Introduction to Research Ethics: Research vs. Clinical Therapy

Introduction to Research Ethics: Research vs. Clinical Therapy 4 October 2012 Joal Hill, JD, MPH, PhD

Objectives • Define research • Distinguish research from “experimental” (clinical innovation) • Distinguish research from practice • Who should review/approve? And why?

Research (legal) • A systematic investigation designed to develop or contribute to generalizable knowledge (45 CFR 102(d)). • Implies more than one subject, future application • Sufficient numbers needed for statistically valid information (but pilot studies OK)

The Belmont Report (4/18/79)Research • Contributes to generalizable knowledge • Activity that tests a hypothesis, permits conclusions to be drawn (peer review) • Usually described in formal protocol with an objective and defined procedures

PRACTICE (Belmont) • Intervention used solely for individual patient well being with a reasonable expectation of success • Intervention = diagnosis, therapy, prevention (particular patient) • Clinical practice includes “experiment”

Clinical “experiment” • Notable departure from standard practice • Using a drug “off label” (for an unapproved indication or an unapproved dosage) • Modifying an approved device or using it for a different indication • Experimental departure from clinical practice does not in itself constitute research • The IRB should not intervene in matters of clinical judgment……

Incremental developments most likely in: • Surgery • Neonatology • Pediatrics (that is changing) • The IRB should not intervene in matters of clinical judgment……

However… • “Radically new” procedures should be the object of formal research “at an early stage in order to determine whether they are safe and effective. • “It is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research protocol” (Belmont).

Belmont • “Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. . . . [T]he 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.”

When does a patient become a subject? • When departure from standard practice is notable • When reasonable expectation of success wanes (according to whom?) • When there is some research intent, or when departure from SOC is expected to be repeated on future patients.

Examples from History(therapeutic fallacy) • 1940s and 50s: oxygen to relieve respiratory difficulty among newborns • Late 1950s antibiotics proven safe and effective in adults and older children administered to newborns • 1980s: routine airway suctioning in newborns • HRT for symptoms of menopause

On the other hand • FDA is slower than other countries • Systematic study may be impossible • Systematic study cannot occur without some mastery of technique • Systematic study may be unethical or at least ethically problematic

Three Requirements for HSR • Mandatory informed consent (respect for persons) • Determination that anticipated benefits are proportionate to the risks (beneficence/nonmaleficence) • Fair selection of subjects so that no group is disproportionately burdened (justice)

If innovation (clinical experimentation) is not research… • Innovation or exploitation? • What is proper (proportionate) institutional/departmental review and oversight? • Off-off-label use of drugs is often captured by Pharmacy Committees, but similar accountability for devices is often lacking.

FDA: “Off-Label” & Investigational Use of Marketed D/D/Bs • Criteria: • Good medical practice + best interest of the patient • Must use legally available D/D/B according to best knowledge and judgment • Off-label = use of D/D/B for indication not approved (Many practitioners confuse frequency and comfort of use with actual approved indications.)

Off-Label Responsibility (FDA) • Be well informed about the product • Base use on firm scientific rationale and sound medical evidence • Maintain records of product use and effects • Off-label use in this manner when intent is “practice of medicine” does not require IND, IDE, or IRB review…

HOWEVER • “[T]he institution at which the product will be used may, under its own authority, require IRB review or other institutional oversight.”

Ethical Issues • Excitement about possibilities, assumption that new is better. • Informed consent when risks are not fully known • Acquiring new skills • Burden of proof to describe the scientific rationale and sound medical evidence (more than a theory)

Internal, non IRB Considerations • How far off label are we going? • Alternatives at other institutions • Peer review of rationale & evidence • Risk analysis (Do we need to increase insurance coverage?) • Consent form review

Informed Consent • Experience at this site • Alternatives • Animal studies, human studies elsewhere • Known side effects • What is unknown • Costs (insurance coverage for this patient, including treatment for adverse events)

Recap • Research = systematic study designed to develop or contribute to generalizable knowledge • Innovation = alteration of accepted, standard of care for the benefit of a particular patient (experiment); safety, reliability, effects, side effects, and complications are unestablished/unknown.

Challenge • At some point a string of off-label uses becomes practice with little or no research to establish outcomes (good and bad). • The fact that innovation does not require IRB review does not mean there should be no other accountability. • How to responsibly encourage and follow innovative practice.

Example: Dr. Zamboni • Late 2008 – “New type of treatment” reported: stenting 65 patients in 2007, 73% reported no symptoms in 2009. • Zamboni’s hypothesis: chronic cerebo-spinal venous insufficiency • March 2010 – WSJ reports shut down of Stanford research (40 patients) after one death and one near miss following balloon angioplasty.

Stanford • Dr. Hauser: Off-label use was overly experimental and potentially dangerous. • Dr. Dake: Neurologists “don’t want to acknowledge that a vascular surgeon in Italy found something that’s been right under their noses.” Maintains that his work is necessary before scientists can initiate a research program that would require formal oversight. “I’m sort of viewed as the crazy uncle locked up in the woodshed out back.”

June 2010 International commitment to fund studies exploring the CCSVI theory = $3.4 million. Placebo-controlled trial (30 subjects) underway at University of Buffalo. Funding commitment proffered to fund therapeutic trials in Canada. • August 2010 “Multiple sclerosis theory dealt a blow by studies.”

September 2012 – Press release: $6 million dollar Canadian study of 100 patients will begin recruitment November 1st.

As a member of the MPC, how would you evaluate a request to offer this procedure as a clinical treatment at your institution? • What factors would sway you to support or refuse such a request?

Bibliography • Peter Angelos MD, PhD, “When the Evidence Isn’t There—Seeking Informed Consent for New Procedures.” AMA Virtual Mentor, January 2011, Volume 13, Number 1:6-9. • The Belmont Report, http://ohsr.od.nig.gov/ /guidelines/belmont.html. • FDA, “’Off-Label’ and Investigational Use of Marketed Drugs, Biologics and Medical Devices.” http://www. fda.gov/RegulatoryInformation/Guidances/ucm126486.htm

Introduction to Research Ethics: Research vs. Clinical Therapy