2. FDA Warning Letters: Don’t Make the Same Mistakes! Neysa Rhoads, RN, CCRC Preventive Medicine nrhoads@utmem.edu May 3, 2015

3. “Experience is the name everyone gives to their mistakes” --Oscar Wilde

4. What are Good Clinical Practices? Guidelines for the Investigator Guidelines for the Trial Sponsor Guidelines for the Clinical Trial Protocol Guidelines for the Investigator’s Brochure

5. Fraud In the broadest sense, a fraud is a deception made for personal gain. The specific legal definition varies by legal jurisdiction. Fraud is a crime, and is also a civil law violation. Many hoaxes are fraudulent, although those not made for personal gain are not technically frauds. Defrauding people of money is presumably the most common type of fraud, but there have also been many fraudulent "discoveries" in art, archaeology, and science. From http://en.wikipedia.org/wiki/Fraud

6. Objectives Identify different types of misconduct and falsification in research Discuss causes and consequences of misconduct Learn from other’s mistakes

7. Synonyms for Fraud & Misconduct Wrong Doing Deception FelonyMalpractice Unethical BehaviorMischief CheatingFelony UnprofessionalSwindling DeceitCrime

8. Misconduct Three categories of misconduct: –Illusion of Knowledge –Surprisingly Sloppy –Malicious Malfeasance Detecting, Correcting and Preventing FDA Sanctions Resources Woollen, S.W., n.d.

9. The Illusion of Knowledge Lack of understanding Misconduct of the uninformed kind Examples: Backdating the subject’s signature on a consent form because the subject forgot to date the form, creating source documents from CRF’s, discarding source document after accurate transcription and reporting transcribed data as original.

10. Surprisingly Sloppy Lazy Inaction, inattention to detail, inadequate staff, lack of supervision Examples: ICF inadvertently not obtained from subjects, blood pressures rounded to the nearest 10mmHg, data estimated rather than actually measured, protocol ignored or shortcuts taken

11. Malicious Malfeasance Deliberate action to deceive or mislead F _ _ _ _ Examples: creating, altering, recording, or omitting data Data does not represent what actually occurred

12. Falsification of Data FDA focus: Falsification of Data –Deliberate or repeated noncompliance can be considered misconduct and is secondary focus of FDA

13. Recognizing Research Misconduct Research misconduct means falsification of data in proposing, designing, performing, recording, supervising or reviewing research or in reporting research results

14. Consequences Places subjects at possible safety risk Jeopardizes the reliability of the data

15. What Causes Fraud Study staff that does not have the necessary resources and support to accomplish their tasks Study staff have unreasonable demands placed upon them Grand enrollment incentives Just tell the truth

16. “Research for Hire: Second of Two Articles. A Doctor’s Drug Studies Turned Into Fraud ” New York Times, May 1999 Dr. Robert Fiddes Reports of Fraud by his staff went unnoticed June 1996, auditors took notice Plead guilty to fraud

17. “The Emperor Has No Clothes!”

18. Do’s and Don’ts Do –Fill in all blanks –Enter date and times –Make sure information is accurate and matches throughout the chart –Complete documentation the day of the visit –Write a progress note! –Do the right thing!

19. Do’s and Don’ts –Don’t Cut corners –Don’t Backdate –Don’t use liquid paper or pencil –Don’t re-create –Don’t perform study related procedures before the ICF is signed

20. FDA Sanctions Warning Letters Formal Disqualification Clinical Hold Voluntary Agreements Debarment Prosecution

21. Expectations of an Audit Auditors work on the assumption the records are bogus and the study is a fraud They are taught to carefully review and evaluate the Labs, ECGs & X-Rays Question missing information Look out for denial and shifting of blame Verify then trust

22. FDA Misconduct

23. You failed to obtain informed consent of each human subject in accordance with 21 CRF 50 [21 CRF 312.60] Lab samples drawn prior to signing and dating the ICF IRB approved ICF required actual time in which legally effective IC was obtained. No documentation of the actual time. Unable to verify subjects signed & dated prior to protocol specific procedures being conducted on them

24. You failed to obtain informed consent of each human subject in accordance with 21 CRF 50 [21 CRF 312.60] ICF not approved by IRB ICF not signed prior to implanting investigational device

25. You failed to obtain informed consent of each human subject in accordance with 21 CRF 50 [21 CRF 312.60] No written documentation that IC was obtained IRB approved a 3 page document. Found subjects who were consented with a 1 page ICF and unapproved ICF’s IRB approved ICF signed after study device was utilized

26. You failed to obtain informed consent of each human subject in accordance with 21 CRF 50 [21 CRF 312.60] Subject signed consent form for incorrect study Consent not signed until 11 days after study related procedure. Handwritten note states, “I was informed about study and risk-did not sign consent 6-26-03” No documentation that subject was given copy of the signed informed consent

27. You failed to obtain informed consent of each human subject in accordance with 21 CRF 50 [21 CRF 312.60] Prior to any study related procedures being performed, subject was given a copy of the ICF to read. Subject was given the opportunity to have her questions answered and wishes to participate in the TREAT trial. Subject willingly signed consent with witness present and copy of signed consent given to subject for her records. Neysa Rhoads, RN

28. Characteristics of Quality Data Accuracy Immediacy Legibility Durability Integrity Consistency Honesty

29. Warning Letter Most Recent Warning Letters are on the FDA website Read Them, See What Others Did Wrong Learn from the Mistakes of Others

30. Summary Knowledge is Power If it Looks Like a Skunk, Acts like a Skunk and Smells Like a Skunk…… IT’S A SKUNK!!!!

31. “The only real mistake is the one from which we learn nothing” --John Powell

32. References www.fda.gov/foi/warning_letters Wollen, S.W. (2003). Retrieved on 6/13/08 from http://www.fda.gov/oc/gcp/slideshows/2003/gcp2003. ppt http://www.fda.gov/oc/gcp/slideshows/2003/gcp2003. ppt Wollen, S.W. & Hage, A.E. (2001). Retrieved on 6/13/08 from http://www.fda.gov/oc/gcp/slideshows/misconduct200 1/misconduct.ppt http://www.fda.gov/oc/gcp/slideshows/misconduct200 1/misconduct.ppt Eichenwald, K. & Kolata G. (1999). A doctor’s drug trials turn to fraud. Retrieved from http://www.nytimes.com http://www.nytimes.com