Research Non-Compliance & Research Non-Compliance & Scientific MisconductSeptember 15, 2010

Presented byMay Al Kassar

Responsible Research Conduct

The ethical conduct of research is a shared responsibilityamong:among:

� The institution� Agencies sponsoring research� Investigators� The research teams� IRB members and staff

Role Of the IRB

The IRB is the administrative body responsible for assuring thatall parties involved in human subjects research activities areguided by the principles of the Belmont Report.

Definition of Non-Compliance

Noncompliance:Any failure to follow:

(a) Provisions of an IRB-approved research study(a) Provisions of an IRB-approved research study(b) Institutional policies(c) Local laws or federal laws (for federally-sponsored research) (d) The requirements and determinations of the IRB

� Noncompliance can be categorized as non-serious (minor), serious, or continuing noncompliance.

� Noncompliance may pertain to the Principal Investigator (PI), the PI’s research team.

Definition of Serious Noncompliance

Serious Noncompliance:

Any failure to comply with regulations that:

(a) creates an increase in risks to research subjects

(b) adversely affects the rights, welfare and safety of the research subjects

and/or(c) adversely affects the integrity of the University’s HRPP

Examples of Serious Noncompliance

� Failing to obtain informed consent from research participants

� Starting and/or completing research under a protocol before meeting the conditions required by the IRB and receiving IRB meeting the conditions required by the IRB and receiving IRB notification of approval

� Providing inadequate supervision of research that involves potential risks to subjects

� Implementing changes to a research study without obtaining prior IRB approval

CON’T

� Failing to recruit participants according to the inclusion/exclusion criteria, or recruiting more participants than what was previously approved by the IRB

� Recruiting participants in the research study whose approval has already lapsed or the study has been suspended or terminated

� Failing to report or review serious adverse events and/or unanticipated problems to the IRB

� Failing to act on recommendations communicated by the IRB Office

Definition & Examples of Non-serious (minor) noncompliance

Non-serious (minor) noncompliance: Noncompliance that does not affect the rights and the welfare of the research participants or put them at risk of harm. It also does not affect the integrity of the University’s HRPP. the integrity of the University’s HRPP.

Examples:� Introducing minor changes or deviations to an IRB-approved

protocol� Using an approved, but non-IRB stamped, consent form

� Failing to respond to official correspondence (e-mail, letter) from theIRB Office which does not compromise the welfare of the researchparticipants

� Not including dates of pt. consenting on ICF itself (but the date of visitdocumented in study log sheet)

Definition & Examples of Continuing Noncompliance

Continuing Noncompliance:

Repeated failure to understand and consistently comply with AUB IRB policiesAUB IRB policies

Examples:

� Repeated failure to comply with continuing review requirements

� Multiple recurrent problems with noncompliance with the same PI over a lengthy period of time, or

� The PI has a problem with multiple existing or previously-approved studies

Reporting of Noncompliance

� Any minor, serious or continuing noncompliance observed or suspected by individuals should be reported to the IRB Office.

� Reports can be submitted by the Principal Investigator (PI)via Self-Reporting, or by any other source via telephone, e-mail, or letter to the IRB office.

What happens after reporting noncompliance ?

� If the event is determined to be minor noncompliance, the IRBChair/Vice Chair will direct the IRB Officer/Administrator to make everyeffort to correct the issue (s) at the administrative level, in conjunctionwith the PI.with the PI.

� If the event is considered to involve serious noncompliance orcontinuing noncompliance, the IRB Chair/Vice Chair will initiate anInquiry/Investigation.

Inquiry/InvestigationThis is a fact-finding process that may involve review of researchrecords, research data (both published and unpublished), informedconsent/assent forms, interviews with associated researchers, researchassistants, students, and/or direct correspondence with the PI.

CON’T

� Following an Inquiry and/or Investigation, determinationby the IRB as to whether noncompliance has occurredby the IRB as to whether noncompliance has occurredand what corrective actions, if any, will take place.

� Corrective actions may even be recommended wherethere is a determination that there was nononcompliance, if the conduct of the human researchcould be improved and subject safety enhanced if certainactions were taken.

Spectrum of IRB Determinations for Corrective Measures

� Approve continuation of research without changes� Develop a corrective action plan (for minor noncompliance

only). The plan may include, but is not limited to, the following: – Additional training and education of the PI/research team– Additional supervision of PI– Limiting research activities of the PI– Limiting the number of enrolled participants

� Require modifications to the protocol � Revise the continuing review timetable

CON’T

� Modify the consent process� Modify the information disclosed in the consent document� Provide additional information to current &/or past participants� Provide additional information to current &/or past participants� Require that current participants re-consent to participation � Require additional training of an investigator and/or study staff� Reconsider approval� Monitor the research� Monitor the consent process

CON’T

� Suspend IRB approval for one or more of the PI’s studies until proper modifications to the study protocol under scrutiny are completeTerminate IRB approval for one or more of the PI’s studies � Terminate IRB approval for one or more of the PI’s studies

� Recommend further administrative action to the University� Recommend further reporting to federal agencies and

department heads, as required under the FWA � Disallow use of data and/or deny confirmation of IRB approval

for publication submissions, in cases where data were gathered in research determined to be noncompliant

� Conduct announced and/or unannounced audits of this project (or any of this PI’s protocols)

New Unit: Quality Improvement Program/Research Compliance

� The QIP/RCU is charged with evaluating and enhancing human research protections through monitoring and coordinating education and training with the Research Education Unit of the HRPP. HRPP.

� The QIP/RCU conducts periodic spot audits, as well as for-cause assessments as directed by the IRBs, the HRPP Director or the

Institutional Official (IO).� New Policies pertaining to:

– Noncompliance and Allegations of Noncompliance – Quality Improvement Program (QIP) – Monitoring and Auditing– Scientific Misconduct

� New IRB website https://cms.aub.edu.lb/irb/Pages/index.aspx

Death of a Normal Volunteer

� An Asian American student at the University of Rochester responded to an advertisement for a study

� March 31, 1996 undergo bronchoscopy for the harvest of alveolar macrophagesMarch 31, 1996 undergo bronchoscopy for the harvest of alveolar macrophages

� The bronchoscopy was difficult and required numerous doses of topical lidocaine.

� The subject returned to the hospital in cardiac arrest from an overdose of lidocaine and died April 2, 1996.

� An investigation into this death revealed:� The protocol did not limit lidocaine doses.� The doses were not documented.� The subject was not observed after the bronchoscopy .� The concentrations of lidocaine were increased without IRB

approval.

Death on Gene Therapy Trial

� In the fall of 1999, an 18-year-old Jesse Gelsinger died asa result of his participation in a gene transfer trial.

� Jesse had a rare metabolic disorder, ornithine transcarbamylase� Jesse had a rare metabolic disorder, ornithine transcarbamylasedeficiency syndrome (OTC) that was being controlled by medicationand diet.

� Researchers were testing an innovative technique using adenovirusgene transfer. Shortly after treatment, Jesse Gelsinger experiencedmultiple organ failure and subsequently died.

� Serious concerns related to the integrity of research with human subjects :� Conflict of Interest � Data Safety Monitoring� Informed Consent

The Challenges Continue….

New challenges of violating the norms relating to honesty and objectivity in research are coming up:

� Scientific misconduct : "fabrication, falsification, or plagiarism" (or FFP)

� Conflicts of Interest

Definition of Scientific Misconduct

NIH defined Research misconduct as fabrication, falsification, or plagiarism in research.

� Fabrication is making up data or results and recording or Reporting them.

� Falsification is manipulating research materials, equipment, orprocesses, or changing or omitting data or results such that theresearch is not accurately represented in the research record.

� Plagiarism is the appropriation of another person's ideas,processes, results, or words without giving appropriate credit.

� There will be an Institutional policy to describe how allegations of scientific misconduct are treated

Allegation of Scientific Misconduct

� Inquiry phase – fact finding to determine that there is allegation of misconduct - proceed to investigation

� Investigatory phase – in-depth examination of situation involving meeting with involved parties

� Outcome of investigation – if proven, sanctions imposed by institution

Conflict of Interest

� Financial interests and arrangements of clinical investigatorsthat could affect the reliability of data to be submitted to theFDA should be identified.

� An applicant is required to submit to FDA a list of clinicalinvestigators who conducted covered clinical studies andcertify and/or disclose certain financial arrangements asfollows:

1. Certification � that no financial arrangements with an investigator have been

made where study outcome could affect compensation� that the investigator has no proprietary interest in the tested

product

CON’T

� that the investigator does not have a significant equity interestin the sponsor of the covered study

� and that the investigator has not received significant paymentsof other sorts (cumulative monetary value of $25,000)

&/or2. Disclosure of specified financial arrangements and any

steps taken to minimize the potential for bias

Case of Scientific Misconduct

� Andrew Wakefield, a British surgeon and researcher, who is best known for his work regarding the MMR vaccine and its claimed connection with autism and inflammatory bowel disease

� He was the lead author of a 1998 study, published in The Lancet, which reported bowel symptoms in twelve children diagnosed with autism spectrum disorders, to which the authors suggested a possible link with the MMR vaccine

� The paper, press conference and resulting media coverage were linked to a steep decline in vaccination rates in the United Kingdomand a sharp rise in confirmed cases of measles, with two child fatalities, as well as others seriously ill on ventilators

CON’T

� Subsequent investigation failed to confirm or reproduce Wakefield's findings. The interpretation section of the 1998 paper was subsequently retracted by ten of the paper's thirteen authors

� In 2004, an investigation revealed unreported conflicts of interest; � In 2004, an investigation revealed unreported conflicts of interest; and an allegation of scientific misconduct was claimed against Wakefield

� In March 2004, the British General Medical Council (GMC) announced an inquiry into Deer's allegations of misconduct against Wakefield and two former colleagues

� In 2009 alleged scientific misconduct by Wakefield in that he "fixed" the results of the Lancet paper

� The panel ruled that Wakefield had "failed in his duties as a responsible consultant", acted against the interests of his patients, and acted "dishonestly and irresponsibly" in his controversial research

CON’T

� On February 2, 2010, The Lancet retracted his 1998publication, noting elements of the manuscript had beenfalsified.

� Wakefield does not have a medical license in the United States, and was struck off the United Kingdom medical register in May 2010.

� Inability to present/publish data when investigators arerequired to provide evidence of IRB approval

Inability of student to use data collected without IRB

Consequences of Unethical Research Conduct

� Inability of student to use data collected without IRBapproval in thesis/dissertation

� Inability to use data generated by unapproved research inexternal or internal grant proposals (particularly to federalagencies or other sponsors that adhere to requirements for protectionsof human subjects)

� Harm done to institutional reputation if the absence ofrequired oversight by IRB becomes publicly known, andthe loss of trust in the institution’s commitment for ethical

CON’T

treatment of human subjects

� Most harmfully, the message of the intentional disregardof institutional requirements that is being sent to studentand other members of research team about the ethicalintegrity of investigator

Thank you