FDA Warning Letters: Don’t Make the Same Mistakes!

FDA Warning Letters: Don’t Make the Same Mistakes! Neysa Rhoads, RN, CCRC Preventive Medicine nrhoads@utmem.edu June 6, 2014

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

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

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

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

Synonyms for Fraud & Misconduct Wrong Doing Deception Felony Malpractice Unethical Behavior Mischief Cheating Felony Unprofessional Swindling Deceit Crime

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

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.

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

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

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

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

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

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

“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

“The Emperor Has No Clothes!”

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!

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

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

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

FDA Misconduct

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

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

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

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

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

Characteristics of Quality Data • Accuracy • Immediacy • Legibility • Durability • Integrity • Consistency • Honesty

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

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

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

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 • Wollen, S.W. & Hage, A.E. (2001). Retrieved on 6/13/08 from http://www.fda.gov/oc/gcp/slideshows/misconduct2001/misconduct.ppt • Eichenwald, K. & Kolata G. (1999). A doctor’s drug trials turn to fraud. Retrieved from http://www.nytimes.com

FDA Warning Letters: Don’t Make the Same Mistakes!