Presentation on theme: "Scientific Misconduct -The “F” word-"— Presentation transcript:
1 Scientific Misconduct -The “F” word- Stan W. WoollenAssociate Director for Bioresearch MonitoringOffice for the Good Clinical PracticesandAntoine El Hage, Ph.D.,ChiefGood Clinical Practices Branch II, DSIFDAOctober 2001
2 Questions for the Session "FDA Misconduct Focus Areas: What are They and Does the Data Reinforce the Agency Concerns?”Falsification, yes"How can Industry/QA Vigilance Minimize Scientific Misconduct?”QA Role=Prevention, detection, correction
3 What is Misconduct? FDA’s Focus Recognizing Research MisconductResearch misconduct means Falsification of data in proposing, designing, performing, recording, supervising or reviewing research, or in reporting research results.Falsification includes acts of omission and commission.
4 Types of Falsification Acts of omissionconsciously not revealing all data(e.g. reportable adverse events, concomitant meds., etc)Acts of commissionconsciously altering data or Fabricating data (e.g. lab values, BP readings, bogus specimens)Data is interpreted broadlyindividual facts, statistics, tissue samples, items of information, statements made by individuals
5 What is Misconduct? FDA’s Focus Deliberate or repeated noncompliance with the regulations can be considered misconduct, but is secondary to falsification of data.Research misconduct does not include honest error or honest differences of opinion.
6 Consequences of FraudIf fraud takes place in a clinical trial, it places all subjects in that trial at possible safety riskFraud jeopardizes the reliability of submitted and/or published data and undermines the Agency’s mission to protect and promote the public health
7 Consequences of FraudThough Fraud is encountered on a relatively rare basis, its impact is broad.Seriously noncompliant CIs are often used by multiple sponsors on multiple trialsSmall number of investigators can have a broad impact on many applications by many sponsors
8 Applications and Sponsors Associated with Violative CIs CI Applications SponsorsABCDEFG
9 Falsification -A chronic problem- Tony’s TalesWhat types of data were falsifiedHow was data falsifiedWhy was data falsifiedWho did itHow was it detectedQA- tips for preventing, detecting correcting
10 Types of Data Falsified EKGsBlood Pressure DataPhysical and lab examinationsBiological SpecimensSubject IdentitiesDrug Compliance RecordsYou name it
11 EKGs -a common problem Circa 1990 Kept stock files of EKGs etc. Made identical/duplicate prints of x-rays with different namesObtained blank copies of lab reports. Used a different numbering system than numbering system used by the labMultiple copy records:No originals of a particular lab report - all were photocopiesDr. SFaked subjects: used names obtained from the obituary columnCRF completed after subjects diedHad unopened cartons of the investigational drug
12 EKGs a common problem- 1998Dates were misrepresented on EKGs to coincide with protocol required visits (5)Used 5 year old EKG tracingsDates were changed in 5 records to match the washout periods required by the protocolFive subjects received prohibited medication while on the studyFive subjects did not sign consent forms before entering the studySeven subjects EKGs were not done at Visit 1 per protocol4 subjects had discrepancies between progress notes and what was reported in the CRFs
13 How is Data Falsified EKGs Continuous strip run on one patient then torn in half and represented as coming from two subjectsPreprinted subject identifying information altered or obliterated on existing EKGsDr. Xerox will see you now
14 How is Data Falsified Blood Pressure Data Blood pressure measurements and times changed in source documents to match CFR and vice versa
15 Blood pressure data questioned during in-house review 94 subjects Data Listing
16 Mind if we inspect? Sponsor’s answer- It was concluded that inconsistencies in the source documentation would make it difficult to trace or verify some of the key information. As a result of our findings, we recommend that the agency’s planned visit to the study sites for June 1997 be cancelled.NDA Withdrawn
18 What we find on siteReading Week 4 Week 8 Week 4 * Week 8 * 10/30/92 11/27/92 10/30/92 11/27/92First 195/ / / /95Second 185/ / / /90Third 198/ / / /90Fourth 195/ / / /90Average 193.2/85 185/ / /Original Case Report Form* Handwritten changes by G. Mon /18/93 - Changes are to reflect the medical chart (No source data)
19 The explanation How about the BP readings? You cannot find them in “books”They are “rare” but real, and they occur in this countryOur population is different from the U.S. population and that is why you see consistent BP readings over time (6 months)
20 How is Data Falsified Physical and/or Lab Exams Documented only by checked blocks in CRF signed by study coordinator and co-signed by PI. No corroborating source documents.Bogus lab results reported
22 How is Data Falsified Biological Specimens Samples purported to come from a large number of individual subjects actually derived from only a few different subjects.
23 The “F” Case Robert Fiddes, MD Guilty - Conspiracy to commit an offense against the United StatesGuilty - Making false statements in matter within jurisdiction of the FDA (18 USC 1001)Sentenced - 15 months in jail (see newspaper)Fined - $800,000Deported
24 New York Times May 17, 1999 RESEARCH FOR HIRE: SECOND OF TWO ARTICLES A Doctor's Drug Studies Turn Into FraudBy KURT EICHENWALD and GINA KOLATA
25 NY Times Allegation Fabrication the undetectable crime? “Another study on an antibiotic required that patients have a certain type of bacteria growing in their ear. No problem for Fiddes. He bought the bacteria from a commercial supplier and shipped them to testing labs, saying they had come from his patients' ears.”
26 NY Times AllegationThe FDA investigators asked (Fiddes), what evidence of fraud is there in the records reviewed by monitors and the government? What could the watchdogs have seen that would have allowed them to detect his fraud?
27 NY Times Allegation“Nothing, Fiddes replied. Had it not been for a disgruntled former employee, he would have still been in business.”
28 Bogus specimens A new era in detection? Chronic Bronchitis Study84 subjects enrolled, required to produce positive sputum samples to qualify for studyMonitor reported that sputum samples were not collected per the protocol (i.e. in presence of the investigator)FDA inspected and sponsor audited to validate data. No direct evidence of a problem with specimen integrity
29 Clinical Fraud Cases detecting the undetectable Sponsor performed DNA analysis on sputum and serum samples to put concerns to rest.Analysis showed 35 of 84 sets of subject serum and sputum samples did not match26 sputum samples were found to be derived from only 3 subjects
30 How is Data Falsified Subject Identities Same subject enrolled more than once under two different names and subject numbersNonexistent subjects created
31 Clinical Fraud Cases Dr. P Fabricated laboratory data and eye exams - all subjectsCreated data for subjects by using available results from different subjectsRecycled subjects (3x) and invented data (EKG tracings, duplicate lab results)Used 2 year old EKG tracingsDisqualified (Hearing)
32 Clinical Fraud Cases Dr. K. - 1987 Disqualified 85 cases submitted - ONLY 15 were real subjectsFaked approximately 70 subjects recordsNever used test article - used marketed productsDid not obtain informed consentDisqualifiedSentenced hours of community serviceFined - $30,000
33 How is Data Falsified Drug Compliance Records Returned study drug dumped, 100% compliance in taking test medication recorded in CRF
34 Why is Data Falsified? We might be cynical, but we weren’t born that way Reasons why records not available:“They were destroyed in a hurricane”“They were lost in a boating accident”(burglary, robbery or vandalism)“They were lost in the mail”“The mover threw them out”“My father-in-law threw them out”
35 Why is Data Falsified? We might be cynical but we weren’t born that way I destroyed the records. You were not informed by the sponsor!!?I did not know that the medical charts and CRFs (data) must correspond.I do not remember why I changed the dates (visits)I care for my subjects, used the “best available local therapy”I do not see a problem with re-entering a subject 5 or 6 times (considering them as six different subjects)
36 Why is Data FalsifiedReasons are not always known or clear, and often can only be inferredTo qualify ineligible subjects to enroll or continue on the studyTo please the bosses by filling in the blanks and making the source documents match the CRFFor fun and profit
37 Why is Data Falsified? “Edged into it” - rarely primary intent Not enough time or loss of interestStaff turnoverNot enough subjectsFor “good of subject”Pressure to publishPower & prestigeMoney
38 Who Does It?? Anyone at investigator’s site who has access to data Principal InvestigatorStudy coordinatorResearch SubjectsStudy Nurse?????????
39 NY Times Allegation THENURSEDIDIT Maneuver The last refuge of a scoundrel "Dr. Fiddes replied that they were going to blame the study nurse for all of the problems, and he was going to say he had no knowledge of what was going on."
40 The Blame Game Who gets the blame? 4%4%39%9%9%9%9%n (parties blamed) = 23n (cases) = 2017%
41 QA’s Role in Dealing with Misconduct PreventionIdentify and eliminate/minimize risk factors for misconductDetectionMonitor and recognize signs of fraudCorrectionPromptly investigate and report fraud
42 Tips for Preventing Fraud Make sure all study staff have the necessary resources and support needed to accomplish their tasksDon’t place needless requirements or unreasonable demands on the siteMonitor sites closely and pay attention to complaints from site personnelMinimize the use of enrollment incentives
43 Approaches in Detecting Fraud (Rules?) Tip/nose/experience/gut feelingUnderstand the protocol or planParameters that determine eligibility (inclusion/exclusion criteria)Accept no copies - originalsIdentify all source/supporting documentsLook for mistakes/changes/inconsistenciesFrequency of changes - identify who made themDetermine & document if changes are justifiedChallenge suspicious dataAsk for all information (data) pertinent to the study (CRF, AB, CPF, MV-MR, X-R, EKG, DIA, etc.)
44 Tips for Detecting Serious Misconduct Get Technical-Read x-rays, EKGs, lab results, don’t just inventoryFill in the Blanks-Question missing dates, times, information,offer to retrieve records yourselfDon’t be intimidated-tell the emperor he has no clothes
45 Tips for Detecting Serious Misconduct Don’t shoot the messenger-believe the monitor, put the burden of proof on the CIBe suspicious of blame shifting-tell CI he/she is totally responsible for the conduct of the studyExpect Fraud-Start from the assumption the records are bogus and the study is a fraud, and work back
46 Tips for Detecting Serious Misconduct Cultivate Whistleblowers-establish rapport with study staff, be approachable and available, listen to grievances, observe working conditions
47 Who Complains?---Everybody! FY 2000 2%2%14%5%8%3%3%11%9%8%8%9%19%n = 118
48 What Are They Complaining About? Everything!! Failure to follow the protocol (70)Falsification (67)Informed Consent Issues (55)Failure to report adverse events (40)Qualifications of persons performing physicals (27)Inadequate Records (25)Failure to get IRB approval, report changes in research (20)Failure to follow FDA regulations (13)Charging for the test article (9)Drug accountability (7)No active IND (7)Violations of GLP regs (7)Misleading advertisements (5)Blinding (3)No 1572 (2)Monitoring practices (2)IRB shopping (1)
50 Complaints Inspected and Their Classifications 26%26%26%(n= 27)n= 27n= 10552%
51 Correcting Misconduct How You can help FDA Wants You to Recognize and Report Research Misconduct
52 FDA Believes Sponsors should Promptly Report... Any information they have that any person involved in human subject trials committed research misconductWhenever the sponsor discovers misconductNot just for clinical investigators and not just when a clinical investigator is terminated
53 Correcting Misconduct Reporting Research MisconductName of the person(s)Contact informationSpecific identity of the affected researchIND/IDE #, protocol, study title, and study datesAs much information regarding the research misconduct as is available to the sponsor.
54 Where to Report Misconduct DrugsDivision of Scientific Investigations (HFD-45), Office of Medical Policy, Center for Drug Evaluation and Research, FDA, 7520 Standish Place, Room 103, Rockville, Maryland , (301) , fax (301)
55 Where to Report Misconduct Biological ProductsOffice of Compliance and Biologics Quality, Division of Inspections and Surveillance, Center for Biologics Evaluation and Research, (HFM-650), FDA, 1401 Rockville Pike, Room 400S, Rockville, Maryland , (301) , fax (301)
56 Where to Report Misconduct Medical DevicesOffice of Compliance, Division of Bioresearch Monitoring, (HFZ-310), Center for Devices and Radiological Health, FDA, 2098 Gaither, Room 130, Rockville, Maryland 20850, (301) , fax (301)
57 Tips for Dealing with Serious Misconduct Be Prepared- have a system in place to capture, document and deal with complaints of misconduct in a timely fashion. Follow your SOPs!!!!