Caldwell, Jacques R., M.D. Notice of Opportunity for Hearing (NOOH)
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Public Health Service Food and Drug Administration |
Department of Health and Human Services
Date: February 09, 2006
Memorandum
From: Consumer Safety Officer
Division of Compliance Policy (HFC-230)
Subject: Notice of Opportunity for Hearing
Disqualification of Clinical Investigator - Jacques R. Caldwell, M.D.
To: Associate Commissioner for Regulatory Affairs (HFC-1)
Thru: David K. Elder, Director, Office of Enforcement (HFC-200)
Lana L. Ogram, Director, Division of Compliance Policy (HFC-230)
The Center for Drug Evaluation and Research (CDER) has prepared a Notice of Opportunity for Hearing (NOOH) alleging that Dr. Jacques R. Caldwell violated federal regulations governing the conduct of clinical trials with investigational new drugs. The notice sets forth grounds for the withdrawal of eligibility of Dr. Caldwell to receive investigational new drugs on the basis that he is in violation of 21 CFR Part 312. Briefly, the disqualification action is based on Dr. Caldwell's:
1. Failure to adequately supervise three clinical trials. [21 CFR 312.60]
2. Submission of false information to the sponsor. [21 CFR 312.70]
3. Failure to protect the rights, safety, and welfare of his research subjects [21 CFR 312.60]
4. Failure to follow investigational plans (study protocols). (21 CFR 312.60]
5. Failure to prepare and maintain adequate and accurate case histories. 121 CFR 312.62]
I have reviewed the grounds and underlying evidence and I consider that the Center has a substantial basis for proposing that a NOOH be issued. The proposed letter has been reviewed by Office of Chief Counsel and by HF-2. I recommend that we follow the course of action CDER has proposed, and sign and issue the NOOH letter.
/S/
Rodney T. Allnutt
__________________________________________________________________________________
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Public Health Service Food and Drug Administration |
| Rockville MD 20857 |
NOTICE OF OPPORTUNITY FOR HEARING
CERTIFIED MAIL-RESTRICTED DELIVERY
RETURN RECEIPT REQUESTED
Jacques R. Caldwell, M.D.
11951 Mays Chapel Road
Timonium, MD 21903
Dear Dr. Caldwell:
The Center for Drug Evaluation and Research (the Center) of the Food and Drug Administration (FDA) has information indicating that you repeatedly or deliberately violated federal regulations in your capacity as an investigator in clinical trials with the investigational drugs Tramadol (b)(4) and Nexium. The Center also has information indicating that you repeatedly or deliberately submitted false information to FDA or the sponsor in required reports. These violations provide the basis for withdrawal of your eligibility as a clinical investigator to receive investigational new drugs.
The Center's findings are based on information obtained during an FDA inspection, discussed below, of the following clinical studies for which you were the investigator of record:
Protocol (b)(4) entitled, "Double-blind, randomized dose-titration, parallel-group comparison of the efficacy and safety of (b)(4), Tramadol (Tramadol (b)(4) and placebo in the treatment of osteoarthritis of the knee." This study of the investigational drug Tramadol (b)(4) was performed for (b)(4).
Protocol (b)(4) entitled, "Open label assessment of the safety and effectiveness of (b)(4) Tramadol (Tramadol (b)(4) in the treatment of chronic non-maligant pain." This study of the investigational drug Tramadol (b)(4) was performed for (b)(4)
Protocol (b)(4) entitled, "A comparative efficacy and safety study of Nexium (Esomeprazole Magnesium) delayed-release capsules (40mg and 20mg qd) versus placebo for the prevention of gastric ulcers associated with daily NSAID use in patients at risk." This study of the investigational drug Nexium (Esomeprazole Magnesium) was performed for AstraZeneca.
FDA conducted an inspection between February 19 and April 3, 2002. After the inspection, and pursuant to section 312.70(a) of Title 21 of the Code of Federal Regulations [21 CFR 312.70(a)], the Center informed you, by letter titled "Notice of Initiation of Disqualification Proceedings and Opportunity to Explain" (NIDPOE) dated June 10,2004, of the specific matters complained of and offered you an opportunity to respond in writing or at an informal conference. The NIDPOE also offered you the option of entering into a consent agreement with FDA, thereby terminating any administrative proceeding against you. In response to the NIDPOE, you requested an informal meeting which was held on August 30, 2004. After a review of all available information, the Center has concluded that your explanations are unacceptable because they fail to adequately address the violations set forth below.
Accordingly, you are being offered an opportunity for a regulatory hearing pursuant to 21 CFR parts 16 and 312, to determine whether you are entitled to receive investigational new drugs. You have the right to be advised and represented by counsel at all times. Any regulatory hearing on this matter will be governed by the regulations in 21 CFR part 16 and FDA's guidelines on electronic media coverage of administrative proceedings, 21 CFR part 10, subpart C. Enclosed you will find copies of these regulations. A listing of the specific violations follows. These are matters that will be considered at the regulatory hearing. Applicable provisions of the CFR are cited for each violation.
1. You failed to adequately supervise the above-referenced clinical trials [21 CFR 312.60]
When you signed the investigator statement (Form FDA 1572) for the above-referenced clinical investigations, you agreed to take on the responsibilities of a clinical investigator at your site. Your general responsibilities (21 CFR 312.60) include ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; protecting the rights, safety and welfare of subjects under the investigator's care; and ensuring control of drugs under investigation. You specifically agreed to personally conduct the clinical studies or to supervise those aspects of the studies that you did not personally conduct. While you may delegate certain study tasks to individuals qualified to perform them, as clinical investigator, you may not delegate your general responsibilities. Our investigation indicates that your supervision of personnel to whom you delegated study tasks was not adequate to ensure that clinical trials were conducted according to the signed investigator statement, the investigational plan, and applicable regulations, and in a manner that protects the rights, safety and welfare of human subjects.
a. You delegated certain tasks to individuals not qualified to perform such tasks.
Your calendar indicates that you were only at the Gainesville site once a week and study records indicate that you had little or no contact with study subjects. When you were not present at the Gainesville site, you permitted employees without appropriate medical qualifications to perform clinical assessments of subjects. For example, your study coordinator who has no medical qualifications, evaluated whether subjects met inclusion/exclusion criteria, documented subjects' medical histories, assessed symptoms and adverse events, and took blood pressure measurements. Of note, in your discussions with our investigator, you admitted that some study assessments were completed in error by your study coordinator.
b. You failed to adequately supervise individuals to whom you delegated study tasks.
Our investigation indicates that you had little personal involvement in the conduct of the study and individuals to whom you delegated study functions had little or no supervision or training in the conduct of study tasks. It appears that you also failed to review study records generated by your staff with reasonable care. For example, your study coordinator admitted fabricating standing blood pressure measurements in case reports forms (CRFs) for certain subjects in Protocol (b)(4). In almost all cases, the fabricated readings for standing blood pressure were not clinically plausible when compared with the measurements obtained for seated blood pressure. Had you reviewed these CRFs with reasonable care, it would have been obvious to you that many of the measurements were fabricated.
During the informal conference, you acknowledged that the three above referenced clinical studies were conducted by two study coordinators. You claimed at the informal conference that "the delegation was appropriate to the training and experience and education of each of the people to whom those tasks were delegated." You also claimed that you thought you supervised the studies by personally training all of the people that were involved, by signing the case report forms, by being available to study staff by telephone, and by having regular meetings with the staff. Your response is inadequate. Available documentation indicates that the study coordinator who was responsible for evaluating inclusion/exclusion criteria, documenting subjects' medical histories, assessing symptoms and adverse events, and measuring blood pressure, had neither medical qualifications nor training for the coordinator position. Documentation also indicates that you were not present at any of the study subjects' visits. You admitted during the informal conference that you were generally present at the Gainesville site one day per week.
Your lack of supervision and personal involvement, and inappropriate delegation of study tasks, resulted In submission of false information to the sponsor, failure to protect the safety and welfare of study subjects, failure to adhere to study protocols, and failure to maintain adequate and accurate study records, as described below.
2. You submitted false information to the sponsor [21 CFR 312.70].
a. You submitted CRFs to the sponsor that contained fabricated blood pressure measurements.
Protocols (b)(4) and (b)(4) required that subjects "... be assessed for syncope, fainting spells, orthostatic hypotension (10-20 mmHg drop in blood pressure from supine or sitting to standing position), dizziness and drop attacks... at Screening and every study visit thereafter." Inspection of subject records revealed standing blood pressure measurements for multiple subjects that did not appear to be clinically plausible when compared to seated blood pressure measurements for those subjects. For example, there are many subjects for which standing blood pressure (diastolic or systolic) measurements were usually ≥ 2 mmHg higher than the sitting blood pressure. It is a well-known physiological fact that the gravitational stress of sudden standing normally causes pooling of blood in the venous capacitance vessels of the legs and trunk and subsequent transient decrease in venous return and cardiac output, resulting in lower blood pressure in the standing position. In your written response to the Form FDA 483 dated June 21, 2002, you admit that standing blood pressure readings and a laboratory report were falsified during the conduct of these studies. In particular, you stated that ..... the coordinator assistant admitted that she only took seated blood pressure measurements and had not taken standing blood pressure measurements. When she realized the standing blood pressure measurements also were needed, she fabricated the standing measurements..." The following are examples:
Protocol (b)(4)
| Subject # | Visit | Sitting Pressure | Standing Pressure |
|---|---|---|---|
| 003 -(b)(6) | Screening | 140/76 | 140/80 |
| Baseline | 140/76 | 140/82 | |
| V-3 | 140/78 | 140/80 | |
| ET (Early Termination | 130/80 | 130/82 | |
| 006 -(b)(6) | Screening | 120/80 | 122/82 |
| ET | 118/60 | 120/64 | |
| 012 -(b)(6) | V-4 | 130/78 | 130/80 |
| V-6 | 128/80 | 130/80 | |
| V-7 | 138/70 | 140/70 | |
| 013 -(b)(6) | V-6 | 130/70 | 130/72 |
| 015 -(b)(6) | Baseline | 140/70 | 140/78 |
| V-5 | 140/80 | 140/82 | |
| 016 -(b)(6) | Baseline | 110/70 | 110/70 (corrected to 76) |
| V-4 | 130/70 | 130/70 (corrected to 76) | |
| 018 -(b)(6) | V-3 | 120/80 | 120/82 |
| 021 -(b)(6) | Baseline | 120/80 | 120/82 |
| 026 -(b)(6) | Baseline | 140/82 | 142/82 |
| 028 -(b)(6) | ET | 130/72 | 132/72 |
Protocol (b)(4)
| Subject # | Visit | Sitting Pressure | Standing Pressure |
|---|---|---|---|
| 002 -(b)(6) | Screening | 140/84 | 142/86 |
| V-2 | 130/80 | 132/82 | |
| V-3 | 140/80 | 140/82 | |
| V-7 | 130/80 | 130/82 | |
| (b)(6) | V-1 | 140/78 | 140/80 |
| V-2 | 130/76 | 130/78 | |
| (b)(6) | V-1 | 122/84 | 132/78 |
| V-2 | 120/80 | 122/86 | |
| (b)(6) | V-1 | 122/70 | 122/82 |
| V-2 | 120/68 | 124/72 | |
| V-4 | 120/80 | 120/70 | |
| V-5 | 130/80 | 122/80 | |
| (b)(6) | V-3 | 140/80 | 130/82 |
| (b)(6) | Screening | 140/84 | 140/82 |
| V-4 | 140/78 | 140/86 | |
| V-6 | 130/90 | 140/80 | |
| (b)(6) | V-2 | 120/78 | 132/90 |
| V-6 | 120/78 | 122/80 | |
| V-7 | 102/70 | 110/72 |
During the informal conference, you stated that you never submitted false information to FDA. However, submission of false information to the sponsor also constitutes grounds for disqualifying clinical investigators from receiving investigational drugs (see 21 CFR 312.70). We note that although you stated that "we found these data were bad, we reported them, that they were bad,.. the blood pressure falsifications were actually detected by the sponsor's monitor during review of the data you submitted to the sponsor.
b. You submitted falsified laboratory results for Protocol (b)(4)
There were two reports for the campylobacter-like-organism (CLO) test for subject (b)(6) in the Nexium study: one was positive and the other was negative. Only one of these lab results can be correct. A positive result would have excluded the subject from the study. Your signature appears on both the positive and the negative results and both of your signatures were dated 4/11/01. The subject was enrolled into the study. Of note, you admitted in your June 21, 2002, letter that this lab report was falsified.
c. You submitted false source documents.
Your calendar indicates that you were only at the Gainesville site once a week on Mondays, and study records indicate that you had little or no contact with study subjects. Multiple source documents, including physical examinations and lab reports generated at the Gainesville site, were signed and dated as completed by you on dates that you were not physically present at the Gainesville site. Therefore, as you were unable to complete examinations of subjects on those dates, and signed documents representing that you had, the documents contain false information. Although you stated in your letter of June 21, 2002, that your physician assistant performed many of these exams, there is no documentation to that effect. Furthermore, even if your physician assistant had performed the exams, you are required to be physically present or within reasonable physical proximity to provide supervision and oversee the examinations. Some examples follow:
Protocol (b)(4)
1) The consent forms signed by subject (b)(6) are dated 1/23/01 and 1/30/01. Your signatures are dated on the same day. However, your schedule shows that you were working in Daytona on these dates.
2) Your signature on the consent form for subject (b)(6) is dated 1/26/01. However, your schedule shows that you were in Geneva on that date.
Protocol (b)(4)
3) Your signatures on the baseline visit date, baseline gastrointestinal symptom assessment and the physical examination sections of the CRF are dated 3/29/01 for subject (b)(6) However, your schedule shows that you were "...at the Capitol" on that date.
4) Your signatures on the baseline gastrointestinal symptom assessment and the physical examination sections of the CRF are dated 4/20/01 for subject (b)(6). However, your schedule shows that you were working in New Smyrna Beach on that date.
During the informal conference, you stated that you delegated the dating of your signature to your coordinator and that your dated signature on physical exams, lab reports, GI symptom assessments and other documents did not mean that you personally performed these tasks on the stated date. You stated that your dated signature merely indicated that you reviewed and concurred with the document contents. Your response is unacceptable. The only reasonable inference that can be drawn from the fact that your dated signature is the only one appearing on these documents is that you performed the stated tasks on the designated dates.
3. You failed to protect tube rights, safety, and welfare of subjects under your care [21 CFR 312.60].
An investigator is responsible for protecting the rights, safety, and welfare of subjects under the investigator's care. You failed to ensure the safety and welfare of study subjects enrolled in Protocol (b)(4), because you failed to evaluate adverse events in a timely manner, and failed to take appropriate action to protect subjects who experienced adverse events. For example:
a. Subject (b)(6) reported experiencing dizziness on 1/28/01, 2/4/01, 2/13/01, and 2/18/01. She also reported sweating on 2/18101 and flu on 2/20/01. Dizziness is a known and expected adverse reaction of the investigational drug as noted in the protocol. The protocol requires that subjects be evaluated and closely monitored for syncope, orthostasis, dizziness, drop attacks, and flushing. You did not evaluate the adverse events until 8/13/01, and only then at the sponsor's request. Therefore, the subject continued in the study without appropriate medical oversight.
b. Subject (b)(6) suffered dizziness on 1/08/01 while on 300 mg of the investigational drug. Notwithstanding the subject's complaint of dizziness, you increased the dose to 400 mg on 1/10/01. This subject continued to experience dizziness despite having stopped taking the drug on her own on 1/13/01, and, subsequently, requested to be removed from the study on 2/14/01. There is no indication that you evaluated the adverse event or provided appropriate medical oversight.
During the informal conference, you claimed that you made a clinical decision that the dizziness suffered by these subjects was unrelated to the study drug and most likely due to pre-existing benign medical conditions. Your response is unacceptable for several reasons: Dizziness is a known and expected adverse reaction of the investigational drug as noted in the protocol, and you were therefore required to evaluate and report it as such. There is no documentation in your records that these subjects had symptoms of dizziness as pre-existing conditions nor was there a clinical evaluation of these subjects to determine if there was an identifiable cause of their dizziness. You placed subject (b)(6) at an increased risk of a serious adverse event by increasing the dose of the investigational drug when she was already experiencing an adverse event that was likely related to a lower dose of the drug.
4. You failed to conduct tube study according to the protocol [21 CFR 312. 60].
a. Protocol (b)(4) requires that physician assessments be performed by the investigator or another physician designated for this task, There is no documentation that the protocol-required physician assessments were always performed by you or a physician at each visit:
1) The "Physician Assessment" for subject (b)(6) was marked "yes" indicating that it was completed by a physician. An accompanying note read "Assessment was completed on 2/28/01(Wednesday), PI (principal investigator) signed source at a later date," followed by your signature and date on 4/2/01. Your calendar indicates that you were in Daytona on 2/28/01. There is no documentation that another physician performed the exam on 2/28/01.
2) The "Physician's Global Assessments" performed at the Gainesville site on 2/28/01 for subject (b)(6) had no signature or initials. The assessments performed at the Gainesville site on 3/14/01 and 3/21/01 for subject (b)(6) bear your signature. The assessments performed at the Gainesville site on 4/18/01 and 6/15/01 for subject (b)(6) had no documentation that they were completed by you or another physician. Your calendar indicates that you were not in Gainesville on any of the dates listed.
3) The "Physicians Global Assessments" for subject (b)(6)at the Gainesville site had no signature for assessments performed on 3/09/01, 3/24/01, 4/20/01, 5/18/01, and 6/15/01. There is no documentation that you or a qualified physician investigator performed these "Physician Global Assessments." The assessment on 3/29/01 for subject (b)(6) bears your signature. However, your calendar indicates you were not in Gainesville on any of these dates (although it does indicate you were on call on 3/24/01).
b. Protocol inclusion and exclusion criteria were not always followed.
1) Subject (b)(6) was enrolled in protocol (b)(4) despite a blood glucose level of 303 mg/dl on 12/27/2000, indicating diabetes mellitus. The protocol-specified exclusionary criteria include"... a recognized risk of seizure such as head trauma, metabolic disorder, alcohol or drug withdrawal, or central nervous system (CNS) infection." On the basis of the existence of a metabolic disorder, i.e. uncontrolled diabetes mellitus (as indicated by a blood glucose level of 303 mg/dl), this subject should have been excluded from participating in the study.
2) Subject (b)(6), enrolled in protocol (b)(4) and received Darvocet from 2/3/01 to 2/27/01. According to the protocol, Darvocet, an opioid analgesic, was a prohibited concomitant medication.
3) Subject (b)(6) was enrolled in protocol #(b)(4) without documentation of either gastric or duodenal ulcer within the antecedent 5 years as required by the protocol. Of note, you admitted enrolling this subject in the study "in error" in your October 22, 2001, "Memo to file.
c. Protocol (b)(4) specifies that "Gastrointestinal (GI) Symptom Investigator Assessments" must be performed by the investigator. The study monitor wrote a letter to you on May 1, 2001, and clarified that only the principal investigator (or his designee with similar qualifications) should perform these "Gastrointestinal (GI) Symptom Investigator Assessments." However, for subjects (b)(6) and (b)(6), the Gastrointestinal (GI) Symptom Investigator Assessments" were not done by the principal investigator or a similarly qualified designee. Mr. (b)(6) the physician assistant, signed a "Memo to file" stating that he obtained GI symptom assessment from subject (b)(6) on visit 3, and from subject (b)(6) on visits 3 and 4.
During the informal conference, you admitted that you delegated the "Physician's Global Assessment," and the "Gastrointestinal (GI) Symptom Investigator Assessment" to the physician's assistant at the sites. Although you claimed that this was a permissible practice, your response is unacceptable because the protocol clearly states in reference to the "Physician's Global Assessment" that: ''the physician will answer the question how the patient is doing today; a visual analog scale (VAS) will be used...The physician will be instructed to make a vertical mark on the line to indicate the assessment of osteoarthritis." In reference to the Gastrointestinal (GI) Symptom Investigator Assessment." the protocol states "the investigator will record on the CRF his/her assessment of NSAID-associated GI symptoms for each patient at every visit."
5. You failed to prepare and maintain adequate and accurate case histories [21 CFR 312.62(b)].
The violations listed above also document multiple instances of failure to prepare and maintain adequate and accurate study records, including fabricated, contradictory, and misdated records.
During the informal conference, you stated that you delegated the dating of your signature and that the regulations do not prohibit this. This response is inadequate. The regulations require adequate and accurate case histories and your case histories are not adequate or accurate if it is unclear on what dates subjects were seen (and by whom) and on what dates charts were reviewed.
Your request for a hearing must be made, in writing within ten (10) business days after receipt of this letter, and should be directed to Lana Ogram, Director, Division of Compliance Policy (HFC-230), ORA Office of Enforcement, 5600 Fisher's Lane. Rockville, MD 20857, Telephone (240) 632-6860, FAX (240) 632-6861. If no response to this letter is received by that time, you will be deemed to have waived any right to a regulatory hearing, and a decision in these matters will be made based on the facts available to FDA. No hearing will be held.
A request for a hearing may not rest upon mere allegations or denials but must present specific facts showing that there is a genuine and substantial issue of fact that warrants a hearing. Pursuant to 21 CFR 16.26, a request for a hearing may be denied, in whole or in part, if the Commissioner or his delegate determines that no genuine and substantial issue of fact had been raised by the material submitted. A hearing will not be granted on issues of policy or law. Written notice of a determination of summary judgment will be provided, explaining the reasons for denial of the hearing.
If you wish to respond but do not desire a hearing, you should contact Ms. Ogram within the time period specified above and send a written response containing your reply. The letter should state that you waive your right to a hearing and that you want a decision on the matter to be based on your written response and other information available to FDA.
FDA's offer to enter into a consent agreement, attached to the NIDPOE dated June 10, 2004, remains available. Entering into a consent agreement would terminate the administrative procedures, but would not preclude the possibility of a corollary judicial proceeding.
No final decision by FDA has been made at this time on your eligibility to continue to receive investigational new drugs. Moreover, there will be no prejudgment of this matter if you decline to enter into a consent agreement and decide instead either to request a regulatory hearing or to request that the decision be based on information currently available to FDA.
Please inform Ms. Ogram within ten (10) business days of whether you wish to request a hearing or to have this matter resolved by consent agreement or information available to FDA.
Sincerely,
/S/
Margaret O'K Glavin
Associate Commissioner
for Regulatory Affairs