • Special requirements* exist for research because of history of violations of basic human rights and of physical and other harms • Application of these requirements to all research is appropriate, for several reasons • Obtaining consent from all able to give it is basic right • Need IRB to determine completeness/comprehensibility • Need IRB to scrutinize investigator’s conclusion that risks have been minimized & are outweighed by potential benefits • Requirements apply to wide range of activities not just clinical trials * Requirements =the Common Rule, or “twin pillars” of voluntary informed consent & prior review and approval by an IRB]

5. Origins of the Problem • To regulate ethical review of human subjects research need first to decide what constitutes “research” • When regulation began in 1970s, major concern was undue interference with ordinary medical practice • Criteria such as “novelty,” “uncertainty” & “experiment” didn’t help • As to each individual patient, beginning treatment is a novel intervention with uncertain consequences (“an experiment”) • Choice made to take a taxonomic approach: identify the features of the activity that distinguish it from ordinary treatment

6. The Five Features of “Research” Research means “a systematic investigation, . . ., designed to develop or contribute to generalizable knowledge” –- 45 CFR 46.102(d)

7. Some Problems with the Regulation Regarding the definition of research, Dr.Baily has written: “You know you are in the presence of dysfunctional regulations when people can’t easily tell what they are supposed to do.” Some problems are immediately apparent: • Circularity (“research” means “investigation”) • Adjectives need elaboration (what is “systematic” or what would make knowledge “generalizable”?) EXPANDED: “a planned and organized scientific activity designed to develop or contribution to knowledge that is applicable to persons and situations other than those studied”

8. Solves One Problem, Leaves Others • Physician treating individual patient is not engaged in a planned and organized scientific activity nor are results likely to be applicable beyond the patient • Does not address other situations that weren’t central to debates 40 years ago as definition of research arose • QI activities, carried out by clinical managers, that are planned and organized to develop knowledge about how health care can be organized and delivered more safely and effectively • Activities, such as surveillance for new diseases, carried out by public health authorities Large numbers = statistically sound results • Generalizable and, indeed, perhaps publishable

9. How to Respond? • Put through regular IRB review & obtain consent • Widely viewed as “overkill” that will prevent the activity • Add explicit exemption for these activities (existing: types of educational and government benefit studies) • Possible, but lacks history and, at least for QI, basic rationale • Rely on another portion of regulations --example: Pronovost-MHA QI activity (3/04 to 9/05) • No “human subjects” because data was aggregated by unit • Is research (studying hypothesis about effects of prospective alteration of environment of care) but IRB-expedited and no need for consent on grounds “could not have increased the risk of hospital-acquired infection” Miller & Emanuel, NEJM • Problem = entirely ad hoc & sometimes wrong

10. Alternative: Borderlands • Try a topographic, rather than a taxonomic, approach • Don’t pretend that the ethically correct answer emerges from an ever-more elaborate description • Similarity to existing “practice” • Degree of uncertainty • Extent and probability of harm • Amount of information gathered • Manner in which information will be held, stored & analyzed • How and to whom analysis will be disseminated – particularly, whether it will be published • Who will use the results • Useful “definition” will not emerge from this process

11. Alternative: Borderlands • “Definition” is in service of goal = to bring appropriate subset of activities under IRB review and explicit process of subject’s explicit choice to participate • That subset reflects potential “conflict of interest” that arises in research between interests of investigator and interests of subject • Principal difference between treatment and research is that the former is undertaken to benefit a particular patient and the latter is carried out to produce new scientific knowledge • Subject may or may not benefit • Following the protocol may or may not increase risk/ decrease benefit to particular subject – as an ethical matter, if the likely result is any significant detriment to the subject, the investigator should withdraw that subject or even end the experiment

12. Alternative: Borderlands • Investigators can have wide range of intents • Purpose (or intention) is notoriously slippery concept, difficult to apply (esp. retrospectively) • People hold multiple intents • People’s view of what facts are relevant to a decision is shaped subconsciously –we adjust facts to fit outcome • Healthcare professionals are particularly sensitive to any suggestion of a “conflicting interest” • Nonetheless, the change from serving-the-individual to serving-knowledge is the fundamental ethical concept • Explains why “outsiders” (IRB) must review research plans • Needs to be made clear to subjects (especially if they are also patients)–but hard because of “therapeutic misconception” • Does not provide sharp definition but justifies a search for boundaries in contested territory

13. Apply to QI Activity Question of “Research?” arises at three levels of QI • Implementation in Individual Hospital • Practices supported by evidence (AHRQ) • Record-keeping re: safety & effectiveness • Adjust practices in light of experience • Consent is to practice, not to QI activity • Development of QI Intervention • Right thing to do may be known, but not how to get it reliably adopted • Record-keeping re: results • Adjust practices in light of experience • Implementation in Multiple Hospitals • Practices supported by evidence (AHRQ) Practices supported by evidence (AHRQ) • Records: internally & shared • Adjust recommendations

14. Apply to Public Health • Difficulty for public health is that the individual is not the unit of “benefit” • In ordinary public health data-gathering activity (such as surveillance), intention is not to benefit individuals • Data-analysis may produce new “generalizable knowledge” • Individual consent may not be required • In effect, permission provided by public health legislation & regulation, subject to popularly elected representatives • Same shift of focus can occur when public health officials move beyond routine activities to research for the purpose of producing new knowledge • Appropriate oversight – may be IRB or may be another body with specialized expertise in public health ethics • Common problem: observational research

15. Apply to Therapeutic Innovation • Close to starting point of the definition of research that determines whether activity needs IRB review • When innovation (for example, off-label use) involves single patient, physician is acting for patient’s benefit • Keeping observations on outcomes • Making variations in light of experience • What about a “series” of patients? • Observations in one influences “knowledge” applied to others • Complicating factor = FDA regulations and interest of pharmaceutical companies in encouraging additional uses and publication of data

16. Thank You acapron@law.usc.edu