Introduction to Research Ethics: Introduction to Research Ethics: Research vs. Clinical TherapyResearch vs. Clinical Therapy

4 October 20124 October 2012Joal Hill, JD, MPH, PhDJoal Hill, JD, MPH, PhD

ObjectivesObjectives

Define researchDefine researchDistinguish research from “experimental” Distinguish research from “experimental” (clinical innovation)(clinical innovation)Distinguish research from practiceDistinguish research from practiceWho should review/approve? And why?Who should review/approve? And why?

Research (legal)Research (legal)

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

The Belmont Report (4/18/79)The Belmont Report (4/18/79)ResearchResearch

Contributes to generalizable knowledgeContributes to generalizable knowledgeActivity that tests a hypothesis, permits Activity that tests a hypothesis, permits conclusions to be drawn (peer review)conclusions to be drawn (peer review)Usually described in formal protocol with Usually described in formal protocol with an objective and defined proceduresan objective and defined procedures

PRACTICE (Belmont)PRACTICE (Belmont)

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

Clinical “experiment”Clinical “experiment”

Notable departure from standard practice Notable departure from standard practice – Using a drug “off label” (for an unapproved indication Using a drug “off label” (for an unapproved indication

or an unapproved dosage)or an unapproved dosage)– Modifying an approved device or using it for a Modifying an approved device or using it for a

different indicationdifferent indication

Experimental departure from clinical practice Experimental departure from clinical practice does not in itself constitute researchdoes not in itself constitute researchThe IRB should not intervene in matters of The IRB should not intervene in matters of clinical judgment……clinical judgment……

Incremental developments most Incremental developments most likely in:likely in:

SurgerySurgeryNeonatologyNeonatologyPediatrics (that is changing)Pediatrics (that is changing)

The IRB should not intervene in matters of The IRB should not intervene in matters of clinical judgment……clinical judgment……

However…However…

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

BelmontBelmont

““Research and practice may be carried on Research and practice may be carried on together when research is designed to together when research is designed to evaluate the safety and efficacy of a evaluate the safety and efficacy of a therapy. . . . [T]he general rule is that if therapy. . . . [T]he general rule is that if there is any element of research in an there is any element of research in an activity, that activity should undergo review activity, that activity should undergo review for the protection of human subjects.”for the protection of human subjects.”

When does a patient become a When does a patient become a subjectsubject??

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

Examples from HistoryExamples from History(therapeutic fallacy)(therapeutic fallacy)

1940s and 50s: oxygen to relieve 1940s and 50s: oxygen to relieve respiratory difficulty among newbornsrespiratory difficulty among newbornsLate 1950s antibiotics proven safe and Late 1950s antibiotics proven safe and effective in adults and older children effective in adults and older children administered to newbornsadministered to newborns1980s: routine airway suctioning in 1980s: routine airway suctioning in newbornsnewbornsHRT for symptoms of menopauseHRT for symptoms of menopause

On the other handOn the other hand

FDA is slower than other countriesFDA is slower than other countriesSystematic study may be impossibleSystematic study may be impossibleSystematic study cannot occur without Systematic study cannot occur without some mastery of techniquesome mastery of techniqueSystematic study may be unethical or at Systematic study may be unethical or at least ethically problematicleast ethically problematic

Three Requirements for HSRThree Requirements for HSR

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

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

FDA: “Off-Label” & Investigational FDA: “Off-Label” & Investigational Use of Marketed D/D/BsUse of Marketed D/D/Bs

Criteria:Criteria:– Good medical practice + best interest of the Good medical practice + best interest of the

patientpatient– Must use legally available D/D/B according to Must use legally available D/D/B according to

best knowledge and judgmentbest knowledge and judgment– Off-label = use of D/D/B for indication not Off-label = use of D/D/B for indication not

approved (Many practitioners confuse approved (Many practitioners confuse frequency and comfort of use with actual frequency and comfort of use with actual approved indications.)approved indications.)

Off-Label Responsibility (FDA)Off-Label Responsibility (FDA)

Be well informed about the productBe well informed about the productBase use on firm scientific rationale and Base use on firm scientific rationale and sound medical evidencesound medical evidenceMaintain records of product use and Maintain records of product use and effectseffectsOff-label use in this manner when intent is Off-label use in this manner when intent is “practice of medicine” does not require “practice of medicine” does not require IND, IDE, or IRB review…IND, IDE, or IRB review…

HOWEVERHOWEVER

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

Ethical IssuesEthical Issues

Excitement about possibilities, assumption Excitement about possibilities, assumption that new is better.that new is better.Informed consent when risks are not fully Informed consent when risks are not fully knownknownAcquiring new skillsAcquiring new skillsBurden of proof to describe the scientific Burden of proof to describe the scientific rationale and sound medical evidence rationale and sound medical evidence (more than a theory)(more than a theory)

Internal, non IRB ConsiderationsInternal, non IRB Considerations

How far off label are we going?How far off label are we going?Alternatives at other institutionsAlternatives at other institutionsPeer review of rationale & evidence Peer review of rationale & evidence Risk analysis (Do we need to increase Risk analysis (Do we need to increase insurance coverage?)insurance coverage?)Consent form reviewConsent form review

Informed ConsentInformed Consent

Experience at this siteExperience at this siteAlternativesAlternativesAnimal studies, human studies elsewhereAnimal studies, human studies elsewhereKnown side effectsKnown side effectsWhat is unknownWhat is unknownCosts (insurance coverage for Costs (insurance coverage for thisthis patient, patient, including treatment for adverse events)including treatment for adverse events)

RecapRecap

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

ChallengeChallenge

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

Example: Dr. ZamboniExample: Dr. Zamboni

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

StanfordStanford

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

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

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

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

BibliographyBibliography

Peter Angelos MD, PhD, “When the Evidence Peter Angelos MD, PhD, “When the Evidence Isn’t There—Seeking Informed Consent for New Isn’t There—Seeking Informed Consent for New Procedures.” Procedures.” AMA Virtual MentorAMA Virtual Mentor, January , January 2011, Volume 13, Number 1:6-9.2011, Volume 13, Number 1:6-9.The Belmont Report, The Belmont Report, http://ohsr.od.nig.gov/ http://ohsr.od.nig.gov/ /guidelines/belmont.html./guidelines/belmont.html.FDA, “’Off-Label’ and Investigational Use of FDA, “’Off-Label’ and Investigational Use of Marketed Drugs, Biologics and Medical Marketed Drugs, Biologics and Medical Devices.” http://www. Devices.” http://www. fda.gov/RegulatoryInformation/Guidances/ucm1fda.gov/RegulatoryInformation/Guidances/ucm126486.htm26486.htm