DEPARTMENT OF HEALTH AND HUMAN SERVICES
U.S. FOOD AND DRUG ADMINISTRATION
REGULATORY HEARING ON THE PROPOSAL TO DISQUALIFY
ARTHUR RIBA, M.D.
FROM RECEIVING INVESTIGATIONAL NEW DRUGS
DECISION OF THE·PRESIDING OFFICER
As provided in title 21 of the Code of Federal Regulations ("C.F.R.") Parts 16 and 312, I have reviewed:
• The transcript of the 21 C.F.R. Part 16 hearing held December 12 and 13, 2000, and documentary evidence submitted by the parties,1
• The Initial Request for Summary Decision and supporting exhibits submitted by the Center for Drug Evaluation and Research ("CDER" or the "Center) ("CDER IRSD"), and
• Respondent's Memorandum in Opposition to CDER's Motion for Summary Judgment ("Respondent's Mem.).
The hearing was held and the documents were submitted following Dr. Riba's request for a hearing to consider CDER's proposal to disqualify him from being eligible to receive investigational drugs as provided in 21 C.F.R. § 312.70.
This document is my report on the hearing in accordance with 21 C.F.R. § 16.60(e), and it constitutes my findings on the charges brought by CDER. In accordance with 21 C.FR. §§ 16.95 and 312.70, this report along with the administrative record of the proceedings will be referred to the Commissioner of Food and Drugs, who will make a final determination of whether to disqualify Dr. Riba.
A. Summary of the Basis for CDER's Proposal to Disqualify Dr. Riba
There are two primary, interrelated bases for the disqualification action brought by CDER. The first is the alleged failure of Dr. Riba to supervise a study (known as the "PURSUIT" study) for which Dr. Riba was the principal investigator, in violation of 21 C.F.R. §§ 312.60 and 312.53(c)(1)(vi)(c) (Charge 1).2 CDER alleges that this failure to supervise caused the second primary basis for this disqualification proceeding -submission of false information to the sponsor in violation of 21 C.F.R. § 312.70(b) (Charge 2).3 The false information consisted of false reports of electrocardiograms (ECGs) that were to have been obtained during the second segment of the study, known as the 30-day follow-up. The Center made three additional charges (Charges 3-5), which in part arose from the study coordinator's ECG falsifications. 4 These changes include: 1) failure to conduct the clinical study in accordance with the approved protocol;
2) failure to maintain adequate and accurate case histories; and 3) failure to report adverse events.
B. Initiation of the Study
Dr. Arthur Riba is Medical Director of the Coronary Care Unit and Director of Cardiology Education and Research at the Oakwood Hospital and Medical Center, Dearborn, Michigan.5 He is also a Clinical Associate Professor of Medicine at the University of Michigan School of Medicine.6 He has been involved in clinical research since 1984, has been principal investigator for 35 trials, and has approximately 30 publications.7
Dr. Riba's clinical research coordinator for the past seven years has been (b)(6) ,R.N. Ms. (b)(6) has coordinated 25 studies under Dr. Riba's direction. She has a B.S. in nursing, an M.S. in nursing administration and is completing a clinical M.S. in nursing.8
On December 13, 1995, Dr. Riba and Oakwood Hospital entered into an agreement with the sponsor, Cor Therapeutics ("Cor"), and a data coordinating center, the (b)(4) "Coordinating Center (b)(4), under which Oakwood would serve as one of approximately 500 sites involved in the phase III clinical trial of Integrelin.9 (b)(4)s coordination of the study was to be through the (b)(4) acting as a contract research organization (CRO) for Cor.10
On December 14. 1995; Dr. Riba signed FDA Form 1572. 11 for the study. under which he agreed among other things to personally conduct or supervise the investigation.12
C. Description of the study
The PURSUIT trial was a "randomized double-blind evaluation of the efficacy and safety of Integrelin versus placebo for reducing mortality and myocardial (re)infarction in patients with unstable angina or non-Q wave myocardial infarction.13 The primary efficacy variable was the composite endpoint of the first occurrence of death or myocardial (re)infarction (MI) in 30 days.14
The drug was designed to both prevent clots from forming in coronary arteries, and dissolve clots already there. The importance of testing this drug was to see whether Integrelin actually possessed these dual properties. Until the Integrelin clinical trial, the drugs used for prevention or dissolution of clots were capable of accomplishing only one of either of these tasks, so patients had to be administered one drug in conjunction with another drug to accomplish the two goals of prevention and dissolution of clots. 15
The drug is a platelet inhibitor, an IV medication intended for patients in the acute-care setting, i.e., patients presenting with an acute coronary syndrome (chest pain, either unstable angina or a non-Q MI).16
2. Overview of the Study Plan
The study Was to consist of three segments. The first was the baseline segment, which extended from the time the hospitalized patient was randomized until discharge.17 The second was a 30-day follow-up, during which the patient would be re-evaluated, 30 days post-enrollment, for occurrence of any component of the composite efficacy endpoint of death or myocardial (re)infarction.18 The third segment was a 6- month follow-up.19 The first two segments are discussed in detail below; the third is not relevant to this action.
The roles and responsibilities of Dr. Riba and (b)(4) varied according to the segment. Briefly, Dr. Riba had a major responsibility in the baseline segment for evaluating data, determining patient eligibility for the study and completing an extensive Case Report Form (CRF). (b)(4) was charged, among other things, with monitoring 5% of the enrollment during the baseline segment, specifically the case report forms through discharge,20 and performing source documentation of all clinical events (in-hospital death, myocardial (re)infarction)21 In the 30-day segment, Dr. Riba's role was to collect ECGs and complete-a 30-day Visit Form and send them to (b)(4) for clinical endpoint adjudication by (b)(4) Clinical Events Committee (CEC).22 Thus, (b)(4) had the responsibility for analyzing the 30-day ECG and evaluating information in the 30-day Visit Form.23 (b)(4) apparently was not responsible for monitoring Oakwood's activities in collecting the ECG and completing the 30-day Visit Form.24
3. Baseline Segment
During the first segment, Dr. Riba was responsible for conducting a pre-enrollment assessment of the patient, enrolling and randomizing the patient, treating the patient with a single infusion of the experimental drug, and following established post-infusion procedures. During this first segment, several 12-lead ECGs, including an ECG conducted during pre-enrollment assessment of the patient, were required. Based on the pre-enrollment ECG and laboratory tests, Dr. Riba was expected to determine whether the patient met the entry criteria25 before contacting the randomization center a (b)(4) though it appears that (b)(4) expeditiously reviewed" Dr. Riba's assessment "at the time of randomization."26 A complete schedule of evaluations is shown in the protocol.27
For each enrolled patient, Dr. Riba was also expected to complete the baseline CRF, which was a 10-page form encompassing the entire baseline hospitalization, 28. and which required entry of nearly 500 data points.29 The last item on the baseline CRF was for the Investigators and Coordinators signatures. This item contained the statement "I have reviewed all the data recorded on these CRF pages and certify that they are accurate and·complete to the best of my knowledge."30 The instructions to the baseline CRF directed the investigator to submit the completed baseline CRFs to (b)(4) within seven days of hospital discharge.31
Documents that guided the study required the maintenance of certain source documents in the baseline segment. For example the Case Report Form booklet stated: "Be certain all data entered on the Case Report Form (CRF) is verifiable from a source document such as the medical record, diagnostic reports, or worksheets."32 The booklet also provided for the keeping of a number of documents in the "Patient CRF Folder," including copies of ECGs, lab reports and other documents.33
4. 30-day Follow-up
The second segment was the 30-day follow-up. According to the protocol, the 30-day follow-up will consist of a clinic visit. Information regarding (re)infarction, stroke, recurrent ischemia, revascularization procedures, and death will be collected, and an ECG will be obtained.
The patient does not need to be seen at the enrolling center for the 30-day visit. Instead, the patient can be seen by the referring physician and an ECG and necessary event information obtained. ECG records performed between 28 days and 42 days after enrollment will be allowed as the "30-day ECG".34
According to nurse (b)(6) this language meant that "we could obtain that EKG from a variety of sources, not necessarily from Oakwood Hospital itself. So we could go to a physician's office, if the patient had an EKG done there, to a cardiologist's office. All we were meant to do with the 30-day information was gather the EKG, contact the patient, gather the information for completion of the CRF...."35
The Study Coordinator's Manual36 outlined the follow-up stages, including completion of the 30-day Visit Form. Instructions for completion of the 30-day Visit Form were included in the Case Report Form booklet.37 The 30-day Visit Form was a one-page form requesting five categories of information: Patient Status; ECG; Angina Classification at Time of Contact; Rehospitalization; and Events Between Discharge and 30 Day Contact or Death.38 This information could be obtained directly from the patient.39
The ECG section of the form contained spaces for the date and time the ECG was conducted, and a box to check if the ECG was not done. This section of the form also contained the parenthetical direction to forward the ECG to the Coordinating Center. In addition, the 30-day Visit Form contained an ECG label (the "30-day sticker"), which was to be removed from the form and affixed to the 30-day ECG.40 The PURSUIT Case Report Forms booklet stated that the 30-day Visit Form was to be faxed to (b)(4), and the 30-day ECG was to be delivered to (b)(4) by overnight delivery. 41
In contrast to the baseline CRF, the 30-day Visit Form did not require the signature or even the identity of the person completing the form.42 Also unlike the baseline CRF, source documents were not specified for the 30-day Visit Form, although specified medical records were required for clinical events that occurred between discharge and the 30-day visit.43 In addition, a 30-day rehospitalization form was required for patients rehospitalized during that period.44
Dr. Riba understood that he was not required to render a medical opinion in this segment.45 (b)(4) Clinical Events Committee (CEC) was to interpret/adjudicate the data.46 The CEC reviewed the 30-day form and the ECG "to determine whether they had achieved an end point,"47 and compared the 30-day data with the baseline and see if there were any differences in that EKG that would indicate ischemia or an ischemic event had occurred.48
D. Conduct of the Study
1. Hiring, Training and Supervision of Nurse (b)(6)
Dr. Riba realized that there would be a large number of patients enrolled in the PURSUIT study, and therefore he needed to have an additional coordinator.49 Thus, (b)(6), R.N., was hired specifically as the study coordinator for the PURSUIT study. Ms. (b)(6) interviewed 12 candidates, and narrowed the field to six. She and Dr. Riba interviewed the final six, and selected Mr.(b)(4). They selected him because he had six years experience in the coronary care unit (CCU) at Oakwood, was interested in research, and was completing an M.S. in administration. They checked references including nurse managers of the CCU and some of his peers, all of whom "felt he'd be appropriate for the department and would be an excellent employee for us."50 There was no indication that there might be a problem with his honesty.51 However, Dr. Riba and Ms. (b)(6) did not check Mr. (b)(6) personnel file at the hospital.52
Nurse (b)(6) started about two weeks before the date set to start the trial, in March 1996.53 Ms.(b)(6) provided a six to eight week orientation.54 The first two weeks prior to start-up included briefing on general guidelines for research, including Good Clinical Practices, the Code of Federal Regulations, and informed consent.55 Mr. (b)(6) shadowed Ms. (b)(6) on other trials, learning how to screen patients, how to follow study protocols, and inclusion/exclusion criteria.56 He also spent time during the first two weeks with Dr. Riba - following him on rounds, to learn Dr. Riba's general .practice pattern and his clinical expectations for the patients, and to improve his clinical skills. In addition,he spent time in Dr. Riba's outpatient office, to learn about stress testing, the catheterization lab, and acute care.57
Nurse (b)(6), as chief clinical research nurse coordinator of all of Dr. Riba's trials, was predominately responsible for the orientation and in-servicing of Nurse (b)(6).58 Dr. Riba acknowledged that he was responsible for supervising Mr. (b)(6).59
2. Conduct of the Baseline Segment
Dr. Riba stated that Mr. (b)(6) 's responsibilities in the baseline segment were "well summarized in the manual ... [he needed to] understand the protocol ... [he] was going to actually recruit the patients ... [and to] make sure all the inclusion and exclusionary criteria were being met... [he was responsible for] administration of the drug ... [and to] monitor any ill effects as the drug was being administered. [Mr. (b)(6) was to] obtain all the data necessary for the case report form ... [and to] monitor patients during hospitalization to make sure any events that occurred were fully documented.... [He was to] fill out [the] case report form and make sure that [Dr. Riba] complete[s] and sign[s] it.60
Mr. (b)(6) took his recruiting responsibilities seriously. The Oakwood site enrolled 93 patients 61 from March 1996 to January 1997,62 the highest enrollment site for the region.63
Dr. Riba reviewed every EGG taken - four or more per patient - during the baseline segment.64 The ECGs were source documentation for adjudication; Dr. Riba adjudicated the EGGs "to make sure [the patients met] eligibility criteria and during the subsequent hospitalization to see whether there [was] any confirmatory findings that suggest[ed] that there was a myocardial infarction,"65 Nurse (b)(6) reviewed some of the EGGs, and Dr. Riba reviewed them after Nurse's (b)(6) review.66
After the patients were discharged, Mr.(b)(6) completed the CRFs and submitted them to Dr. Riba for review.67 The CRFs included "the demographics of the patient, what treatments they were receiving, all the supportive laboratory data, the EKGs, the cardiac enzymes, which were very important to adjudicate whether a patient had any myocardial infarctions, the cardiac catheterization reports, the subsequent course of the patient during the hospitalization and the final event part ..."68
Dr. Riba reviewed every one of the close to 500 data points in each patient's CRF.69 In doing so, he reviewed source documents to verify the data in the CRFs. "One of the requirements.. of the study coordinator is that When I review the charts I want to see a shadow chart. I want to see a complete photocopy of the patient's record ... to see whether all the data points match..."70 Dr. Riba did not find many errors in
the forms Mr. (b)(6) filled out.71 Dr. Riba "reviewed every actual cardiac catherization with (b)(6) sitting in front of the films ... [it was a) wonderful opportunity to do one-on-one teaching.72
Ms. (b)(6) added the following perspective to Nurse (b)(6)'s supervision: "... the beginning [Dr. Riba] worked with (b)(6) very closely clinically, and they would identify patients. If (b)(6) would identify patients, they would work [together] in looking at the data, at ... interpreting the EKG[s], making sure the patient met criteria."73 She also testified that "[w)e also met on a routine basis, the three of us, to go over how things were going with the study, how recruitment was going. ...74 Ms. (b)(6) concluded that Mr. (b)(6)'s performance with regard to the baseline reports was satisfactory, and there was nothing to indicate he had problems with the truth. 75
(b)(6) conducted six monitoring visits between April 17, 1996 and April 16, 1997;76 presumably the first four concerned the baseline segment, and the last two were conducted after the 30-day visit problems were encountered.
An FDA inspection, described below, did not disclose serious problems in the baseline segment of the Oakwood study.77
3. Conduct of the 30-day Follow-up
In contrast to the baseline segment, which involved close supervision of Nurse (b)(6) by Dr. Riba, completion of the 30-day requirements was delegated, essentially without supervision, to Mr. (b)(6). As explained above, there were two primary requirements. The first was obtaining an ECG within 28 to 42 days after enrollment, either on a return to Oakwood or from the patient's primary physician. According to the FDA inspector the patients normally returned to Oakwood for the 30-day visit. 78 The second requirement was completing the 30-day Visit Form with information obtained from phone calls to patients or from other sources.79 Ms. (b)(6) testified that within 24 hours after completion, the 30-day ECG was sent to (b)(4) by overnight delivery, and the form was faxed. 80
As explained above, the study documents did not require source documents in the 30-day segment. Neither Dr. Riba nor Ms. (b)(6) required Mr. (b)(6) to prepare or collect source documents. For example, they did not require Mr. (b)(6) to maintain a log of telephone calls with patients or others.81
Ms. (b)(6) watched Mr. (b)(6) initiate the 30-day follow-up for about the first four patients.82 She then made the decision (with Mr. (b)(6) that the 30-day documents were his responsibility without further supervision.83
Dr. Riba's involvement with Mr. (b)(6) in the 30-day segment appears to have been limited to the 12 study subjects who were also Dr. Riba's patients. For those patients, Mr. (b)(6) would go to Dr. Riba's office and obtain the ECGs, and Dr. Riba would review the ECGs as part of patient care.84
Dr. Riba indicated that neither he nor Ms. (b)(6) reviewed the 30-day Visit Form since it involved a simple follow-up visit and did not require their signatures.85 [He acknowledged that this aspect of the study was unusual in that in "[p]retty much every study that I've been in the last page gets signed off."]86 There was no PURSUIT requirement for him to review the ECGs.87 Dr. Riba saw his role as that of a conduit, not that of an interpreter88 Dr. Riba noted that there was no place for Mr. (b)(6) to sign the 30 day form either,89 but conceded that Mr. (b)(6) was obligated to tell the truth even though no statement in the protocol said so.90
According to Dr. Riba, the protocol provided for the study coordinator to collect the data required for the 30-day Visit Form;91 there was no requirement for Dr. Riba to collect the information himself.92 Further, Dr. Riba contended that even if he had reviewed the 30-day reports after Mr. (b)(6) prepared them, he would not have been able to verify their accuracy; he would have needed source documents, which did not exist.93 However, he would have reinterviewed patients if he had been suspicious that Mr. (b)(6) was acting inappropriately.94
Dr. Riba and Ms. (b)(6) stated that (b)(6) did not monitor the 30-day study (until the problem surfaced) because the CEC essentially monitored that phase; the CEC received the data directly from Dr. Riba's group.95
E. Discovery of the Problem. and Response
1. Discovery of the Problem
Dr. Riba and Ms. (b)(6) first learned of a potential problem with the 30-day ECGs in discussions with a (b)(4) employee in March, 1997, during a meeting of the American College of Cardiology.96 On returning to their offices, they verified from their records that the dates of a number of the ECGs had been falsified.97 The ECGs that had been submitted as 30-day ECGs (with dates indicating that they had been obtained at the time of the patient's 30-day evaluation) were actually ECGs that had been obtained while the patient was hospitalized (during the baseline period) or at another time than 28-42 days post-enrollment in the study. These falsifications allowed the data obtained from the ECGs to fit within the time frame required by the approved protocol.
Specifically, the computer generated time and date on the ECGs had deliberately been covered with the "30 day sticker"; a new time and date were handwritten on that label. The handwritten dates were then reported on the 30-day, Visit Forms, falsely indicating that the ECGs had been taken at a 30-day post enrollment visit.98
The first false ECG went to (b)(4) on June 28, 1996.99 CDER states, based on, results of (b)(4) monitoring visits, that falsified ECGs were submitted for 65 of the 93 subjects in the Oakwood, study.100 However, the FDA investigator reviewed only 17 patients' documents, finding false ECGs in the files of nine patients.101
When confronted, Nurse (b)(6) admitted to the falsifications.102 He told Ms. (b)(6) that he had nevertheless contacted the patients to obtain information for completing the 30-day Visit Form; however, a review of the records by Ms. (b)(6) raised doubts about the accuracy of his statement.103
The falsification was easily recognized because the "30-day sticker," which was to have been placed in the lower right corner of the ECG, had instead been placed over the original date and time at the top of the form. 104 "The label [was] put over the computerized indicator of the time and date on which the EKG was obtained and it was a requirement that it be put over on the side.... [P]lus [it was] over the interpretation.105
Dr. Riba would have recognized that the ECG dates were falsified - "a first year medical student would have realized that"106
Testimony as to whether the Oakwood files contained originals or copies of the ECGs was conflicting. The FDA inspector, Nancy Bellamy, appears to have testified that most of the falsified ECGs in the Oakwood files were copies, while the ECGs in the files that had not been falsified were originals.107 She also testified that Ms. (b)(6) was not aware of where the originals were located.108
Ms. (b)(6) testified that (b)(4) preferred to receive the originals and that the protocol so stated, but also testified that an original or copy could be sent.109 She further testified that the original was an official source document, and was required by the PURSUIT study's Inservice Manual to be in the CRF.110 Dr. Riba testified that some of the originals were retained in the Oakwood files. 111
2. Actions to Correct the ECG Problem
Mr. (b)(6) 's employment was terminated after the discovery of the falsified records.112 Dr. Riba and Ms. (b)(6) undertook an effort to "clean up" the data, following recommendations and instructions from (b)(6) and Cor.113 They were to try to obtain ECGs that might have been in the computerized archival system of the hospital and that might have coincided with the 30-day (28 to 42 day) time period, and to contact primary care physicians and cardiologists to determine if ECGs had been obtained by those physicians during post-release follow-up.114 If these efforts were not successful, they were to bring the patients back to Oakwood and try to obtain an ECG;115 in the end, the latter option was necessary for a majority of the patients.116
Dr. Riba and Ms. (b)(6) submitted "data clarification forms" to specify when the ECGs were actually obtained.117 They did not recall (b)(4) instructing them to label the new ECGs as "30-day ECGs.118 Dr. Riba and Ms. (b)(6) were commended by (b)(4) for their efforts to Correct the data.119
3. Other Actions Taken
Dr. Riba requested and received an external audit of the Oakwood research program by Dr. (b)(4), Chief of Psychiatry, and Dr. (b)(4) Director of Clinical Trials, Clinical Trials Office, (b)(4). 120 The audit team concluded that the episode of misconduct appeared to be an isolated one, and that Oakwood's hiring practices were consistent with national standards.121 However,the team made a number of recommendations, including hiring a second cardiologist "to permit closer supervision of trials," and mandatory training programs that included ethics training.122
Dr. Riba and Oakwood have implemented many of the recommendations of the (b)(4) Team including a new data quality assurance program, which demands, among other things, stricter source documentation. The program operates under the philosophy that all data are suspect unless proven to be valid. 123 According to Dr. Riba, the new precautions cause staff members to think their professional judgment and integrity have been questioned.124 Dr. Riba has been reviewing, interpreting and signing every ECG.125 Oakwood has also hired other staff members for its research activities.126
Dr. Riba explained that Mr.(b)(6)'s actions "undermined the validity and integrity of important data and after a 20-year career in medicine that has been unblemished, I cannot begin to describe what's it's like to have this pall cast over my professional reputation. What happened is terrible but not a result of something that I could have or should have foreseen. This could have happened to ... any responsible
investigator.... I've been punished.... I've been embarrassed professionally and personally."127 Dr. Riba (b)(4) noted that" does not hold him responsible for the falsifications. 128
III. REGULATORY HISTORY
FDA first learned about the falsifications during a pre-approval data validation inspection conducted from February 5, 1998 through March 12, 1998.129 Dr. Riba and Nurse (b)(6) supplied information on the 30-day ECG problem at the start of the inspection.130
As explained above, the inspector examined the files of 17 patients, documenting that the 30-day ECGs of nine of these patients had been falsified. The inspector issued an eight-point FDA-483 (Inspectional Findings) at the conclusion of the investigation.131 Most of the points related to the 30-day segment of the PURSUIT study. As explained above, the inspector examined, but did not find serious problems with, the baseline segment of the study. "For-cause" audits of two additional studies performed by Dr. Riba, initiated as a result of the adverse findings in the 30-day segment of the PURSUIT study, found no evidence of discrepancies.132 Dr. Riba responded to the inspectional findings on March 19, 1998.133
FDA issued a Notice of Initiation of Disqualification Proceedings and opportunity to Explain (NIDPOE) to Dr. Riba on May 19, 1999.134 Dr. Riba responded to the NIDPOE by counsel on June 22,1999.135
FDA issued a Notice of Opportunity for Hearing (NOOH) to Dr. Riba February 19, 2000.136 The NOOH included five charges, and an allegation that Dr. Riba repeatedly and deliberately violated the regulations:
Charge 1: Failure to personally conduct or supervise the clinical investigation as Dr. Riba committed to do by signing the Form FDA 1572, in violation of 21 C.F.R.§§ 312.60 and 312.53(c)(1)(vi)(c). This lack of supervision allowed the submission of false information to the sponsor.
Charge 2: Submission of false information to the sponsor, in violation of 21 CFR § 312.70(a).
Charge 3: Failure to conduct the clinical study in accordance with the approved protocol, in violation of 21 CFR §§ 312.60 and 312.53(c)(1)(vi)(a), by "resubmitting" new "30-day ECGs" (replacement ECGs) when in fact these new ECGs were done anywhere between three months to one year after randomization; and failure to ensure that the information recorded and forwarded to the sponsor on the "30-Day Form" regarding the subjects' status at approximately 30 days post-enrollment was complete and accurate.
Charge 4: Failure to maintain adequate and accurate case histories for two subjects in violation of 21 CFR § 312.62(b). One subject, who died one day after release from the hospital, was reported as alive 30 days after release. The ECG for the second subject does not have a computer-generated date and time to show when the ECG was performed.
Charge 5: Failure to report all adverse effects, in violation of 21 CFR §§ 312.64(b) and 312.53(c)(1)(vi)(e). Rehospitalization of one subject was not reported to the sponsor. Counsel for Dr. Riba submitted a request for hearing and denial of all allegations on March 10, 2000.137 CDER filed its Initial Request for Summary Decision on November 3, 2000. In it, CDER argues for summary decision on the first four of the charges (excluding adverse effects). Counsel for Dr. Riba filed a Memorandum in Opposition to CDER's Motion for Summary Judgment December 1, 2000.
I decided that a hearing should be held, and one was held under 21 C.F.R. Part 16 on December 12 and 13, 2000. CDER presented three witnesses: Ms. Nancy Bellamy (Nancy Mundo at the time of the inspection); the FDA inspector; Charles Ganley, M.D., Director, Division of Over-the-Counter Drugs, CDER; and Stan Woolen, Deputy Director of Scientific Investigations. Counsels Leigh Hayes and Robert Spiller appeared on behalf of the Center. The Center also submitted documentary evidence, the exhibits to its IRSD.
Dr. Riba testified on his own behalf, and presented the testimony of two additional witnesses: Ms. (b)(6) and Dr. (b)(6) a cardiologist at (b)(6) and Clinical Director of the (b)(6), among other responsibilities. Dr. (b)(6) provided site management for two trials (not PURSUIT) for which Dr. Riba was a clinical investigator.138 Dr. Riba also submitted documentary evidence (Respondents Documentary Evidence, RDE) which included letters from (b)(4) M.D., Chairman of the Department of Cardiology at the (b)(4) and a member of the PURSUIT Executive Committee,139 and (b)(4), M.D. Co-Director, Clinical Trials, (b)(4). 140 Counsels Robert Charrow, Laurel Pike Malson and Philip Katz appeared for Dr. Riba.
IV. REGULATORY FRAMEWORK
FDA's regulations governing the clinical evaluation of investigational new drugs, such as those that were administered in the studies for which Dr. Riba was the principal investigator, are set forth in 21 C.F.R. Part 312. Section 312.70 of the regulations provides for the disqualification of clinical investigators for violations of these regulations:
After evaluating all available information, including any explanation presented by the investigator, if the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the requirements of this part, Part 50, or Part 56, or has deliberately or repeatedly submitted false information to the sponsor in any required report, the Commissioner will notify the investigator and the sponsor of any investigation in which the investigator has been named as a participant that the investigator is not entitled to receive investigational drugs. The notification will provide a statement of basis for such determination. 21 C.F.R. § 312.70(b).
As explained elsewhere, CDER has alleged both that Dr. Riba repeatedly and deliberately failed to comply with specified requirements of 21 C.F.R. Part 312, and that he repeatedly and deliberately submitted false information to the sponsor.
"Repeatedly" means" more than once, or again and again."141 An investigator can commit violations "repeatedly" in one study, i.e. disqualification does not require transgressions in more than one study.
The term "deliberately" includes conduct that is "willful...142 When an investigator engages in conduct that the investigator either knew, or showed reckless disregard for the possibility that the regulations in 21 CFR Part 312 were being violated or that information submitted by the investigator was false, the clinical investigator is liable to being found to have "deliberately" violated the regulations.
CDER has the burden of proof and thus is required to show by a preponderance of the evidence that Dr. Riba repeatedly or deliberately violated the regulations, or repeatedly or deliberately submitted false information.
v. ANALYSIS OF CHARGES
Charges 1 and 2
1. Failure to supervise the investigation as required by the Form FDA 1572, in violation of 21 CFR §§ 312.60 and 312.53(c)(1)(vi)(c).143
2. Submission of false information to the sponsor, in violation of 21 CFR § 312.70(a).144
CDER stresses the medical significance of the study, specifically that the investigational drug is for the treatment of heart disease.145 The Center also emphasizes that the segment in which problems were found was the segment in which clinical endpoints were measured.146
CDER asserts that Dr. Riba repeatedly submitted false data because false ECGs were submitted to the sponsor for 65 subjects.147 Emphasizing the interrelationship between Charges 1 and 2, the Center contends that the alleged lack of supervision (Charge 1) allowed (or caused) submission of false information (Charge 2): 148 CDER argues that Dr. Riba was the principal investigator and thus was ultimately responsible for everything that happened in the study -- he should be disqualified because of his lack of supervision as demonstrated by the falsifications. 149 CDER cites the Form FDA 1572 for the position that Dr. Riba was responsible for the integrity and accuracy of the submitted data, even though he did not personally submit the false information.150 During the hearing, CDER noted that Drs. Riba and (b)(6) testified that principal investigators are responsible for overall supervision and conduct of their studies,151 and asserts that as a policy matter FDA can not allow principal investigators to blame their nurses every time something goes wrong.152
CDER argues that Dr. Riba needed to take prophylactic measures to ensure that the regulations would be followed,153 but that he had no system in place to detect intentional misconduct. Because of the lack of supervision, CDER asserts, nurse (b)(6) knew that he could get away with the falsifications.154 In closing argument, CDER's counsel asserted that Dr. Riba "admitted that he was responsible for the nurse's conduct because he didn't have an adequate supervising system in place." 155
During the hearing CDER presented testimony as to supervisory actions Dr. Riba could have taken; presumably the testimony was intended to describe the prophylactic system that CDER contends Dr. Riba needed to have in place. First, CDER suggested.that completion of the 30-day Visit Form needed input from a physician, namely Dr. Riba. Dr. Ganley testified that because the 30-day segment was the pivotal part of the entire study, Dr. Riba as the principal investigator should have had some oversight.156 He stated that answers to some questions on the form were fairly obvious, but that
it becomes more difficult when you're getting into suspected MI, because ... this was one of the triggers that caused the CEC to adjudicate this event. So there would have to be someone that would be questioning the patient that would have an understanding of whether the person actually had an MI, and that may require them to look at source documentation.157
The Center suggests that source documentation (e.g., worksheets and medical records) should have been maintained in addition to copies of the ECGs.158 CDER also asserts that Dr. Riba could have compared the information on the 30-day Visit Form with the source documentation 159 including the ECG.160
CDER states that the study was "somewhat unique" in that Dr. Riba was responsible for collecting 30-day data even though he was not required to see the patients during that segment.161 Dr. Ganley also testified that it would be preferable if the 30-day Visit Form had a signature or initial block.
CDER takes the position that Dr. Riba deliberately violated the regulations requirement to supervise because although Dr. Riba states that his failure to detect immediately the nurse's improper conduct was, at most, "inadvertent," the
vast number of falsifications and numerous violations prove that even if the nurse was responsible, the nurse knew that Dr. Riba would not detect these egregious violations because of his flagrant lack of supervision.162
CDER further contends that Dr. Riba deliberately submitted false information to the sponsor because original dates and times were blacked out, and were replaced with false labels. According to CDER; although Dr. Riba claims he was not personally responsible, "[i]f any of his staff violated FDA regulations, Dr. Riba, as he acknowledged when he signed Form 1572, was ultimately responsible for any inaccurate data.163
Dr. Riba's position
Dr. Riba argues that the question in a disqualification proceeding is whether the investigator is honest and competent.164 With regard to supervision, Dr. Riba argues that the relevant question is "did Dr. Riba act reasonably under the circumstances?"165
Dr. Riba contends that he met the specific sponsor-directed requirements of the 30-day segment of the study.166 According to Dr. Riba, he was not expected to review the EGGs and other data submitted in the 30-day segment.167 Further, the 30-day Visit Form did not require verifiable source documents 168 other than the original EGGs, and the EGGs were sent to (b)(4) for review.
Dr. Riba also offered testimony and statements from colleagues to establish that his conduct of the 30-day segment met the standard of care of the clinical trial community. Dr. (b)(6) testified that he would not have expected a principal investigator to have reviewed the ECGs and the 30-day Visit Form, and that he didn't think "most investigators would feel an obligation to directly review those EKGs."169 He added that a clinical investigator necessarily delegates many of the activities of clinical trial coordination based on an assessment of Character, training, and other factors,170 and that the clinical investigator routinely trusts coordinators to find the right films, draw blood correctly,and the like.171 Dr. (b)(6) noted that "[o]f course we're responsible for their supervision and their overall conduct."172
Dr. (b)(4) described by. Dr. Riba as the most eminent cardiologist in the United States and a member of the PURSUIT Executive Committee, explained by letter that other principal investigators would have acted in the same manner in that collection of the ECGs is "quite a perfunctory item" and that the circumstances that occurred were quite extraordinary.173 Dr. (b)(4), Co-Director of Clinical Trials at (b)(4)described the situation with Nurse (b)(6) as "highly unusual" and Dr. Riba as "an honest, diligent and effective principal investigator in clinical trials."174
Dr. Riba admitted to "naivete" in failing to have prophylactic systems in place,175 but contends that a researcher is not a cop; he was entitled to assume that people are fundamentally honest.176 He argues that detection of falsification would have been difficult because the originals were to be sent to (b)(4) 177 Ms. (b)(6) testified that "... the only way you could tell that anything else got tampered with is by having the original, because by holding it up you can see where it was blacked out."178 She opined that if Mr. (b)(6) had been required to maintain original source documents, such as a telephone log, he would have falsified them.179
Thus, Dr. Riba contends that he did not fail to personally conduct or supervise the study. He also argues that he did not violate the regulatory prohibition against submission of false information because, he contends, the false information was not "submitted to the sponsor," he asserts that (b)(4) could not be deemed to be the sponsor.180 The thrust of his argument appears to be that the information from the 30-day Visit Forms and ECGs would not have been received by Cor in the form in which they were submitted to (b)(4) and that (b)(4) would have verified the information as accurate before submission to Cor. That is, he stated that it was CDER's duty to prove that (b)(4) was accepting the data as sponsor and wasn't going to do something to the data,181 and that all information submitted to the sponsor was adjudicated and verified prior to submission. 182 Therefore, Dr. Riba asserts, CDER did not submit evidence that the false information went to the sponsor.183 Dr. Riba also argues that CDER did not establish that (b)(4) was the sponsor because the Center did not establish that any sponsor functions had been contractually passed to (b)(4) as specified in 21 C.F.R. § 312.52.184
CDER responds to Dr. Riba's position that the false data was not "submitted to the sponsor" by pointing out that it was not unusual that Dr. Riba did not send any data directly to Cor, because sponsors often use Contract Research Organizations (CROs) to gather data from the investigators.185 CDER argues that Dr. Riba admitted that (b)(4) was acting in a sponsor's capacity.186 For example, Riba's response to the NIDPOE letter stated "it was (b)(4) who told him to resubmit new ECGs ......187 Therefore, CDER concludes, Dr. Riba considered (b)(4) to be a sponsor.
Dr. Riba asserts that even if he violated the regulations, e.g., by submitting false information, he did not do so repeatedly. He defines "repeatedly" as meaning "again and again."188 He further argues that: "repeatedly ... involves a qualitative analysis, not merely quantitative, analysis.... [the] issue is whether the investigator's actions are frequent enough to call into question the individual's eligibility to continue the investigation., "citing an FDA Federal Register preamble statement 189 which also says that the agency "does not intend isolated or inadvertent failures to be the basis for disqualification."190 Thus, Dr. Riba argues, the agency intends to examine not just the number of violations, but also the nature and context in which they occurred.191
Analysis of Charge 1 - failure to supervise
By its plain language, the regulation that requires the clinical investigator to personally conduct or supervise the study places a personal obligation on the investigator. That is, although the actions of subordinates in violating other clinical investigator regulations might be imputed to the clinical investigator, 21 C.F.R. § 312.53(c)(1)(vi)(c) focuses on the actions (or inactions) of the investigator.192
CDER's primary argument with respect to this charge is that Mr. (b)(6)'s submission of false ECGs is prima facie evidence of Dr. Riba's failure to supervise Mr. (b)(6). That is, CDER argues that Dr. Riba's failure to personally conduct or supervise the study is established by the number of falsifications submitted by the study nurse. CDER stated that "even if Dr. Riba's nurse was responsible for the repeated and deliberate violations, the nurse knew that Dr. Riba would not detect their egregious violation because of his flagrant lack of supervision."193
I believe that in certain circumstances, e.g. where there is pervasive violation of the regulations by subordinates, those violations could support a charge of lack of supervision. However, I believe that a determination as to whether an investigator violated the requirement to "personally conduct or supervise"a study requires a complete assessment of the investigator's actions. Therefore, I am unwilling to conclude that the single violative episode of falsification by Nurse (b)(6) by itself establishes that Dr. Riba violated the regulation that required Dr. Riba to personally conduct or supervise the study.
Instead, I believe that it is necessary to examine the evidence in the record as to Dr. Riba's supervisory responsibilities and actions, before determining whether Dr. Riba violated the regulation. This includes the evidence that Dr. Riba submitted to support his position that he acted appropriately; other inspectional evidence, i.e. evidence concerning the baseline segment and the other Riba studies that were subject of "for cause" investigations; and CDER's testimony concerning Dr. Riba's supervisory responsibility.
With regard to the evidence submitted by Dr. Riba,194 although it is significant that he was required to sign the baseline CRF but not the 30-day Visit Form, I disagree with his position that the mere fact that he was not required to sign the 30-day Visit Form by itself absolves him of responsibility for Mr. (b)(6)'s actions. Nor can I agree with Dr. Riba's position that he could not have determined whether the ECGs had been falsified because the originals were not in the Oakwood files. He and Ms. (b)(6) were able to document falsifications from their records after (b)(4) informed them of the falsifications. Also, it appears that the falsifications could be detected from copies, as an examination of the copies submitted by CDER for the record reveals. 195
However, other items of evidence submitted by Dr. Riba, though not dispositive individually, collectively tend to support Dr. Riba's position. These include:
• The testimony by Dr. (b)(6) and the letter from Dr. (b)(4) both of Which support Dr. Riba's position that he met the prevailing standards of care in the clinical trial community with respect to the hiring, training and supervision of Mr. (b)(6). This evidence tends to support the position that the collection and submission of the ECGs was a perfunctory item, and that the circumstances of the falsification were extraordinary.
• The differences between the baseline segment and the 30-day follow-up segment in terms of the responsibilities placed on Dr. Riba, especially the fact that the (b)(4) CEC adjudicated the ECGs and made the clinical endpoint determinations. As noted, the fact that Dr. Riba was required to sign the baseline CRF but not the 30-day Visit Form is also significant although not dispositive. I agree with Dr. Riba that his role, in the 30-day follow-up segment was primarily that of a conduit.
• Dr. Riba's meticulous supervision of Mr. (b)(6) in the baseline phase. including his point-by-point review of each CRF and his review of each of the many ECGs.
As for the other inspectional. evidence, I find support for Dr. Riba's position in:
• The failure of the FDA investigator to find any serious deficiencies in the baseline phase; and
• The failure of the FDA investigator to find any significant deficiencies in the two "for cause" investigations of other studies conducted by Dr. Riba, initiated following discovery of the problem with the 30-day segment of the PURSUIT study.
CDER submitted evidence as to the kinds of prophylactic measures it believed Dr. Riba should have taken, and also asserted that Dr. Riba admitted that he did not have an adequate supervisory system in place. As in the case of a portion of Dr. Riba's evidence, I find some of CDER's evidence to be unpersuasive.
CDER's witness, Dr. Ganley, opined that certain questions on the 30-day Visit Form required input from a physician, in this case, Dr. Riba. However, CDER did not identify any reference in the study documents that established such a requirement; the fact that (b)(4)'s CEC adjudicated the ECGs and made the medical determination as to the clinical endpoint reinforces the notion that the sponsor did not expect Dr. Riba to interject his medical expertise into the completion of the 30-day form. In addition. Dr. Riba was not required to sign the 30-day form.
Further, CDER purports to establish, from the Pursuit Case Report Form booklet, a requirement for source documentation for 30-day reports in addition to the ECG.196 However, the material described relates to the baseline CRF, not the 30-day Visit Form.197 CDER does not cite any other authority for this proposition, either from the regulations or the study documents.
CDER's claim that Dr. Riba "admitted that he was responsible for the nurse's conduct because he didn't have an adequate supervising system in place"198 deserves careful consideration. CDER does not cite the source of Dr. Riba's "admission" but apparently refers to Dr. Riba's statement that the problems "are traceable to the intentional misconduct of ... (b)(6), R.N., and the naivete of those involved in failing to have prophylactic systems in place to detect such intentional misconduct......199
It is not clear that this statement, considered in light of exculpatory testimony by Dr. Riba,200 is sufficient to prove an admission.
More importantly, the Center overlooks the key question: whether Dr. Riba was required by the supervision regulation to institute prophylactic measures to guard against extraordinary circumstances. It is tempting, with perfect hindsight, to say that it would have been prudent for Dr. Riba to have done so. CDER asserts that Dr. Riba could have compared the information in the 30-day Visit Form with the ECGs. Perhaps a plausible argument could be made that implementation of such a measure would be within the ultimate responsibility of the clinical investigator.
I conclude, however, that CDER did not meet its burden of proving that Dr. Riba violated the regulation that required him to personally conduct or supervise the study. I reach this conclusion after considering relevant factors established by the evidence,201 and after applying the regulation that governs Dr. Riba's supervisory responsibility. I have considered also that FDA regulations and guidelines do not provide guidance as to what constitutes proper supervision, and the PURSUIT study documents do not provide specific direction as to the principal investigator's responsibilities. Because I find that CDER did not meet is burden of proving that the regulation was violated, I do not reach the question of whether the violation occurred repeatedly or deliberately.
Analysis of Charge 2 - submission of false information
The first question with respect to charge 2 is whether the submission of the false ECGs by Mr. (b)(6) was an action for which Dr. Riba should be held responsible.202
I conclude that it was. Although I believe that the clinical investigator's responsibility for a subordinate's actions is not unlimited, the prohibition against submission of false information provides little opportunity for the supervisor to escape responsibility for submission of data and information. Essentially, information submitted is submitted in the name of the clinical investigator. Allowing principal investigators like Dr. Riba to evade responsibility for submission of false information - merely because the data were physically submitted by an assistant - would open the door to abuse that would undermine the concept of ultimate responsibility of the clinical investigator, as well as fundamental objectives of the clinical investigator regulations. Dr. Riba's failure to argue that he did not submit the data amounts to a tacit agreement that he was responsible for the submission of the data.
Dr. Riba's primary argument with respect to the false information charge is that the data were not submitted "to the sponsor." CDER asserts that Dr. Riba admitted that (b)(4) stood in the role of sponsor (Section IV.A.1.b.), but the statements made by Dr. Riba that CDER cites to support the proposition are inconclusive. One statement was that (b)(4) instructed Dr. Riba to submit new ECGs, and the other was that "the sponsor" told. him to submit new ECGs. The second statement could have been intended to refer to Cor; in any event, I am not willing to conclude that the two statements prove what CDER contends they prove.
Nevertheless, I must reject Dr. Riba's contentions. He appears to assert that his submissions were not "to the sponsor" because (b)(4) might not have submitted the information to Cor in the same form as Dr. Riba submitted it to (b)(4) and because the data would have been verified by (b)(4) before submission to Cor. The argument concerning the form of the data is a novel, hypertechnical position that must be rejected because it defies common sense and could readily lead to abuse. Similarly, Dr. Riba's assertion regarding verification by (b)(4) must be rejected, again because of the potential for abuse, and because it would eliminate the important role that the clinical investigator ordinarily plays in helping to assure that false information is not submitted to the sponsor. The apparent failure of (b)(4) to detect the ECG falsifications for more than six months after the first false submission dramatically illustrates this point. In view of the foregoing, Dr. Riba's argument that CDER did not establish that (b)(4) was the sponsor because the Center did not prove that any sponsor functions had been contractually passed to (b)(4) is irrelevant.
Because Dr. Riba submitted false information, it follows that he repeatedly did so, because he submitted the false information "again and again." This, then, provides a basis for disqualification. However, I do not believe that Dr. Riba deliberately submitted false information.
CDER did not establish that Dr. Riba personally submitted the false data, that he knew or had reason to suspect that false data were being submitted, or that he acted with reckless disregard with respect to the accuracy of the data submitted. This information, evaluated along with all the other evidence in the record, leads to my conclusion that Dr. Riba's actions or inactions were not deliberate.
In addition, holding that Dr. Riba deliberately submitted false information would conflict directly with my conclusion that. Dr. Riba did not deliberately fail to supervise the study (Charge 1). lf, as CDER asserts, a lack of supervision led to the submission of false information, it would be inconsistent to conclude that Dr. Riba's supervisory performance is not worthy of disqualification for lack of deliberateness, but that he should be disqualified for the deliberate submission of false information in the same circumstances for which his supervisory performance was found acceptable.
Thus, although I conclude that Dr. Riba repeatedly submitted false information to the sponsor, I do not believe that he did so deliberately.
Charge 3 - failure to follow protocol by resubmitting ECGs
Charge 3 arose from the "clean-up" effort following discovery of the false ECGs.203 CDER charges that Dr. Riba violated the protocol by submitting "30-day" ECGs when in fact these ECGs were done outside the prescribed 28-42 day window. Dr. Riba responds that the ECGs were requested by (b)(4) and Cor in an effort to salvage data from the study, and therefore neither (b)(4) nor Cor were misled by the submission. I agree with Dr. Riba, and I note that Dr. Ganley - CDER's witness - testified that such corrections are not unusual in some instances.204 Therefore, I find that Dr. Riba did not violate the regulations as charged by CDER in Charge 3.
Charge 4- failure to maintain adequate and accurate case histories Charge 4 involves two alleged violations of the regulatory requirement to maintain adequate case histories.205 The first concerned a patient who died one day after release from the hospital but was reported on the 30-day Visit Form as being alive 30 days after release. The second alleged violation involves an ECG that did not have a computer-generated date and time. Even if these were repeated technical violations, I consider the incidents to be of insufficient significance to serve as a basis for disqualification. Further, CDER provided no evidence to support a conclusion that these deficiencies represented deliberate violations by Dr. Riba.
Charge 5 - failure to report adverse effects.
Charge 5 involved failure to report rehospitalization of one patient.206 CDER did not include this charge in its IRSD and did not present evidence on this charge during the hearing. Therefore, I will not find that Dr. Riba violated the regulations as alleged in Charge 5.
Agency regulations call for the disqualification of an investigator who has repeatedly or deliberately submitted false information in a required report to the sponsor or the agency. See 21 CFR § 312.70(b). The Commissioner retains the discretion not to disqualify an investigator if disqualification is not warranted by the facts of a particular case. See Preamble to Investigational New Drug Regulations, 52 FR 8826 (1987); Report of the Presiding Officer in the Matter of E. Alan Paulk, Jr., M.D., June 16, 1989; Commissioner's Decision in the Matter of E. Alan Paulk, Jr., M.D., January 8, 1990.
The facts of this case inevitably lead to the conclusion that false information was repeatedly submitted under Dr. Riba's name. Nevertheless, numerous mitigating factors in this instance have persuaded me that disqualifying Dr. Riba would be unjust to him personally, and would create incentives for undesirable behavior in the investigator community at large. These mitigating factors are discussed below. It must be emphasized that by discussing these mitigating factors, I am in no way endorsing Dr. Riba. I am simply relaying the impressions of Dr. Riba I drew during my review of the written record, and my conversation with Dr. Riba and CDER at the day and a half long hearing in December 2000. My impressions of Dr. Riba are further influenced by my experiences as a physician who has been a subinvestigator in a clinical trial, who has evaluated clinical trials as a reviewer in CDER, and who now deals with investigators through the Office of Orphan Product Development grants program. Based on all this information and experience, I urge the Commissioner to consider an alternative to disqualifying Dr. Riba.
A full discussion follows.
While the facts of this case inevitably lead to the conclusion that false information was repeatedly submitted under Dr. Ribas name, the complexities of the case lie in the mitigating factors; It is clear from the evidence presented that Dr. Riba did not personally participate in the submission of the false data, did not encourage or indicate that he would tolerate the submission of false data, and took immediate and appropriate corrective action when he learned that nurse (b)(6) had submitted the false data. He did not try to hide any information from either the sponsor or the FDA, occurred. The audit of Part I of this study and of previous studies conducted by Dr. Riba indicate that he is a meticulous and careful investigator. It is also clear that Dr. Riba actively participated in the education and supervision of nurse (b)(6) discussing cases several times per week and personally checking with nurse (b)(6) all 500 data points per patient in the patient report forms from Part I of the study against source documents. In addition he would frequently go over the films of cardiac catheterizations with Mr. (b)(6) to increase his understanding of the subjects. Both Dr. Riba and nurse (b)(6) his study coordinator, exercised reasonable caution in selecting nurse (b)(6) and nurse (b)(6) was more than qualified to do the simple information collection required in Part II. At no time did Dr. Riba ask nurse (b)(6) to do tasks which should have been completed by Dr. Riba.
Given the above information it would appear that these violations occurred because Dr. Riba drew a conclusion that turned out to be untrue. The conclusion was that nurse (b)(6) was an honest professional who could be trusted to do a task that was well within his training and capabilities. He made this assumption based on his frequent contacts with nurse (b)(6) and after observing his performance in parts of the study that could be considered much more demanding than Part II. Considering the information presented in the record, I do not think this conclusion was unwarranted. In today's medical environment it is impossible for a researcher to do all the tasks in a study personally; therefore, it is absolutely necessary that researchers delegate some tasks and rely on properly trained subordinates. In hindsight it is easy to point out that Dr. Riba's trust in nurse (b)(6) was misplaced; however, it is easy to understand why Dr. Riba concluded that nurse (b)(4)
No one would characterize the submission of false information as insignificant. This act strikes at the very heart of the drug approval process since the decisions made by the FDA can be no better than the information the Agency receives. It is also clear that, with significant justification, the FDA ordinarily views with great skepticism the claim that the nurse did it. However, this case is different. Dr. Riba's role in this submission of false information was to rely on a person whom he had trained, and because of their frequent contacts, had reason to believe was trustworthy to do a job that was clearly within his capabilities. It is my opinion, after examining the evidence, that Dr. Riba's expectations of nurse (b)(6) were reasonable.
I have concluded after listening to the testimony at the hearing and reviewing the written submissions, that Dr. Riba conducts studies in an extremely meticulous and careful manner. His work in previous studies was very carefully scrutinized by FDA inspectors. They found no indication that he does not fully appreciate the absolute necessity of accurate data, or that he does not take his responsibilities as a clinical investigator very seriously. It is my conclusion as Presiding Officer, after reviewing the evidence presented in this case that Dr. Riba acted responsibly, both in the conduct of this study and in his attempt correct the problems created by Nurse (b)(6). I further study an anomaly.
Disqualifying Dr. Riba would leave this Presiding Officer with a sense of injustice. I hope the Commissioner will consider an alternative to disqualifying Dr. Riba.
Date John J, McCormick
1 The Center for Drug Evaluation and Research's documentary evidence consisted of exhibits to the Center's Initial Request for Summary Decision ("CDER Exhibits"); Dr. Riba's documentary evidence is referred to as "Respondent's Documentary Evidence" ("RDE).
The witness list is in section III.
2 Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE letter), May 19,1999, Page 2.
5 Riba testimony, Transcript of Hearing Proceedings (Transcript), page 166. Dr. Riba received his M.D. from the Albert Einstein College of Medicine, served his internship and residency in internal medicine at the Hospital of the University of Pennsylvania, and was awarded a Cardiology Fellowship at the Department of Medicine, Yale University. RDE, page R00001.
6 RDE, page R00002.
7 Transcript pages 167-8.
8 testimony, Transcript pages 118-9. MSN in Adult Chronic Health,(b)(6) CV, RDE R00016.
9 The (b)(4) Coordinating Center also served as a data coordinating center for this study, but it appears that Dr. Riba worked only with the (b)(4) Coordinating Center. Riba Response to the NIDPOE, CDER Exhibit 4, page 2.
10 Establishment Inspection Report (EIR), CDER Exhibit 9, page 4.
11 The Form 1572 is the Statement of Investigator" and is to be completed and signed by the investigator. One section of this Form outlines the commitments being made by the investigator. See Form FDA-1572. Before permitting an investigator to begin participation, the sponsor must obtain a signed Form FDA-1572. See 21 C.F.R. § 312.53(c)(1).
12 CDER Exhibit 7.
13 Protocol Title, CDER Exhibit 8, page 20.
14 PURSUIT protocol Sections 2.0 (a) and 8.1, CDER Exhibit 8, pages 30 and 45.
15 CDER IRSD, page 716 (b)(4) testimony, transcript page 126.
16 (b)(6) testimony, transcript page 126.
18 PURSUIT protocol, Section 3.0, CDER Exhibit 8, page 31.
19 PURSUIT protocol, Section 3.0, CDER Exhibit 8, page 31, [A]t six months, patient status will be followed up (via telephone call) and information obtained regarding the possible occurrence of any clinical endpoints .... Hospital or other appropriate source documents associated with incidences of death and myocardial infarction occurring at 6 months will be retrospectively collected and reviewed and those events will be adjudicated." Id.
20 (b)(6) testimony, transcript pages 133-4.
21 (b)(6) testimony, transcript page 266.
22 (b)(6) testimony, transcript page 136·
23 PURSUIT protocol section 10.3, CDER Exhibit 8, page 52.
24 (b)(4)testimony, transcript page 136; Riba testimony, transcript page 187. See PURSUIT Protocol Section 10, CDER Exhibit 8, pages 52-4. The protocol's discussion of monitoring visits appears to describe monitoring of baseline data and clinical events, but not the routine 30-day processing. Pursuit Protocol, Section 10.6. CDER Exhibit 8, page 53.
25 Inclusion and exclusion criteria are contained in the PURSUIT protocol, section 4.2 and 4.3, CDER Exhibit 8, page 32.
26 PURSUIT protocol, section 5.2, CDER Exhibit 8, page 34.
27 Pursuit Protocol, Appendix A, CDER Exhibit 8, page 58.
28 PURSUIT Case Report Form Booklet, Baseline Case Report Form, RDE pages R00126 through R00148.
29 Riba testimony, transcript, page 181.
30 PURSUIT Case Report Form Booklet, Baseline Case Report Form, RDE page R00148.
31 Id., General Guidelines for Completion of the PURSUIT Case Report Form, RDE page R00128.
32 Case Report Form Booklet, RDE page R00127. Emphasis in the original.
33 Id., page R00128
34 PURSUIT protocol, Section 5.4, CDER Exhibit 8, page 35.
35 (b)(6) testimony, Transcript, page 130. It is likely "CRF" meant "case report file" in this quote. The "30-Day Visit Form" was referred to as "CRF" in some testimony, and "CRF" was used to refer to "Case Report File" in some instances. The protocol stated that the "Case Report Form" was to be divided into the baseline and 30-day follow-up segments. Pursuit Protocol, Section 10.6, CDER Exhibit 8, page 53. "EKG" and "ECG" were used interchangeably throughout the hearing.
36 PURSUIT Inservice Manual, RDE R00267 et seq.
37 RDE pages R00150-1.
38 PURSUIT Case Report Form Booklet, 30-Day Visit Form, RDE page R00151.
39 "It may be best for you to contact the patient directly to obtain the information for the 30-day Visit Form." PURSUIT Inservice Manual (Study Coordinator Manual), RDE page 00309.
41 PURSUIT Case Report Form Booklet, Forms Check List, RDE page R00106. Note that the protocol stated that the 30-day Visit Form should be mailed to (b)(4) within 24 hours of the 30-day visit. PURSUIT Protocol, Section 11.2, CDER Exhibit 8, page 55.
44 RDE page R00150-1.
45 Riba testimony, transcript page 273-4.
46 The protocol described the CEC as follows: An independent committee ... will be formed to review abstracted clinical data to determine when safety and efficacy endpoints have been met ... All patients reaching an adjudicable endpoint or suspected of reaching an endpoint occurring within 30 days will be reviewed by this committee." PURSUIT Protocol, Section 10.3, CDER Exhibit 8, page 52.
47 Ganley testimony, transcript page 69.
48 (b)(6) testimony, transcript pages 150-1.
49 Riba testimony, transcript page 171-2.
50 (b)(6) testimony, transcript page 122
51 (b)(6) testimony, transcript pages 120-2.
52 Riba testimony, transcript page 272.
53 Id. at 122.
54 Id. at 123.
57 Riba testimony, transcript pages 176-7.
58 (b)(6) testimony, transcript pages 122-3.
59 Riba testimony, transcript page 261.
60 Riba testimony, transcript pages 172-3; See also Riba testimony, transcript pages 179-183 describe the tasks.
61 EIR, CDER Exhibit 9, page 1.
62 Riba testimony, transcript page 229.
63 (b)(6) testimony, transcript page 271. Oakwood received (b)(6) for each patient that was enrolled, provided that certain benchmarks were met. RDE R00285.
64 Riba testimony, transcript page 180. ECGs were taken when the patient entered the hospital; at the time of enrollment to help determine whether the patient met inclusionary criteria; during clinical events (any acute coronary ischemic event, a myocardial infarction);
after interventions; and at discharge. Riba testimony, transcript, pages 179-180.
65 Riba testimony, transcript page 233.
66 Riba testimony, transcript page 180.
67 (b)(6) testimony, transcript page 132.
68 Riba testimony, transcript page 181
70 Id., pages 181-2.
71 Id., page 183.
72 Id., page 182-3.
73 (b)(6) testimony, transcript page 132.
74 Id., page 133
76 EIR, CDER Exhibit 9, pages 4 and 12.
77 Id., page 2.
78 Bellamy testimony, transcript page 36.
79 (b)(6) testimony, transcript page 130.
80 (b)(6) testimony, transcript page 130.
81 Id., pages 138-9.
82 Id., page 125. I worked with [Mr. (b)(6)] to set up the 30-day follow-up date, and then at the time of the 30-day follow-up worked with him on ways - what were the variety of ways we could bring the patient in and obtain the EKGs if we needed to" Id.
83 Id., page 269. The following exchange occurred between Ms.(b)(6)and counsel for
CDER: MR SPILLER: Whose job was it to make sure that (b)(6) actually sent complying ECGs to (b)(4) MS. ((b)(6): Basically was responsible for sending those to (b)(4) MR. SPILLER: Was it then no one's job to supervise that part of his job? MS. (b)(6):(b)(6) was trained and oriented with adequate orientation under my supervision and at a point where he felt comfortable and I felt comfortable that he knew what to do, then he was able to be on his own and send the information, as indicated by the protocol. I was always available for resources, for questions, to help him out. ... MR. SPILLER: Was it then no one's job at Oakwood to make sure that (b)(6) sent the right content for the 30-day visit form and ECG? MS. (b)(6): Once we made sure he knew the protocol, what the process was, knew where the mailers were and the FedEx forms were and he felt comfortable, he was responsible for sending that on. (b)(6) testimony, Transcript, pages 268-9.
84 Riba testimony, transcript pages 184 and 237-8.
85 Id., page 250.
86 Id., pages 281.
87 Id., page 185.
88 Riba testimony, transcript page 281.
89 Id., page 234.
90 Id., page 235.
91 Id., page 184.
92 Id., page 186.
95 (b)(6) testimony, transcript page 136; Riba testimony, transcript page 187.
96 (b)(6) testimony, transcript page 152; Riba testimony, transcript pages 189-90.
97 (b)(6) testimony, transcript page 153.
98 CDER's (IRSD), pages 7 and 8. Examples of false ECGs are included in CDER Exhibit 13, and related testimony by the FDA investigator is at transcript pages 36-7 Bellamy testimony.
99(b)(6) testimony, transcript page 150. Id, transcript pages 150-51. As explained above, the ECGs would have gone to (b)(4)'s CEC, whose job was to review the ECGs and compare them to the baseline to see if there were any differences that would Indicate whether an ischemic event would have occurred.
100 CDER's IRSD, page 8.
101 FDA 483 (Inspectional Findings), CDER Exhibit 10, item 2. Note that the EIR, CDER Exhibit 9, page 1 states that eight of 15 files had false ECGs.
102 (b)(6) testimony, transcript age 153.
103 Id., pages 153-4. Ms (b)(6) based her statement on her discovery that a woman who died the day after discharge was reported to be alive after 30 days. Id., page 154.
104 (b)(6) testimony, transcript pages 146-7, 151-2.
105 Riba testimony, transcript page 188.
106 Id., page 276.
107 Bellamy testimony, transcript pages 37, 39 and 94-6.
108 Id., page 38.
109 testimony, transcript pages 130 and 257.
110 Id., pages 256-7. Ms. •testimony on page 256 may have referred to "case report file."
111 Riba testimony, transcript pages 255-6
112 (b)(6) testimony, transcript page 153.
113 Riba testimony, transcript page 193; (b)(6) testimony, transcript pages 276-7.
114 (b)(6) testimony, transcript page 159
116 EIR, CDER Exhibit 9, page 6.
117 Riba testimony, transcript page 243.
118 Riba testimony, transcript pages 242-5; testimony (b)(6), transcript page 246.
119 Riba testimony, transcript pages 193 and 195.
120 Riba testimony. transcript page 193-4.
121 Riba testimony, transcript page 194; Riba NIDPOE Response, CDER Exhibit 4, page 6.
122 Riba NIDPOE Response. CDER Exhibit 4, page 6.
124 Riba testimony, transcript page 303.
125 Id., page 302.
126 Id., page 303.
127 Riba testimony, transcript page 304.
128 Id., page 194.
129 The EIR and FDA-483 are CDER exhibits 9 and 10, respectively.
130 EIR, CDER Exhibit 9, page 6.
131 CDER Exhibit 10.
132 EIR, CDER Exhibit 9, page 2.
133 CDER Exhibit 11.
134 CDER Exhibit 1.
135 CDER Exhibit 4.
136 CDER Exhibit 5.
137 CDER Exhibit 6.
138 (b)(6) testimony, transcript pages 208-10.
139 RDE R0002110.
140 RDE R000213.
141 Webster's Ninth New College Dictionary. 1991, Merriam-Webster Inc. See also Commissioner's Decision In the Matter of James A. Halikas, M.D., January 17, 2001
142 Black's Law Dictionary at 426 (6th ed. 1990); Mclaughlin v. Richland Shoe Co., 486 U.S. 28,133 (1988).
143 By signing the Form FDA 1572, the investigator agrees "to personally conduct or supervise the described investigation(s):
21 CFR § 312.60 states that an "investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement. ..."
21 CFR 312.53(c)(1)(vi)(c) states that before permitting an investigation to begin, the sponsor shall obtain signed investigator statement containing a commitment by the investigator that he or she will personally conduct or supervise the described investigation.
144 21 CFR 312.70(a) states that an investigator may be disqualified if he or she "has submitted to FDA or to the sponsor false information in any required report....."
145 NIDPOE e.g. Hayes statement, transcript page 88.
146 Ganley testimony, transcript page 104.
147 IRSD, page 10. CDER maintains that "repeatedly" means submission of more than one ~iece of false information in a single study. IRSD, page 5.
148 IRSD, page 17; NOOH, page 2.
149 Transcript, page 11; IRSD pages 10 and 14-16.
150 IRSD, page 11-12.
151 Hayes statement, transcript, page 290.
152 Hayes statement, transcript, page 11
153 Citing U.S. v. Dotterweich 320 U.S. 277 (1943) and U.S. v. Park, 421 U.S. 658(19xx).
154 IRSD, page 12.
155 Hayes statement, transcript page 288.
156 Ganley testimony, transcript page 69- 71.
157 Ganley testimony, transcript page 105.
158 Id., page 70; Hayes statement, transcript page 291. Dr. Ganley was troubled by the feeling that "because, whether there was no signature block or whatever, that there's no responsibility on the part of the investigator to actually have documentation of the information that actually goes onto that case report form." Transcript, page 278.
159 "the expectation on our part is that there is oversight, that there is some mechanism where someone is comparing what is put on the case report form with the source documentation." Ganley testimony, transcript page 71.
160 Hayes statement, transcript page 292.
161 Ganley testimony, transcript page 70.
162 IRSD, page 12. CDER defines "deliberate" as "intentional, with reckless disregard, grossly negligent." IRSD, page 6.
163 Id., page 10.
164 Charrow statement, transcript page 115.
165 Charrow statement, transcript, page 297.
166 Riba testimony, transcript page 185.
168 NIDPOE Response, CDER Exhibit 4, page 4
169 (b)(6) testimony, transcript, pages 212-14.
170 Id., pages 214-15.
171 Id., page 225.
172 Id., page 214. .
173 "In the setting of such large clinical trials it is impossible for the principal investigator at each site to verify each and every data point, particularly something so routine as the electrocardiogram that is incorporated In the case record collection of data. This is quite a perfunctory item and I am certain that the principal Investigators of several hundred sites in the Pursuit trial, as well as the other trials we have been involved in, would have done a similar thing." Letter from (b)(4), M.D., RDE R00211
174 RDE R00213.
175 NIDPOE Response, CDER Exhibit 4, p. 1.
177 ·The originals were supposed to be sent to (b)(4). That's what the protocol said. You could send a copy but in most cases the originals were sent and the originals made it easy to detect the falsification:
178 (b)(6) testimony, transcript page 147.
179 Id., page 139.
180 Dr. Riba argued that CDER did not establish that any sponsor duties were contracted in writing to (b)(6) as provided in 21 CFR § 312.52; see Bellamy testimony, transcript page 101. Therefore, (b)(4) could not be considered a sponsor.·
181 Charrow statement, transcript page 296.
182 NOOH Response, CDER Exhibit 6, page 1.
183 Charrow statement. transcript page 295.
184 Respondent's Memorandum in Opposition to CDER's Motion for Summary Decision, page 10. Section 312.52 provides that a sponsor may transfer responsibility for any or all of its regulatory obligations to a contract research organization. but that the transfer shall be described in writing.
185 Bellamy testimony, transcript pages 98-9.
186 Hayes statement. transcript pages 288-9.
187 CDER Exhibit 4, page 5.
188 Charrow statement. transcript page 296. It appears that Dr. Riba did not discuss whether he deliberately violated the regulations.
189 Investigational Device Exemptions: Disqualification of Clinical Investigators (Final Rule), 62 Fed. Reg. 12087, 12089 (March 14, 1997).
190 62 Fed. Reg. 12090.
191 Respondent's Memorandum in Opposition to CDER's Motion for Summary Judgment, page 8.
192 The regulation is as follows: "(c) .... Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following: (1) a signed investigator statement (Form FDA-1572) containing ... (vi) a commitment by the investigator that he or she ... (c) will personally conduct or supervise the described investigation(s) ..... 21 C.F.R. § 312.60 states that "[a]n investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement."
193 ISRD, p. 12.
194 See "Dr. Riba's position, section IV.A.1.b., and pertinent portions of sections II.C.,D. and E
195 CDER Exhibit 13 includes copies of falsified ECGs. Dr. Riba's statement that the protocol provided for the study coordinator, not the principal investigator, to collect the data required for the 30-day form (11.0.3.) could not be verified but is probably inconsequential.
196 Bellamy testimony, transcript 47-8.
197 See RDE R00127-149 (Baseline CRF) and R00150-1 (30 day Visit Form).
198 Hayes statement, transcript page 288.
199 NIDPOE Response, CDER Exhibit 4, page 1. "
200 [w]hat happened is ... not a result of something that I could have done Or should have foreseen.- Riba testimony, transcript page 304. "
201 The documentary and testamentary evidence in this case establish the following relevant facts, i.e., that Dr. Riba:
1. Acted responsibly in the process of selecting and training Mr. (b)(6)
2. Did not have unrealistic or unreasonable expectations of Mr. (b)(6), i.e. Dr. Riba's expectation that Mr. (b)(6) could be trusted to complete routirie functions properly and would submit only correct ECGs was realistic and reasonable;
3. Was not required by the sponsor to review the 30-day follow-up data, or maintain source documents for the 30-day follow-up segment other than copies of the ECGs;
4. Did not know of, or have reason to suspect, the ECG falsifications;
5. Did not encourage or participate in Mr. (b)(6)'s violative conduct;
6. Took action to correct the problem immediately when he became aware of it, and took actions to preclude future violations;
7. Met the prevailing standards of the clinical trial community in the selection, training, and supervision of Mr. (b)(6); and
8. Conducted other parts of the study, i.e. the baseline segment, in such a meticulous manner as to establish that he was not negligent or casual about the conduct of the study
202 According to 21 C.F.R. § 312.70, the Commissioner is to disqualify an investigator if "the Commissioner determines that the investigator has ... deliberately or repeatedly submitted false information to FDA or to the sponsor in any required report.II
203 21 CFR 312.60 states that an investigator is responsible "for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations...."
21 CFR 312.53(c)(1)(vi)(a) states that a sponsor shall obtain a signed investigator statement containing a Commitment from the investigator that he or she will personally conduct or supervise the investigation.
204 Ganley testimony, transcript page 72.
205 21 CFR 312.62(b) states that an investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug...."
206 21 CFR 312.64(b) states that investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug.
21 CFR 312.53(c)(1)(vi)(e) states that the sponsor shall obtain a signed investigator statement containing a commitment from the investigator that he or she will report to the sponsor adverse experiences that occur in the course of the investigation .3