Ziering, William H., M.D Text
DEPARTMENT OF HEALTH AND HUMAN SERVICES
U.S.FOOD AND DRUG ADMINISTRATION
REGULATORY HEARING ON THE PROPOSAL TO DISQUALIFY
WILLIAM H. ZIERING, M.D.
FROM RECEIVING INVESTIGATIONAL NEW DRUGS
SUMMARY DECISION OF THE PRESIDING OFFICER
In this disqualification proceeding, the Center for Drug Evaluation and Research (CDER) asserts that William H. Ziering, M.D., repeatedly and deliberately violated the investigational drug regulations in Title 21 of the Code of Federal Regulations ("C.F.R.") Part 312. On this basis, CDER requests that Dr. Ziering be disqualified from receiving investigational new drug shipments, as provided in 21 U.S.C. § 355(i) and 21 C.F.R. §312.70. Dr. Ziering responds by denying that he repeatedly or deliberately violated the regulations.
CDER requests summary decision in its favor. As provided in 21 C.F.R. Parts 16 and 312, I have reviewed:
• the Memorandum in Support of CDER's Motion for Summary Decision ("MSD") with exhibits, filed by CDER September 7, 2000; and
• Dr. Ziering's Response in Opposition to the Government's Motion for Summary Decision ("Response to MSD"), filed November 9, 2000.
The parties submitted these documents following Dr. Ziering's request for a hearing to consider CDER's proposal to disqualify him from being eligible to receive investigational drugs.
I have concluded that CDER has supported two of its four charges, as enumerated below, by evidence sufficient to warrant granting CDER's MSD. Dr. Ziering has failed to raise genuine and material issues of fact with regard to virtually all of CDER's evidence associated with charges 2 and 3 that he violated the regulations in 21 C.F.R. Part 312, and did so repeatedly and deliberately. Specifically, I have found that Dr. Ziering repeatedly and deliberately failed to maintain adequate and accurate case histories and failed to assure that the investigations he supervised were conducted according to the investigational plan
As specified in 21 C.F.R. § 16.26(b), this summary decision constitutes my ruling on the Center's request for summary decision. I recommend to the Commissioner of Food and Drugs that Dr. Ziering be disqualified from receiving investigational new drugs. In accordance with 21 C.F.R. §§ 16.95 and 312.70, this decision will be referred to the Commissioner, who will make a final determination whether to disqualify Dr. Ziering.
William H. Ziering, M.D., is a specialist in allergy and respiratory care. His clinical practice, the Ziering Allergy and Respiratory Center, is located in Fresno, California. Dr. Ziering began conducting clinical research in the early 1980s, conducting approximately two clinical studies per year in the context of his clinical practice.2 However, as the number of study opportunities increased, Dr. Ziering recognized that "we Had reached our research capabilities under the 'clinical practice' umbrella."3
Accordingly, Dr. Ziering created the Central California Research Institute (CCRI) in July 1994 4 to organize and focus the research activities that had been conducted at the Ziering Allergy and Respiratory Center. CCRI is an independent research firm operated in conjunction with Dr. Ziering's clinical practice. In addition to being the president of CCRI, Dr. Ziering is also the principal investigator of clinical research studies conducted at CCRL 5 Dr. Ziering's focus in his clinical research activities, as in his clinical practice, is on "patient examination and evaluation, with the majority of recordkeeping and routine medical procedures such as temperature; blood draws and data collection responsibilities delegated to the professional assistants." 6
This proceeding concerns six studies, sponsored by five different pharmaceutical organizations and conducted by CCRI and Dr. Ziering, as follows:7
Protocol [redacted]"A Placebo-Controlled, Double-Blind Study of [redacted] Aqueous Nasal Spray in Pediatric Patients with Spring Grass Seasonal [redacted] Allergic Rhinitis" sponsored by [redacted]
Protocol [redacted] "A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Evaluation of the Safety, Efficacy and Effect of Asthma Quality of Life (AQL) of Salmeterol in Subjects Receiving Inhaled Corticosteroids" sponsored by Glaxo Pharmaceuticals Protocol [redacted] "A Randomized, Double-Blind, Double-Dummy, Parallel Group, Comparative Trial of Inhaled, Fluticasone Propionate Rotadisks via Diskhaler 500 mcg BID, Multi-Dose Powder Inhaler 500 mcg BID, and Placebo in Adolescent and Adult Patients with Mild to Moderate Asthma" sponsored by Glaxo Research Institute
Protocol #[redacted] "An Open-Label Study of Fluvastatin in the Treatment of Patients with Hypercholesterolemia in Clinical Practice Settings" sponsored by Sandoz Pharmaceuticals
Protocol #[redacted] "A Multicenter, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of Oral Twice Daily Administration of [redacted] in Patients with Mild to Moderate Asthma" sponsored by [redacted]
Protocol #[redacted] "A Randomized, Double-Blind, Parallel-Group Trial to Assess the Topicai Versus Systemic Efficacy of Fluticasone Propionate Rotadisks Via Diskhaler 500 MCG and Placebo in Adult Patients With Moderate Asthma" sponsored by Glaxo Pharmaceuticals
After forming CCRI, Dr. Ziering hired a clinical research manager (CRM) and clinical research coordinator (CRC) "to provide the necessary clinical trial supervision, staff training and evaluations." 8 He employed [redacted] as CRM in June 1994. In October 1994, however, he terminated [redacted] employment for failure to handle research and supervision responsibilities. In November 1994, he terminated the employment of [redacted], an employee in the research department. In December 1994, Glaxo notified CCRI that it was suspending its studies. The firm discontinued its studies at CCRI in January, 1995.9
The reasons for termination included: "minimal to little involvement of the principal investigator in the research study," conduct of numerous Pulmonary Function Tests (PFTs) until the site obtained the three best acceptable results; alteration of PFT and blood draw times "to provide acceptable windows for study inclusion without providing an existing paper trail to substantiate the changes;" failure to follow the protocol with respect to the time of PFTs; and untimely conduct of chest x-rays.10
Quite appropriately, Dr. Ziering noted that "by very late 1994, sponsors began to express concern with data collection, recordkeeping and personnel issues, particularly as to one CRC."11 Dr. Ziering stated that he had difficulty accepting such a view of the Institute and its personnel.12 Nevertheless, CCRI conducted an internal evaluation and requested an audit by an out of state auditing firm.13 Dr. Ziering learned from these reviews that there were shortcomings by professional staff, and that [redacted] had known about the problems but had not fully informed Dr. Ziering. He states that the "level to which the lack of professionalism existed was not readily clear from a review of the records. It was apparent, however, that potentially serious problems did exist." 14 Dr.Ziering concluded that the internal review indicated that one of the CRCs had not effectively managed and supervised certain clinical trials resulting in unevaluable data.15
In early 1995, CCRI initiated a second independent audit, by [redacted], because of the "potentially serious problems." Dr. Ziering reported that even as he and CCRI attempted to gain a full understanding of the issues involved, staffing problems continued. [redacted] employment was terminated, and [redacted] resigned, 16 so that "most of the research staff who had been conducting the studies in the beginning of 1994 had left CCRI or been terminated by February of 1995."17
Dr. Ziering began implementing the auditor's recommendations regarding staffing oversight, study management, and standard operating procedures (SOPs).18 Nevertheless, Dr. Ziering "continued to be concerned about the quality of work performed over the preceding months. At this point, CCRI voluntarily contacted [redacted] notifying the firm that data accumulated by [redacted] were suspect and should not be used in their IND [investigational new drug] application. Subsequently, the [redacted] study was terminated" 19 (Dr. Ziering also explained that he hired a new CRM [redacted] see EIR. p.5) in February 1995, and that once the CRM was on board, CCRI conducted a comprehensive internal audit of the [redacted] study, which resulted in the notification to the firm). 20 [redacted] decision to terminate its study was based in part on "numerous violations of the protocol, failure to provide adequate record keeping and source documentation . . . ." 21
Counsel for CCRI contacted FDA (Dr. Frances Kelsey) by letter dated March 14, 1995, reporting CCRI personnel problems and indicating that extensive changes would be made. The letter asked for an opportunity to meet with FDA to discuss the results of the audit, remedial steps being taken, and procedures that would be implemented in the future. 22 About this time, CCRI became aware that FDA investigators had contacted former CCRI employees. CCRI notified the FDA investigators of its willingness to address issues about which FDA had concerns.
A preliminary verbal audit report from [redacted] in April 1995 "suggested that there were a number of situations in which the professional staff had not followed the study protocols or had operated in a manner that was unexpected of people with their medical qualifications and training ."23 There was particular concern with studies that had been conducted under the supervision of [redacted]
The auditor suggested a number of changes; "CCRI aggressively adopted these recommendations and created SOP forms designed to prevent inappropriate record keeping." 24 CCRI implemented training and staff monitoring on a daily and weekly basis. Before CCRI could implement all of the consultant's recommendations, FDA began a five-week inspection of the CCRI facility in April 1995, culminating in the issuance of an FDA 483 in May 199. According to Dr. Ziering, almost all the FDA observations involved staff members no longer employed by CCRI. He states that he "readily acknowledged to the investigators that there had been problems because of inept employees and deficient management oversight."25
A later internal audit, in November 1995, suggested that the necessary level of oversight was not in place; CRM [redacted] was asked to leave. An outside audit conducted a few months later indicated that the requisite improvements had been made. 26
However, by this time Dr. Ziering was no longer able to obtain clinical studies and the CCRI operation became essentially dormant. 27
II. PROCEDURAL HISTORY
FDA inspected the CCRI studies between April 12, 1995, and May 16, 1995. The investigators issued an FDA 483 on May 24, 1995. 28 Dr. Ziering provided a written response to the FDA 483 on July 11, 1995. 29
FDA conducted a limited inspection of CCRI on October 15, 1998, to obtain documentation with regard to one subject in Glaxo Study [redacted] 30. Investigators visited Glaxo at about the same time to obtain records, including records for the same subject, 31
The agency issued a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) letter to Dr. Ziering on November 6, 1998.32 Dr.Ziering provided a written response December 4, 1998. 33
On August 16,1999, FDA issued a Notice of Opportunity for Hearing (NOOH) under 21 C.F.R. Part 16 to determine whether Dr. Ziering should be disqualified from receiving investigational drugs. 34 Briefly, the charges and relevant regulations were as follows:
Charge 1 - submission of false information in required reports to the sponsor (21 §312.70(b);
Charge 2 - failure to maintain adequate and accurate case histories (21 C.F.R. § 312.62(b));
Charge 3 - failure to follow the investigational plan (21 C.F.R. § 312.60); and Charge 4 - failure to personally conduct or supervise the investigation (21 C.F.R.§ 312.53(c)(1)(vi)(c)).
Dr. Ziering responded to the NOOH and requested a hearing on September 8, 1999.35
CDER filed its Motion for Summary Decision on September 7, 2000, requesting that Dr. Ziering be disqualified because of repeated and deliberate violations of the regulations. Dr. Ziering filed his response October 9, 2000, asking that CDER's motion be denied and again requesting a hearing.
IV. STANDARD FOR SUMMARY DECISION
Under 21 C.F.R. § 16.26(b), the Presiding Officer is authorized to issue a summary decision on any issue in the hearing if the Presiding Officer determines from material submitted in connection with the hearing, or from matters officially noticed, that there is no genuine and substantial issue of fact respecting that issue. A summary decision may be issued any time after FDA receives a request for a hearing in response to an NOOH. 36 The standard for administrative summary decision contained in 21 C.F.R. § 16.26(b) mirrors that contained in Rule 56 of the Federal Rules of Civil Procedure ("Fed.R.Civ.P."), which provides that summary judgment "shall be rendered ..if there is no genuine issue as to any material fact and ...the moving party is entitled to a judgement as a matter of law." Fed.R.Civ.P. 56(c). Therefore, the Presiding Officer may be guided by the body of law developed under Rule 56 in determining whether summary decision is warranted. 37
The party moving for summary judgment bears the burden of establishing the absence of a genuine issue of material fact. Adickes v. S.H. Kress, 398 U.S. 144, 157 (1970). The burden extends to each element that is material to each issue in its case. C.A.R. Transportation Brokerage Co. v. Darden Restaurants, Inc., 213 F.3rd 474, 480 (9th Cir. 2000). The movant must show affirmatively the absence of any meaningful factual issue. Niagara Mohawk Power Corp. v. U.S. Dep't of Energy, 169 F.3rd 16, 18 (D.C. Cir. 1999), citing National Assoc. of Gov't Employees v. Campbell, 593 F. 2d 1023, 1027 (D.C. Cir. 1978).
A party opposing a properly supported motion for summary decision has the burden of showing that a rational trier of fact could find for the nonmoving party and thus that there is a "genuine issue for trial." Matsushita Electrical Indus. Co. v. Zenith Radio Corp., 475 U.S. 574,586 (1986). To fulfill this burden, the nonmoving party "must set forth specific facts showing that there is a genuine issue for trial." Fed.R.Civ.P. 56(e); Matsushita Electrical, 475 U.S. at 586; First Nat'l Bank v. Cities Service Co., 391 U.S. 253, 289 (1968). The mere existence of a scintilla of evidence in support of the non-moving party's position will be insufficient to overcome a motion for summary judgment Anderson, 477 U.S. at 252. Further, the opposition to a properly supported motion for summary judgment "must do more than simply show that there is some metaphysical doubt as to the material facts," Matsushita Electrical, 475 U.S. at 586, and cannot rest on mere allegations. First Nat'l Bank, 391 U.S. at 289. Conclusory arguments unsupported by factual statements or evidence do not meet this burden. In re Lewis, 97 F.3rd 1182, 1187 (9th Cir . 1996), citing Taylor v. List, 880 F.2d 1040, 1045 (9th Cir. 1989).
Any doubts are to be resolved in favor of the non-moving party, and the nonmoving party is entitled to all justifiable inferences. Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 255 (1986). It is not the role of the trier of fact to weigh evidence and decide issues of contested fact, but instead to determine whether triable issues of fact exist. Clicks Billiards, Inc. v. Sixshooters, Inc., 251 F.3 Td 1252, 1264 (9th Cir. 2001).
V. 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. Ziering was the principal investigator, are set forth in 21 C.F.R. Part 312. Section 312.70(b) 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.
As explained elsewhere, CDER has alleged both that Dr. Ziering 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.
FDA has interpreted the word "repeatedly" to mean "more than once." 38 The plain meaning of "repeatedly" is "again and again." 39 An investigator can commit violations "repeatedly" in one study, i.e. disqualification does not require transgressions in more than one study. 40
"Deliberate" includes willful. Willful conduct could be viewed as conduct demonstrating reckless disregard. Since willful or reckless conduct is almost never admitted, and can be proved only by the conduct and the circumstances, an objective standard must be applied. When a clinical investigator engages in conduct that he or she knows fails to comply with FDA's regulations, or engages in conduct that shows reckless disregard for whether his or her conduct complies with FDA's regulations, he or she is liable to being found to have "deliberately" violated the regulations. Similarly, an investigator whose conduct shows a reckless disregard for whether his or her conduct may result in a regulatory violation is liable. to being found to have "deliberately" violated the regulations. A deliberate regulatory violation may be found in the absence of knowledge that a regulatory violation would occur, or in absence of any specific intent to cause such a violation. 41
As the initiator of the enforcement action, CDER has the burden of proof, i.e., the Center is required to prove by a preponderance of the evidence that Dr. Ziering repeatedly or deliberately violated the regulations, or repeatedly or deliberately submitted false information. 42
VI. GENERAL ISSUES RAISED BY DR. ZIERING
Dr. Ziering raised several general issues of fact and policy in his response to the NOOH. These issues are discussed in subsections A. and B., below.
A. Alleged Issues of Fact
Dr. Ziering lists three matters that he claims raise "material issues of disputed fact."43. These matters, which are not limited to specific charges made by CDER, are as follows:
1. Whether the cited activities were performed by or undertaken at the direction of Dr. Ziering.
Dr. Ziering states that he did not perform the activities cited in the NOOH as violative, and contends that FDA has not provided any evidence that Dr. Ziering did so. Further, he claims that he had no knowledge of the study discrepancies at the time they were committed. He blames the people he hired, e.g., [redacted] and for the problems. Dr. Ziering's position is, essentially, that the investigator is not responsible if violative activities are not performed by him, or undertaken at his direction. He argues that whether he performed or directed the violative activities is an issue of fact 44.
Dr. Ziering has not raised an issue of fact with this assertion. I agree with CDER's position that Dr. Ziering assumed responsibility for proper execution of the studies conducted at his site when he agreed to be principal investigator for the clinical trials. 45 Regulation 21 C.F.R. § 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." If Dr. Ziering did not conduct all portions of the studies, then he was required to adequately supervise those to whom he delegated responsibility. His supervisory responsibility includes taking appropriate measures to ensure that violations do not occur. He can delegate duties but not his responsibility.
Thus, whether Dr. Ziering personally undertook or directed the violative actions is not an issue of fact.
2. Whether the alleged activities were deliberate on the part of Dr. Ziering.
Dr. Ziering states that on learning of the problems, he took corrective action that was inconsistent with that of a "principal investigator who deliberately changed patient records and repeatedly and purposely failed to follow study protocol." 46 He asserts that FDA has not provided facts that establish Dr. Ziering's deliberate failure to comply with the regulations since he was not the "bad actor" in these cases and, instead, worked diligently to ensure that similar situations did not reoccur.47 He points out that his corrective actions included revising CCRI procedures, training his present employees on compliance with FDA requirements, implementing a peer review program for study documents, and enhancing managerial oversight.48
Dr. Ziering argues, therefore, that he has raised a factual issue for hearing essentially, whether his corrective actions prove that the violations were not deliberate.
I must reject Dr. Ziering's argument in light of the definition of "deliberate" (see Section V., Regulatory Framework, above), and conclude that he has not raised an issue of fact. An objective standard applies in the definition of the term "deliberate," and a deliberate regulatory violation may be found in the absence of any specific intent to cause such a violation. A finding of "deliberateness" focuses principally on the investigator's actions (or inactions) before and during the occurrence of violations, rather than afterward as Dr. Ziering contends. CDER put it well: " . . . as the principal investigator, he was responsible for the studies from the outset, not solely after he had been notified by a sponsor of problems existing at his clinic."49
Therefore, Dr. Ziering's corrective actions do not raise a factual issue with regard to whether his acts or failures to act were "deliberate." Here, whether Dr. Ziering deliberately violated the regulations is a question of law, not fact. I will consider whether Dr. Ziering deliberately violated the regulations in the section on Analysis of Charges (Sec. VII).
3. Whether deficient management oversight by the principal investigator provides sufficient proof of "repeated or deliberate "failure to comply with FDA regulations to properly support Dr. Ziering's permanent disqualification, especially when changes were timely made to remedy the situation.50
Dr. Ziering states that FDA inspections of 434 clinical investigators over a period of almost 20 years have found that 46% had objectionable conditions or practices representing significant departures from the regulations. Thus, he argues, data generation and recordkeeping discrepancies are not uncommon in clinical studies. Dr. Ziering states that, even if he had deliberately and independently conducted the activities which FDA has cited (which he contends is not the case), it is unclear why FDA has jumped directly to a disqualification proceeding, without an intermediate regulatory action such as issuing a regulatory letter or terminating other studies under Dr. Ziering's direction.
Dr. Ziering states that he "does not claim that the studies cited by FDA were free of errors or mistakes. No clinical study on humans ever is." He concedes that at most he "may have supervised his employees inadequately." However, he states that his actions "do not rise to the level of requiring his disqualification as a clinical investigator."51
Dr. Ziering argues, essentially, that his supervisory deficiencies were insignificant, especially in light of the corrective actions he took. I find that Dr. Ziering does not raise factual issues with this argument. The determination that I must make is whether Dr. Ziering has raised a genuine issue of material fact regarding whether he violated the regulations and, if so, whether the violations were repeated or deliberate. Once such a finding is made, disqualification generally must follow, subject to the Commissioner's discretion not to disqualify an investigator in extraordinary circumstances.52 The regulations do not provide for factual findings that violations are not repeated or deliberate based on the insignificance of the violations or corrective action taken by the investigator.
B. Policy Arguments
Dr. Ziering raises several issues which he terms "policy arguments."53 CDER responds by asserting that policy and legal arguments are not to be addressed in the context of a Part 16 hearing, 54 although CDER does address Dr. Ziering's argument that disqualification is inappropriate for punitive purposes. (See discussion under Policy Issue No. 2, below.) I will consider Dr. Ziering's policy arguments briefly. 55
1. Due process necessitates a regulatory hearing.
Dr. Ziering argues that FDA has never afforded him the opportunity, outside the written responses to the FDA 483, to respond formally to FDA's inspectional observations. I believe that a brief review of the regulatory history reveals not only that Dr. Ziering has had ample opportunity to respond to the inspectional observations, but also that he has in fact responded in detail. In addition to the chance to respond to the FDA 483, he was also given opportunity to respond to the NIDPOE, the NOOH, and the MSD.
In his response to the NIDPOE, Dr. Ziering requested a regulatory hearing for a prompt resolution of the matter, rather than providing information informally in writing or in an informal conference. 56 He provided detailed information in his response to the NOOH, however, including point-by-point responses to the specific charges. He claimed that the existence of genuine and substantial issues of material fact required a hearing. 57 Nevertheless, his response to the NOOH stated that he had not attempted to dispute each and every allegation posited by FDA. If such a response was required, he requested notice and time to prepare a more detailed response before a regulatory hearing was scheduled. 58 In his Opposition to CDER's MSD, Dr. Ziering stated that he had raised issues of fact in his NOOH response. In summary, I conclude that Dr. Ziering's due process rights have been satisfied, and that consideration of CDER's motion for summary decision is appropriate. Dr. Ziering's argument is, in essence, a denial of the validity of administrative summary judgment, which is well established by case law and regulation.
Dr. Ziering asserts that FDA has not provided him with any of the factual information that FDA gathered from former CCRI employees, so Dr. Ziering has been unable to respond to that information. He argues that a regulatory hearing is necessary so that he can be advised of the information upon which FDA's allegations rely, and to ensure that the disqualification proceeding is based on facts. 59
CDER has set forth its factual contentions by incorporating into the record the FDA 483 and subsequent documents (NIDPOE, NOOH, and MSD). All the information that CDER relies on (and that I will consider) has been made known to Dr. Ziering. Any additional information that might have been collected from former CCRI employees is irrelevant to this proceeding.
Dr. Ziering further states that due to pending criminal proceedings against him, he has been unable to categorize genuine and substantial issues in a detailed manner. He claims that his responses have been hampered by the risk of self-incrimination that could arise in the ongoing criminal investigation. 60 He moves to suspend the administrative proceeding until completion of the criminal proceedings. 61
The decision whether to suspend this administrative proceeding is one that I understand to be directed to the discretion of the Commissioner. The pendency of Dr. Ziering's request does not require that I suspend work on the preparation of this report to the Commissioner, and I will not do that. I would point out, however, that Dr. Ziering has in fact responded in detail to CDER's charges, in his responses to the FDA 483 and in the NOOH.
2. Disqualification is inappropriate for punitive purposes 62
Dr. Ziering states that FDA regulations make it clear that disqualification is not to be punitive but prophylactic, i.e. disqualification is to help ensure the safety of the subjects involved and the integrity of the testing process generally. To support his position, he cites the preamble to proposed regulations for disqualification of clinical investigators from receiving investigational drugs. 63 That preamble states that disqualification would be utilized when, among other things, the deficiencies are of such a nature that the safety of subjects or the quality and integrity of the studies have probably been compromised. Thus, Dr. Ziering argues that disqualification is inappropriate in his case because he was not the bad actor but instead worked to correct conditions perceived by FDA as violative.
CDER says that this argument must fail because Dr. Ziering assumed responsibility for the conduct of the study when he agreed to be a principal investigator.If this argument had any merit, according to CDER, every clinical investigator would attempt to shift blame for violative conduct onto his staff. 64
I agree with CDER's reasoning. More to the point, the final regulations do not support Dr. Ziering's reliance on the preamble to the proposed regulations. The proposed regulations specified criteria for disqualification, including those mentioned by Dr.Ziering. 43 Fed. Reg. 35218. The criteria, however, were not included in the final regulation. As explained in the preamble to the final regulation, the criteria, which related to the significance of the regulatory violation, "are so subjective as to make them extremely difficult to apply fairly in disqualification proceedings."65 Again, I emphasize that my task is to determine whether Dr. Ziering repeatedly or deliberately violated the regulations, so I must reject his "policy" argument.
3. Disqualification can be used only when "lesser sanctions have not been or probably will not be effective in achieving compliance."43 Fed Reg. 35217. Therefore, FDA must consider the use of lesser sanctions such as warnings or rejection of individual studies. 43 Fed. Reg. at 35218.66
In Dr. Ziering's opinion, FDA is required (by, the preamble language cited above) to consider the possibility of applying lesser sanctions against him. He also asserts that disqualification is inappropriate when, as in this case, an investigator has demonstrated that compliance with FDA's requirements has been substantially achieved.
As explained above, the Commissioner has determined that once he makes a finding that an investigator has repeatedly or deliberately failed to comply with the applicable requirements, disqualification generally must follow. The regulations provide little discretion for an alternative resolution. FDA proposed to include, as a criterion for disqualification, a finding that other, lesser regulatory actions have not or probably will not be adequate to achieve compliance by the investigator.67 However, the agency rejected the requirement that lesser sanctions be considered when it adopted the final regulations for disqualification of clinical investigators from receiving investigational new drugs. The agency did so for the same reason that it decided not to include the criterion having to do with patient safety and study integrity: the criterion would be too subjective to apply fairly.68 Thus, I reject this "policy" argument as well.
VII. ANALYSIS OF THE CHARGES
CDER summarizes its argument in support of summary judgment with this statement: "Dr. Ziering does not contest the violations discussed in the NOOH letter.Instead, he blames his staff for the numerous violations and asserts that his sole transgression during these clinical trials was a lack of adequate supervision. Accordingly, there are no genuine issues of material fact with respect to these violations."69
I believe that CDER oversimplifies Dr. Ziering's responses. He does make factual assertions and offers factual explanations in response to several of the charges. CDER has the burden of establishing the absence of any genuine issue of material fact.
The burden extends to each element that is material to each issue. Accordingly, in this section I will carefully examine the evidence presented by CDER, and Dr. Ziering's opposition and evidence.
A. Charge 1- Submission of False Information
CDER charges that Dr. Ziering submitted false information to the sponsor of in required reports, in violation of 21 C.F.R. § 312.70(b).70 The regulation provides in part:
. . . if the Commissioner determines that the investigator . . . 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.
Specifically, the Center alleges four incidents of falsification of Case Report Forms (CRFs) in two studies. CDER alleges that submission by CCRI staff of the false information to the study sponsor shows that Dr. Ziering, as principal investigator and the person who was responsible for ensuring that all FDA regulations were followed, submitted false information in violation of the regulation.71 CDER alleges that the violations were repeated and deliberate.
In response, Dr. Ziering asserts that the FDA investigational observations allege a simple case of mismanagement, and not fraud or a deliberate submission of fraudulent information.72 He states that he " . . . has not submitted false information to study sponsors or FDA, nor has he proffered any intentional misrepresentations. Rather, FDA has identified recording mistakes and protocol deviations that were, initially, improperly handled by CCRI's medical professionals and, later, covered up by those employees."73
For each of the studies CDER identified, I will present a summary of the evidence that CDER cites, the investigator's opposition and evidence, CDER's response, and my analysis and conclusions.
To be entitled to summary judgment, CDER has to establish that there is no genuine issue of material fact that the documents in question contained false information, were required to be submitted to the sponsor, and in fact were submitted to the sponsor.
Although CDER did not offer specific proof to establish that the documents discussed below were reports required by the sponsor, I can take notice of the fact that CRFs by their nature are documents that are required to be submitted to the sponsor.
Therefore, my analysis with respect to violation of the regulations will focus on whether the documents contained false information, and whether they were submitted to the sponsor.
2. Glaxo Pharmaceuticals Study [redacted]
a. CDER's Evidence 74
CDER states that pulmonary function test (PFT) records were altered to qualify a patient (subject 3713) who would not otherwise have qualified for this study. CDER also states that records were altered to meet time frame requirements for a blood specimen for the same patient. CDER asserts that the information was submitted to the sponsor in CRFs.
PFT Record. The protocol's inclusion criteria required that patients meet a certain numerical standard in a pre-reversal PFT. A post-reversal PFT test for subject 3713 was deliberately modified to appear as if it were a pre-reversal PFT in order to qualify the subject for this study. The figures were transcribed onto the subject's CRF, which was then submitted to the sponsor.75
Blood specimen. The protocol required investigators to draw a blood specimen for a morning plasma cortisol determination between 7 a.m. and 10 a.m. Records obtained from Glaxo's contract laboratory [redacted]document that the specimen for subject 3713 was drawn at 1 p.m. However, records obtained from Dr. Ziering demonstrate that the collection time was changed to falsely report that this specimen was collected at 8 a.m. These falsified figures were transcribed onto the subject's CRF, and submitted to the sponsor.76
b. Investigator Opposition and Evidence
Dr. Ziering's response to the NOOH states that this study was not identified in the FDA 483, and that. the time frame for response to the NOOH was too short for Dr.Ziering to provide specific information. The response stated that he was still in the process of identifying and analyzing the records in this study, and reserved the right to supplement his response to the NOOH in the near future when he had responsive information."
c. Center Response
CDER responds that Dr. Ziering did not dispute the charges, nor did he offer any explanation for the discrepancies. He has not provided additional information, even though he stated in response to the NOOH that he wanted more time to develop a response because the violations were not included in the original FDA 483.78
d. Presiding Officer's Analysis of the Charge
Dr. Ziering is correct in his assertion that FDA did not audit this study during the 1995 inspection. Instead, records for patient 3713 were the subject of a limited inspection of CCRI 79 and visits to Glaxo Wellcome, 80 both in October 1998. However, as CDER points out, Dr. Ziering has had adequate opportunity to respond to the material obtained in October, 1998, starting with the November 1998 NIDPOE, but has not done so.
Pulmonary function test (PFT). The violation, according to CDER, is that a postreversal PFT report was-deliberately modified to appear as if it were a pre-reversal report, in order to qualify the subject for the study. The inclusion criteria required that a patient have a pre-reversal test with a percent predicted Forced Expiratory Volume (FEVI) between 50 and 80%. Original (and presumably correct) pre-reversal tests for the subject's Visit 1 (conducted at 09:07) showed the percent predicted FEVl to be 47% and 45%,81 which would not qualify the individual for the study. The NIDPOE states that in the trial 13 post-reversal PFT record the time (09:44) was crossed out, and changed to the pre-reversal time of 09:07.82 The trial 13 PFT record shows a percent predicted FEV1 of 57%, 83 within the range for qualification for the study. Apparently this NIDPOE statement was based on the statement of the FDA investigators, who examined the original trial 13 document and whose report suggests that the original recorded time on the trial 13 record was 09:44. 84 The investigators also noted that other post-reversal tests (trials 1-3) were done at 09:44. 85 The visit 1 CRF for subject 3713 reports the pre-reversal percent predicted FEV 1 to be 56.8%. 86 I conclude, based on a review of the evidence and Dr. Ziering's response, that there is no genuine issue of material fact as to the falsity of this document.
Evidence that the CRF was submitted to the sponsor consists primarily of an assertion by the FDA investigators, who visited Dr. Ziering in October 1998, that the CRF had been submitted to the sponsor. 87 While Glaxo's statement in its termination letter that PFT data appears to have been altered to provide acceptable windows for study inclusion provides supportive evidence that the CRF for subject 3713 was submitted to Glaxo, 88 there is nothing in the record that clearly documents Glaxo's receipt of this particular CRF. The Center has the initial burden to show the absence of a genuine, material factual issue with respect to all elements of the alleged violation. Dr. Ziering did not admit that he had submitted the CRF for subject 3713 to the sponsor. The mere fact that he did not deny doing so does not relieve the Center of its obligation to make its prima facia case, based on proven facts and not mere allegation. Therefore, I find that a genuine issue of material fact exists at this point in this proceeding with respect to whether the CRF was submitted to the sponsor. Summary judgment is, therefore, denied on this charge.
Blood specimen. The alleged violation is that the blood specimen for subject 3713 was drawn at 13:00, but that the records were changed to show that the specimen was taken at 08:00. The latter hour is within the protocol's time frame. MSD Exhibit 12 documents that Glaxo's contract laboratory received a laboratory requisition showing that the specimen was collected at 13:00, presumably the correct time. The exhibit also includes a Visit 8 CRF, collected from Dr. Ziering, 89 which shows the falsified time, 08:00. (The investigators also collected from Dr. Ziering a copy of the laboratory requisition, altered to show that the blood was drawn at 08:00. See Exhibit 12.)
I conclude that the document found in Dr. Ziering's possession contained false information. There is, however, no direct evidence in the record that the CRF which contains the false information was submitted to the sponsor. The record indicates only that the FDA investigator obtained a copy of the CRF from Dr. Ziering. CDER alleged in the MSD that Dr. Ziering submitted the CRF to the sponsor, but provided no documentation to support its allegation. The Center has the initial burden of showing affirmatively the absence of a genuine issue of material fact with regard to each element of its case. Dr. Ziering did not admit CDER's unsubstantiated allegation; the fact that he did not specifically deny it does not relieve CDER of its burden of proof of making a prima facie case, which cannot be made on the basis of mere allegation.
Therefore, I find that an issue of material fact exists at this point in this proceeding with respect to whether the CRF was submitted to the sponsor. Summary judgment is, therefore, denied on this charge.
2. Glaxo Study [redacted]
a. CDER Evidence
CDER alleges that records were falsified to qualify two subjects for the study, and that the false information was submitted to the sponsor in required reports (CRFs).
The protocol excluded subjects with chronic obstructive pulmonary disease (COPD) from the study. The Screening Visit checklist for one subject (0665) reported that the subject did not suffer from COPD, and therefore qualified for the study.
However, the subject's chart records document a history of COPD. CDER alleges that the CRF was submitted to the sponsor. 90
A similar discrepancy occurred with regard to another subject (0667), who had a history of diabetes. Subjects with that condition were to be excluded from the study, according to CDER. CDER says that the CRF for this subject reported no medical condition covered by section 3.2-2 of the protocol, and did not report insulin as a concomitant medication, although office records specified that the subject was prescribed insulin. CDER contends that the CRF was submitted to the sponsor. 91
b. Investigator Opposition and Evidence
With regard to patient 0667, Dr. Ziering states in his response to the FDA 483 that "the [redacted] protocol only excluded patients that exhibited any clinically significant uncontrolled disease state, other than asthma, at the Screening Visit and did not exclude Patients with controlled diabetes mellitus or neuropathy." 92
Dr. Ziering also asserts that at the time of the event documented by FDA, CCRI policies clearly stated that he was to approve any deviation from the study protocol. The record deviations were not done by Dr. Ziering or at his direction. Once Dr. Ziering learned of the discrepancies he informed Glaxo and the study was terminated. 93
c. CDER Response
CDER states that Dr. Ziering does not dispute these charges in his response to the NOOH, but asserts that his staff was responsible for the falsifications.94
d. Presiding Officer's Analysis
Subject 0665 (COPD) The protocol excluded subjects with COPD. As alleged by CDER, a CRF (Screening Visit checklist) for this subject reported that the subject did not suffer from COPD and therefore qualified for the study. 95 However, the subject's medical records document a history of COPD. 96. On the basis of this information and Dr. Ziering's failure to rebut it, I conclude that the CRF contained false information.
The evidence in the record that the CRF was submitted to the sponsor is not conclusive. Although there was indirect evidence that FDA investigators obtained the Screening Visit checklist from Glaxo during October 1998, rather than from Dr Ziering's files, 97 and there is an entry in the box "For Glaxo Use Only" on the CRF, presumably made by Glaxo personnel after receiving the document from CCRI, there is no direct evidence that the CRFs were submitted to Glaxo, such as a record of receipt by Glaxo, a signed statement from a Glaxo official that the CRF was received, or an admission from Dr. Ziering that the CFR was sent. Although the "For Glaxo Use Only" block contains an entry, presumably made by a Glaxo official, the entry in the box. bears the date 2/22/95, one day earlier than the date of the CRF. The absence of direct evidence of the mailing or receipt of the CRF coupled with the conflicting date of entry on the CRF raises enough of a question of fact to preclude granting summary judgement on this allegation.
Although I conclude that the CRF contained false information, I find that the Center has not met its burden of making its prima facia case. An issue of material fact exists at this point in this proceeding regarding whether the CRFs were submitted to the Sponsor. Summary judgment is, therefore denied.
Subject 0667 (diabetes). The protocol excluded subjects that exhibit "any clinically significant uncontrolled disease state, other than asthma, at the Screening Visit.. . . [this includes] . . . diabetes mellitus." 98 (emphasis added) Question 2 on the Screening Visit checklist asks whether the subject exhibits "any clinically significant uncontrolled disease state other than asthma."99 CDER alleged, and the record shows, that subject 0667 had a history of diabetes and treatment with insulin.100 However, question 2 on the Screening Visit checklist for subject 0667 was checked "no." 101
As noted above, Dr . Ziering states in his response to the FDA 483 (at page 5) that the protocol did not exclude patients with controlled diabetes mellitus or neuropathy. My review of the medical records in MSD Exhibit 16 supports the conclusion that the disease condition in subject 0667 was controlled and therefore, the protocol was not violated by including this subject in the study. CDER did not respond to Dr. Ziering's factual assertion with respect to control of the condition. I find that there is no genuine and substantial issue of material fact with respect to this issue. Summary judgment is, therefore, denied.
I conclude that CDER has not established violations of the regulation in Charge 1. CDER's motion for summary judgment on Charge 1 is, therefore, denied.
B. Charge 2- Failure to Maintain Adequate and Accurate
CDER charges that Dr. Ziering failed to maintain adequate and accurate case histories in violation of 21 C .F.R. § 312.62(b). That regulation provides:
Case histories. 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 or employed as a control in the investigation . Case histories include the case report forms and supporting data including, for example, . . . progress notes of the physicians, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained
prior to participation in the study.
The Center provides documents intended to show that dates, times and/or demographic data on machine-generated records, for a number of subjects in three studies, bear handwritten changes. The changes are not accompanied by documented explanation as to the basis for correction, i.e., there is no "paper trail."102 In some instances the changes were allegedly intended to qualify subjects who would not otherwise qualify for the studies. In addition, the Center alleges that a large number of records contained signatures purporting to be Dr. Ziering's that in fact were made by members of his staff who were not authorized to sign his name.
With regard to the data discrepancies, Dr. Ziering offers generic theories as to why the records might have been changed, and blames his staff for any violations. He admits that his staff signed his name without authorization, but maintains that such signatures were contrary to CCRI policy. CDER points out that Dr. Ziering does not offer specific evidence in response to any of the inspectional observations concerning data discrepancies. The Center also argues that the evidence shows that Dr. Ziering both tolerated and accepted the unauthorized signatures by staff members.
2. Glaxo Study [redacted]
a. CDER Evidence
CDER alleges that handwritten changes of date, time and/or demographic data were made on machine-generated records for four subjects, as described below. These changes were made without explanation as to who made them, or why the changes were made.
Dates and times were changed on six PFT records for one subject (0664). CDER did not indicate the significance of the changes. However, the changes apparently were made to establish the protocol-mandated 30-minute separation between pre- and post-dosing PFTs. Pre-dosing times were changed from 20:27 to 08:30, and post-dosing from 21:03 and 09:10 to 09:00. The tests were dated in October 1994; the explanation "PFT machine error low batt 2-22-95" was written on the records.
The age, height, weight, and gender (demographics) were changed on the PFT records for another subject (0665), more than a month after the PFT tests were conducted. An explanation for the time change, "pt information entered too quickly," was written on the records. Records for still another subject (0671) show that pre- and post-dosing PFTs were conducted at the same time, rather than 30 minutes apart as required by the protocol. No explanation was given for this discrepancy.
The times for three pre-dosing PFTs for one patient (0674) were changed from 06:35 to 08 :00, apparently so the intervals between pre- and post-dosing would comply with the 30-minute protocol requirement. The post-dosing PFTs were conducted at 08:30.
b. Investigator Opposition and Evidence 104
Dr. Ziering states in his response to the NOOH that he does not have specific information as to why or when the results cited by CDER were recorded, or who recorded the information. However, he says that he can provide logical explanations. That is, data may have been entered incorrectly into the PFT spirometer; or certain data may not have been entered for a subject, and the spirometer recorded the previous subject's data by default. In either case, the correct data may have been entered directly onto the chart instead of conducting a second procedure with the patient. In addition, data re-entry or other corrective actions could have resulted in the spirometer recording incorrect dosing times and time intervals.
A more detailed explanation with regard to some of the discrepancies is in Dr. Ziering's response to the FDA 483. For example, he states that "the time recorded on the spirometer print-out is the time that demographic information is entered into the spirometer and not necessarily the time that the test was actually performed or the time the results were printed out."105
Dr. Ziering delegated performance of the PFTs and recording of the data to the professional staff. He states that his employees were to blame for the discrepancies, and the employment of the persons responsible for these activities was terminated. SOPs were revised, and training has been conducted, to address the proper use of the PFT spirometer.
c. CDER Response 106
CDER notes that in his response to the FDA 483, Dr. Ziering does not dispute that the PFT dates and times were altered, nor does he offer explanation of when the changes were made or by whom. He also admits that problems occurred with respect to the changes in demographic data. He speculates that the equipment may have malfunctioned, but does not offer any documentation to support the speculation. In his response to the NOOH, Dr. Ziering does not dispute the charges but blames his staff.
d. Presiding Officer's Analysis
I must reject two general arguments made by Dr. Ziering. First, even if his "logical explanation" correctly diagnosed the reasons for inaccurate and inadequate records, the fact remains that the records are inaccurate and inadequate because the handwritten changes are not documented as correct. Second, as explained above (section VI.A.1.), Dr. Ziering cannot shift the blame to his staff, because his supervisory responsibility includes taking appropriate measures to ensure that violations do not occur.
With regard to CDER's specific allegations:
Subject 0664 (Exhibit 17, times were altered with an explanation (low battery)). I agree with CDER that there is no genuine issue of material fact, and that the altered records indicate a violation of the regulation. Although it may be more reasonable to believe that the tests were conducted during the daytime (as corrected) rather than at night (as in the original), there is no evidence to support the accuracy of the corrected times.
Subject 0665 (Exhibit 15, demographic data were changed with an explanation (data entered too quickly)). I agree with CDER that there is no genuine issue of material fact, and that the altered record shows a violation of the regulation. Even if the explanation is correct, the documents included in Exhibit 15 remain inconsistent with respect to demographic data.
Subject 0671 (Exhibit 18, same times for pre- and post-dosing PFTs). Records that show the same time for pre- and post-dosing PFTs are inherently inaccurate and inadequate. I agree with CDER that there is no genuine issue of material fact, and that the records represent a violation of 21 C.F.R. 312.62(b), as well as violation of 21 C.F.R. 312.60 (failure to follow the investigational plan, see Charge 3).
Subject 0674 (Exhibit 19, times changed to 30-minute intervals on PFTs). I agree with CDER that there is no genuine issue of material fact, and that the altered record indicates a violation of the regulation. The record provides no credible documentation to support the accuracy of the corrected times.
I conclude with regard to this study that CDER has established violations as alleged, and there is no genuine issue of a material fact for hearing. Dr. Ziering essentially admits the inadequacy of the records, for example by his statement that the employment of those responsible was terminated.
3. Glaxo Study [redacted]
a. CDER Evidence 107
CDER asserts that the protocol required that all PFT tests for all visits be conducted between 07:00 and 10:00. However, the date, time, demographics and sequence of PFTs were not taken during the prescribed times for an unspecified number of subjects. Further, CDER alleges that extensive undocumented changes were made to at least fifteen spirometer-generated PFT records. No further details to support these allegations are given in the MSD, except for four subjects as described in the following paragraph.
CDER provides information on the alteration of PFT test dates and times for four subjects (01303, 01308, 01311, 10316). The altered times allowed the first three subjects to meet the protocol requirement that the PFT tests be conducted between 07:00 and 10:00. For example, times were changed from 12:43 to 08:43 on three PFT records for subject 01303, and from 20:08 to 07:00 for subject 01308. For subject 01311, the time on a pre-dosing PFT was changed from 02:49 to 07:00, and on a post-dosing PFT from 03:14 to 08:15. Dates were also changed on some of the PFT records for subjects 01308 and 01311. CDER also alleges that on one of the PFTs for subject 01316 the label had been changed from "pre" to "post" and the time had been changed from 08:08 to 08:42. However, CDER does not explain the significance of this change.
b. Investigator Opposition and Evidence
Dr. Ziering's response for this study is the same as his response to Glaxo Study [redacted] 108. That is, he provides a "logical explanation" for the discrepancies, and asserts that his staff was responsible for them.
c. CDER Response 109
CDER states that for subject 01303, Dr. Ziering admits that the alteration permitted protocol restrictions to be met, and that he does not otherwise dispute the FDA's observations.110
CDER also responds, for one of the four subjects cited above as examples (subject 01308), that "the alteration also shows that the problems could not be attributed simply to errors in the equipment or the programming of the demographics by the staff. According to the response from Dr. Ziering, the equipment would maintain the demographics programmed in until new ones were entered to override previous entries, including the time (MSD Exhibit 5, p. 28, c.). Therefore it would be impossible for one subject to have three PFTs performed, but have the unit record one time for two of the tests, 07:00, and record a different time, 20:08, for the third test. In his response to the FDA 483, Dr. Ziering does not dispute FDA's observations and states that 'there is no documentation to explain the observed corrections.'''111
d. Presiding Officer's Analysis
I conclude that times and dates were altered on PFT records for four subjects (01303, 01308, 01311 and 01316), allowing protocol standards to be met for three of the subjects: Dr. Ziering does not dispute the observations, or offer documentation to support the accuracy of the corrected times and dates. It may be more reasonable to believe that the tests for subjects 01308 and 01311 (Exhibits 24 and 25), were conducted at 8:00 a.m., as shown on the corrections, rather than very early in the morning (e.g. 2 a.m.) or in the evening (8 p.m.), but there is no evidence to support the accuracy of the corrected times.
I agree with CDER that there is no genuine issue of material fact, and that the altered records document violations of the regulation.
4. [redacted] Study [redacted]
a. CDER Evidence 112
CDER charges-that one of three PFTs for one subject (90099) indicated significantly different age and weight than the other two PFTs for the same subject and for the same visit. The pre-dosing PFTs for a second subject (90101) showed a different gender as well as significantly different ages and weights than did the post-dosing PFT for the same subject and the same visit.
b. Investigator Opposition and-Evidence 113
Dr. Ziering states that he did not perform the PFTs at issue, or change the recorded data. The discrepancies most likely reflect inadvertent data entry mistakes and an effort to correct inaccurate data, as explained more fully in his opposition to the charge related to Glaxo Study [redacted]. He stated that he cannot offer specific evidence on the matter, since the employee who conducted these activities is no longer employed by CCRI. In addition, Dr. Ziering questioned the integrity of the data in this study, notified the sponsor, and terminated the study, all prior to the FDA inspection.
c. CDER Response 114
CDER notes that in his response to the FDA 483, Dr. Ziering does not specifically address any of the observations pertaining to the study, but attributes the problems with this study to the coordinator. In his response to the NOOH, he stated that he could not offer any specific evidence.
d. Presiding Officer's Analysis
The Center's evidence shows unexplained discrepancies in demographic data in the records for subject 90099.115 and subject 90101. 116 Dr. Ziering's opposition is based primarily on his assertion, supported by detailed discussion, that there were logical explanations for the discrepancies and that the discrepancies were inadvertent. He also states that he did not personally participate in the creation of the records, that he delegated the responsibility to his staff, and that responsible employees have been terminated.
Dr. Ziering's opposition does not raise genuine and substantial issues of fact as to whether the case reports were adequate and accurate. At most, it provides an explanation as to why the records are inadequate and inaccurate, but his explanation is insufficient as well as irrelevant to these proceedings. I conclude that there is no genuine issue of material fact, and that the discrepancies are violations of the regulation.
5. Unauthorized Signatures in Several Studies
a. CDER Evidence
CDER alleges that numerous signatures appearing throughout study records, including signatures on several of the Forms FDA 1572 (Statement of Investigator), subject consent forms, and CRFs were submitted to the sponsor and represented as Dr. Ziering's authentic signature, but were in fact made by staff members. The FDA 483 provides more detail, i.e., it reports the finding of unauthorized signatures in various study documents including informed consent forms, case report forms, laboratory reports, Form FDA 1572s, protocol amendments, source documents, and other documents including an IRB Application Letter and a Clinical Study Medication Shipping Form. 117 The FDA 483
documents unauthorized signatures on Forms FDA 1572 for four studies, and an authentic signature on the Form FDA 1572 for Dr. Ziering provided samples of his signature, and the FDA inspectors examined more than 900 signatures in the records. 118 CDER alleges that Dr. Ziering admitted during the inspection, and in his response to the FDA 483, that numerous signatures represented as his authentic signature were made by others. 119 Additional details with respect to unauthorized signatures are in MSD Exhibit 48 and the EIR (MSD Exhibit 6),
pp. 15, 16, 20, 27, 34-5.
b. Investigator Opposition and Evidence
Dr. Ziering does not dispute that a number of study records contain signatures that purport to be his, but are not. He states that he provided specific instructions to the professional staff that all documents required to be signed by the principal investigator must be signed by him . Nevertheless, several employees disregarded this policy. 120 "It has become clear to me that my reliance on the professional staff was misplaced," he said, "there was . . . no reason for my signature not to be obtained by research staff. This is particularly true for the FDA Form 1572." 121
c. CDER Response 122
CDER argues that "the fact that Dr. Ziering's staff falsified numerous signatures on documents submitted to both FDA and the study sponsors shows that such falsification was both tolerated and accepted behavior. These falsifications alone prove that Dr. Ziering failed to prepare and maintain adequate and accurate records . .. ."123
CDER also points out that as an experienced investigator with twenty-one studies on record with FDA, Dr. Ziering "would be well aware of the requirements to sign a Form FDA 1572 for each study he performed, and cannot now claim ignorance of this requirement. Similarly, he would be well aware that the clinical investigator must sign the CRFs. Dr. Ziering's attempt to shift the blame to his staff for these violations
d. Presiding Officer's Analysis
The Center's evidence establishes that signatures purporting to be Dr. Ziering's, but signed by his staff, appear on a large number of documents. Dr. Ziering does not dispute the unauthorized signatures, but states that they were done in spite of his instructions to the staff that he must sign all documents requiring the principal investigator's signature.
Dr. Ziering's response does not raise genuine and substantial issues of fact. He admits that his staff signed his name many times without authorization. He cannot shift the blame to his staff for these actions. Even if his instructions to staff were relevant, he did not document that those instructions were provided to staff before the unauthorized signatures occurred. There is no documentation of such instructions until a February 13, 1995 staff meeting, long after many if not all of the unauthorized signatures occurred.125
I conclude that the regulation was violated as alleged by CDER, but only with respect to records that are part of the "case histories," because the regulation applies only to case histories. This probably excludes Forms FDA 1572 and certain other documents, but includes all CRFs, informed consent forms and other case history documents. A case history document that has an unauthorized signature is neither "adequate" nor "accurate."
6. Conclusion - "Repeated and Deliberate" Analysis
For summary judgment purposes, CDER has established that there is no issue of material fact that Dr. Ziering failed to maintain adequate and accurate case histories for four subjects in Glaxo Study [redacted] four subjects in Glaxo Study [redacted], and two subjects in [redacted] Study [redacted]. The Center has also established that Dr. Ziering was responsible for inadequate and inaccurate case histories because those documents bear unauthorized signatures of his name.
The Center maintains that Dr. Ziering's violations under this charge were repeated, because of the numerous instances listed above, and that the violations were also deliberate.126 The Center points out that by signing the Form FDA 1572, an investigator commits to conducting the studies in accordance with the regulations. Although the record documents Dr. Ziering's signature on only one Form FDA 1572 for the audited studies, Dr. Ziering cannot claim that he was unaware that he was violating FDA regulations, because he conducted at least 21 studies between 1992 and 1995. 127 He can be presumed to know the requirements for conducting clinical studies. Until Glaxo notified Dr. Ziering that Glaxo was suspending its studies, thereby forcing Dr. Ziering to take note of the study conduct, FDA's evidence demonstrates that he showed a reckless disregard for the requirements of 21 C.F.R. § 312.62(b).
I find that the violations established in Charge 2 were repeated and deliberate. They were repeated because there were more than one. They were also deliberate. Dr. Ziering took so little care with respect to his supervisory duties that he showed reckless disregard for the possibility that a regulatory violation would result. This deficiency is illustrated by the dramatic difference in Dr. Ziering's involvement in record review
before and after the formation of CCRI. Dr. Ziering stated that prior to his creation of CCRI, "I requested written reports weekly from each CRC that were to include copies of all activities and case report forms ("CRFs"). I normally reviewed patient schedules and often looked at documentation for potential protocol deviations and proper completion." 128 (emphasis added). The only documentation as to his involvement aftercreation of CCRI was that "the staff was expected . . . to provide written weekly reports including copies of all case report forms . . ."129
Whether the spirometer malfunctioned is irrelevant not only to whether a violation occurred, but also to Dr. Ziering's claim that he did not act deliberately. Even if the corrections were made due to machine malfunction, there is no evidence that Dr. Ziering instructed his staff in proper procedures for correcting machine errors. Nor is there evidence that he took timely steps necessary to determine whether the equipment was malfunctioning, to train staff in their proper use, or to obtain better equipment.
The violations with respect to unauthorized signatures were especially egregious. In addition to all but one of the Forms FDA 1572, nearly 100 percent of the CRFs and informed consent forms bore unauthorized signatures.130 It is difficult to believe that Dr. Ziering was unaware of the unauthorized signatures in view of the very few Forms 1572 and case history documents that were presented to him for his signature.
I find that Dr. Ziering repeatedly and deliberately violated 21 C.F.R. § 312.62(b) as alleged in Charge 2.
C. Charge 3- Failure to Follow the Investigational Plan
The Center alleges that Dr. Ziering failed to ensure that the investigations were conducted according to the signed investigator statement, the investigational plan, and applicable regulations, in violation of 21 C.F.R. § 312.60. That regulation provides in relevant part that:
An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations . . .
CDER offers documentation as to deviation from protocols for chest x-rays, PFTs and blood samples for a number of subjects in three studies. Dr. Ziering states that he delegated the conduct of these patient procedures to his staff, but admits that he had responsibility for insuring protocol compliance.
2. Glaxo Study [redacted]
a. CDER Evidence 131
The protocol required a chest x-ray at Visit 1(screening visit), or a negative x-ray during the previous 12 months. However, there was no documentation for four subjects (01301, 01302, 01304 and 01306) that either event had occurred. In addition, records for nine subjects (01303, 01305, 01310, 01312, 01313, 01316, 01319, 01271 and 01273) revealed that the x-rays were not taken before or at the time of the screening visit, but afterward.
The post-dosing PFT was conducted at 10:26 for one subject (01303), after the prescribed time limit of 10:00. In addition, the same post-dosing test for the same subject was performed approximately two hours after the pre-dose test, instead of at the prescribed 15-minute interval.
b. Investigator Opposition and Evidence 132
Dr. Ziering states that he delegated the patient procedures to his professional staff. He relied on the staff to be knowledgeable about protocol requirements, to review clinical charts for protocol issues, and to inform him of any problems. He was not informed of any difficulties. Nevertheless, Dr. Ziering acknowledges his responsibility to ensure that the protocol is strictly adhered to.
In response to the FDA 483, Dr. Ziering committed to providing proper instruction to the staff, and reviewing each protocol in detail with the staff, among other actions.
c. Center Response 133
CDER notes that in response to the FDA 483, Dr. Ziering states that "there is no documentation to explain the noted observations." In his response to the NOOH, Dr. Ziering does not dispute the charges. Although he attributes the discrepancies to his staff, he admits that it was his responsibility to ensure that the protocol was strictly followed.
d. Presiding Officer's Analysis
CDER's allegations are well documented, and Dr. Ziering's response does not raise genuine and substantial issues of fact. He does not dispute CDER's evidence with regard to specific deviations from the investigational plan, and admits that he was responsible for ensuring that the protocols were followed. I find that there is no genuine issue of a material fact, and that Dr. Ziering violated the regulation as alleged.
3. Glaxo Study [redacted]
a. CDER Evidence 134
For one subject (0661), two post-dosing PFTs were conducted 12 minutes after the pre-dosing PFTs, despite the protocol's requirement of a 30-minute interval.
b. Investigator Opposition and Evidence 135
Dr. Ziering states that his response with respect to this study is the same as his response to CDER's allegation in response to Charge 2 for Glaxo Study [redacted] above. That is, he provides a "logical explanation" for the discrepancies, and asserts that his staff was responsible for them.
b. Presiding Officer's Analysis
Again, CDER's allegation is well documented, and Dr. Ziering's response does not raise genuine and substantial issues of fact. I conclude that Dr. Ziering violated the regulation as alleged.
4. [redacted] Study [redacted]
a. CDER Evidence 136
CDER asserts that for one subject (90089), the chest x-ray was not taken until 18 days after Visit 1, despite the protocol's requirement that the x-ray be taken at Visit 1 or in the twelve preceding months. However, this alleged departure from the protocol is not documented in the MSD exhibits. For the same subject there was no record that a blood sample was drawn at Visit 5 as required by the protocol, or that a pre-dose ECG was performed at Visit 5 as required by the protocol. 137
b. Investigator Opposition and Evidence 138
Dr. Ziering states that he could not offer specific evidence on this matter since the responsible employee is no longer employed by CCRI. He adds that CCRI independently identified the data integrity issues, and properly notified the sponsor.
c. CDER Response 139
CDER points out that Dr. Ziering does not dispute the FDA observations, but attributes the problem to a former employee. However, CDER contends that Dr. Ziering cannot shift the blame to others.
d. Presiding Officer's Analysis
CDER's allegation with respect to the incident involving the chest x-ray for [redacted] study subject 90089 was not documented. However, CDER did document its allegation regarding the blood sample for the same subject. Dr. Ziering's response does not raise genuine and substantial issues of fact with regard to the latter incident. I conclude that Dr. Ziering violated the regulation as alleged with respect to the blood sample.
5. Conclusion - Repeated and Deliberate Analysis
I conclude that Dr. Ziering violated the regulation by failing to follow the investigational plans for the several protocols, with respect to chest x-rays, PFTs and blood samples.
CDER did not specifically allege "repeated or deliberate" violations with respect to this charge. (The Center did point out that the Form FDA 1572 places clear responsibility on the clinical investigator to ensure that his staff complies with applicable regulations, citing 21 C.F.R. § 312.60. 140) I conclude, nevertheless, that the violations were both repeated and deliberate. They were repeated because CDER proved more than one violation. They were also deliberate for reasons noted with regard to Charge 2, e.g., there is no indication in the record that Dr. Ziering checked any of the records to ensure that the protocols were being followed. Dr. Ziering showed a reckless disregard for
whether his conduct would result in a regulatory violation.
I find that Dr. Ziering repeatedly and deliberately violated 21 C.F.R. § 312.60 as alleged.
D. Charge 4- Failure to Personally Conduct or Supervise the Investigations
The Center alleges that Dr . Ziering failed to personally conduct or supervise the investigations, as required by 21 C.F.R. § 312 .53(c)(1)(vi)(c).141 That regulation places responsibility on the sponsor to ensure that the investigator signs the investigator statement, Form FDA 1572, which contains a commitment that he or she will personally conduct or supervise the described investigation(s).
2. CDER Evidence 142
Dr. Ziering informed [redacted] the sponsor of Study [redacted], by memo dated January 12, 1995, that "all subjects involved in this study were seen by me" for physical examinations, interpretation of skin tests, review of history at screening visit, fungal examinations, and global assessment. 143 However, in an interview with FDA investigators, Dr. Ziering retracted the statement that he personally saw all of the patients. The inspection revealed that Dr. Ziering was not at the clinic on several of the days on which the examinations took place.144
CDER also asserts that Dr. Ziering, in his response to the FDA 483, does not deny his lack of supervision or failure to personally conduct the clinical studies, but blames all violations on his staff."145
3. Investigator Opposition and Evidence
Dr. Ziering recognizes there were areas of the practice that would have benefited from enhanced employee training, and acknowledges that supervision was not adequate in light of the casual disregard with which the professional employees viewed their minimal professional standards.146 He stated, "In reflecting on the independent audit conducted prior to FDA's inspection and on FDA's observations, as principal investigator. I fully realize my need to exercise strong oversight of each study, especially with regard to recordkeeping and management practices."147
With regard to the January 12, 1995 memo to [redacted], Dr. Ziering states that the memo was generated in response to an inquiry from the sponsor, and was based on information provided to him by his staff. He explains that by the time FDA conducted its inspection (in April and May, 1995), he had learned about questionable data recording practices and the unauthorized signing of his name. Therefore, he truthfully informed the FDA investigators during the April-May 1995 inspection that he had insufficient information to confirm the accuracy of the memo. CCRI documents have been revised to reiterate CCRI policy that Dr. Ziering must be scheduled to personally examine each study subject, and that he must sign documents requiring the principal investigator's signature.148
4. Presiding Officer's Analysis of the Charge
a. Authority - Viability of 21 C.F.R. § 312.53(c)(1)(vi)(c) in Charging Dr. Ziering
CDER charges a violation of a regulation which reads as follows:
21 C.F.R. § 312 .53(c) Obtaining information from the investigator. 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) . . .
The plain language of the regulation states that it places responsibility only on the sponsor. The Commissioner has recently ruled that an investigator cannot be charged with violation of a regulation that applies to sponsors and not investigators.149 More importantly, due process requires that Dr. Ziering receive adequate notice of the precise regulation that he is alleged to have violated, so that he may properly defend against it. This did not happen here, therefore, I must deny CDER's motion for summary judgment with respect to Charge 4.
VIII. CONCLUSIONS AND RECOMMENDATIONS
I conclude that there are no genuine and material issues as to whether Dr. Ziering repeatedly and deliberately violated the regulations, as alleged by CDER with respect to Charges 2 and 3.
Throughout his several responses, Dr. Ziering attempts to shift responsibility for the violations to his staff members. He also argues that his corrective actions indicate that the violations were not deliberate and were not significant. I have addressed these arguments in the discussions above, but their pervasiveness in Dr. Ziering's responses causes me to provide additional comment in this concluding section.
With regard to blaming staff members, I agree with CDER's position that if the argument made by Dr. Ziering were upheld, every clinical investigator would attempt to shift blame and responsibility for violative conduct onto his or her staff. CDER points out that in U.S. v. Dotterweich, 320 U.S. 277 (1943), the Supreme Court found that a supervisor may be held criminally liable for the actions of his employees, even without knowledge that the actions had occurred. It follows that, if a person can be held criminally liable for such conduct, a person can be held responsible in an administrative proceeding for similar conduct. 150 Furthermore, this case involves numerous violations committed by many members of Dr. Ziering's staff, with no explanation of why Dr. Ziering's staff should be held responsible for the violations rather than he.
In fact, Dr. Ziering admitted that he was responsible for ensuring compliance with the protocols, and that his supervisory efforts were inadequate. As CDER points out, Dr. Ziering does not dispute that it was his duty, as a clinical investigator, to know and understand FDA regulations. (This includes, of course, regulations that impose a supervisory responsibility on clinical investigators.) His complete lack of oversight shows a blatant disregard for FDA regulations. 151 Dr. Ziering's unsupervised delegation of responsibilities to his staff, documented in the CCRI studies audited by FDA, stands in stark contrast to the careful review of study records described by Dr. Ziering before the formation of CCRI and the rapid expansion in the number of studies.
As emphasized above, the corrections Dr. Ziering allegedly made are irrelevant to the factual findings that I must make. This is clear from the final regulations concerning disqualification of clinical investigators of new drugs. In those regulations, FDA deleted a provision of the proposed regulation which would have allowed a clinical investigator to avoid disqualification through the submission of "adequate assurances" of future compliance, e.g. proof of corrections made. The agency concluded that the more subjective question of when assurances of future compliance are adequate should be addressed independently of the hearing proceeding, i.e. when the agency initiates a disqualification action, at the informal conference offered before a hearing, during negotiation of a consent decree, or after an investigator has been disqualified as part of the effort to obtain reinstatement. 52 Fed. Reg. 8826 (March 19, 1987)
Although Dr. Ziering's claim that CCRI is now in compliance with the regulations is irrelevant, I note that his assertion is uncorroborated and his changes apparently have not been implemented in ongoing studies.152 His responses include a number of self-serving statements, with some inconsistencies (for example, he fired employees in October and November 1994 because of their shortcomings, yet stated that
very late in the year 1994 he had difficulty accepting the idea that problems existed.)153 Further, documented problems continued to occur after October 1994, when Dr. Ziering states that he first took action because of problems in the conduct of the studies. CDER points out that despite Dr. Ziering's claim that he attempted to make corrections once he became aware of the problems, the fact is that he was unaware of the vast number of problems until he was notified by a sponsor (Glaxo) that it was suspending its trial.154 Furthermore, the record documents specific problems that continued to occur after October 1994, e.g. in November 1994,155 December 1994 156 and January 1995.157
In summary, the violations that can be attributed to Dr. Ziering are pervasive and significant. For example safety of patients can be compromised when they are admitted to studies for which they do not qualify. Further, the kinds of violations documented in this case calls into question the integrity of studies. Indeed, this is clearly illustrated by the termination of several of the CCRI studies by their sponsors.
Based on my findings with respect to Charges 2 and 3, I recommend that the Commissioner disqualify William H. Ziering, M.D., from being eligible to receive investigational new drugs.
Date Henry H. Startzman III, M.D.
1 The source of the information in this section, unless indicated otherwise, is Dr. Ziering's Response to the Notice of Opportunity for Hearing ("NOOH," MSD Exhibit 2), pp. 2-6.
2 Response to NOOH, p. 2. However, the record contains conflicting information as to the number of studies and when they were conducted. Dr. Ziering's Response to the FDA 483, Exhibit 5 to the MSD, p. 4, indicates that he began clinical research in 1987. The FDA Establishment Inspection Report ("EIR,"MSD Exhibit 6), p. 2, indicates that Dr. Ziering participated in a clinical investigation in the late 1970s, then conducted two or three studies each year beginning in 1990. CDER asserts that Dr. Ziering has 21 studies on record with FDA. MSD, p. 15, MSD Exhibit 9.
3 Response to FDA 483, p. 6. Evidently Dr . Ziering intended to write that "we had reached the limit of our research capabilities . . . "
4 EIR, p. 2.
5 Response to FDA 483 p. 2.
6 Id., p. 5.
7 FDA audited five of the studies, and conducted a limited inspection of the sixth (Glaxo Study [redacted]) The MSD does not allege violations with respect to the Sandoz study. The EIR refers to a seventh study, [redacted], sponsored by [redacted], but points out that that protocol appeared to be a post-marketing study that was exempt from the IND regulations. EIR, p. 13.
8 Response to FDA 483, p. 7.
9 The three studies sponsored by Glaxo Pharmaceuticals and Glaxo Research institute were terminated. EIR, pp. 6-7.
10 Excerpts from January 26, 1995 letter from Glaxo, included in the EIR at pp. 6-7. The letter itself is not in the record. There is no written record of the December notification.
11 Response to FDA 483, p. 7. The CRC was not identified, but presumably was [redacted]
13 This was "due in part to the employee turn-over and the concerns raised by Glaxo." Response to NOOH, p 4
14 Response to NOOH, p. 4
15 Response to FDA 483, p. 8. The CRC was not identified.
16 Both were CRCs. EIR, p. 5. The record does not indicate when they were employed .
17 Response to NOOH, p. 4.
18 Presumably these were the recommendations of the first independent auditor.
19 Response to NOOH, p. 4. Dr. Ziering's 3/15/95 letter to [redacted] contract research organization (CRO), regarding reliability of data in Study [redacted] Exhibit 47 to the CDER MSD.[redacted] 3/24/95 letter in response, terminating [redacted] is also at Exhibit 47. See also EIR, p. 5.
20 Response to FDA 483, p. 8.
21 Letter from [redacted] to Dr. Ziering, 3/23/1995, MSD Exhibit 47.
22 Apparently the meeting did not take place, for reasons not indicated in the record.
23 Response to NOOH, p. 5.
26 The record provides no details on this audit.
27 The report of the limited inspection of Dr. Ziering in October 1998 stated that Dr . Ziering was "only doing post studies and not doing any current investigations of new drugs or old drugs with new uses." MSD Exhibit 7, p. 3.
28 Exhibit 6 to the CDER MSD.
29 Exhibit 5 to the CDER MSD.
30 A memorandum of the inspection, dated October 19, 1998, is Exhibit 7 to the CDER MSD.
31 A memorandum of the visits to Glaxo is Exhibit 8 to the CDER MSD.
32 Exhibit 3 to the CDER MSD.
33 Exhibit 4 to the CDER.MSD. Exhibit 4 also includes an interim response dated November 24, 1998.
34 Exhibit 1 to the CDER MSD.
35 Exhibit 2 to the CDER MSD.
36 For the purposes of 21 C.F.R. § 16.26(b), a hearing commences upon receipt by FDA of a request for a hearing submitted under 21 C.F.R. § 16.22(b).
37 John D. Copanos and Sons, Inc. v. FDA, 854 F.2d 510, 523 (D.C. Cir. 1988) (finding that the principles of Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 247-248 (1986) "apply with equal force in the context of administrative judgment."). See also 53 Fed. Reg. 4613, 4614 (February 17, 1988) (stating that the standard for summary decision set forth in 21 C.F.R. § 16.26 "conforms to well-settled law."); and Puerto Rico Aqueduct and Sewer Authority v. EPA, 35 F.3d 600, 604-608 (1st. Cir. 1994) (finding that "[f]rom its inception, the concept of administrative summary judgment has been linked inextricably to Fed .R.Civ.P.56," and that "(m]any agencies habitually look to Rule 56 case law for guidance in respect to administrative summary judgments.")
38 Report of the Presiding Officer, In the Matter of Layne Q. Gentry, M.D. (2001), p. 11.
39 Id at 12, citing Webster's New College Dictionary (Merriam-Webster, Inc. 1991).
40 Commissioner's Decision, In the Matter of Stephen Steen, M.D. (1984), pp. 16-18.
41 Commissioner's Decision, Regulatory Hearing on the Proposal to Disqualify Hubert M Vriesendorp M.D. (2001), Section II1.C.
42 Id., Section III.A.
43 Response to NOOH, pp. 7-9.
44 Id., p. 7-8.
45 MSD, pp. 22-3.
46 Response to NOOH, p.8.
47 Id., p. 17.
48 Id., p. 2. Dr. Ziering also expressed concern that the NIDPOE does not mention that he contacted FDA in March 1995 when he realized that his staff had not fulfilled their responsibilities, and that the NIDPOE failed to mention the management changes that he had implemented. Response to NIDPOE.
49 MSD, p. 22.
50 Response to NOOH, p. 8, unless indicated otherwise.
51 Response to NOOH, p. 2.
52 Commissioner's Decision, Regulatory Hearing on the Proposal to Disqualify Hubert M. Vriesendorp
M.D. (2001), Section III.E. "Extraordinary circumstances" include circumstances where the violations are truly insignificant. Id.
53 Response to NOOH, pp. 16-18.
54 MSD, p. 3 and p. 22 n. 11.
55 Dr. Ziering also claimed that there was a "procedural flaw" in the proceeding in that an official without authority to do so issued the NOOH letter. Response to NOOH, p. 2. Dr. Ziering does not explain the basis for his contention, however, so there is no need to address this issue.
56 Response to NIDPOB.
57 Response to NOOH, p. 1.
58 Id., p. 9.
59 Id., pp. 16-17.
60 Id., p. 16
61 Response to MSD
62 Response to NOOH, pp. 17-18, unless indicated otherwise.
63 43 Fed . Reg. 35210, 35217 (August 8, 1978).
64 MSD pp. 22-3.
65 52 Fed. Reg. 8826 (March 19, 1987).
66 Response to NOOH, pp. 17-18.
67 52 Fed. Reg . 35218 .
68 52 Fed. Reg. 8826.
69 MSD, pp. 6-7. CDER also states that Dr. Ziering does not contest any material and substantial fact at issue in this case, but only the interpretation of the facts. MSD, p. 21.
70 MSD, pp. 7-9. The NOOH, p. 3, which cites the same violations as those listed in the MSD, charges that Dr. Ziering "failed to conduct his investigations according to the signed investigator statement, investigational plan, and applicable regulations in violation of 21 CFR 312 .60, in addition to charging violation of 21 CFR § 312.70(b).
71 MSD, pp. 7-8.
72 Response to NIDPOE.
73 Response to NOOH, pp. 1-2.
74 MSD, pp. 7-8.
75 Id., p. 7, Exhibit 11.
76 MSD, p. 8, Exhibits 10 and 12.
77 Response to, NOOH, p. 9.
78 MSD, pp. 7-8.
79 MSD Exhibit 7.
80 MSD Exhibit 8.
81 MSD Exhibit 11, trials 4 and 5. The FEVI percent predicted is shown on the second line of test data on the forms.
82 NIDPOE, pp. 2-3.
83 MSD Exhibit 11.
84 MSD Exhibit 7, p. 2. The investigators found that the original last digit for the time on the trial 13 report was a 4, and the digit prior to that appeared to be a 4 although it was somewhat difficult to tell.
85 The post-reversal tests for trials 1-3 are in Exhibit 11.
86 MSD Exhibit 11. The FEVI calculation of 56.8%, shown on the Visit I CRF, is based on the FEV 1 line (second test data line) of the first page (spirometry report for trial 13) of Exhibit 11. That line shows 1.50 "premed" and 2.64 "pred". The percent predicted (1 50 divided by 2.64) is 56.8; the spirometry report rounded to 57%.
87 The copy of the CRF that is in Exhibit 11 was identified by the FDA inspectors as Attachment 2; their
report states that "Attachment 2 is a copy of the Case Report Form submitted to Glaxo on this particular
subject, #03713." MSD Exhibit 7, p. 4.
88 EIR, p. 6:
89 That the FDA investigators collected the document from Dr. Ziering is established by identifying information in the upper right corner of the document that references the inspection of Dr. Ziering's facility.
90 MSD, p. 8; NIDPOE, p. 3. CDER states that MSD Exhibits 14 and 15 document a history of COPD, and that the falsified CRF is in Exhibit 14. In fact, both the CRFs and medical history documents are in Exhibit 11. Exhibit 15 contains PFT records for subject (}665 Exhibit 14 includes a single page title "Case Report Form," and a Screening Visit checklist, which indicates that the subject did not have COPD.
91 MSD, pp. 8-9 and Exhibit 16; NIDPOE, p. 3. Exhibit 16 contains a Screening Visit checklist, and chart records for the subject.
92 Response to FDA 483, p. 25.
93s' Response to NOOH, p. 10.
94 MSD, p. 9. See Response to FDA 483, pp. 24-5.
95 MSD Exhibit 14.
96 See the May 24, 1993 letter from Dr. Ziering to Department of Social Services, included in Exhibit 14.
97 Unfortunately, the record does not identify which documents were obtained from Glaxo but the inspectors appear to have obtained not only records for subject 3713 in study but also other records .
98MSD .Ex.hibit 13, p. 11.
99 MSD Exhibit 16.
100 Id ., subexhibit 148D, pages 3 and 5.
101 MSD Exhibit 16.
102 See except from Glaxo letter, EIR., p. 6.
103 MSD, pp. 10-11, unless indicated otherwise. Documents are in MSD Exhibits 15, 17,18,19.
104 Response to NOOH, pp. 11-12 unless indicated otherwise.
105 Response to FDA 483, p. 28.
106 MSD, pp. 10-11.
107 MSD, pp. 11-14, Exhibits 21, 24, 25, 26,
131 MSD, pp. 16-18, Exhibits 31-4 (x-rays) and 23 (PFT test).
132 Response to NOOH, pp. 13-14.
133 MSD, p. 17.
134 Id., p. 18, Exhibit 44.
135 Response to NOOH, p. 14.
136 MSD, p. 18.
137 CDER alleges discrepancies with regard to x-rays for two additional subjects, 94098 and 90099, MSD p.19, but the allegations are not supported by the documentation referenced (Exhibit 29).
138 Response to NOOH, p. 14.