Legal Aspects of Research -2002

Edward B. Goldman, J.D.

Health System Attorney

University of Michigan

March 26, 2002 3:30-4:30

Introduction

2001 was a year full of exciting developments in the legal aspects of research.

This outline will review some of the highlights and provide references for more detailed analysis.

All elements of research regulation are under review.

Some General Concerns

Greg Koski, Director of the Office of Human Subject Protections (8/24/01): OHRP will have a new quality improvement program.

Science v. 290, page 1701-2 1Dec. 2000: “Privatizing the University-the New Tragedy of the Commons”. Research results must be public.

More General Concerns

“Quantifying Risk in Clinical Trials” CenterWatch Oct. 2001, V. 8, issue 10

JAMA 14 Nov. 2001 V. 286, #18 2315-21 “Informed Consent for Population-Based Research Involving Genetics” .

HHS OIG 2002 Work Plan includes Medicare payments for clinical trials, (continued)

More General Concerns

HHS OIG 2002 Work Plan: conflict of interest; sponsors’ oversight of clinical trials; recruiting subjects for trials in a timely fashion; research service costs charged by Universities; Office of Research Integrity (ORI) referrals

Can research be risk free? (Or, do the risks justify the benefits).

Age of Assent

The regulations require “assent’ from a child when the IRB believes the child is “capable of providing assent”. The FDA says look at age and maturity.

The American Academy of Pediatrics suggests an intellectual age of 7. www.aap.org.policy/0065.html.

How to create a uniform policy?

Public Access to Research Data

The Federal “Shelby Amendment” says Federally sponsored research published in a peer reviewed journal cited by a Federal agency for rulemaking is discoverable under Federal FOIA but access is limited to final data (completed studies) not covered by trade secrets. 04/17/2000.

Public Access to Research Data

FDA has a proposed rule to make human gene therapy and xenotransplantation research data available. 66 FR 4688-4706.

Accreditation

VA has a draft research protection accreditation program created by NCQA. Theory: Surveyors determine if a VA and its IRB are in compliance.

The Association for the Accreditation of Human Research Protection Programs (AAHRPP) formed 04/00 by AAMC and others has draft standards 09/01.

Accreditation

The Institute of Medicine published: “Preserving Public Trust: Accreditation and Human Research” to begin to set standards for human research programs. They endorse the VA pilot and recommend accreditation for all programs. 04/17/01.www.nap.edu/books/0309073286.html.

Adverse Event Reporting

Some IRB’s say any occurrence which could increase risk of harm must be reported.

The FDA has a detailed approach (Appendix A).

Failure to report to the IRB and to the FDA can result in sanctions.

Federal Wide Assurance

IRB’s and medical centers must provide OHRP an assurance that research will be conducted according to Federal rules. Issue: All research or only Federal research?

Terms: ohrp.osophs.dhhs.gov/irbasur.htm.

Animals

Chimpanzee Sanctuaries: Legislation created a sanctuary for retired research chimpanzees.

Rats, Mice, Birds did not fair as well. The USDA is prohibited from issuing a final rule on including them under the Animal Welfare Act during the 2002 fiscal year.

Federal Certificates of Confidentiality The Federal government will issue, for

Federal or non-Federal research, a Federal certificate helping to protect personally identified participant data during the pendency of research.

www.nida.nih.gov/intranet/confidentiality/parts/03html.

Children

The FDA 04/24/01 published an interim rule to provide safeguards for children essentially similar to 45 CFR 46 Part D but with provisions for wards of the State.21 CFR 50.50 et. seq.

This complements the FDA’s expectation of an increase in enrollment of children in drug trials.

Conflict of Interest

Association of American Universities (AAU) has proposed guidelines both for institutional and individual conduct.10/01www.aau.edu/research

No investigator with financial interest in the research should participate.

No institution should do research where they have a royalty or equity.

Conflict of Interest

Assoc. of American Medical Colleges (AAMC) has a final report 12/01 saying standing C of I committees tied to IRB’s are needed. www.aamc.org/coitf.

The GAO issued a report 11/26/01 finding a need for universities to improve collection and review of conflicts. www.gao.gov report 02-89.

Conflict of Interest

The Fred Hutchinson Cancer Research Center hired an independent consultant to conduct a study on conflicts. The study, released 09-21-01 found the Center ‘is adequately addressing the issues”. Www.fhcrc.org/response/times.

Issue: What is the proper standard?

Data Safety Monitoring Committees Are increasingly being required. See: Center for Drug Evaluation and

Research draft report: Guidance for Clinical Trial Sponsors: On the Establishment and Operation of Clinical Trial Data Monitoring Committees.

Www.fda.gov/cder/guidance/index.htm

Data Safety Monitoring

Morse, et. al., Monitoring and Ensuring Safety During Clinical Research, JAMA, March 7, 2001, V. 285, #9, 1201-5 discusses adverse event reporting and DSMB’s.

Genetic Research

Issues: Should subjects share the wealth in genetic research discoveries?

Should subjects be allowed to consent to future use of DNA?

Should subjects be told present/future research results?

Should results be placed in the subjects’ medical record?

Genetic Research

Deschenes, et. al., Human Genetic research, Clinical Genetics, April 2001, v. 59, #4, 221-239 discusses informed consent in DNA banking.

McGill University has a model genetic research consent form. www.mni.mcgill.ca/forms/ethics/gencon2000-08.pdf

Globalization of Research

HHS, OIG 09-01 published: The Globalization of Clinical Trials. Oig.hhs.gov/oei.

It recommends procedures so that protection for foreign research is equivalent to US research.

Good Clinical Practices

The FDA has a site explaining Good Clinical Practice to ensure credible study results while protecting subjects. The site looks at FDA and HHS regulations. 08/21/01.

www.fda.gov/oc/gcp/default.htm.

Helsinki Declaration

Oct. 2000 it was revised to include independent consent if the subject is in a dependent relationship with the researcher; use of placebo only if no proven treatment method exists, and assurance that at the end of the research the subject will have access to the best methods found by the study.

HIPAA Privacy and Research

The HIPAA rules are enforceable 04/14/03. They include new regulations for waiver of consent. They also require a privacy notice and “consent” plus a research assent.

They raise questions about the use of hospital based registries for research.

Informed Consent

The National Cancer Institute (NCI) has a model document on use of tissue for research which says “you will not receive the results of research done with your tissue”.

Cancertrials.nci.nih.gov

Injury to Participants

Issue: Should participant be compensated? National Bioethics Advisory Commission (NBAC) says probably yes but first do a study to assess level of risk and cost of program.

NBAC website: bioethics.georgetown.edu/nbac.

Federal Inspections

See the OHRP and FDA sites for their compliance program suggestions.

OHRP: ohrp.osophs.fhhs FDA: www.fda.gov/ora/compliance_ref/

Litigation

Alan Milstein, J.D. sued Penn. in the Jesse Gelsinger case and is suing Oklahoma, the Fred Hutchinson Cancer Center, Johns Hopkins and Penn. (subject 11 in the Gelsinger research) in research cases.

See: www.sskrplaw.com for his world view and the Washington Post of 12/21/01 for it’s report.

Johns Hopkins Cases

Johns Hopkins cases: 1. Death of volunteer in asthma study 2. Children exposed to lead paint. 3. Cancer trial in India without IRB or

FDA approval. Issue: Does litigation help or hinder

medical progress?

The Lead Paint Litigation

Grimes v. Kennedy Krieger Institute, Md. 08/16/01.The Md. Ct. of Appeals held that non-therapeutic research with any risk on children,even with parental consent, is improper.

Lead paint abatement procedures study. The Court allowed the two negligence cases to proceed.

Litigation-Duty to Disclose

In Schiff v. Prados, 112 Cal. Rptr. 2d 171 (09/28/01) the California Court of Appeals held that there is a duty to inform patients of other treatment options even “legal but unorthodox treatments”. Does that mean patients must be informed of possible research protocols?

NBAC

Out of existence as of Oct. 3, 2001. Issued reports on stem cell research

and research involving human participants (08/01) suggesting a uniform Federal rule enforced by one agency; certification of IRB’s and researchers, disclosure rules for conflict of interest and monitoring.

OHRP Guidelines

IRB Protocol review standards: ohsr.od.nih.gov/info/. Note: OHSR is the NIH office for human subjects research.

Common OHRP findings of noncompliance (11/30/01): OHRP site. 18 pages of noncompliance issues. Mostly documentation matters.

FDA Self-Evaluation Checklist

The FDA has a detailed self-evaluation checklist for IRB’s at www.fda.gov/oc/ohrt/irbs/irbchecklist.html. In its 11 pages it reviews all necessary policies to comply with the FDA regulations.

Race/Ethnicity Policy

NIH 08/08/01 issued a minimum standard for data on race and ethnicity for grant applications. Investigators need to collect and report this data during annual reviews.

Issue: Should IRB’s require collection and reporting to them?

Grants.nih.gov/grants/guide/

Research Design

Does the IRB have a role in evaluation of sound research design and scientific validity?

OHRP suggested in its review of the Hopkins asthma study that the IRB should have evaluated the safety of the study medication used to induce broncospasm.

Research Design

See: Editorial, Ensuring Patient Safety in Clinical Trials for Treatment of Acute Stroke, JAMA 12/05/01 V. 286, #21 2718-19 commenting on “another failed trial of neuroprotection” and saying the study should have been stopped sooner than it was.

Research Design

The regulations at 45 CFR 46.107(a) say the IRB needs expertise to review studies and 45 CFR 46.111 (a) (1) says the IRB must determine risks are minimized.

Issue: If a study has bad design then is any risk excessive?

Stem Cell Research

Federal policy: Federal funding only for research with adult stem cells or pluripotent cell lines established by 08/09/01 and conducted in line with NIH guidelines. See: www.nih.gov/news/stemcell/index.htm.

NIH has an agreement with WiCell to distribute cell lines subject to patents.

Pregnant Women and Fetus

HHS as of 11/13/01 issued a final rule replacing Subpart B of 45 CFR 46. The new rule went into effect 12/13/01.

A summary is found in appendix B.

Vulnerable Subjects-Prisoners

Research on prisoners must be conducted in accord with subpart C even if prison status is incidental to the research.

Women and Minorities

NIH policy on inclusion in research: grants.nih.gov/grants/funding/

women_min/women_min. htm. 10/09/01

Final Thought

An editorial by Robert Levine in the Annals of Internal Medicine 16 Jan. 2001 V. 134 #2 161-163 entitled: “Institutional Review Boards: A Crisis in Confidence” made the point that IRB’s have problems because “low-yield, time consuming tasks dissipate their energy”.

Issue: Is best the enemy of good in this debate?