Biomedical Research Ethics Overview

University of PennsylvaniaUniversity of PennsylvaniaSchool of MedicineSchool of Medicine

Scientific Integrity

Research is collegial by nature we are “a community of scientists” Communicate results Verify observations and conclusions Review proposals and ideas

Public trust is inherent in this process Purity of purpose Funds use and conflicts of interest Clinical care ethics “Humane” treatment of animals

Scandals Drive Societal Change (unfortunately)

Criminal or other Egregious Conduct Nazi War Crimes - defined vulnerable populations and overall

ethics in research Tuskegee experiments – informed consent and patient rights The appearance of conflict by accepting excessive corporate

payments

Unethical Behavior comes in multiple forms Deception and fraud vs bad science Willful withholding of knowledge Can be clinical or basic research

• Clinical Trials: Tuskegee and Gene Therapy• Basic research: Mendel, Sloan Kettering, Brigham, Whitehead

Responses from Without

Creation of Regulatory Oversight Bodies OPRR - OHRP – IRB process - AALAC – IACUC ORI (NIH/DHHS) (’89)

Definition of Scientific Misconduct The “Final Rule” (1989) DHHS Report (’95)

• Misappropriation, interference, misrepresentation• Rights to whistleblowers

Mandated Bioethics Training NIH training grant recipients (NRSA fellows - ‘90) Shelby Amendment – FOIA (’00) OHPR – PHS (’00 - HSR training for all sponsored funds) PHS - all key personnel engaged in research (’01)

Mandated Confidentiality of Patient Information HIPAA - (‘03)

“Final Rule”

Responsibilities of PHS Awardee and Applicant Institutions for Dealing with and Reporting Possible Misconduct in Science (54 Federal Register 32446, August 8, 1989)

Misconduct in science if defined as fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting, or reporting research. It does not include honest error or honest differences in interpretations or judgments of data.

Creates Office of Scientific Integrity in the OD, NIH, and Office of Scientific Integrity Review in OASH, DHHS.

Each institution supported by the PHS must have relevant administrative processes in place for review of allegations of misconduct.

What is research?

“A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge” 45 CFR 46

Poorly constituted or conducted activities that reflect the above are still research

Key criterion: Is there a hypothesis? Does this still hold?

When does standard clinical care become research?

Our First Example – Research and Consent

Dr. O is a well-known orthopedic surgeon. His specialty is tendon repair/reconstruction. He routinely uses either autologous or cadaveric tissue in this. Depending on the site and nature/extent of the injury he offers patients the option of using either – pointing out the relative risks and benefits of each. Indeed, he bases his recommendation on a study of outcomes from his own patients, which he is preparing for publication. Is this research?

What if he wishes to add novel auxiliary treatments such as VEGF to the surgery? Is this research? Does it require IRB approval? Patient consent?

The Common Problems in Human Research

Human subject research requires a knowledge base linked to the type of study proposed and linked to responsibility e.g., IND/IDE & sponsors

Common mistakes• Poorly written protocols• Poor adherence to GCP• Follow through on appropriate consents• When to modify protocols or consents• When to use consents• AE/SAE what is it & when to report • Monitoring – data, care, quality

Data Management

Research data, experimental protocols, primary procedures & analysis = The currency of research

Notebooks must be meticulously constructed & maintained

DatedObjectives ProceduresRaw DataInterpretationSigned

Must be available at any time Who owns data?

The University (sponsor institution)Faculty entrusted with supervisory responsibility

Data Management

Case Study

The case of Ron Wu and Dr. Christine Morris. Ron completes his research on transcription factors with

Dr. Morris and secures a fellowship with Dr. Link with a promise of a faculty position two years later.

Dr. Link suggests that work will go faster if Ron could bring materials from his previous lab.

Dr. Morris denies access to these materials asserting that these materials belong to the lab and not Ron. She states “I can’t

allow you to take notebooks, probes or other reagents with you”.

Ron feels that he has a legitimate right to these materials since he generated them.

Credit & Authorship

Authorship

Complex: probably the most contested area

We have a guide for students – not faculty

1. Qualifications for inclusion

2. Order

3. General rules

4. Conflict resolution

Biomedical Graduate Studies Authorship PolicyThe Biomedical Advisory Committee of BGS agreed unanimously to develop a single policy on authorship for all biomedical graduate groups. This policy was devised in accordance with the Graduate Council of Faculties’ Policy on Fairness of Authorship Credit in Collaborative Faculty-Student Publications.

Most journals in which BGS faculty and students would publish are represented in the International Committee of Medical Journal Editors (ICMJE). This committee (formerly known as the Vancouver Group) has met annually since 1978 to develop and revise its Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Their Requirements form the basis of section 1 below, Qualifications for Authorship. Issues of authorship in publications by BGS students and faculty should be determined as follows:

1. Qualifications for Authorship1 All persons designated as authors should qualify for authorship.a) Each author should have participated sufficiently in the work to take public responsibility for the

contentb) Authorship credit should be based only on substantial contributions to each of the following areas:

1. Conception and design, or analysis and interpretation of data2. Drafting the article or revising it critically for important intellectual content3. Final approval of the version to be published

c) Conditions 1, 2, and 3 must all be met in assignment of authorshipd) Participation solely in the acquisition of funding or the collection of data does not justify authorship e) General supervision of the research group is not sufficient for authorship f) Appropriate credit for the contributions of other individuals to the work described in the publication

should be made as an acknowledgementg) Any part of an article critical to its main conclusions must be the responsibility of at least one

author. If that author is a student, then the faculty mentor shares the responsibility

Biomedical Graduate Studies Authorship Policy2. The order of Authors2

a) The first author is that person who contributed most to the work, including writing of the manuscript (an author is a person who writes)

b) The sequence of author listing is determined by the relative contributions to the work. In the instance that equal credit is due, this should be footnoted (by asterisk) and authors should be listed alphabetically (you may wish to note this policy on your CV)

c) Decisions about authors and the order in which their names appear should be discussed as early as possible, even at the outset

d) Decisions about authors and the order in which their names appear should be made by group consensus, and under the guidance of the lead investigator(s)

3. Other General Rulesa) The data presented in the publication must preserve full protection of patients’ rights to privacy at their

institution(s) as specified in Informed Consent and IRB approval documentsb) The data presented in the publication must be generated under the approval of, and in full compliance with,

Animal and Human Subject codes at the authors’ institution(s)c) All authors are responsible for recognizing and disclosing financial and other conflicts of interest that might

bias their workd) Decisions of the suitability of a manuscript for a particular journal should be made by group consensus and

under the guidance of the lead investigator(s)e) All items presented in the publication must be original (inclusive of other submitted publications), unless

otherwise specifically stated in the publicationf) Secondary publication of manuscripts, either in full or in part, in review form, in another language and/or in

another country, is justifiable provided that the authors have received approval from the editors of both journals, that the secondary manuscript includes a footnote to this effect, and that the secondary version faithfully reflects the data and interpretations of the primary version

g) In the instance of review articles, which may include previously published and/or unpublished data, appropriate consent and acknowledgements must be made; however, generation of such data does not necessarily warrant authorship (for example, if a faculty member writes a review based on a student’s published work and acknowledges the student’s contributions, the student does not necessarily have the right to co-authorship)

Biomedical Graduate Studies Authorship Policy

4. When conflicts arise It is recognized that even when the above guidelines are followed, conflicts of opinion may arise. The process for handling disagreements regarding authorship between students and faculty members is as follows:

a) The faculty member and student should seek mediation with the graduate group chair. If the faculty member wishes, his or her departmental chair may be included in this process as well.

b) If mediation with the graduate group chair fails to satisfy both student and faculty member, the Director of BGS should be consulted. The Director of BGS will convene a committee of three BGS standing faculty members and one BGS student for arbitration. The committee will consider the opinions of the student, the faculty member, the graduate group chair, and if appropriate, the faculty member’s department chair. However, it must be understood that the opinion of the appeals committee is not binding without the consent of the lead investigator.

Failure to adhere to these guidelines may represent a violation of University policies and consequently may be subject to judicial proceedings.

If the complaint represents a violation of the BGS Code of Academic Integrity, the investigation and adjudication of the complaint will be conducted in accordance with the Policies Governing Biomedical Graduate Student Conduct (9/20/96) on file in the Biomedical Graduate Studies Office and the Office of the Vice Dean, Research and Research Training at the School of Medicine.

If the complaint alleges research misconduct by a member of the faculty, the investigation and adjudication of the complaint will be conducted in accordance with the University’s Procedures Regarding Misconduct in Research, provided in the Handbook for Faculty and Academic Administrators.

1Based on ICMJE Requirements, Ann Intern Med. 1977;126:36-472Based on editorial by D. Riesenberg and G. Lundberg, JAMA 19990;264:1857

Collaborations, Conflicts of Interest and Peer Review Collaborations, Sharing Materials & Data

Obligated to enable verification of published work Federal sponsored work requires reagent and data sharing to all who request Public Presentations (talks, abstracts & posters) are in the public domain Grants – Confidential, but must be totally accurate

Case Study

Ed, a senior student, was still several months away from finishing an ongoing research project when a new fellow arrived from a laboratory doing similar work. After the two were introduced, Ed automatically asked about the work going on in the other lab and was surprised to hear that researchers there had successfully developed a reagent that he was still struggling to perfect. Knowing that both labs had policies requiring the sharing of research materials, Ed wrote a letter to the head of the other lab asking if the laboratory could share some of the reagent with him. He didn’t expect there to be a problem, because his project was not in competition with the work of the other lab, but a couple of weeks later he got a letter from the lab director saying that the reagent could not be shared because it was still “poorly developed and characterized.” The new postdoc, upon hearing the story, said, “That’s ridiculous. They just don’t want to give you a break.”

Questions:1. Where can Ed go for help in obtaining the materials?2. Are there risks in involving other people in this situation?3. What kinds of information is it appropriate for researchers to share with their

colleagues when they change laboratories?

Conflict of Interest and Peer Review

General Guidelines

Expert in field (don’t pass on) Avoid real or perceived conflict of interest (e.g. competitor) Be objective – sole scientific evaluation Maintain confidentiality Avoid or disclose financial conflicts ($10,000 - 5% rule) When in doubt - REFUSE

Peer Review and COI

Case Study

Don is a full professor at a renowned university and has a reputation as an outstanding scientist. His work has had a number of potentially profitable practical applications, which led him to join with some venture capital partners in forming a company to commercialize his inventions. Don is also a member of a National Institutes of Health (NIH) study section. Although he believes it is an excellent way of keeping absolutely current with the work done in his and related fields, he is very aware of the importance of confidentiality as reiterated in the statement read before each study section meeting.

Don just returned from reviewing a fascinating grant application from a scientist working in a closely related area of research. After evaluating the application’s preliminary work report, Don came to realize that much of his own current NIH-funded and corporate research was proceeding down a blind alley. A meeting to review his research team’s progress is fast approaching.

Questions:1. What could Don report to his research team? To his company?2. Should Don have proceeded differently in the case of his grant review?3. If you were in Don’s situation, how would you ensure that you did not benefit

inappropriately from information or ideas acquired during the course of your duties as a study section member?

Confidentiality

Case Study

Dr. P serves as a DSMB for a phase 2 trial on Drug X. He is asked to serve as a consultant by the New York Times on his clinical area of expertise. During that discussion he is asked about the ongoing trial of Drug X.

Questions:1. Can he discuss this?2. What if he is asked about previously reported trials on Drug X?3. What about the general class of drugs that X is in?4. What if the consulting is with an investment firm?5. What if he is asked these questions at a scientific conference?

Consulting and Other Potential Conflicts of Interest

Faculty at Penn may conduct outside “consulting” or other activity for compensation. A right or a privilege?

What are you obligated to report? To whom? How often?

Can you conduct human subject research (e.g., a clinical trial) and accept consulting/activity payments from the sponsor company?

What about basic research (SRA)?

Are you allowed to accept payments and still use products of a company in your standard care and/or research? Are there limits?

Conflict Resolutions

Seek an objective opinion/advice Attempt to resolve with open discussion File a written “formal complaint”

• Include evidence• Don’t overstate of conclude

Cooperate in process

Remember

All parties at some risk

Consequences can be serious

Can progress to federal agencies (ORI) and criminal courts

A Practical Guide to Questions of Scientific Misconduct

A. What to do if you have a question, or suspect unethical behavior or scientific misconduct

If a member of the research community suspects that research by a particular individual, group of individuals, or laboratory is not being conducted in accordance with the generally accepted ethical standards, the individual should make his/her concerns known to one of the following: the appropriate departmental chair, graduate group chair, the Director of Biomedical Graduate Studies, the Vice Dean for Research and Research Training of the School of Medicine, the Ombudsman for Ethics in Biomedical Research in the Medical Center or University (see below), or the dean of the appropriate school. This disclosure should be made with utmost discretion, confidence, and guard for the rights of the alleged transgressor and the accuser. Further actions of the accuser should then be in full accord with the stated University policy.

B. What to do if you are accused of misconduct

If an individual is accused of misconduct in research, that individual should promptly consult with the Vice Dean for Research of the School of Medicine or the dean of the appropriate school for complete information about the inquiry and review process as well as the rights of the accused person. The accused person has the right to engage legal counsel at any stage, including prior to meeting with any University official or faculty member.

C. Ombudsman for Ethics in Biomedical Research in the Medical Center

The mandate for the Office of the Ombudsman is to provide a confidential, disinterested forum for individuals engaged in biomedical research including students, faculty and staff, who believe that their individual rights in this arena have been abrogated or who believe that a breach in ethical conduct of research has occurred. The general charge to the Ombudsman is well stated in the 1983 Report of the University Ombudsman (Keen, J.C. Almanac, May 3, 1983) – The Ombudsman is an advocate, not for one class of university citizen or another, but for fairness, adherence to University regulations, due process,

A Practical Guide to Questions of Scientific Misconduct

individual responsibility, and, from time to time, the softening of the effects of legitimate bureaucratic regulation in the service of broader considerations of equity.

It is not intended that the Medical Center Ombudsman will replace his or her University counterpart. Records of the University Ombudsman and it is intended that this avenue for redress of injustices be continued. The attention of the Medical Center Ombudsman, rather, will be directed specifically to issues of presentation of disputed data, claims of ownership of research results, disputes over priority of authorship, concerns over inappropriate use of research funds, problems arising in the use of human or animal subjects, plagiarism and data distortion or fabrication.

The primary activity of the Ombudsman is as an advisor and mediator. The Ombudsman can advise the complainant of his or her rights and duties and can recommend that individuals bring their case to the appropriate University judicial and/or sanctioning offices. The current Ombudsman for the medical center is Dr. Marilyn Hess, 36 John Morgan/6084, 898-6631

D. Policy on accusation and response to allegations of misconduct at the University of Pennsylvania

In December 1989 the Vice Provost for Research issued a statement defining the University’s expectations regarding ethical standards in research and its policy for dealing with allegations of misconduct in research. Published in Almanac, and then revised and published again in 1991, “Procedures Concerning Misconduct in Research” superceded earlier policies already in place within individual schools. The document states that “Part of the maintenance and perpetuation of high ethical standards includes the responsibility to report research misconduct.” The main steps in the procedure are summarized below:

A Practical Guide to Questions of Scientific Misconduct

Preliminary Inquiry

An inquiry into an allegation of misconduct in research is initiated when a written complaint is filed with the dean of the appropriate school. The dean informs the Provost, who in turn notifies the Chair of the Faculty Senate as to the nature of the complaint; neither the complainant nor respondent is identified at this stage.

The dean informs the respondent of the charges without identifying the complainant. The dean appoints a preliminary inquiry committee of at least two impartial individuals and notifies the complainant and respondent of the names of the individuals on the preliminary committee.

The preliminary inquiry committee gathers information and determines whether the allegation warrants a formal investigation. They submit a written report to the dean with a copy to the Provost, the complainant, and the respondent. Their report should be submitted within 30 calendar days of the receipt of the original complaint by the dean.

The respondent has the opportunity to make a written reply within 15 calendar days; any reply is incorporated as an appendix to the report.

If the preliminary inquiry committee finds that a formal investigation is not warranted, the dean, in consultation with the Provost, may: (1) initiate a formal investigation despite the recommendation of the preliminary inquiry committee; (2) not initiate a formal investigation, but take such other action as the circumstances warrant; or (3) drop the matter.

If the preliminary committee finds that a formal investigation is warranted (or if the dean and Provost decide to proceed with a formal investigation), the dean notifies the complainant and respondent, identifies the complainant to the respondent, and initiates a formal investigation. The Provost notifies the relevant funding agencies and the Senate Consultation Subcommittee.

A Practical Guide to Questions of Scientific MisconductFormal Investigation

A formal investigation is initiated within 30 calendar days of the completion of the preliminary inquiry. The dean appoints a formal investigation committee of at least three impartial individuals, none of whom may have served on the preliminary inquiry committee. The formal investigation committee reviews the allegations and all relevant information, conducts interviews with the respondent, complainant, and other appropriate parties, and consults with University counsel. Within 90 calendar days of the appointment of the formal investigation committee they submit their written report and documentation to the dean, with copies to the Provost and respondent.

The respondent has an opportunity to submit a response to the Provost within 21 calendar days; any response is appended to the formal investigation committee’s report.

The Provost reports the outcome to the research funding agencies and to the Senate Consultation Subcommittee. The entire Process must be completed within 120 calendar days of the initiation of the formal investigation.

Resolution

If the formal investigation committee finds that the allegations are unfounded, the matter is dropped. The dean and Provost have the responsibility to take an active role to repair any damage done to the reputation of the respondent or the complainant (provided the complainant acted in good faith), and to take appropriate action should they determine that the accusation was knowingly false.

If the charges are substantiated, the dean imposes appropriate penalties in accordance with University procedures. In the case of a major offense, the dean consults with the appropriate faculty to determine if there is just cause for suspension or termination. If the offense is found to be less serious, the dean may impose a lesser penalty. The respondent has access to the University’s grievance procedures.

If the charges are substantiated, the Provost takes the steps necessary to correct any resulting misrepresentations by notifying collaborators, professional societies, and publishers involved.