Patricia Kerby, MPA Office of Research Compliance April 8, 2010

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The Office of Research Integrity (ORI)

oversees and directs Public Health Service (PHS) research integrity activities on behalf of the Secretary of Health and Human Services with the exception of the regulatory research integrity activities of the Food and Drug Administration.

National Institutes of Health.

The Centers for Disease Control and Prevention

The Food and Drug Administration

The Substance Abuse and Mental Health Services Administration

The Health Resources and Services Administration

The Agency for Healthcare Research and Quality.

The Agency for Toxic Substances and Disease Registry

The Indian Health Service

Office of Regional Health Administrators

protecting the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products, medical devices, our nation’s food supply, cosmetics, dietary supplements, and products that give off radiation

Research misconduct means fabrication, falsification or plagiarism in proposing, performing or reviewing research, or in reporting research results.

42 CFR 93.103

_______ is making up data or results and recoding or reporting them.

Fabrication is making up data or results and recoding or reporting them

________ is manipulating research

materials, equipment, or processes or changing or omitting data or results such that the research is not accurately represented in the research record

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

________ is the appropriation of

another person’s ideas, processes, results, or words without giving appropriate credit.

Plagiarism is the appropriation of

another person’s ideas, processes, results, or words without giving appropriate credit.

Innocent Ignorance- misconduct of the uninformed kind

Noncompliance is based on lack of

understanding the regulatory consequences of an action. The act itself is usually intentional but the noncompliance is unintentional, not usually done to deliberately deceive

Backdating the subject’s signature on a consent form

Discarding source documents after accurate transcription and reporting transcribed data as original.

Using Case Report Forms as only source document

Surprising Sloppiness- misconduct of

the lazy kind Noncompliance is due to inaction,

inattention to detail, inadequate staff, lack of supervision. The act itself may be intentional or unintentional and is usually repeated.

Consent forms inadvertently not obtained from subjects

Blood pressures rounded to the nearest 5mm

Data estimated rather than actually measured

Data inaccurately transcribed as recorded

Protocol ignored or shortcuts taken

In FDA’s review of the source

documents for the records audited during the inspection, there were numerous instances where either (a) information entered into the case report forms (CRFs) did not match the information in the source documents or (b) information in the source documents was changed after the subject had completed the study, up to two years post-completion, and it could not be determined where the information related to the change was derived.

Surprising Sloppiness

Four subjects signed the 2002 ICD

version in 2004. The 2002 ICD version did not include updated data regarding sample purity rates, subject pregnancy rates, malformation rates and changes in success rates that would have been available to subjects had the proper version been used.

Innocent Ignorance

In FDA’s review of 12 of 12 subject

records, there were numerous study visits where your site’s records do no indicate that your site conducted the protocol specified physical exams and at either the screening visit, during study treatment visits and/or termination visits. In addition, in review of your site’s records, documentation could not be found to verity comments made in the CRF that a physical exam was done.

Surprising sloppiness

Our investigation indicates that you

permitted individuals to conduct study tasks which they had not been delegated the authority to execute, and that your supervision of personnel to whom you delegated study tasks was not adequate to ensure that the clinical trials were conducted according to the signed investigator statement, the investigational plan, and applicable regulations and in a manner that protected the rights, safety and welfare of human subjects.

Innocent Ignorance

The case history for Subject #002 had two different copies of CRF page 12 from Visit 1. One copy was a pink duplicate copy of CRF page 12, signed and dated as having been completed by Barbara Harris on May 10, 2007. The second copy was a photocopy of CRF page 12 also signed and dated as having been completed by Barbara Harris on May 10, 2007 but apparently filled out by a different person (as evidenced by different handwriting) and contains different information.

Surprising sloppiness

Does not include honest error or differences of opinion

Malicious Malfeasance- misconduct of the sleazy kind

Usually noncompliance is due to

deliberate action to deceive or mislead: Falsification

Creating data that were never obtained Altering data that were obtained by

substituting different data Recording or obtaining data from a

specimen, sample or test whose origin is not accurately described or in a way that does not accurately reflect the data

Omitting data that were obtained and ordinarily would be recorded

The FDA is revamping its debarment anddisqualification procedures against clinicalinvestigators by increasing staff and centralizingcoordination, and will list investigators againstwhom it has completed proceedings on its

website.“The number of clinical investigators debarred will rise in the near term as the agency reviewscases,” said Matthew Warren of the agency's

Office of Research Integrity and Responsibility

Ref: Washington Drug Letter 41(32), 17 Aug 2009

The FDA Classification of the Inspections

is according to the following: NAI – No Action Indicated VAI – Voluntary Action Indicated OAI – Official Action Indicated Recommend that Study Data be

Disqualified Recommend Restrictions placed on the PI Recommend Disqualification of the PI Recommend that the PI be prosecuted

Defined as the deliberate reporting of false or misleading data or the withholding of reportable data.

Altered data - generating biased data or changing data

that is legitimately obtained. E.g. changing laboratory data,altering weights, breaking the blind and/or randomization

Omitted data - not reporting data that has an impact on

study outcome. E.g. removing subjects from a study forbogus reasons, disguising AEs, and replacing subjects

Manufactured data - Fabricating information or creating

results without performing the work. E.g. filling in values(BP, lab values, x-ray reports) for which no data wereobtained, photocopying data from one patient for another,and creating fictitious patients

From Restrictions to Disqualifications to Prosecution

“If an explanation is offered but not accepted by CDER orCBER, the investigator will be given an opportunity for aregulatory hearing under part 16 on the question ofwhether the investigator is entitled to receiveinvestigational new drugs”. Ref: 21 CFR 312.70(a)

An investigator who has been determined to be ineligibleto receive investigational drug may be reinstated aseligible when the commissioner is assured that theinvestigator will comply with all applicable regulations. Ref: 21 CFR 312.70(f)

Fortunately not common but one can check theFDA web sites for a listing of:

FDA Debarmentwww,fda.gov/ora/compliance_ref/

debar/ FDA Disqualified / Restrictedwww.fda.gov/ora/compliance_ref/

bimo/dis_res_assur.htm FDA Warning letterswww.fda.gov/foi/warning.htm

Signing a 1572 is the PI’s legally bindingcommitment in writing that she / he will

beresponsible for the study in question;totally responsible and for everything This means she / he agrees to follow: 21 CFR 50 - Protection of Human Subjects - IC process

21 CFR 56 - Institutional Review Board

21 CFR 312 - Investigational New Drug Application

21 CFR 312.64 - Investigator Reports - AE reporting

21 CFR 312.62 - Record keeping and retention

21 CFR 312.68 - Being audit ready

Truth of the MMR vaccine scandal After an epic misconduct hearing, the

doctors who caused panic over the vaccine are about to learn their fate. A report on the greatest health scare of recent times

Doctor pleads guilty to health care fraud

A Massachusetts doctor pleaded guilty to one count of health care fraud stemming from accusations that he faked research for a dozen in published studies that suggested after surgery benefits from painkillers including Vioxx and Celebrex. He agreed to repay $361,932 of research grants and forfeit assets worth atleast $50,000. Prosecutors have recommended up to 10 years in prison.

Cuomo: NY Research used actors to fake testimony

A former University of Buffalo addictions researcher hired professional actors to testify on his behalf in a investigation into whether he fabricated data in federally funded studies.

He paid 3 actors to speak by phone during a university misconduct hearing in 2007– and then sued the state for $4 million when their false testimony helped exonerate him. The Attorney General’s Office charged him with grand larceny, perjury, identity theft, and falsifying business records.

Accused Scientist Dies

A researcher who was suspected of fabrication data and who hired actors to lie at his misconduct trial in New York in 2004 was found dead last week.