• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Regulatory Information

  • Print
  • Share
  • E-mail

Macapinlac, Manuel M.D. 4/19/10

   

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  Rockville, MD 20855

 

From: Sharon J. McCoy, RPh, Regulatory Operations Officer,
         Robert Wesley, Case Review Officer (HFC-210),
         DCMO/OE/ORA/FDA


Through: Eugene R. Leger, Director, DCMO/OE/ORA/FDA


To: Manuel Macapinlac, M.D.


Subject: Confirmation of Receipt of Notice of Opportunity for Hearing (NOOH) letter

 

The Notice of Opportunity for Hearing (NOOH) letter delivered to you provides important information about steps you will need to take to address the FDA proposal to disqualify you as a clinical investigator entitled to receive investigational drugs. No final decision by FDA has been made at this time. You are being offered an opportunity for a regulatory hearing pursuant to 21 CFR parts 16 and 312.

 

Your request for a regulatory hearing must be made, in writing within ten (10) business days after receipt of the provided NOOH letter and should be directed to Eugene R. Leger, Director, Division of Compliance Management and Operations (HFC-210), Office of Enforcement, ORA, FDA, 10903 New Hampshire Avenue, WO32-4360, Silver Spring, Maryland 20993, telephone (301) 796-8203. If no response to this letter is received by that time, you will be deemed to have waived any right to a regulatory hearing, and a decision in these matters will be made based on the facts available to FDA.

 

If you wish to respond but do not desire a hearing, you should contact Mr. Leger within the time period specified above and send a written response containing your reply. The letter should state that you waive your right to a hearing and that you want a decision on the matter to be based on your written response and other information available to FDA.

 

FDA's offer to enter into a consent agreement, attached to the NIDPOE dated February 23, 2009 remains available. Entering into a consent agreement would terminate the administrative proceedings, but would not preclude the possibility of a corollary judicial or other administrative proceeding.

 

Please inform Mr. Leger within ten (10) business days of whether you wish to request a hearing or to have this matter resolved by consent agreement or information available to FDA.

I have read these statements and confirm receipt of the FDA Notice of Opportunity for Hearing letter addressed to me.


Signed, 

/S/

Manuel Macapinlac, MD

/S/

Witness (FDA)

/S/

Witness (FDA)


   

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  ORA, Office of Enforcement
Division of Compliance Management and Operations
10903 New Hampshire Avenue
Silver Spring, MD 20993

 

April 19, 2010


Manuel Macapinlac, M.D.
65-47 110th Street, 1st Floor
Forest Hills, New York 11375


Dear Dr. Macapinlac:

The Office of Enforcement will be moving its offices from Rockville to Silver Spring, Maryland on Friday, April 23, 2010. If you plan to request a hearing as provided in the enclosed Notice of Opportunity for Hearing letter send your written request to our new address, which is as follows: Eugene R. Leger, Director, Division of Compliance Management and Operations (HFC210), ORA, Office of Enforcement, 10903 New Hampshire Avenue, W032-4360, Silver Spring, Maryland 20903, telephone (301) 796-8203.

 

Sincerely,
/S/
Eugene R. Leger
Director, Division of Compliance
Management and Operations
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           

   

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  Rockville, MD 20857

 


NOTICE OF OPPORTUNITY FOR HEARING (NOOH)


CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Manuel Macapinlac, M.D.
65-47 110th Street, 1st Floor
Forest Hills, NY 11375


Dear Dr. Macapinlac:


The Center for Drug Evaluation and Research (the Center) of the U.S. Food and Drug Administration (FDA) has information indicating that you repeatedly or deliberately violated federal regulations in your capacity as an investigator in clinical trials with multiple investigational drugs. The Center also has information indicating that you repeatedly or deliberately submitted false information to FDA or the sponsor in required reports. These violations provide the basis for withdrawal of your eligibility as a clinical investigator to receive investigational new drugs.


The Center's findings are based on information obtained during an FDA inspection, discussed below, of the following clinical studies for which you were the investigator of record:


1. Protocol (b)(4): "A Phase II, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study of (b)(4) Therapy for (b)(4)" This study of the investigational drug (b)(4) was performed for (b)(4)


2. Protocol (b)(4) "A Phase II, Multi-Center, Open-label Study of (b)(4) in Subjects with (b)(4) Cancer (b)(4) Previously Treated with At Least One Prior Chemotherapy Regimen." This study of the investigational drug (b)(4) was performed for (b)(4)


3. Protocol (b)(4): "An Open Label, Repeat Dose, Randomized, Two Period Crossover Study to Investigate the Potential Pharmacokinetic Interactions Between Oral (b)(4) and Intravenous in Cancer Patients." This study of the investigational drug (b)(4) was performed for (b)(4)


FDA conducted an inspection of these clinical trials between September 24 and October 24, 2007. After the inspection, and pursuant to section 312.70(a) of Title 21 of the Code of Federal Regulations [21 CFR 312.70(a)], the Center informed you, by letter titled "Notice of Initiation of Disqualification Proceedings and Opportunity to Explain" (NIDPOE) dated February 23, 2009, of the specific matters complained of and offered you an opportunity to respond in writing or at an informal conference. The NIDPOE also offered you the option of entering into a consent agreement with FDA, thereby terminating any administrative proceeding against you. In response to the NIDPOE, you requested that an informal conference be held. On July 7, 2009, the informal conference was held at FDA's facilities in Silver Spring, MD. At the informal conference, you provided verbal explanations to the findings noted in the NIDPOE letter and also provided some supporting documentation. A written copy of the transcript of the informal conference was sent to you on September 3, 2009.


After a review of all available documentation, the Center has accepted your response to the NIDPOE item 3.c. (regarding enrollment of Subject #108 into protocol (b)(4)). However, we find that your explanations fail to adequately address the other violations set forth in the NIDPOE, as detailed below.


Accordingly, you are being offered an opportunity for a regulatory hearing pursuant to 21 CFR parts 16 and 312, to determine whether you are entitled to receive investigational new drugs. You have the right to be advised and represented by counsel at all times. Any regulatory hearing on this matter will be governed by the regulations in 21 CFR part 16 and FDA's guidelines on electronic media coverage of administrative proceedings, 21 CFR part 10, subpart C. Enclosed you will find copies of these regulations. A listing of the specific violations follows. These are matters that will be considered at the regulatory hearing. Applicable provisions of the CFR are cited for each violation.


1) You repeatedly or deliberately submitted false information to the sponsor in a required report [21 CFR 312.70(a)].


Protocol (b)(4) specified that subjects were to be distributed patient daily diary cards every 4 weeks, beginning with Week 0, and ending on Week 53. Per the protocol, patients should have received only one set of diary cards for each four-week period. However, during its inspection, FDA discovered that your records contained multiple diary entries for the same subjects on the same dates. Furthermore, the information you reported to the case report form (CRF) excluded some of the data from one or more sets of patient diaries. This is a violation of 21 CFR 312.70.

Protocol (b)(4) specified that the study coordinator was to review the patient diary cards with the patient during each scheduled visit and, if possible, query the patient to obtain any missing information at the scheduled visit. Thus, patient diaries should have contained dated entries only for dates that occurred between two scheduled visits.

The daily diary cards included information concerning whether the subject took the doses of medication in the morning and the evening (diary question #1); whether any concomitant medications were taken (diary question #2); the name of the concomitant medication taken (diary question #3); usual daily activity interruptions due to (b)(4) pain (diary question #4); whether any medical facility was visited due to (b)(4) pain (diary question #5); the name of the medical facility visited (diary question #6); and the daily pain level experienced, on a scale of 0 to 10 (diary question #7). Per the protocol, information in patient diary cards was to be recorded onto the appropriate CRF.

 

FDA's audit identified that 2 of 12 subjects enrolled in the study, Subjects #003 and #010, each had two patient diaries which contained different information for the same dates. From our review of the two diaries, we were unable to determine which diary provided the correct information. In addition, we note that the information reported to the CRF was either (1) obtained from one diary but not the other, or (2) could not be verified in our review of either of the two diaries' entries for specified dates. The discrepancies we observed included, but were not limited to, the following:

a. For Subject #003, source records indicated that his/her Week-4 visit (i.e., Visit 3) occurred on July 22, 2005, and his/her Week-8 visit (i.e., Visit 4) occurred on August 12, 2005. Thus, patient diaries that covered the time period between these two visits would have been collected on August 12, 2005, during the Week-8 visit. FDA's investigation found that there were two different diaries that contained different information for the dated entries that occurred between July 22, 2005, and July 28, 2005. We were unable to confirm how you determined which diary contained the correct information, and/or where you derived the information that was reported to the CRF.

One patient diary listed the start date as July 22, 2005, and the stop date as August 5, 2005. The first page of this diary stated that the diary was to be brought back to your site on August 19, 2005. Information in the diary for the dates of July 22, 2005, through July 28, 2005, only showed a checkmark in response to question #1, noting that the subject took medication in the morning. There were no answers provided in the diary for any of the remaining diary questions. These included, but were not limited to, diary question #4, which asked whether the subject's daily activity was interrupted due to (b)(4) pain, or diary question #7, concerning the level of pain experienced.

 

The second patient diary for this same time period listed the start date as July 15, 2005, and the stop date as July 28, 2005. Per the first page of this diary, the diary was to be brought back to your site on July 22, 2005, which would have been prior to the stop date noted on the diary card. Information in the diary for the dates of July 22 through July 28,2005, showed checkmark responses for diary question #1, noting that the subject took medication in the morning. There were also checkmark responses to diary questions #2, #4, and #5. There was no written documentation within the diary card on these dates that answered diary question #7, concerning the level of pain experienced.

The CRF for the Week-8 visit noted that during this covered time period, the number of days the subject's daily activity was interrupted due to (b)(4) pain since the previous visit was 00 (i.e., diary question #4) and the subject had experienced 21 days of 00 pain on the pain scale (i.e., diary question #7). The patient diary provided the sole source documentation for this information, so FDA was unable to determine where you obtained the information documented in the CRF, or how you reconciled the conflicting data contained in the two patient diaries.

b. For Subject #010, we identified two different patient diaries that covered the time period between the Week-16 visit (i.e., Visit 6) on January 3, 2007, and the Week-20 visit (i.e., Visit 7) on February 5, 2007. FDA's investigation identified two diaries for the following dates: (1) January 3, 2007, to January 16, 2007; (2) January 17, 2007, to January 30, 2007; and (3) January 31, 2007, with no stop date. In FDA's comparison of the two patient diaries, we noted numerous discrepancies where information placed in one patient diary was different from the information placed in the' second diary for the corresponding dates. We were unable to determine which, if either, of the two diaries contained the correct information. In addition, we note that in many cases, information reported to the CRF could be traced (1) to only one of the two diaries, or (2) to neither one of the diaries.

 

In both of these cases, the identification of two different patient diaries raises significant concerns regarding the study's conduct and the integrity of the data collected at your site.

In your response to this finding at the informal conference, you stated that for the time frames of the two diary entries for Subjects #003 and #010 noted in the NIDPOE letter, you were not present at the site. You hypothesized that a subject could have had two diaries for the same time period if the subject forgot to bring his/her diary to a study visit, and a study coordinator gave the subject a second diary to fill out. Subsequently, the subject could have found the original diary and given it to the study coordinator, who kept both diaries in the study record. You further noted that from your recollection, the protocol allowed a subject"... to get an extra diary if, for whatever reason, they won't be able to basically get the previous diary" [Page 24 of Informal Conference Transcript). As to why the CRF contained information from one diary and not from the other, you surmised that the study coordinator captured the information in the CRF from the first diary that was given to him, without noticing that the other diary was inconsistent. You also stated that you were not aware of the existence of duplicate diaries, and you could not explain why some information in the CRF did not correlate to information found in either diary.

The response you provided at the informal conference is unacceptable. Protocol (b)(4) specified that during each scheduled visit, the study coordinator was to review the patient diary cards with the patient, and to question the patient to obtain any missing information, if possible. Furthermore the patient was to be educated on how to complete the diary card for compliance. Protocol (b)(4) did not specify that subjects could be distributed an extra diary if they did not bring back their diary at a scheduled study visit. In addition, FDA is unable to determine, based on the scenario that you hypothesized, how your site could adequately determine which diary contained the correct information to be placed on the appropriate CRF, if the subject had indeed been given an extra diary to fill out. You also acknowledged that if this situation had occurred, the study coordinator should have made a notation in the subject's records. There were no such notations in the subject's records. Also, in reviewing the diaries with duplicate dates, we could find no documentation to determine which diary was contemporaneously or retrospectively filled out. Furthermore, at the informal conference, you were unable to address how information reported on the CRF could not be found in either of the two diaries.

2) You failed to personally conduct or supervise the clinical investigations [21 CFR 312.60].

 

When you signed the investigator statements (Form FDA 1572) for the above-referenced clinical investigations, you agreed to take on the responsibilities of a clinical investigator at your site. Your general responsibilities (21 CFR 312.60) include ensuring that the investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; protecting the rights, safety, and welfare of subjects under your care; and ensuring control of drugs under investigation. You specifically agreed to personally conduct the clinical studies or to supervise those aspects of the studies that you did not personally conduct. While you may delegate certain study tasks to individuals qualified to perform them, as clinical investigator, you may not delegate your general responsibilities. Our investigation indicates that your supervision of personnel to whom you delegated study tasks was not adequate to ensure that clinical trials were conducted according to the signed investigator statement, the investigational plan, and applicable regulations, and in a manner that protected the rights, safety, and welfare of human subjects.

We note that your failure to adequately supervise this study led to significant problems identified with the conduct of the studies. For example,

a. With respect to Protocol (b)(4), we noted the following:

i. Your initials were present on many source documents, including those documenting physical examinations conducted during study-related office visits. This created the appearance that you examined these subjects and/or personally performed these study-related procedures. For 5 of 12 subjects, however, FDA's investigation found that, in many instances, you were on leave during the times of these visits, and thus could not have performed the evaluations. In addition, you informed FDA investigators that you did not authorize anyone else to initial these documents on your behalf. These examples include, but are not limited to, the following:

1. Subject #004 had his/her Week-8 visit on July 18, 2006. The progress note for this subject's visit was signed only by your study coordinator, (b)(6). Your initials (i.e., "MM") and the date "7/18/06" were found on other source records for this subject's visit. We note, however, that you were on leave during the time of this visit. Thus, you could not have participated in the subject's examination or initialed.the documents at the time of the examination.

2. The following observations were noted with respect to the records for Subject #005:

a. Subject #005 had his/her Week-8 visit on July 19, 2006. The progress note for this subject's visit was signed only by your study coordinator, (b)(6). Your initials (i.e., "MM") and the date "10/10/06" were found next to the physical exam portion of other source records for this subject's visit. We note, however, that you could not have performed the physical exam on "10/10/06," as this subject's visit occurred on July 19, 2006. In addition, we note that you were on leave during the time of the Week-8 visit. Thus, you could not have participated in the subject's examination or initialed the documents at the time of the examination.

b. Subject #005 had his/her Week-24 visit on November 21, 2006, and his/her Week-28 visit on December 12, 2006. The progress notes for these visits were signed only by your study coordinator, (b)(6). The initials "(b)(8)" appear next to the physical exam section of these source documents. Your initials (i.e., "MM"), however, are written over someone else's initials on the line "Investigator Initials." We note, however, that you could not have attended the visits on November 21 and December 12, 2006, because you were on leave during the times of these visits.

c. Subject #005 had his/her Week-36 visit on January 29, 2007. The progress note for this subject's visit was signed only by your study coordinator, (b)(6). Your initials (i.e., "MM") were found on the source records for this subject's visit. We note, however, that you were on leave during the time of this visit. Thus, you could not have participated in the subject's examination or initialed the documents at the time of the examination.

3. Subject #008 had his/her Week-28 visit on December 4, 2006. The progress note for this subject's visit was signed only by your study coordinator, (b)(6). Your initials (i.e., "MM") and the date "12/4/06" were found on the source records for this subject's visit. We note, however, that you were on leave during the time of this visit. Thus, you could not have participated in the subject's examination or initialed the documents at the time of the examination.

4. Subject #009 had his/her Week-4 visit on August 1, 2006. The progress note for this subject's visit was signed only by your study coordinator, (b)(6).Your initials (i.e., "MM") were found on the source records for this subject's visit. We note, however, that you were on leave during the time of this visit. Thus, you could not have participated in the subject's examination or initialed the documents at the time of the examination.

5. Subject #012 had his/her Day-0 visit on November 15, 2006. The progress note for this visit was signed only by your study coordinator, (b)(6) Your initials (i.e., "MM") with the date" 11/15/06" were found on the source records for this subject's visit. We note, however, that you were on leave during the time of this visit. Thus, you could not have participated in the subject's examination or initialed the documents at the time of the examination.

You informed FDA investigators that, although you did not authorize anyone else to initial any of the above-referenced documents on your behalf, you acknowledged that you observed that other individuals had signed your initials on numerous case records. You further acknowledged to FDA investigators that you failed to recognize this in a timely manner, and that you also failed to report, correct, and prevent the recurrence of this unauthorized use of your initials.

ii. FDA's review of the study's laboratory reports identified that, for 8 of 12 subjects: (1) the reports were not documented as having been reviewed by anyone; (2) there were significant delays in review of the laboratory reports; and/or (3) there were discrepancies in the dates on the lab reports documenting when they were reviewed.

You informed FDA investigators that, on the dates you were not at the hospital, you remotely accessed the subjects' electronic medical records in order to review their laboratory results. However, during FDA's review of the (b)(6) Medical Center's electronic records, which document when an individual remotely accesses a subject's record, FDA was unable to confirm your assertion that you reviewed these subjects' records remotely on the dates noted on several laboratory reports. FDA further notes that some electronic records indicated that no one at your investigative site reviewed these subjects' records on the dates documented on the laboratory reports. For example,

1. The laboratory reports for visits that occurred on December 15, 2006, and January 3, 2007, for Subject #010 did not include any written documentation that they were reviewed by you or your subinvestigators.

2. The laboratory report for the visit that occurred on November 21, 2006, for Subject #005 was not documented as having been reviewed until February 6, 2007.

 

3. The laboratory report for a January 4, 2007 visit for Subject #004 shows a handwritten signature with the date February 7, 2007, indicating an electronic review on January 4, 2007. However, FDA's review of the (b)(6) Medical Center's electronic records could not verify that any individual listed on your site's clinical site authorization list had electronically reviewed this subject's record on January 4, 2007.

4. The laboratory report for an October 31, 2006, visit for Subject #006 shows what appears to be your handwritten signature with the date November 15, 2006, and the evaluation "NCS" (i.e., not clinically significant). However, in FDA's review of the (b)(6) Medical Center's electronic records, we note that no one listed on your site's clinical site authorization list had electronically reviewed this subject's record on November 15, 2006. In addition, we note that documents provided to FDA during its inspection stated that you were on leave on the date documented on the laboratory report. Thus, you could not have reviewed the subject's records on that date.

Your lack of oversight of these studies, particularly with regard to conflicting documentation of laboratory reports, raises significant concerns regarding subject safety.

iii. According to the study's monitoring reports, the monitor repeatedly instructed you and your study coordinators to sign and date the progress reports of physical exams as verification that you personally conducted them, even if you dictated the progress reports to your study coordinators. However, FDA reviewed several of the progress reports written by your study coordinators, and there was no documentation regarding who had performed the subject's evaluation, including the physical exam, during study visits. Also, as noted in item 2.a.i. above, while your initials appeared on source documents for many of the study visits, we note that you were not present at the site during these visits, and thus could not have performed these physical examinations. The only individuals whose names appeared on these progress reports were your study coordinators; therefore, it appears that they conducted the study evaluations. We note that your study coordinators were not certified or licensed within the U.S. to conduct study related evaluations, and per the clinical site authorization, they were not authorized to perform these evaluations.

You acknowledged to FDA investigators that you had lost control of the studies and were unable to manage them effectively. You further informed FDA investigators that you were unaware of the status of the studies during your absence.

In your response to this finding during the informal conference, you stated that your research coordinators were"... not well trained. They meant well, but they lacked good documentation practices" [page 37 of Informal Conference Transcript]. You further noted that this comment extended to your sub-investigators, as well. You also stated your belief that your study coordinators assumed that every study document should have been signed under the investigator's name. You confirmed that you did not initial the documents cited in the NIDPOE letter yourself, and that the initials were made by the study staff. In reference to the question of whether you had reviewed source documents at any time to see that somebody else had filled in your initials with a date when you were not there, you noted that your review was " ... not basically going to be, basically, a detailed review, right, particularly if there are no SAE-involved patients. So we go through the chart there very fast...." [page 40 of Informal Conference Transcript]. You further stated that it was only when you returned to the study from (b)(6) leave (approximately (b)(4)) that you started noticing that your initials were on source documents that you did not authorize, and started discussing documentation practices with your team. With respect to the NIDPOE finding concerning the review of laboratory reports, you stated that during the time you were on (b)(6) leave (between (b)(6)), you did not access the subjects' records remotely.

Your response is unacceptable. As the clinical investigator, you are responsible for ensuring that the studies were conducted properly and in compliance with FDA regulations, in order to protect the rights, safety, and welfare of study subjects. Your lack of adequate review of study documentation causes FDA to question the integrity of the information provided in those documents. Also, because many progress notes were signed only by your study coordinators, we are unable to verify that anyone other than your study coordinators performed study-related physical exams on subjects. As noted above, your study coordinators were not certified or licensed within the U.S. to conduct study-related evaluations, nor were they authorized to perform such evaluations. In addition, you stated at the informal conference that during the time you were on (b)(6) leave between (b)(6), you did not review any of the subjects' records remotely. This statement contradicts the statement you made to CAPT Steyert during the FDA inspection, in which you noted that during the times you were off-site, you remotely accessed the subjects' electronic medical records in order to review their laboratory results.

We wish to emphasize again that, as the clinical investigator, it was your ultimate responsibility to ensure that the studies were conducted properly and in compliance with FDA regulations, in order to protect the rights, safety, and welfare of study subjects. In our review of the inspection report and the documents submitted with that report, we note that you failed to have such adequate involvement with and oversight of the studies. Your failure to adequately supervise the studies resulted in the submission of false information to FDA and/or the sponsor in required reports, in violation of 312.70(a).

3) You failed to conduct the studies, or ensure they were conducted, according to the investigational plan [21 CFR 312.60].

a. The following violations were noted with respect to Protocol (b)(4):

i. The protocol specified that, in order to be included in the study, a subject was to have had at least two episodes of painful crises within 12 months of the screening visit. Subject #006 was enrolled into the study on April 14, 2006. A source document dated after the subject's enrollment into the study noted that the subject had not had any crises since the subject moved to the United States in 2002.

ii. The protocol specified that subjects were to be distributed patient daily diary cards every 4 weeks, beginning with Week 0 and ending with Week 53. The diaries should have been exchanged at your site every 4 weeks. Thus, patient diaries should have contained only four weeks of dated entries that covered the time period between the subjects' visits. However, when FDA reviewed the diaries for Subject #003, we found several patient diaries with dated entries that spanned the time period before and after the date of an office visit. For example:

1. Subject #003 's Week-4 visit (i.e., Visit 3) occurred on July 22, 2005, and his/her Week-8 visit (i.e., Visit 4) occurred on August 12, 2005. As noted previously, there were two patient diaries that contained entries that were dated the same, but with different responses for several dates. It was noted that one of the patient diaries, which listed the start date as 7/15/05 and the stop date as 7/28/05, had dated entries that covered a time period both before and after the Week-4 visit.

2. Subject #003 had his/her Week-36 visit (i.e., Visit II) on March 3, 2006. In the patient diary which listed the start date as February 20, 2006, and the stop date as March 5, 2006, there were dated entries and responses to the diary questions that covered a time period before and after the Week-36 visit. We further note that ill this diary, the responses for the dates of March 4 and 5 were subsequently crossed out, with the notation "cancelled." FDA's investigation found that, in a different diary, the dates of March 4 and 5 were repeated, but the subject's responses concerning the concomitant medications taken on these two dates differed between the diaries.

b. The following violations were noted with reference to Protocol (b)(4)

i. The protocol specified that, at the baseline visit, subjects were to be reevaluated to assess eligibility to remain in the study. Among other inclusion criteria, a subject's eligibility to remain in the study required that the subject's serum (b)(4) level be < 50 ng/dL. We note that the laboratory report for the sample collected on April 20, 2006, showed that Subject #1546001's total (b)(4) level was 409 ng/dL. We note that this subject was subsequently treated with study drug on April 26, 2006.

ii. The protocol specified that the screening period was to be completed within 28 days prior to the administration of (b)(4) in Cycle 1, and that after obtaining informed consent the subject was to undergo assessments that included a bone scan. There was no documentation that a bone scan was performed on Subject #1546001 until May 15, 2006, which was after the time in which the subject had already received the first dose of study medication (i.e., April 26, 2006).

In your response to this finding during the informal conference, you stated that Protocol (b)(4) allowed subjects who met eligibility criteria but" ...with lack of source of documentation... " to enroll into the study and be allowed to get at least one month of study drug [Page 58 of Informal Conference Transcript). You stated that if, during that time period, the subject could not provide source documents verifying their eligibility, the subject would be removed from the study. Thus, Subject #006 was allowed to enroll into the study, but was later removed from the study due to failure to provide the source documents confirming eligibility. You further stated that the subject told you that he/she had  two (b)(4) crises, and the documentation sent to you was from Nigeria and from hospitals in (b)(6). You then stated that after cycle two was given to the patient, it was revealed that you did not have documentation for that subject, and the subject was therefore removed from the study.

With respect to Subject #1546001, who was enrolled into Protocol (b)(4), you stated that you had called the laboratory at the time and were informed that the units for the (b)(4) measurement were in micrograms per deciliter, and when you converted the units to nanograms per deciliter, " ... the patient meets inclusion criteria, because it is .409 nanograms per deciliter" [Page 64 of Informal Conference Transcript). You later stated that after the subject had been treated, you recognized that the units were originally in nanograms per deciliter, and you then informed the medical director that you had made this mistake.

Your response is unacceptable. Protocol (b)(4) required that a patient must meet all of the inclusion criteria, which included having at least two episodes of painful crises within 12 months of the screening visit, to be included in the study. Protocol (b)(4) also noted that eligibility of the subject into the study was to be confirmed at two separate visits. Specifically, the protocol noted that at the screening visit (i.e., during the first four weeks of the study), subjects were to be screened for enrollment into the study by meeting inclusion and exclusion criteria; and then, at the baseline visit (i.e., during week 0), after the investigator's review of all screening and baseline evaluations, each patient who qualified by meeting the inclusion and exclusion criteria was to be randomized to receive either the study drug or placebo.

FDA notes that the protocol did not state that subjects could receive study drug for at least a month before providing documentation to confirm their eligibility for enrollment into the study. In addition, we note that you appeared to contradict yourself at the informal conference. You stated that you had received documentation from Nigeria and hospitals in (b)(6) confirming that Subject #006 had  two (b)(4) crises, but you stated later that this subject was withdrawn because no documentation to confirm the subject's eligibility could be found.

With respect to Protocol (b)(4),documentation provided to CAPT Steyert showed that the (b)(4) lab was calculated in ng/dL. Subject #1546001 was therefore ineligible for enrollment into the study.

4) You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual [21 CFR 312.62(b)].

a. The following violations were noted with reference to Protocol (b)(4) for 4 of 12 subjects enrolled:

i. The following were noted in the review of records for Subject #001:

1. There were four versions of the CRF for the General Medical History for Visit 1 (Week -4) for Subject #001, with each version adding a new disease or condition. Source documents could not validate where the added diseases or conditions came from.

2. Two different versions of page 2 of the Visit 1 source documents were found for Subject #001. The two versions contained slightly different information.

ii. Per the patient enrollment log, Subject #007 was screened for enrollment into the study on May 4, 2006. FDA's audit of this study found no records for Subject #007.

iii. The CRF and the enrollment log noted that Subject #008 had his/her Week-0 visit on May 19, 2006. This is the date when the diary would have been initially distributed to the subject. The patient diary for this subject, however, included responses that started on May 14, 2006, which was five days before the Week-0 visit.

iv. It was noted that Subject #009 had labs drawn on November 27, 2006. However, the corresponding lab report was dated November 23, 2006, which was four days prior to the subject's labs being drawn. We were unable to determine who signed this lab report because the signature did not match any of your investigative staff's signatures, per the clinical site authorization list for this study.

In your response to finding 1.a. during the informal conference, you noted that for Protocol you did not recall having any problems with Subject #001. For Subject #007, you noted that this subject was a screen failure who never enrolled into the study. You believed there was a chart for this subject, but you stated that these charts were no longer under your protection.

Your response is unacceptable. Protocol (b)(4) specified that the investigator/institution was to maintain copies of all CRFs, all source documents that support the data collected from each patient, and all study documents, as specified in ICH/GCP. With respect to Subject #001, there were four separate CRFs for the General Medical History for Visit 1 (Week 4), with each version adding a new disease or condition. In addition, FDA was unable to find any source records for Subject #007.

5) You failed to maintain adequate investigational drug disposition records with respect to quantity and use by subjects [21 CFR 312.62(a)].

The following was noted for Protocol (b)(4):

a. There were several dispensation logs for Subject #001 containing different information for the same date. Specifically, one log noted that on September 27, 2005, the subject was dispensed 200 packets of investigational drug. On two other logs, it was noted that on September 27, 2005, the subject was dispensed 220 packets of investigational drug.

b. For many entries in the investigational drug disposition records for Subject #010 (listed erroneously in the NIDPOE Letter as Subject # 110), the amount of investigational drug returned to the site did not equal the amount that was dispensed. There was no indication on the log as to why there was a discrepancy. For example,

i. On October 11, 2006, Subject #010 was dispensed 150 packets of investigational drug. On November 7, 2006, the subject returned 124 packets of investigational drug. There were 26 packets of investigational drug that were not accounted for on the investigational product accountability form.

ii. On March 20, 2007, Subject #010 was dispensed 150 packets of investigational drug. On April 17, 2007, the subject returned 140 packets of investigational drug. There were 10 packets of investigational drug that were not accounted for on the investigational product accountability form.

In your response to this item during the informal conference, you stated that according to the protocol, each subject was to be given extra sachets of study drug in case the subject missed study visits. You further stated that the pharmacy logs for Protocol (b)(4) were not well-designed, and that the subjects received a " ... trash bag full of these sachets, 220... " that were"... not even packaged correctly" [page 76 of Informal Conference Transcript]. With respect to Subject #001, you noted that the copy of the documentation you had with you showed that the subject was dispensed 200 packets. You stated further that the monitor who visited the pharmacy at your site did not find this problem. With respect to Subject #010, you noted that neither the pharmacists nor the study monitors ever informed you that there was a discrepancy with this subject's drug-dispensation records.

Your assertion that neither the pharmacists nor the study monitors informed you of this discrepancy is an unacceptable response. As the clinical investigator, you are ultimately responsible for maintaining adequate investigational drug disposition records with respect to quantity and use by subjects. In addition, FDA was unable to verify your statements concerning the drug-accountability logs that were in your possession during the informal conference, because you did not provide us with any copies for review.

Your request for a hearing must be made in writing within ten (10) business days after receipt of this letter, and should be directed to Eugene R. Leger, Director, Division of Compliance Management and Operations (HFC-210), ORA Office of Enforcement, 15800 Crabbs Branch, Rockville, MD 20855, Telephone (240) 632-6868, FAX (240) 632-6859. If no response to this letter is received by that time, you will be deemed to have waived any right to a regulatory hearing, and a decision in these matters will be made based on the facts available to FDA.

A request for a hearing may not rest upon mere allegations or denials, but must present specific facts showing that there is a genuine and substantial issue of fact that warrants a hearing. Pursuant to 21 CFR 16.26, a request for a hearing may be denied, in whole or in part, if the Commissioner or his delegate determines that no genuine and substantial issue of fact has been raised by the material submitted. A hearing will not be granted on issues of policy or law. Written notice of a determination of summary judgment will be provided, explaining the reasons for denial of the hearing.

If you wish to respond but do not desire a hearing, you should contact Mr. Leger within the time period specified above and send a written response containing your reply. The letter should state that you waive your right to a hearing and that you want a decision on the matter to be based on your written response and other information available to FDA.

FDA's offer to enter into a consent agreement, attached to the NIDPOE dated February 23, 2009, remains available. Entering into a consent agreement would terminate the administrative procedures, but would not preclude the possibility of a corollary judicial proceeding.

No final decision by FDA has been made at this time on your eligibility to continue to receive investigational new drugs. Moreover, there will be no prejudgment of this matter if you decline to enter into a consent agreement and decide instead either to request a regulatory hearing or to request that the decision be based on information currently available to FDA.

Please inform Mr. Leger within ten (10) business days of whether you wish to request a hearing or to have this matter resolved by consent agreement or information available to FDA.

Sincerely,
/S/

Michael Chappell
Acting Associate Commissioner
for Regulatory Affairs