Curs 2 MCS Misconduct Research 1.ppt

7/27/2019 Curs 2 MCS Misconduct Research 1.ppt

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Comprehending Research Misconduct

Peter H. Abbrecht, M.D., Ph.D.

Medical ExpertOffice of Research Integrity


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Why be concerned about prevention

of research misconduct?

Advances in research depend on the reliability of theresearch record.

In clinical trials, the research results may be the

basis for life or death decisions

Sustained public trust in the research enterprise

requires confidence in the research record and the

processes Involved in its ongoing developmentOccurrence of research misconduct has serious

consequences for all involved respondents,

co-workers, complainants, institutions, sponsors,

journals


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What is research misconduct?

Fabrication, falsification, or plagiarism in proposing,performing, or reviewing research, or in reporting

research results

(a) Fabrication is making up data or results andrecording or reporting them.

(b) Falsification is manipulating research materials,

equipment, or processes, or changing or omittingdata or results such that the research is not

accurately represented in the research record.

42 CFR Part 93.103


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(c) Plagiarism is the appropriation of

another persons ideas, processes,

results, or words without giving

appropriate credit.

(d) Research misconduct does not

include honest error or differences of

opinion.

42 CFR Part 93.103


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Requirements for findings of

research misconduct

There must be a significant departure fromaccepted practices of the relevantresearch community.

and

The misconduct must be committedintentionally, knowingly, or recklessly.

and The allegation must be proven by a

preponderance of the evidence.

42 CFR Part 93.104 (Proposed)


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Not all allegations of misconduct in

clinical research meet the definition

for Research MisconductThe distinction between research misconduct and otherproblems (such as protocol violations or fiscalmalfeasance) is important because

(a) institutions have different mechanisms for handlingthe different situations (e.g.inquiry/investigation researchmisconduct process vs IRB oversight and corrective

actions for protocol violations)

(b) reporting requirements (to oversight agencies suchas ORI, OHRP, FDA, sponsors, etc) are different


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Examples of Falsification

Substituting one subjects record for that of

another subject

Altering dates and results from subjects

eligibility visits

Altering results of laboratory tests

Backdating test or interview dates to fitprotocol time window


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Examples of Fabrication

Creating records of interviews that werenever performed

Making up progress notes for patient visits

that never took place and inserting theminto the medical record

Preparing records for calls and follow-up

contacts for participants who had alreadydied


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IRB, OHRP, FDA issues that

are not research misconduct(in the absence of falsification/fabrication):

Failure to report adverse event to

IRB/sponsor

Protocol deviations (entering ineligible

participant or using off-protocol drug)

Forging physicians signature on orders

Failing to obtain or properly document

informed consent

Breaching human subject confidentiality


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Examples of Research

Misconduct Allegations

Examples of IRB Issues

Backdating enrollment

form to make patient

eligible

Enrolling patient outsideof time window, but

recording true date

Fabricating a lab reportrequired for admission to

clinical trial

Failure to order lab testrequired to confirm

patient eligibility

Reversing end pointresults between

treatment and control

patients to improve the

statistics

Accidentally reversing[Ca++] and [K+] values in

report to data center


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Some illustrations of instances of

falsification or fabrication in clinical

records from cases with PHSfindings of research misconduct


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Circumstances That Led to

Misconduct Detection in ORI Cases

Detection by co-workers or colleagues 14

Detection by an external quality control group

(data coordinating center, external audit) 12

Discovery by direct supervisor or graduate advisor 9

Detection by an institutional quality control

group (separate from supervisor) 7

Detection by others (patients or caregivers contacting the

appointment desk, IRB member noting discrepancies) 3


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Lessons From ORI Clinical Cases

Any person involved in clinical research maybe responsible for scientific misconduct,regardless of rank or duties on the project

The majority of respondents in ORI clinical

cases are in technical positions (not doctoraldegree holders)

Many of these respondents worked withinadequate supervision or training

Respondents may have had excessive workloads or time pressure or pressure to enrollsubjects


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There are many different motivations for F / F

financial (enrollment or accrual bonuses)

professional advancement (papers,grants, tenure, job promotion/change)

personal

misguided altruism

Falsification / fabrication may be accompanied

by sloppiness or carelessness in recordkeeping

Misconduct commonly discovered by routine data audit

whistle blower

substitute staff member


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Common areas of F/F include:

protocol entrance criteria(date, lab,

history)biased randomization assignmentsfilling in missed data f/u visits, etc.

Interview protocols are at high risk for

misconduct, especially if single interviewerand/or lack of adequate quality assurance

Both scientific misconduct and violations ofhuman subjects protection may occur in thesame clinical activity

In such cases all oversight agenciesinvolved (ORI, OHRP, FDA, IRBs, etc.)work together


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Suggestions for Preventing and

Identifying Scientific Misconduct

The P.I., Lab director, etc. must establish a

climate in the lab in which scientific integrity (and

the reasons for it) are emphasized

All staff must be thoroughly trained in integrityprinciples and in conducting their portion of the

protocol

The P.I. and other supervisors must maintain

strong communication with staff and a

presence in the study setting, verifying

personally at least a sampling of the research

records


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Staff should be questioned about data alterations inthe research record (overwrites, erasures,whiteouts, changes in electronic records)

If possible, in interview studies request informedconsent to recontact the patient for quality controlreasons, and follow up with a sampling of thesepatients

Keep staff work loads reasonable

Protocols should be designed with realisticrequirements that can be met by both staff andpatients


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Protocol research forms should be as

simple as possible, yet with clear

designation of the required information

In continuing studies, if possible, train

more than one staff member to do follow-

up


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Any alterations on data forms must be

done by striking through the original entry

(no whiteout or writing over) and initialingand dating the new entry

Copies of all laboratory reports should be

retained by originating facility (to be spot

checked on routine and special audits)

Protocol sponsors should attempt to

avoid paying bonuses based on number

of patients enrolled


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to conduct the study in accordance with the relevant,

current protocol

personally conduct or supervise the described investigation

ensure that all associates, colleagues, and employees

assisting in the conduct of the studies are informed about

their obligations in meeting the above commitments

maintain adequate and accurate records in accordance

with 21 CFR 312.62

PARTIAL LISTING OF INVESTIGATOR

COMMITMENTS FDA Form 1572

(for studies requiring FDA approval)

e ec ng an an ng


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e ec ng an an ngPossible Scientific Misconduct

in Clinical Research

On routine audits, be alert for possible

clues of F / F on clinical records (whiteouts, overwritten data, numbers out of

physical alignment, errors in form

completion)

Prompt sequestration of records if

suspicion/allegation of scientific

misconduct


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ORI Guidelines for Handling Allegations of

Scientific Misconduct in Clinical Research(currently in draft form)

ORI can provide assistance to institutionsassessing possible scientific misconduct

through its Rapid Response Technical

Assistance (RRTA) program

Documents

Curs 2 MCS Misconduct Research 1.ppt