DEPARTMENT OF HEALTH AND HUMAN SERVICES

U.S. FOOD AND DRUG ADMINISTIUTION

REGULATORY HEARING ON THE PROPOSAL TO DISQUALIFY

PAUL W. BOYLES, M.D.

FROM RECEIVING INVESTIGATIONAL NEW DRUGS

REPORT OF THE PRESIDING OFFICER

 

1. INTRODUCTION

Pursuant to Title 21 of the Code of Federal Regulations ("C.F.R. ") Parts 16 and 312, the U.S. Food and Drug

Administration ("FDA") conducted a hearing on December 18, 1991, to consider the proposal of the FDA’s Center

for Drug Evaluation and Research ("Center") to disqualify Paul Weldon Boyles, M.D. from receiving

investigational new drugs.¹ The center contended that Dr. Boyles should be disqualified for the following

reasons:

(1) submitting false information to the sponsors² in required reports, in violation of 21 C.F.R. § 312.70;

(2) failing to

1An investigational new drug is defined as "a new drug, or biological drug that is used in a clinical investigation. " [See 21 C.F.R. § 312.3(b).] A new drug, which includes drug that is proposed for a new use, is defined in of the Federal Food, Drug, and Cosmetic Act. [See 21 C.F.R. § 310.3.]

2 A sponsor is a person who takes responsibility for and initiates a clinical investigation. " [21 C. F.R. § 312.3(b).]


obtain initial and continuing Institutional Review Board ("IRB")3 approval, in violation of 21 C.F.R. §

312.66; (3) failing to maintain adequate and accurate records, in violation of 21 C.F.R.

§ 312.62; and (4) failing to follow the investigational plan, in violation of 21 C.F.R. § 312.60.

This document constitutes my report on the hearing pursuant to 21

C.F.R. § 16.60(e). This report, along with the parties’ comments with respect thereto and the administrative

record, will be referred to the FDA Commissioner for a final determination on this matter. [See 21 C.F.R. §

16.95.]

3 "Institutional Review Board (IRB) means any board, committee, or other group formally designated by an institution to review biomedical research involving humans as subjects, to approve the initiation of and conduct periodic review of such research. " [21 C.F.R. § 50.20(i) (emphasis added).]


 

2. BACKROUND

In 1983, Dr. Boyles4 conducted a clinical investigation under an Investigational New Drug ("IND")4 application

for the drug          manufactured by the           [See Boyles Exhibit ("BX") C at 40-50, 53.] In 1987 the

FDA audited the clinical           study conducted by Dr. Boyles. [See id.; Trans. at 10.] The Center

testified that Dr. Boyles had told the FDA investigator during the audit that an IRB which he controlled,

i.e., the Boyles Foundation, Inc. ("Boyles Foundation IRB"), reviewed some of the clinical studies. [Trans. at

10.] The Center further testified that at the time of the 1987 audit, the FDA auditor scheduled an inspection

of the IRB at a later date. [Id.]

4 Prior to his current position as a physician at           and Clinical Assistant Professor of Medicine, University of           , School of Medicine, , Dr. Boyles was employed in the following positions: Assistant Director of Medical Research at           from 1965-1968, Assistant Director of Clinical Research at from 1961-1972, and Medical Director of a firm called           from 1988-1990. [See Curriculum Vitae, Boyles Exhibit ("BX") A, Administrative Record ("AR") Vol. II, Tab A, at 3 and 59.]

4 21 C.F.R. § 312.20 requires a sponsor to "submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to 21 C.F.R. § 312.2(a). " A clinical investigation is defined as "any experiment in which a drug is administered or dispensed to, or used involving, one or more human-subjects. " [See 21 C.F.R. § 312.3(b).]


 

The Boyles Foundation IRB was then inspected on July 12-29, 1989, by FDA investigator Ms. Barbara Frazier5 and

an FDA investigator trainee, Ms. Kathleen Workman.6 [See Center Exhibit ("CX") 27.] The FDA inspectors found

that the Boyles Foundation IRB was located in Dr. Boyles’ private practice in Cary, North Carolina. [Trans. at

8-9.] Dr. Boyles was President and Chairman of the IRB at the time of the IRB inspection. [CX 27 at 1.] Dr.

Boyles had been originally elected as chairman of the Boyles Foundation IRB in November 1980, and he was

reelected to this position as recently as January 30, 1989. [Trans. at 9.] Dr. Boyles was the only

investigator7 for whom the IRB reviewed trials, as well as the only physician member of the IRB from 1985

until the 1989 inspection. [CX 27 at 1 and 3.] The IRB had approved twelve clinical studies conducted by Dr.

Boyles starting in 1981. However, it did not review the           study [Trans. At 46 and 151.] Among the

other discrepancies noted on the FDA Form 483, certain problems were listed regarding a study of the

drug          ,(sponsored by           , conducted by Dr.

 

5 Ms. Frazier, who testified at the hearing, has been an investigator with the FDA for 21 years. At the time of this inspection, Ms. Frazier worked out of the Raleigh resident post of the Atlanta district office. [Trans. at 8.]

6 Ms. Workman was not present at the hearing and, therefore, did not testify.

7 An investigator is defined as "an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject.) " [21 C.F.R. § 312.3(b).]


 

Boyles in 1987. [CX 27 at 2-3.]

In response to the findings from the IRB inspection, Frances O. Kelsey, Ph.D., M.D., Director of the Center’s

Division of Scientific Investigations, Office of Compliance, sent Dr. Boyles a "Notice of Adverse Findings"

letter on September 13, 1989, requesting that the IRB terminate all studies subject to 21 C.F.R. Parts 50 and

56, until the Center had received assurances that the IRB had adequately corrected its procedures, to comply

with Parts 50 and 56. [CX 28 at 1-2.] The letter stipulated that Dr. Boyles had 30 days to correct the

deficiencies in his IRB. [Id. at 2.]

Dr. Boyles then apparently attempted to comply with the IRB requirements (e.g., a voting physician member was

added to the IRB; IRB forms were revised), and Dr. Boyles provided assurances that the IRB would improve its

record-keeping. [See CX 28 at 313.]

 

From February 7 - March 9, 1990, a follow-up investigation of the Boyles Foundation IRB was conducted that

focused on two of Dr. Boyles’ studies, a           study (           ) and the previously-

referenced,           study .8 [Trans. at

 

8 Ms. Frazier served as the official FDA investigator for this inspection. Ms. Doralie Segal, who was a physiologist for


 

 26; CX 26.]

The inspection also uncovered numerous problems with both the           and           clinical studies, listed

in an FDA Form 483, of which Dr. Boyles was apprised at an exit interview. [CX 26; Trans. at 150.]

 

As a result of these findings, on July 10, 1990, Dr. Kelsey sent Dr. Boyles a letter, citing the specific

instances of his noncompliance with FDA regulations. [CX 28 at 14-22.] The letter offered him an opportunity

to respond to the allegations in writing or at an informal conference, or to enter into a consent agreement

that would rescind his eligibility to receive investigational drugs. [Id.] The letter concluded by stating

that, in the absence of a consent agreement or a satisfactory response, Dr. Boyles would be offered the

opportunity for a regulatory hearing on these matters under 21 C.F.R. Part 16. [Id. at 21.] On October 5,

1990, the Center sent a second letter

 

the Clinical Investigations Branch in the Center’s Division of Scientific Investigation, Office of Compliance at the time of the inspection, participated in the inspection as a scientific resource and technical assistance person for Ms. Frazier. "

The "for-cause" inspection of Dr. Boyles’           and           studies in 1990 were conducted in follow up to the previous inspection. Among other reasons, the inspection of the study was conducted because the drug sponsor had submitted Dr. Boyles’ study as a pivotal study in support of a New Drug Application ("NDA") for           [Trans. at 53; see also CX 26 at 1.]


 

to Dr. Boyles, because, as the letter stated, the Center had not

received a response to its previous letter. [Id. at 24.] This letter requested that Dr. Boyles call Dr.

Kelsey’s office prior to October 15, 1990, if he wished to take advantage of the options listed in the July 10,

1990 letter. [Id.] The Center advised Dr. Boyles that if no response was received, the Center would initiate an

action that could result in a finding that Dr. Boyles would be ineligible to receive investigational drugs.

[Id.]

  1. PROCEDURAL HISTORY
  2. By letter dated April 26, 1991, Ronald G. Chesemore, FDA Associate Commissioner for Regulatory Affairs,

    informed Dr. Boyles of a "Notice of Opportunity for Hearing" ("NOOH")9 [attached], pursuant to 21 C.F.R. §§

    312.70 and 16.22.10 [CX 28 at 26-35; Administrative Record ("AR") B at 1-10.] On June 4, 1991, FDA re-sent

    the NOOH because Dr.Boyles failed to respond

     

    9 21 C.F.R. Part 16 provides: "FDA will give to the party requesting the hearing reasonable notice of the matters to be considered at the hearing, including a comprehensive statement of the basis for the decision or action taken or proposed that is the subject of the hearing and a general summary of the information that will be presented by FDA at the hearing in support of the decision or action. " [21 C.F.R. § 16.24(f).]

    10 Neither the Center nor Dr. Boyles submitted additional information regarding the concerns raised in the Center’s original July 10, 1990, or the October 5, 1990 letters.


     

    to the April 26, 1991 correspondence, and no postal confirmation of delivery had been received by the

    Agency. [AR B at 11.]

     

    The NOOH informed Dr. Boyles of his opportunity to request a regulatory hearing to determine whether he

    should be disqualified from receiving investigational new drugs. [CX 28 at 34-5; AR B at 9-10.] On June 21,

    1991, Dr. Boyles requested a hearing in a letter addressed to John L. Hauser.11 [AR C.] On September 23,

    1991, a hearing was scheduled for December 18-19, 1991. [AR H.] As Presiding Officer, I provided both the

    Center and Dr. Boyles with information on Part 16 hearing procedures, as well as copies of 21 C.F.R. Parts

    16 and 10 and § 312.70, in a letter dated August 23, 1991. [AR G.] The letter also provided an opportunity

    for each party to submit information for consideration. [See AR G, J and Mc.] Dr. Boyles was repeatedly

    advised of his right to retain an attorney for this matter. [AR J and Mc.]

     

    In a letter that I received November 22, 1991, Dr. Boyles requested a postponement of the hearing. He

    claimed that documents concerning his investigational studies were destroyed as a result of an auction of

    the clinic building and equipment following Chapter 7 bankruptcy. [AR O at l.]

    11 Mr. Hauser was a Consumer Safety Officer in the Center’s Division of Compliance Policy.


     

    I considered the reason for postponement offered by Dr. Boyles to be insufficient and denied his request

    in a facsimile followed by a letter, dated December 9, 1991. [AR U.] Dr. Boyles submitted materials by

    facsimile on December 17, 1991, with a notation that they were in lieu of his appearance at the hearing,

    [See BX A.] The hearing was held on the scheduled date of December 18, 1991; however, Dr. Boyles did not

    appear. [AR XYZ.] Shortly after the hearing convened, I closed it to the public, in accordance with 21

    C.F.R. § 16.60. [Trans. at 4.]

     

    The Center made the following charges, as described in the NOOH, in support of its proposal that Dr.

    Boyles be disqualified from receiving investigational new drugs:

    I. Dr. Boyles violated 21 C.F.R. § 312.70(a) by submitting false information to the sponsor in required reports.

    II. Dr. Boyles violated 21 C.F.R. § 312.66 by failing to obtain initial and continuing IRB review and approval.

    III. A. Dr. Boyles violated 21 C.F.R. § 312.62(a) by failing to maintain adequate records of the disposition of investigational drugs.

    B. Dr. Boyles violated 21 C.F.R. § 312.62(b) by failing to prepare and maintain adequate case histories for study subjects.

    IV. Dr. Boyles violated 21 C.F.R. S 312.60 by failing to follow investigational plans delineated in the           and           protocols.

    The Charges made by the Center against Dr. Boyles were fully described in the NOOH.


     

    To support the charges, the Center presented two witnesses, Ms. Barbara Frazier [Trans. at 8-49.], and Ms.

    Doralie Sega18 [Trans. at 50-150.], and the Center submitted 36 exhibits. As stated previously, although

    Dr. Boyles did not appear at the hearing, he submitted 59 pages of exhibits by facsimile, including his

    Curriculum Vitae, a history of his litigation with a pharmaceutical manufacturer, and several personal

    statements.

  3. REGULATORY FRAMEWORK

FDA’s regulations governing the clinical evaluation of investigational new drugs are set forth in 21 C.F.R.

Part 312. Regulations regarding informed consent and IRBs applicable to clinical investigations are set forth

in 21 C.F.R. Parts 50 and 56.

 

Section 312.70 of the regulations provides for the disqualification of investigators. That section provides,

as here relevant:

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, . . . the Commissioner will notify the investigator and the sponsor of any investigation in which the investigator has been named as a participant that the


investigator is not entitled to receive investigational drugs. The notification will provide a statement of basis for such determination.

[21 C.F.R. § 312.70(b).]

 

Although many of the events cited in the charges of the NOOH took place prior to the revision of the IND

regulations on March 19, 1987, the NOOH referred to the revised IND regulations. However, because the revised

regulations are largely consistent with the regulations in place at the time of the events in issue (except as

noted in the "Analysis" section) , this revision had no effect on the recommended disposition of the charges.

Therefore, for purposes of this report, I have used and cited the current form of the regulations for

analyzing the Center’s charges, unless otherwise noted.

 

5. ANALYSIS

In preparing my report, I reviewed each charge made by the Center in the NOOH, taking into account the

information submitted by the parties and the Center’s presentation at the hearing. I provided both the Center

and Dr. Boyles 30 days to make post-hearing submissions. However, neither the Center nor Dr. Boyles submitted

materials within the 30-day time period. Therefore, I did not consider any post-hearing submissions in

arriving at my recommendations.


 

Charge I. Dr. Boyles violated 21 C.F.R. § 312.70(a) by submitting false information to the sponsor in required reports.

The Center charged that Dr. Boyles submitted false information to his sponsor in required reports, in

violation of 21 C.F.R. § 312.70.Section 312.70 provides the following (emphasis added):

If FDA has information indicating that an investigator has repeatedly or deliberately failed to comply with the requirements of this part, Part 50, or part 56, or has submitted to the sponsor false information in any required report, the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research will furnish the investigator written notice of the matter complained of and offer the investigator an opportunity to explain the matter in writing, or, at the option of the investigator, in an informal conference. If an explanation is offered but not accepted by the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research, the investigator will be given an opportunity for a regulatory hearing under Part 16 on the question of whether the investigator is entitled to receive investigational new drugs.

Subcharaes I.A., I.B., I.C., and I.D.

I.A. IRB approval letters for           the clinical studies appeared to be altered copies of prior IRB approval letters.

I.B. The           study was terminated twice at meetings by the IRB for which there were no records. The signatures on these termination letters appeared to be photocopies, rather than original signatures.

I.C. The acknowledgement letter from the IRB to           sponsor of the           study, appeared to have a signature identical to that of prior IRB approval letters and was therefore, photocopied from a previous letter.


 

I.D. The approval latter for a past study appeared to be an altered copy of the approval letter of an earlier study ). In the letter, the list of people present at the IRB meeting wan inconsistent with the names of individuals mentioned in the minutes of the same IRB meeting.

To support Subcharges I.A, I.B., I.C. and I.D., the Center produced several of the documents listed in the

Surcharges and presented testimony that Dr. Boyles had generated documents from photocopies of other

documents. [CX 29-31, 33; Trans. at 15-23.] However, the Center focused on how the reports submitted by Dr.

Boyles to the sponsors were generated and did not address the issue regarding his submission of "false

information in required reports, " i.e., the veracity of the information contained in the

documents as that information reflected the factual situation.

The Center focused on how the reports submitted to the drug sponsors were generated by Dr. Boyles and his

staff. For example, the Center testified (emphasis added):

When we started comparing approval letters that we located in Ms.           notebook and Dr. Boyles’ folder and in the study records, one with another, we were finding that some of the dates-- some of the information on the approval letters appeared to be changed. For example, we found three approval letters for           . There were two dated May 10, ’87 and December 16, ’87 that appeared to be altered copies of a May 10, 1984           approval letter. Those two letters listed members as being present for meetings that there were no minutes for. There were no minutes showing there was a meeting on May 10, ’87 or December 16, ’87...


 

[Trans. at 16 (emphasis added); see also CX 29.]

During the hearing, the Center presented testimony that Dr. Boyles had admitted that he created documentation

for IRB events after the fact. [See Trans. at 23-6. ]12 Of these four subcharges, only Subcharge I.D.

addressed the veracity of a document, namely the IRB approval form for the           study [CX 29 at 11.],

which listed a member who did not appear on the list of attendees at the minutes of the meeting [CX 30 at 7.].

[Trans. at 16.] However, the minutes of the meeting were illegible13 and had not been signed by the IRB’s

secretary. For these reasons, I find that the Center failed to provide sufficient evidence to prove Subcharge

I.D, and that Subcharges I.A, I.B, and I.C fail to support a charge that Dr. Boyles submitted false

information to the sponsor.

 

12 The following is an excerpt from such testimony: "It was during this discussion [of the protocols] that he [Dr. Boyles] admitted that he had photocopied old approval letters for us." [Trans. at 25 (testimony of Ms. Frazier) .]

13 The Center testified as to the poor condition of Dr. Boyles’ records which had resulted in unreadable photocopies submitted by the Center as exhibits or in the lack of a record altogether, for example: "The laboratory records, the EKG tracings for the           study had been stored in a box on the floor in the basement and become .[sic] wet and mildewed.. So the records were stuck together and part of the tracings were totally obliterated..." [Trans. at 29 (testimony of M. Frazier); see also id. at 18 and 64; see also infra.]


 

The Center asks me to conclude that because the documentation of the IRB review is a photocopied record that

was apparently an altered version from an earlier record, IRB review of the           and           studies

did not occur. I can not find that the Center has met its burden.

 

The Center has the burden of showing that review did not occur. While the state of the record raises

significant questions about the care with which the Boyles Foundation IRB generated letters, and whether the

close relation between Dr. Boyles and the IRB led to a manner of conducting business that does not comply with

professional standards, it does not show that the IRB did not consider the           and           studies. If

the minutes of the IRB meeting at which the study was allegedly discussed were devoid of any mention of it, a

persuasive circumstantial showing might have been made. Those minutes, however, are illegible. Therefore, I

can not draw the inference that the Center suggests can be state of the records, and I find that the Center

failed to substantiate Subcharges I.A., I.B., I.C., and I.D.


 

Subcharge I.E.

The signatures of study subjects           806 and           12003 on some consent forms did not appear to match those of these individuals on other records and an forms in office charts. The name of study subject           12007, who was illiterate, was misspelled on his consent form.

For Subcharge I.E., the Center produced as evidence a consent form for study subject           12007, in

which the study subject’s name was spelled with an "e". [CX 5 at 1.] The Center produced a sample [See CX 5 at

1 and 3.] of the study subject’s signature from a Medicare Card, in which the name was spelled with a "u".

[See id. at 2-3; Trans. at 30-1.] Although Dr. Boyles did not respond to this charge in writing, the Center

alleged in the NOOH that Dr. Boyles had explained that the name was misspelled [with the "e"], because the

study subject was illiterate, and his wife usually signed for him. [AR B and attached, at 3.]

To support this Subcharge further, the Center presented additional excerpts from study subjects’ files where

study subjects’ signatures had allegedly been forged on the consent form. [See CX 2, 3, and 14.] The Center,

however, was uj.able to produce expert handwriting testimony, or a certified signature of a study subject,

e.g., a signature verified by a Notary Public, to compare to the signatures on the consent forms at the

hearing


 

to support this charge. [See Trans. at 31-5. ]14 Moreover, the documents provided at the hearing were

photocopies of Dr. Boyles’ records, making it even more difficult to judge whether the signatures had been

falsified without expert assistance. Therefore, I find that the Center failed to substantiate the allegations

in Subcharge I.E.

 

Subcharqe I.F.

The time to first awareness of angina was changed on the Case Report Form ("CRF") for study subject           12008, which permitted the study subject to meet an eligibility criterion for a subsequent double-blind trial.

In Subcharge I.F the Center alleged that Dr. Boyles falsified the time to first awareness of angina in the

Case Report Form for study subject           12008. The Center presented two versions of the study subject’s

CRF. [CX 6 at 4-5.] Both CRF’S were dated May 12, 1987, and both were labeled as "Page 10 of 27" for

this          study subject. [Id.] On one CRF, page 10 specified a "7:00" minute time for the "Elapsed TIME

From

14 When the witnesses were questioned regarding their specific training and expertise to assess handwriting, Ms. Frazier denied expertise in handwriting analysis. [Trans. at 31.] While Ms. Segal claimed some experience, she denied having credentials or specialized training in handwriting analysis. [Trans. at 34.] Although the Center expressed an intent to submit expert testimony at a later date [Trans. at 33.], no such information was received. In fact, the Center testified that the Center had initially contacted a handwriting expert but the Expert had told the Center that the Center’s copies were "not very good. " [Id. ]


 

Beginning of Test to EVENT [first awareness of angina]. " [Id. at 4.] On the other CRF, an "8" had been

written over the original "7" and appeared to be initialed by Dr. Boyles. [See id. at 5.]

 

The Center also presented a letter to Dr. Boyles, dated September 1987, from           for the           Inc.,

which stated: "With regard to Patient RF [study subject , 12008] , Study Visit 2, first awareness of angina,

Dr.           would rather you left the time as it was originally (7:00) unless the tracing actually shows the

8:00 time. You can send me a new page 10…" [CX 32 at 11.] Based on this letter, it appeared that the CRF page

with the altered time (i.e., "8:00") was the form to which Ms.           referred, and that she was requesting

Dr. Boyles to confirm this change from "7:OO" minutes with the subject’s actual EKG tracing. [See CX 6 at 4

and 5.] Since there existed a another Page 10 with the "7:00" number, it appeared that Dr. Boyles must have

prepared a new page 10 with the time as it was originally, "7:00. " [See id.]

 

The           protocol specifically excluded subjects with "greater than +/- 25%" or "+/- 2 minutes

difference" in "time to angina" [timed treadmill test done to the point of developing chest pain] or "time to

termination" of exercise [timed treadmill test to the point the study subject could no longer tolerate the


 

exercise] from week to week. [CX 24 at 9.] For study subject           12008, the original seven minute time

would have resulted in the exclusion of this study subject from the protocol, whereas the altered eight minute

time resulted in eligibility for the protocol. [See Subcharge IV.F., infra.]

 

Dr. Boyles provided no alternative explanation for why the time would have been changed. Therefore, I find

that the Center provided sufficient information to support Subcharge I.F. Since the Center met its burden of

proof for one of the six surcharges, I find that Dr. Boyles did violate 21 CFR § 312.70(a) and the Center

sufficiently demonstrated Charge I.

Charqe II. Dr. Boyles violated 21 C.F.R. § 312.66 by failing to obtain initial and continuing IRB review and approval.

 

Title 21 C.F.R. Section 312.66 states (emphasis added): "Assurance of IRB review. An investigator shall assure

that an IRB that complies with the requirements set forth in Part 56 will be responsible for the initial and

continuing review and approval of the proposed clinical study. "

 

To support Charge II, the Center cited a number of documents used in support of Charge I. [See CX 29-31;

33.] In its testimony, the Center again focused on the issue that the information


 

supplied in the documents recording IRB protocol, approvals or IRB meetings was "false information" and,

therefore, could not have constituted "initial and continuing IRB review and approval. " As with Charge I,

the Center’s witnesses described how the alleged "altered copies" of documents regarding IRB meetings and

approval letters were generated. [See id.; Trans. 9-22.] Specifically, the supporting paragraph for Charge II

in the NOOH (attached, at 3-4, emphasis added) reads:

As stated in Part I [Charge I.] above, the approval and termination letters for          the approval letter for           and the letter acknowledging receipt of           amendment 250.1 appeared to be altered copies of other letters previously issued by the IRB. You were unable to provicle the FDA investigator with original copies of any of these letters or with any other documentation that the information contained in the letters is accurate.

The Center asks me to conclude that because the documentation of the IRB review is a photocopied record that

was apparently an altered version from earlier record, IRB review of the           and studies           did

not occur. I can not find that the Center has the burden.

The Center has the burden of showing that review did not occur. As I stated above, while the state of the

record raises significant questions about the care with which the Boyles Foundation IRB generated letters, and

whether the close relation between Dr. Boyle’s and the IRB led to a manner conducting


 

business that does not comply with professional standards, it does not show that the IRB did not consider

the           and           studies. If the minutes of the IRB meeting at which the           study was

allegedly discussed were devoid of any mention of it, a persuasive circumstantial showing might have been

made. Those minutes, however, are illegible. Therefore, I can not draw the inference that the Center suggests

can be drawn from the ragged state of the records. In addition, the Center did not point to any requirement

that demanded that "original copies" of letters and documents be maintained.

For these reasons, I find that the Center failed to prove that Dr. Boyles did not obtain initial and

continuing IRB approval, and, therefore, find that he was not in violation of 21 C.F.R. § 312.66, as alleged

in Charge II.

Subcharge III.A. Dr. Boyles violated 21 C.F.R. § 312.62(a) by failing to maintain adequate records of the disposition of investigational drugs.

Section 312.62(a) of the regulations provides that " [a]n investigator is required to maintain adequate

records of the disposition of the drug, including dates, quantity, and use by subjects. " Since the Center’s

charge focused on the absence of records kept by Dr. Boyles, the Center presented testimony to that effect.

Ms. Frazier testified: "There were no records of


 

drug accountability showing when he received test articles or when he distributed them, or when he’d return

any unused supplies to the drug sponsors. " [Trans. at 29.]

 

Ms. Segal testified: " [T]here were no drug accountability records on site at all, other than what was faxed

in by the sponsor. But we had nothing to go on that he provided. " [Trans. at 54.] Ms. Segal further testified

that since Dr. Boylesstudies were double blind, double dummy, the sponsor had probably prepackaged the drug

for specific study subjects and sent the drug to Dr. Boyles to administer to these individuals. Therefore, Dr.

Boyles would not know who actually received the drug. [Trans. at 55-6.]

 

Dr. Boyles had been notified in the NOOH that these matters would be considered at the hearing. However, he

did not affirm or deny them prior to the hearing or after he had received the Center’s exhibits. Dr. Boyles

also failed to address these matters upon receiving the transcript of the hearing. Dr. Boyles had signed the

FDA Form 1573, which stated:

The investigator shall maintain the records of the disposition of the drug and case histories described above for a period of 2 years following the date a new-drug application is approved for the drug; or if the application is not approved, until 2 years after the investigation is discontinued.

From February 7 through March 9, 1990, FDA investigators Frazier


 

and Segal conducted an inspection of Dr. Boyles’           and           protocols. [Supra; see also FN 8 at

5.] Because           was not approved until January 28, 1991,15 at the time of this inspection, Dr. Boyles

was required to have his records for the           study in his possession. Since no information was presented

during the hearing to indicate that either a New Drug Application (NDA)16 had or would soon be filed

for           or that the IND under which Dr. Boyles had been operating was at any time withdrawn prior to the

1990 inspection, Dr. Boyles should also have had the           study records available for the FDA’s 1990

inspection.

 

Dr. Boyles was responsible for insuring that his records were "adequately" maintained, legible, and available

for an FDA inspection. [See 21 C.F.R. § 312.62(c).] This he failed to do.

 

Thus , for the           and           studies described in the NOOH , I find that Dr. Boyles failed "to

maintain adequate records of the disposition of investigational drugs, " as required by 21

 

15 Listing for in Approved Drug Products with Therapeutic Equivalence Evaluations 12th Edition, U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Management, 1992 at 3-244.

16 NDA’s are submitted to FDA in accordance with 21 C.F.R. Part 314 and under section 505 of the Federal Food, Drug, and Cosmetic Act to market a new drug.


 

C.F.R. § 312.62(a), as alleged in Subcharge 111.A.

Charge III.B. Dr. Boyles violated 21 C.F.R. § 312.62(b) by failing to prepare and maintain adequate and accurate case histories for study subjects.

Section 312.62(b) of the regulations provides that (emphasis supplied):

[a]n investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated with the investigational drug . . . .

Subcharge III.B.1. Dr. Boyles failed to keep records of the hypertensive histories of study subjects in the           study.

The Center alleged in Subcharge III.B.1. that Dr. Boyles failed to keep records of the hypertensive

histories of study subjects in the           study . The "hypertensive history" of a subject

who was being studied with an antihypertensive investigational agent, e.g.,           would be part of the

case history required under section 312.62(b). [Supra.]

 

Although the Center did not define the term "hypertensive history" before, during, or after the hearing, it

provided several types of information required to be recorded and maintained for the           study, which

included information


 

about the study subjects’ hypertension, their prior and concomitant medications, and their physical

examinations and laboratory parameters (e.g., blood pressures). [See CX 10-23.] For example, the Center’s

exhibits included a "History" sheet (aka "History and Physical"), which included the study subject’s

"Present Complaints," medications and allergies [See, e.g., CX 18 at l.]; the "Progress Notes" (aka "Office

Visits"), listing the dates of the office visits and the study subject’s weight and blood pressure [See, e.q.,

id. at 2.]; and the data sheet listing previously prescribed antihypertensive medication, [See, e.g.,

id. at 3.] , as well as other study forms.

 

In addition, in Subcharge III.B.2. [infra] charged that "Dr. Boyles failed to report prior or concomitant

therapy..." Such therapy would have included the use of cardioactive drugs that affected the study subjects’

blood pressure. A "hypertensive history" would necessarily encompass this information. For this reason, I will

defer further discussion of "hypertensive histories" to the next subcharge.

 

Subcharqe III.B.2. Dr. Boyles failed to report prior or concomitant therapy, as required on case report forms (CRFS) for study subjects           12009 [Subcharge 111.B.2.a] and           801 [b], 804 [c], 805 [d], 807 [e] and 808 [f].

Subcharge III.B.2. alleged that Dr. Boyles failed to report prior


 

or concomitant therapy on CRFS for six study subjects. As part of the case history required for each study

subject, the recording of concomitant drug use was also considered to be- among the "observations and other

data pertinent to the investigation on each individual treated with the investigational drug." [See 21 C.F.R.

§ 312.62(b).]

 

In addition, the study protocols that were implemented by Dr. Boyles specifically required the recording of

concomitant drugs. The           protocol "required that concomitant drugs, dosages, dates and reason for

taking the drug be reported on the CRF. " [CX 25 at 15.] The           protocol required that the doses and

dates of all concomitant medications be recorded on the CRFS. [CX 24 at 6.]

 

Besides the investigator's records, subject on the study were required to record and maintain an account of

the number of anginal attacks per day and the number of sublingual nitroglycerin ("NTG") tablets consumed

per day. [CX 24 at 10.] The protocol discussed the use of sublingual NTG. Under the subject selection

criteria, it stated: "Patients must have a history of substernal or precordial chest pain, pressure or

distress, provoked by exertion, and relieved by rest or by nitroglycerin in sublingual doses of 0.3 or 0.4

mg…" [Id. at 3.]


 

Subjects would be excluded from the protocol for the following: "Patients who, in the investigator’s judgement

[sic], need to continue other anti-anginal medication aside from sublingua-l nitroglycerin, or to continue

other cardioactive medications, vasodilators, psychotropic agents, or any drug know to affect the ST segment.

" [Id. at 4-5.]

 

With respect to concomitant medications: "Patients may not be given digitalis, or other cardioactive edication

other than sublingual nitroglycerin . . . . " [Id. at 6.]

 

For study subject           12009, the Center presented the subject diary, in which the subject recorded the

use of NTG tablets, administered sublingually, and NTG patches, applied to the skin. As discussed above,

although the use of NTG patches was not explicitly addressed by the protocol, such use would constitute

"other cardioactive medication" which was specifically excluded as a concomitant medication.

 

The Center presented a poorly photocopied CRF for study subject           12009 in which the "Number of NTG

Tablets taken since last visit" differed from the subject’s self-kept diary. [See Trans. at 108-9; CX 7 at 5,

9-11, and 13.] In reviewing the CRF and the diary documents, it appears that Dr. Boyles had completed

the CFR form by combining the number of NTG patches and tablets


 

recorded in the subject diary in the space provided for the reporting of NTG tablets, i.e., sublingual doses

(The form did not provide a space for reporting NTG patch use.) . [See supra; CX 7 at 5 and 11; CX 24 at 6;

see also Subcharges III.B.4. and IV.G., infra.] For this reason, I find that the Center demonstrated that

for study subject           12009, Dr. Boyles failed to report accurately the concomitant drug use to the

sponsor on the CRF.

 

The Center also charged that study subject           801 had taken prior or concurrent medication, which Dr.

Boyles did not report on the CRF. The Center stated that 801 had participated in the          

study from July 8, 1985 until November 1, 1985. For this study subject and for subsequent charges concerning

study subjects, the records which documented the study periods did not clearly state that           was the

investiqational product used. [See, e.q., CX 10 at 2-3.] Instead, the Center contended that the          

study was identified in the subjects’ records as           Study." [Trans. at 64.] When questioned as to

whether the records submitted as exhibits by the Center identified the actual study drug by name, the Ms.

Segal testified: "No , it just says, here for           study . Then it goes into, here for new          

study, which was our           study. is an ACE inhibitor…" [Id. at 64 and 69.] The


 

Center argued that the accuracy of Ms. Segal’s statement could be corroborated by comparing the study subject

record notation to the CRFS and the protocol for           for each of the study subjects, as identified by

either a study number or the subjects’ initials. [Id. at 69.] For each study subject where the notation for

the investigational product was unclear, I, therefore, performed such corroborative analysis.

 

For example, the progress notes for study subject           801 showed that the           Study" started on

July 8, 1985 and ended on November 1, 1985. [CX 10 at 2-3.] The           protocol had been submitted as

"           Protocol 250" for the investigational agent           a code name for the drug           [See CX

25 at 1; Trans. at 62.] The Center exhibit for this study subject included a number of           CRF forms,

which referred to           and protocol 250. [See forms, CX 10 at 5-8.] All of the CRF forms included the

same study subject identifiers (i.e. , the initials of the study subject and subject number 801). [Id.; see

also id. at 2-3.]

          801 apparently participated in the study from July 8, 1985 until November 1, 1985. [CX 10 at 2-3.]

The FDA Form 483 listed the same dates for the           study period and was used to corroborate the dates of

participation. [CX 26 at 4-5.] Therefore, I find that study suubject           801 did participate


 

in the          study from July 8, 1985 until November 1, 1985, based on all of the corroborative evidence, as

described above.

 

           801 was prescribed           on June 19, 1985, and on September 25, 1985,           [See CX 10 at

2-3; CX 26 at 4-5.] Since no "stop" date was recorded for either drug, and since 801 was already enrolled in

the           study on the date that was prescribed, [see, supra],           801 would have had to have taken

the           prior to and           concomitantly with, and concomitantly with, the investigational

drug,          

 

Moreover, an instruction sheet from the sponsor provided guidance regarding the reporting of

current/concomitant medication:

For each prescribed or over-the-counter medication taken by subject at any time during study, enter the required information. If dosage remains unchanged during study, only one entry is required. If medication is stopped or a change in dosage occurs, enter stop date; for a medication that continues at a different dosage, enter new information as

a separate entry.

[CX 10 at 4.] For 801, neither           were listed on the study forms for "Previous Antihypertensive

Medications" [Id. at 7.], or for "Current or Concomitant Medications" [Id. at 8.].

 

Although neither the Center nor Dr. Boyles provided additional information, e.g., a study subject diary of

medication taken, to


 

indicate whether these concomitant medications were actually taken by this study subject, the prescriptions

noted in the hospital notes were sufficient to establish the usage of these medications by study

subject           801. Therefore, I conclude that for this subject, Dr. Boyles failed to report both prior

and concomitant medication on the CRF, as required by the sponsor.

 

The Center alleged that for study subject           804, Dr. Boyles failed to note in the CRF that the subject

had received          during the study. The Center presented an information sheet for this study subject that

lacked any subject identifiers, e.g., initials or study number. Instead, the sheet had only dates, body

weight, and status of the study. As in the previous example, the Center presented an exhibit that referred to

the          There was no actual identification of the investigational product or the protocol used. [CX 12 at

1.] The same document noted that this study began on August 5, 1985 and ended on December 5, 1985, which was

corroborated by FDA Form 483 (CX 26 at 4.] and two other study forms [CX 12 at 1-2.].

 

Information on two of the           "Vital Signs & Physical Examination" forms in the CRF linked the

unidentified study subject’s weight to           804. [See CX 12 at 4-5.] Based on the interconnection of

these documents, I find that the Center


 

established that           804 did participate in the study during the above dates.

 

Next, the Center demonstrated that the records showed that the study subject was prescribed           on July

15, 1985, based on a prescription notation on the clinic record. As described above, the Center showed that

the subject’s records documented the use of           on July 15, 1985, prior to the           study, which

the subject entered on August 5, 1985. [See CX 12 at 1.] Since no "stop" date was recorded, I conclude that

the subject received           prior to and concomitantly with the           study . [See supra.] On the

subject’s "Current/Concomitant Medication" form, however, the only medication entered was           with a

"start" date of October 30, 1985. [Id. at 7.] Therefore, I find that the Center proved that Dr. Boyles failed

to report the concomitant use of           for           804 on the appropriate study form.

 

For study subject           805, the Center alleged that the subject had taken the drugs           and

          during the           study, and that these medications were not duly recorded as concomitant

medications on the CRF. As above, the Center’s exhibit failed to provide the proper identifiers, and the FDA

Form 483 was needed to corroborate the dates of the subject’s study participation (August 5, 1985 to December

2, 1985). [Cx 13


 

at 2; CX 26 at 5.] Since the clinic record noted that          and           were prescribed on August 5,

1985, and since no "stop" date was indicated for either of these medications [supra; CX 10 at 4.], I conclude

that the subject continued to take the two drugs while on the           trial. [Id.] The subject’s

"Current/Concomitant Medication" form reported "None" for medications taken during the study. [CX 13 at 4.]

Moreover, Dr. Boyles did not deny the information presented by the Center prior to, during, or following the

hearing. [See CX 26.] For these reasons, I find that for           805 Dr. Boyles failed to enter the

appropriate information regarding concomitant medications on the CRF.

 

For study subjects           807 and 808, the Center presented clinical records to show that each subject had

been involved in a prior investigational blood pressure study, and that Dr. Boyles had failed to report this

information accurately, as required on the respective CRFs.

 

For           807, the clinic records, in conjunction with the FDA FORM 483, documented that the subject had

participated in an unidentified           Study" from March 18, 1985 to July 9, 1985. [CX 15 at 1-2; CX 26 at

5.] However, the NOOH referred to the stopping date of this study as "July 16, 1985." In her testimony, Ms.

Segal noted the discrepancy in the date recorded


 

in the NOOH and the date in the Center’s exhibit. [Trans. at 127;see also CX 26 at 5.]

 

The Center presented           807’s "Previous Antihypertensive Medication" form, which required the

investigator to "List all previous antihypertensive medications taken within the last 3 months..." [CX 15 at

4.] This form failed to list the dates of 807’s first blood pressure study. [Id.] Although the ending date was

incorrect in the NOOH, the "start" date established that the first blood pressure study took place prior to

the           trial, and either ending date occurred within the 3-month period required for reporting of the

study drug in the CRF.

 

Since the CRF failed to disclose the previous trial with an antihypertensive agent, I find that for          

807, Dr. Boyles failed to report accurately prior therapy, as required on the CRF.

 

The clinic records for           808 showed that, like 807, this subject had participated in an unidentified

blood pressure study, which ran from March 26, 1985 to July 16, 1985. [CX 16 at 4-5.] From August 20, 1985 to

December 10, 1985, the same record stated that the subject started on a           Study" or            Study"

i.e., the           study. [Id.;


 

see also supra.] Since the           form for "Previous Antihypertensive Medication" did not reflect the

subject’s participation in the previous study [Id. at 6.], I find that Dr. Boyles failed to document prior

therapy, as required on the CRF.

 

Therefore, I find that the Center proved Subcharge III.B.2. , because the Center demonstrated that Dr.

Boyles failed to report prior or concomitant therapy on the CRFS for study subjects           12009 and

study subjects           801, 804, 805, 807, and 808.

 

Regarding Subcharge III.B.l., which charged that Dr. Boyles failed to keep records of hypertensive histories

for study subjects in the           study, the Center failed to address this subcharge specifically.

Nevertheless, the evidence presented in Subcharge III.B.2. for           801, 804, 805, 807 and 808

establishes Dr. Boyles’ failure to keep hypertensive histories. The specific relevant examples are as follows:

801 took           and           which was not reported on the CRF; 804 took           which was not reported

on the CRF; 805 took           which was not reported on the CRF; 807 and 808 had participated in unidentified

blood pressure studies, which were not reported on the CRF. Since the above examples demonstrate that Dr.

Boyles did not keep records of hypertensive histories for study subjects in the RAMIPRIL study, I find that

the Center demonstrated Subcharge


 

111.B.1.

Subcharqe III.B.3. Dr. Boyles failed to report intercurrent illnesses or reactions to the sponsors for study subjects           801 [Subcharge III.B.3.a], 804 [b] and 812 [c], and          12006 [d].

In Subcharge 111.B.3., the Center alleged that Dr. Boyles failed to report intercurrent illnesses or

reactions for the above referenced study subjects. The regulations require that the investigator record and

submit information to the sponsor regarding "any adverse effect that may reasonably be regarded as

caused by, or probably caused by, the drug . . . . " [See 21 C.F.R. § 312.64(b).]

 

The instructions provided to Dr. Boyles by the           drug sponsor for completing the "Intercurrent Illness

or Injury" form stated:

Use this form to report incidence or occurrence of any CLEARLY DEFINED infection or injury, totally independent of drug therapy and resulting in symptoms CLEARLY ATTRIBUTABLE to the insult.

This form should NOT be used to report exacerbations of previous or chronic conditions (unless unmistakably related to an injury or infection) , or symptoms of unknown, questionable, or even suspicious etiology. Such symptoms should be reported as SIDE EFFECTS.

[CX 10 at 6.]


 

As discussed under Subcharge IIIB.2., the Center demonstrated that study subject           301 participated

in the trial from September 15, 1985 to November 1, 1985. [See supra.] The Subject’s "Progress Notes" for

September 25, 1985 noted the subject as " [f]eeling tense - dizzy - & nervous - hands are wet - Having episode

of not feeling well most of day until has 2-3 beers . . . . " [CX 10 at 3.] The Center then presented the

study subject’s "Intercurrent Illness or Injury" form which stated "None. " [See id. at 6.] Therefore, I find

that Dr. Boyles failed to record study subject           801’s intercurrent complaint on the CRF.

 

As established in Subcharge 111.B.2. , supra, study subject          804 participated in the trial from

August 5, 1985 to December 5, 1985. The "Current/Concomitant Medication" form stated that 804 had taken "Tuss-

Ornade"for "Sinus & Cold" with a "start" date of October 30, 1985. [CX 12 at 7.] This event was not reported

on the "Intercurrent Illness or Injury" form in the CRF . [Id. at 15.] Therefore, I find that Dr. Boyles also

failed to record the intercurrent illness for study subject           804.

 

Although the NOOH stated that study subject           812 had participated in the study from July 30, 1985 to

November 25, 1985, the clinic records established that the subject did not


 

enter the study until August 6, 1985. [CX 20 at 7.] The Center presented the subject’s progress notes which

reported that 812 had experienced what appeared to be an oral temperature of "100" following a week of not

"feeling well" on October 8, 1985. This intercurrent event was not recorded on the "Noteworthy Comments" form,

which listed the study subject as "Cl. [Clinical] Normal" on October 8, 1985 [CX 20 at l.], or on the

"Intercurrent Illness or Injury" form, which stated "None" (although no dates were referenced on this

particular form) . [CX 20 at 5.] Since the Center demonstrated that           812 experienced the above event

during the study, and the event was not reported in the CRF, I find that the Center established its charge

that Dr. Boyles failed to report an intercurrent illness or reaction for 812 on the CRF.

 

Finally, for study subject           12006, the Center charged that Dr. Boyles had not properly reported

seizure activity experienced by this subject during the study on the CRF. The subject started the

           study on April 27, 1987. [CX 4 at 1-2.] The study "History & Physical" form, dated May 18,

1987, reported the subject as: "Feeling good except for headache this AM - No chest pain - Having more

seizures 4x ["times"] this past week. " [CX 4 at 2; emphasis added.] The concomitant medication form for this

subject listed the drug "PHENYTOIN" for "seizures, " which had been started in 1984, and no "stop" date


 

was recorded. [Jd. at 4.] For this reason, I conclude that for 12006, seizures were a "previous" or "chronic"

event. Also, the CRF form "Adverse Event Record" for May 18, 1987, listed only "headache, " for which no

therapy was required. [Id. at 4.] Since the Center did not address the subject’s baseline seizure activity

prior to the           study, and since the only reference to seizure activity was the clinic note stating

that the subject had experienced "more" seizures while on [supral, I conclude that the effect of           on

the subject’s seizure activity could not be ruled out. For this reason, Dr. Boyles should have recorded this

event on the "Adverse Event Record" form and reported it to the sponsor, as required in section 312.64(b).

 

Therefore, I find that Dr. Boyles failed to record "seizures" properly on the CRF.

Subcharqe III.B.4. Dr. Boyles failed to report use of NTG tablets consistently with the diaries of study subjects           12002 [Subcharge III.B.4.a], 12004 [b], 12006 [c], and 12009 [d].

To support Subcharge III.B.4. for the above           study subjects, the Center presented discrepancies

between the recorded numbers of NTG tablets on the CRFS of the above subjects and the


 

numbers recorded in the subject-kept diaries.17 [Supra.l Since NTG tablet use would represent a concomitant

medication administered during the investigational study, and since NTG might affect the results from the

investigational agent,          such information would be data pertinent to the investigation [See 21 C.F.R. §

312.62(b).] Therefore, Dr. Boyles should have recorded the use of concomitant medication accurately on the

CRFS.

 

For study subject           12002, the Center charged that Dr. Boyles erroneously reported NTG tablet usage on

the CRF for Study Visits 3 and 7. Ms. Segal testified that the NOOH should have stated that Dr. Boyles

erroneously reported NTG tablet usage for Study Visits 2 and 7 [Trans. at 140]. Therefore, Dr. Boyles

was not provided with sufficient notice regarding deficiencies reporting Study Visit 2.

 

According to the CRF, Study Visit 7 should have reported events which transpired between Study Visit 6 (May

17, 1987) and Study Visit 7 (June 10, 1987). The Center failed to demonstrate an inconsistency

between           12002’s CRF and diary report:

 

17 The CRF recording of the subject’s use of NTG tablets was based on the subject’s diary completed during the study. Any discrepencies between the diary and the CRF reporting of the diary entries should have been noted either on the CRF or the diary.


 

The diary report indicated that seven NTG tablets had been taken during this time interval; the CRF reported

on Study Visit 7 that seven NTG tablets had been taken. [See CX 1 at 1 and 4-5.] Therefore, the Center failed

to establish a reporting error in the CRF of NTG tablet usage for           12002 on Study Visits

3 or 7.

For study subject           12004, the Center charged that Dr. Boyles had incorrectly reported the number of

NTG tablets taken by the study subject on Study Visit 3. Since the dates for Study Visit 2 and Study Visit 3

were illegible, and since neither the FDA Form 483 [CX 26 at 7.] nor the NOOH specified the dates

between Study Visits 2 and 3, I was unable to assess the validity of the Center’s charge. [See CX 3 at 1.]

Therefore, I find that the Center failed to prove an NTG tablet discrepancy between the study subject diary

and the CRF fop study subject          12004.

For study subject           12006, the Center charged that Dr. Boyles failed to report an angina attack and

the proper number of NTG tablets taken on the CRF for Study Visit 2. According to the CRF, Study Visit 2

should have reported events that transpired between Study Visit 1 (April 27, 1987) and Study Visit 2 (May 4,

1987). [CX 4.] The Center presented the subject diary which reported that for the above referenced time

interval, 12006 had


 

used 3 NTG tablets and had experienced one anginal attack: On April 28, 1987, the study subject experienced

one angina attack and took one NTG tablet; and on May 1, 1987, the study subject took two NTG tablets. [Id. at

12-3.] However, Dr. Boyles reported for Study Visit 2 that "zero" NTG tablets had been taken and "zero"

anginal episodes had been experienced since Study Visit 1. [Id. at 11.] Therefore, the Center demonstrated

that Dr. Boyles failed to report accurately the number of NTG tablets taken and anginal episodes experienced

in the CRF for Study Visit 2 for           12006.

 

For study subject           12009, the Center presented discrepancies between the NTG tablets taken for Study

Visits 2 and 4. [See CX 7 at 5.] First, the Center charged that the subject diary showed that the subject had

used an NTG patch on December 16, 1987. However, NTG patch use was not reported under Study Visit 2 in the

CRF. [Id. at 5.] This allegation was corroborated by the Center’s exhibits. [See id. at 5 and 9.]

The subject diary, however, noted that the patch was used on the "test day, " i.e., Study Visit 1, which was

recorded in the CRFs as December 16, 1987. Thus, this patch usage did not have to be recorded as an entry for

Study Visit 2 in the CRF, which represented the time interval between December 16 and 22, 1987.

 

Secondly, the Center charged that Dr. Boyles incorrectly reported


 

the NTG tablet usage for Study Visit 4, representing the time interval between December 29, 1987 and January

5, 1988. The Center presented the subject diary. [CX 7 at 11.] In the columns labeled "Number of NTG taken, "

5 doses of NTG were recorded in the diary during the above time interval: one "NTG " on January 2, 1988; two

NTG and one 10 mg NTG patch, on January 3, 1988; and one 10 mg patch on January 4, 1988. [Id.] In the

CRF Dr. Boyles reported in the NTG tablet space for Study Visit 4 that 5 tablets had been taken; he did not

differentiate between NTG tablet and NTG patch doses. As discussed in Charge III.B.2. , the CRF form only

permitted the reporting of NTG tablets. [Id. at 5; see also supra.] Therefore, I find that the Center

demonstrated that Dr. Boyles failed to report accurately the NTG tablet usage for study subject 

          12009 for Study Visit 4.

 

In summary, for Subcharge III.B.4. I find that Dr. Boyles failed to report the use of NTG tablets

consistently with the diaries for study subjects           12006 and 12009.

 

For the above reasons, I find that Dr. Boyles violated 21 C.F.R. § 312.62(b) by failing to maintain adequate

case histories as alleged in the following surcharges: III.A., III.B.1., III.B.2., III.B.3., and

III.B.4.


 

Charqe IV. Dr. Boyles violated 21 C.F.R. § 312.60 by failing to follow investigational plans delineated in the and protocols.

The definition of "General responsibilities of investigators" in 21 C.F.R. § 312.60, states: "An investigator

is responsible for ensuring that an investigation is conducted according to the signed investigator statement,

the investigational plan, and applicable regulations . . . . "

 

Charge IV. alleged that Dr. Boyles failed to insure that the          and           studies were conducted

according to their respective investigational plans, as delineated by their respective study protocols [CX 24

and 25].

Subcharqe IV.A. Dr. Boyles violated the           protocol proteinuria exclusion for study subject           804.

The Center charged that Dr. Boyles admitted study subject          804 to the trial in violation of the

protocol. Specifically, the study protocol excluded subjects with "significant hepatic or renal disease as

evidenced by . . .[p]roteinuria 1+ or greater. " [CX 25 at 9.] The Center presented two data sheets for study

subject           804, which contained laboratory values consistent with proteinuria [protein in the urine].

[CX 12 at 9 and 1A] However, the key dates on


 

the data sheets were illegible. Although Ms. Segal testified as to the dates which she had seen on the sheets

[Trans. at 63-4.], the dates on the respective copies of the laboratory data s-beets were so faint as to be

completely illegible, whereas the remaining information on the sheets was legible. It was evident from the

data sheets that study subject           804 did indeed have "+1 proteinuria" on two occasions. However, it

was impossible to establish whether these occurrences fell within the study time period. [CX 12 at 9 and 12;

Trans. at 62-4.] Therefore, in the absence of additional documentation, I do not consider Ms. Segal’s

testimony sufficient to establish the dates on these particular data sheets. [Id.]. In addition, the Center

had previously testified to the poor condition of Dr. Boyles’ records. [See, e.g., Trans. at 29, 64, and 120;

see also supra.] Therefore, in the absence of other substantiating evidence, the dates of the data sheets

could not be confirmed, and I find that the Center failed to prove the allegation in Subcharge IV.A.

 

Subcharqe IV.B. Dr. Boyles violated the           protocol experimental drug use exclusion for study subjects           809 [Charge IV.B.1] and 810 [2].

The Center alleged that Dr. Boyles admitted study subjects          809 and 810 to the study, in violation of

protocol criteria which excluded subjects who had received prior investigational drugs. Specifically, the

protocol excluded


 

"Patients receiving any investigational new drug for any therapeutic reason within one month of study

initiation. " [CX 25 at 8.] The study protocol did not further define the term "month. "

 

The Center presented the clinic record of study subject          809, which recorded an office visit (noted as

"Here for           Study") on August 26, 1985. [CX 17 at 6; Trans. 64-8.] However, the clinic record also

indicated that on September 3, 1985, eight days later, the study subject was "Here for New           Study/See

Case Report. " [Id.; see also supra.] Since a minimum interval of a month was required between the completion

of a prior study and entry onto the study, the entry of this subject onto the study eight days after the prior

investigation constitutes a protocol violation.

 

For study subject           810, from the progress notes, this subject apparently also participated in a blood

pressure study before entering the           study. [See CX 18 at 2.] An entry, dated August 28, 1985, stated "Here for          study withdrawal, " which was taken by the Center as signaling the conclusion of the

subject’s participation. [See id.] An entry dated September 6,1985 stated "To start           Study" (aka

study). [Id.; see also supra.] These dates


 

clearly indicate a time period of less than one month between the two entries. Since a minimum interval of a

month was required between the completion of a prior study and entry onto the          study, the entry of

this subject onto           the study constitutes a protocol violation.[See Trans. at 68-75.]

 

In the absence of any information indicating that these study subjects had not taken investigational drugs

before entering onto the           study, I find that the Center proved the allegations of Subcharge IV.B.

 

Subcharqe IV.C. Dr. Boyles violated the           protocol weight exclusion for study subject          810.

 

The Center alleged that Dr. Boyles failed to follow the investigational plan by entering study

subject           810 into the study in violation of the protocol’s morbid obesity exclusion. The Center

testified that the           protocol excluded "Subjects with morbid obesity (100 lbs. overweight, based on

desirable weight from the Metropolitan Life Insurance Co. table). "18 [Trans at 78; see CX 25 at 9.] During

the

 

18 In the           protocol submitted as an exhibit by the Center, the section "Exclusions", item "l. " appeared blackened out, rendering it illegible. [See CX 25 at 9.] The Center testified that this section was the exclusion criteria referring to morbid obesity which had been "highlighted" by agency staff creating the appearance that it was deleted in the photocopied


 

hearing, the Center presented testimony that it had erroneously charged Dr. Boyles with violating this

protocol exclusion criteria for study subject           810. The Center stated that it had intended to refer

to study subject           815. [Trans. at 78.]

 

Since the Center failed to establish that study subject          810 violated the exclusion criteria, I find

that the Center failed to provide sufficient evidence to document Subcharge IV.C., as specified in the NOOH.

 

Subcharqe IV.D. Dr. Boyles violated the           protocol EKG exclusion for study subject          12008.

 

The Center alleged that Dr. Boyles violated the           protocol by admitting study subject           12008.

The          protocol excluded study subjects with a resting EKG showing ST depression of greater than 0.5mm.

[CX 24 at 5.] In support of Subcharge IV.D., the Center presented an unlabeled EKG tracing on which no leads

or subject identifiers were marked, and on which a written note stated "slight angina" pointing to a region of

the tracing that was so faint as to be uninterpretable.[CX 6 at 12.] For this reason, it was impossible to

determine

 

exhibit. The Center confirmed that the section [which could not be read] had not been deleted from the protocol. [Trans. at 76.]


 

from the tracing what constituted a "resting EKG, " or which portion had been identified as representative of

"an ST depression of greater than 0.5mm, " as alleged by the Center. [Id.] Therefore, I find that the Center

failed to demonstrate that Dr. Boyles violated the           protocol by admitting study subject            12008 to the study.

 

Subcharqe IV.E. Dr. Boyles violated the           protocol ST segment exclusion for the following study subjects:           12002, 12005, 12007, and 12011.

 

The Center alleged that Dr. Boyles violated the          protocol by admitting study subjects

          12002, 12005, 12007, and 12011, who did not meet the EKG entry requirements. The protocol provided

in its inclusion criteria: "Patients must have classically positive exercise treadmill tests, with ST

segment depression of a horizontal or downsloping type, lasting at least 0.08 seconds after the J-point, of at

least 1 mm below the PR segment, over and above any ST segment depression present on resting ECGs [="EKG"]. "

[CX 24 at 3.]

 

First, the Center charged that study subjects           12002, 12005, and 12007 had not exhibited a 1 mm ST

depression during treadmill tests. The Center submitted correspondence between Dr. Boyles and the sponsor, to

prove this


 

charge. [See CX 32.]

On June 24, 1987,           , M.D., Associate Medical Director, Medical Research, representing the

sponsor,           , wrote Dr. Boyles:

As we discussed I believe that 3 patients who have enrolled in the study at your site are invalid. As you know, for technical reasons, Patient V.D. [19] did not have 12-lead electrocardiograms taken during the exercise tests. . . . Patient T.S. [20] as well as subject L.D. [21] do not demonstrate a classical ST segment depression which is horizontal or downsloping. Both of these patients have upsloping ST segment changes with exercise and therefore, do not comply

 

19 aka subject           12002. [See CX 1 at 2.]

20 The Center exhibits did not clearly identify "Patient           " CX 5, to which the Center’s exhibit list referred as "           Patient 12007, " only included records from "           "but no documents in that exhibit included a subject number for "           " Center testimony identified "Patient " as " Patient 12002" [Trans. at 90 and 102.]. However, the Center exhibit clearly identified subject           12002 as "Patient "           [See CX 1 at 2.] Also, Center testimony identified "           Patient 12007, " as "           " [Trans. at 90 and 102.]

21 Again, the Center’s exhibits failed to identify clearly "           " None of the Center’s exhibits included a subject with these initials. As noted in the previous footnote, Center testimony identified "           "as "           Patient 12007"[Trans. at 90 and 102.]. However, the Center listed "12007" as "           " in its list of exhibits.

One of the sponsor’s monitors,           , identified "          " as          12007 on a "Periodic Monitoring Report, " but this same report also incorrectly identified "           " as          12002 (aka "Patient V.D.") . [CX 32 at 2.]


 

with the protocol requirements.

[CX 32 at 3.]

Since I was unable to determine who study subjects "           " and "           " were in terms of

           study subject numbers used by the Center [See supra FN 20 and 21 at 50.], I find that the Center

failed to demonstrate that Dr. Boyles committed any violations of the protocol related to these study subjects

referenced in the above letter.

 

Regarding study subject           12002 (          ), Dr. Boyles responded by letter on July 2, 1987, stating

that this subject was unable to demonstrate 1 mm ST depression during exercise when tested on July 1, 1987,

and would, therefore, be dropped from the double-blind study. [CX 32 at 4.] The last entry in the CRF for

study subject           12002 (          ) was in June of 1987, so it appeared that Dr. Boyles also dropped

this study subject once he discovered that the subject did not meet the entry requirements. [See CX 1 at 1.]

Nevertheless, the protocol required Dr. Boyles to perform the ST depression tests prior to entering the

subject into the study to determine the subject’s eligibility for the study, which he failed to do. As

discussed, Dr. Boyles only dropped           12002 upon the conclusion of the study at the sponsor’s request

for such a test. Therefore, I find that Dr. Boyles violated the protocol by entering study subject


 

           12002 onto the study.

In terms of this subcharge, the Center provided no ST depression information during treadmill tests in the

exhibits for study subjects           12002 [CX 1.], 1200522 or 12007 [CX 5.]. The Center presented ST

depression information (EKG tracings) for study subject           12011 that was uninterpretable. [ See

CX 9 at 4-5, 8-9; Trans. at 93.] Therefore, based on the information presented, I am unable to determine

whether Dr. Boyles violated the protocol entry requirements for study subjects           12005, 12007, or

12011.

 

Based on the foregoing, I find that Dr. Boyles violated Subcharge IV.E., because the Center demonstrated

that Dr. Boyles violated the protocol entry requirements for study subject           12002.

 

Subcharqe IV.F. Dr. Boyles violated the           protocol "time to angina" exclusion for study subjects           12008 and 12010.

 

The Center alleged that Dr. Boyles violated the           protocol by including study subjects           12008

and 12010 in the study.

 

22 The Center did not submit an exhibit for subject           12005.


 

The double-blind part of the           protocol limited permissible variation between treadmill tests. [CX 24

at 9.] Specifically, on the last test before entering the double-blind portion of the study, the "time to

angina" and "time to termination" could vary no more than two minutes or 25 percent from the values on the

previous treadmill tests. [Id.; see also Trans. at 117.] Subjects who met the study criteria would begin

the double-blind portion of the study following the evaluation of their treadmill tests at Study Visit 3. [CX

24 at 9.] The entry criteria would, therefore, depend on the differences between the treadmill tests at Study

Visits 2 and 3 (or 3 and 3a, if the optional Study Visit 3a is used) . [Id. at 7-8, 25-8.]

 

For study subject           12008, two CRF’s were filed for Study Visit 2. [CX 6 at 4-5; Trans. at 39.] The

first CRF recorded the "time to angina" as "7:00" ("seven") minutes. [CX 6 at 4.] However, in the second CRF

for the same Study Visit 2 an "8" had been written over the original "7" and appeared to be initialed by Dr.

Boyles. [See id. at 5.] For Study Visit 3, the last study visit before entering the double-blind portion of

the trial, the CRF recorded a "time to angina" of "9:31" minutes. [Id. at 6.] The change in time reflected in

the second CRF reduced the difference between treadmill tests for Visits 2 and 3 from 2:31 to 1:31 minutes,

thereby qualifying this subject for the double-blind portion of the study. A difference in time of


 

2:31 minutes between Study Visits 2 and 3 would clearly have exceeded the two minute or 25 percent variation

permitted by the double-blind protocol. Nonetheless, the subject continued on the study through Study Visit 7,

as recorded by the CRF clinical record form. [Id. at 2.]

 

The sponsor also addressed this discrepancy in a letter from Ms.          a medical research associate for the

sponsor, to Dr. Boyles, dated September 18, 1987: "With regard to Subject [study subject           12008],

Study Visit 2, first awareness of angina, Dr. would rather you left the time as it was originally (7:00)

unless the tracing actually shows the 8:00 time. " [CX 32 at 11.]

 

Based on this letter, it appeared that the CRF page with the altered time (i.e., "8:00") was the form to which

Ms.          referred, and that she was requesting that Dr. Boyles confirm this change from "7:00" minutes

with the subject’s actual EKG tracing. [See CX 6 at 4 and 5.] Since there existed another Page 10 with the

"7:00" number, I conclude that Dr. Boyles must have prepared a new page 10 with the "7:00" time as it was

originally. [See id.] Therefore, the Center proved that this study subject,           12008, should have been

excluded from the study, because the correct time of "7:00" would have eliminated this subject from the study,

as discussed, supra.


 

In a similar manner, the CRF for study subject           12010 at Study Visit 2 [CX 8 at 4.] recorded the

"time to angina" as "6:00"minutes, and the CRF for Study Visit 3 [Id. at 6.], which appeared to be this

subject’s last visit prior to the double blind portion of the study, recorded the "time to angina" as

"12:00" minutes. The difference of six minutes between the two measurements clearly exceeded the two minute or

25 percent variation allowed by the protocol, and this subject should not have been entered into the study.

Therefore, I find that Dr. Boyles violated the           investigational plan, as alleged in Subcharge IV.F.

 

Subcharqe IV.G. Dr. Boyles violated the           protocol cardioactive concomitant medication reporting requirement for study subject           12009.

 

The Center alleged that Dr. Boyles violated the          protocol by permitting study subject           12009

to use NTG patches. [See supra (Subcharge 111.B.2.)] The           protocol stated: "Subjects may not be

given digitalis, or other cardioactive medication other than sublingual NTG. " [CX 24 at 6 (emphasis

supplied). ] The subject diary presented by the Center clearly showed the use of NTG patches on January 3,

1988. [CX 7 at 11.] In addition, the Center showed that this subject’s CRF failed to document the patches as

prior or concomitant medication. [Trans. at 108; see also supra.] While the


 

subject’s CRF documented the correct number of doses of NTG which were administered, it did not differentiate

between the patch doses and the tablets of NTG. [Id.]

 

The           protocol stated: "The protocol must be read thoroughly and the instructions must be followed

exactly. Any deviations should be agreed to by both the sponsor and the investigator with appropriate written

protocol amendments made to reflect the changes agreed upon. " [CX 24 at 17.] Neither the Center nor Dr.

Boyles submitted any exhibits that included or suggested that a protocol deviation amendment had been agreed

as alleged in Subcharge IV.G.

 

Subcharge IV.H. Dr. Boyles violated the           protocol concomitant drug reporting requirement for the study subjects           801 and 804.

 

The Center alleged that Dr. Boyles violated the           protocol by allowing study subjects           801

and 804 to continue in the study despite concomitant antihypertensive drug use. The          protocol stated:

The subjects must not take any concomitant therapy without the physician’s knowledge and permission. Documentation of concomitant drugs, dosage taken, dates, and reason will be entered on the case-record forms. Treatment with any other antihypertensive


 

agent will disqualify- the subject from the study except during the follow-up period.

[CX 25 at 8 (emphasis supplied); see also Trans. at 81.]

The Center alleged that          was a concomitant medication for study subjects          801 and 804.

[Supra.] Evidence presented by the Center and discussed in Subcharge III.B.2.b. and c. provide the basis

for finding that the Center proved this charge. Specifically, study subject          801 participated in the

study from July 8, 1985 to November 1, 1985, and was prescribed          on June 19, 1985, and no "stop" date

was recorded. As stated earlier, I conclude that the drug was continued during the study period. [Supra.]

However, this drug was not mentioned in the study subject’s CRF as a prior or concomitant medication. Study

subject          804 participated in the study from August 5, 1985 to December 5, 1985, and was

prescribed          on July 15, 1985. Again, this drug was not mentioned in the subject’s CRF as a prior or

concomitant medication.

 

Therefore, I find that Dr. Boyles violated the          investigational plan by not reporting          as a

prior or concomitant medication for           801 and 804, as alleged in Subcharge IV.H.

 

For the above reasons, I find that Dr. Boyles violated


 

21 C.F.R. § 312.60 by failing to follow the investigational plans as alleged in Charge IV., Subcharges

IV.B., IV.E., IV.F., IV.G., and IV.H.

6. CONCLUSION

After considering the four charges in the NOOH, I find that Dr. Paul W. Boyles violated a number of the

regulations cited one or more times. Specifically, I find that Dr. Boyles violated 21 C.F.R. § 312.7C)(a), as

detailed in Subcharge I.F.; 21 C.F.R., § 312.62(a), as detailed in Subcharge III.A; 21 C.F.R. § 312.62(b),

as detailed in Subcharges III.B.1., III.B.2., III.B.3., III.B.4.; and 21 C.F.R. § 312.60, as detailed in

Subcharges IV.B., IV.E., IV.F., IV.G., and IV.H.

 

7. RECOMMENDATION

Based on my findings as set forth above, I recommend that the Commissioner disqualify Paul W. Boyles, M.D,

from receiving investigational new drugs.

February 16, 1993

/s/

Freddie Ann Hoffman, M.D.

Presiding Officer

Presiding Officer Reports and Commissioner's Decisions | Electronic Reading Room


FDA Home Page | Search | A-Z Index | Site Map | Contact FDA
FDA/Office of the Ombudsman
Web page created by sc 2001-FEB-06.