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U.S. Department of Health and Human Services

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Chappel, Christopher M. M.D. Company Response 2/23/09

February 23, 2009


Tejashri Purohit-Sheth, M.D.
Branch Chief
Good Clinical Practice Branch II
Division of Scientific Investigations, Bldg 51, Room 5358
Office of compliance
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993


Dear Dr. Purohit-Sherth:


This letter is in response to the Warning Letter received on February 02, 2009, pursuant to an audit conducted by Ms Brunilda Torres between the dates of October 22, 2007 and November 21, 2007. Prior to delineating all the changes and improvements that were implemented and those that are in process, I would like to say that as the owner and Principal Investigator of FPA Clinical Research, I take full responsibility for all study related activities conducted within our facility. I realize the full scope of my responsibilities as a Principal Investigator as defined in 21 CFR. I also realize that it is my responsibility to insure that all procedures implemented within our site are efficient, comprehensive and mirror all GCP standards. Further, I realize that it is my responsibility to delegate tasks to adequately trained and qualified personnel, as well as to strictly and personally supervise the conduct of those tasks.


As noted in prior communications to the FDA, much was done in the area of personnel when the above mentioned issues surfaced. In November of 2006, the Clinical Research Coordinator in question was relieved of her employment within the company, at the same time a CFO was hired to bear the burden of the financial side of the research facility, giving me, the Principal Investigator, more time to concentrate on the conduct of the studies and the overall supervision of all staff members working within those studies. Then in July of 2007, I hired a Registered Consultant Pharmacist to take on the responsibilities of Clinical Operations Director. Having been involved in research for over 18 years, I have seen the many regulatory changes and guidance's that have occurred in all areas of clinical trial conduct, especially in the area of subject safety. While I felt that we had the proper staff and supervision to appropriately conduct our trials within the accepted standard of care, adopting these changes allowed us to reach a higher level of performance and to develop, train, supervise and implement the procedures necessary to conduct clinical trials within all above stated guidelines. In reviewing the processes and procedures as they were in mid 2008, it became apparent that we had made great strides in the addressing and correcting of not only the observations noted above, but in all areas of quality clinical research. In mid 2008, a unanimous decision was made by me and my administrative staff to contract with a consultant to take our site to yet another level. In November of 2008, we began working closely with an experienced Clinical Research Consulting firm and the results speak volumes for the progress we have made as a research facility.

The following is a review of the processes and Clinical Operation Guidelines that were implemented prior, during, and after the audit resulting in the issuance of the Form FDA 483. It also outlines the current body of work being conducted to draft, train and implement a comprehensive program that not only addresses all the specific Inspectional Observations noted on the Form FDA 483 and emphasized within the aforementioned Warning Letter; but all areas of clinical trial conduct in accordance with all Federal Regulations, FDA Guidance’s as well as all aspects of GCP. Attached are the Index’s for the Clinical Operations Guidelines that were in use from 2007 to 2008 as well as the Table of Contents for the comprehensive set of Standard Operating Procedures for FPA Clinical Research that begins to replace all previous versions of the Clinical Operations Guidelines. We are in the process of developing a comprehensive set of SOP’s. These documents will be referenced below in the explanation of processes and procedures as they relate to the conduct of trials at FPA Clinical Research.


OBSERVATION #1 “You failed to personally conduct or to supervise the clinical investigation [21 CFR 312.60]”


Observation 1 Section A - Findings resultant of the review of Protocol (b)(4)


Observation 1 Section A1 of your review addresses the “Delegation of Duties & Authorized Signatures Form” and the apparent discrepancy of said form and actual delegation of tasks/authority. The following was done in response to this finding:


• In August 2008 - implemented Operational Guideline Version 1.6 which defined tasks applicable for delegation by the Principal Investigator to trained, qualified clinical staff members. This will be replaced by the SOP #SM-603.


• Current - Standard Operating Procedure SOP # SM-603 “Responsibilities of the Principal

• Investigator” defines the process and limits as defined by Draft FDA Guidance in May 2007 “Protecting the Rights, Safety and Welfare of Study Subjects – Supervisory Responsibilities of Investigators”.


Observation 1 Section A2 of your review discusses “the failure to personally conduct certain aspects of the study and/or to supervise study personnel adequately resulted in serious problems with the study”. As per your letter this area of concern was discussed in more detail in upcoming sections 3, 4 and 6 and as such will be addressed in detail in that portion of this response.


Observation 1 Section B - Findings resultant of the review of Protocol (b)(4)


Observation 1 Section B1 of your review pertains again to Delegation of Authority but expands to encompass source Documentation and Drug Accountability. The following was done in response to this finding:


• In November 2007 – Clinical Operations Guideline Version 1.4 –implementation of a Lab Report stamp used to document and highlight abnormal lab values reported.


• In January 2008 -implemented new standardized chart to be utilized for all trials to eliminate the problems noted in this section


• Current-Development of standardized Adverse Event form


• Current-SOP# CLI-203 “Adverse Events”


• Current-Development of standardized Concomitant Medication Form


• Current-Development of standardized Past Medical History Form


• Current - SOP # CLI-207 “Obtaining Past Medical History”


• Ongoing – Regular review of source documentation and overall clinical trial conduct by Director Clinical Operations, Director Clinical Services and/or Associate Lead Coordinator.


• Ongoing - Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of review of source documentation and overall clinical trial conduct.


Observation 1 Section B2 of your review noted that a follow up review of the site showed improvement but still noted difficulty in resolving source verification issues. Throughout the body of this response letter, I have and will continue to outline the many Clinical Operations Guidelines, Training Classes, Staff Meeting discussions, and SOP’s that we have implemented here at FPA Clinical Research to ensure that we are conducting all clinical trials to the highest level of integrity and according to GCP standards and FDA Regulations. I realize that in this section of findings your office states that “I failed to have adequate involvement and oversight over the studies to ensure that they were properly conducted in compliance with FDA Guidelines”. I feel that the processes and standards we have designed and implemented will effectively eliminate these types of findings.


OBSERVATION #2 “You failed to obtain the informed consent of each human subject in accordance with 21 CFR part 50 [21 CFR 312.60]


Observation 2 Section A - Findings resultant of the review of Protocol (b)(4)
This section addresses execution and proper documentation of informed consent procedures pursuant to 21 CFR 50.20 and 50.27. The following has been done to address this finding:


• In January 2007 - Clinical Operations Guidelines Version 1-The full Informed Consent Process


• In November 2007 - Implementation of Clinical Operations Guidelines Version 1.4 –the implementation of sign in sheets requiring an entry for arrival times for all subjects.


• In November 2007–Implementation Clinical Operations Guidelines Version 1.4 - Daily Clock Log – process used to compare real time as compared to clinic clocks. Discrepancies are corrected and the log is updated daily by the Lab Manager or their designee.


• In November 2007 –Clinical Operations Guideline Version 1.4 – further enhanced the Informed Consent Process.


• In November 2007 - Clinical Operations Guideline Version 1.4 – documentation of start time for all procedures


• Current - SOP # CLI-201 “Obtaining Informed Consent”


• Current - Two 4 hour training programs taught by (b)(4) completed at the offices of FPA Clinical Research on February 9, 2009 and February 23, 2009.The primary focus was on GCP parameters with modules on Overview of GCP, Role of the Principal Investigator, Human Subject Protection, Drug Development Process, Clinical Research in Phase I, Adverse Events, Serious Adverse Events, Concomitant Medications, Source Documentation.


• Ongoing – Regular review of Informed Consent Procedures by Director Clinical Operations, Director Clinical Services or Associate Lead Coordinator.


• Ongoing - Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of review of Informed Process Procedures.


Observation 2 Section B - Findings resultant of the review of Protocol (b)(4)
Findings in this section were similar to Section A and procedural changes are noted above.


Observation 2 Section C - Findings resultant of the review of Protocol (b)(4)
Findings in this section were again similar to Section A and procedural changes are noted above.


OBSERVATION #3 “You failed to conduct the studies or to ensure they were conducted according to the investigational plans [21 CFR 312.60]


Observation 3 Section A - Findings resultant of the review of Protocol (b)(4)

Observation 3 Section A1 through A6 of this review are findings as they relate to the review of Inclusion/Exclusion criteria, the qualification for randomization of specific subjects based on those criteria. The following has been done to address this finding


• In July 2007 Implementation of Inclusion/Exclusion checklists that are developed for each specific study. The completion of these checklists at every visit up to and including the randomization visit is the delegated responsibility of the clinical coordinator and the final review of said documentation and determination of eligibility for enrollment/randomization is my responsibility or that of the Principal Investigator for that particular study.


• Draft - SOP CLI-200 “Approval of Subjects for Study Participation” which further defines and delineates the steps taken by the Clinical Research Coordinator leading up to subject selection and the steps taken by the Principal Investigator to finalize and approve the selection or denial of subjects.


• Ongoing – Review and discuss current enrolling criteria at regular monthly staff meetings


• Ongoing – Regular review of Inclusion/Exclusion review and documentation by Director Clinical Operations, Director Clinical Services and/or Associate Lead Coordinator.


• Ongoing - Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of review.


Observation 3 Section B - Findings resultant of the review of Protocol (b)(4)


Observation 3 Section B1 addresses the obtaining of Past Medical History and Physical Exams. The following has been done to address this finding


• Current - SOP # CLI-207 “Obtaining Past Medical History”


• Current – Implementation of standardized Past Medical History form


• Current - SOP # CLI-205 “Physical Examinations”


• Current – Implementation of standardized forms for Physical Exams and Interim Exams

Observation 3 Sections B2 and B3 addresses findings of abnormal labs and ECG are that were not adequately documented as having been reviewed and medical management decisions made. The following has been done to address this finding:


• In November of 2007 – Clinical Operations Guideline Version 1.4 – implementation of a Lab Report stamp used to document and highlight abnormal lab values reported.


• Current - SOP# CLI-202 “Obtaining a 12 Lead Electrocardiogram”


• Ongoing – Regular review of source documentation by Director Clinical Operations, Director Clinical Services or Associate Lead Coordinator.


• Ongoing - Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of reviews.


Observation 3 Section B4 addresses documentation of subject instruction.


• Ongoing - Documentation items are discussed at regular monthly staff meetings


• Ongoing – Documentation items are discussed one on one with the Clinical Research Coordinators and the Principal Investigator or Sub-Investigator based on their review of source documents for each visit performed.


OBSERVATION #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 CFS 312.62(b)]


Observation 4 Section A – Findings resultant of the review of protocol (b)(4)

Observation 4 Section A1 addresses documentation issues as they related to dual worksheets for the same visit. The following has been done to address this finding:


• Initial Response – Documentation is a standing agenda item at regular monthly staff meetings


• Initial Response –Director Clinical Services conducts review sessions with Clinical Research Coordinators regarding source documentation.


• Current - Two 4 hour training programs taught by (b)(4) completed at the offices of FPA Clinical Research on February 9, 2009 and February 23, 2009.The primary focus was on GCP parameters with modules on Overview of GCP, Role of the Principal Investigator, Human Subject Protection, Drug Development Process, Clinical Research in Phase I, Adverse Events, Serious Adverse Events, Concomitant Medications, Source Documentation.


• Ongoing – Principal Investigator or Sub-Investigator reviews and discusses documentation items one on one with the Clinical Research Coordinator.


• Ongoing – Source documents are reviewed regularly for compliance purposes by Director Clinical Operations, Director Clinical Services and/or Associate Lead Coordinator. Findings are corrected and staff is educated.


• Ongoing - Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of reviews


• Current – Created standard source document format that eliminates double documentation

Observation 4 Section A2 & Section A3 address informed consent issues as they relate to dates and sign – in sheets/times. The following has been done to address this finding:


• In January 2007 - Clinical Operations Guidelines Version 1-The full Informed Consent Process


• In November 2007 –Clinical Operations Guideline Version 1.4 – further enhanced the Informed Consent Process.


• In November 2007 - Clinical Operations Guideline Version 1.4 – documentation of start time for all procedures


Observation 4 Section A2 & Section A3 continued:


• In November 2007 - Implementation of Clinical Operations Guidelines Version 1.4 –the implementation of sign in sheets requiring an entry for arrival times for all subjects.


• In November 2007–Implementation Clinical Operations Guidelines Version 1.4 - Daily Clock Log – process used to compare real time as compared to clinic clocks. Discrepancies are corrected and the log is updated daily by the Lab Manager or their designee.


• Current - SOP # CLI-201 “Obtaining Informed Consent”


• Current - Two 4 hour training programs taught by completed at the offices of FPA Clinical Research on February 9, 2009 and February 23, 2009.The primary focus was on GCP parameters with modules on Overview of GCP, Role of the Principal Investigator, Human Subject Protection, Drug Development Process, Clinical Research in Phase I, Adverse Events, Serious Adverse Events, Concomitant Medications, Source Documentation.


• Ongoing – Principal Investigator or Sub-Investigator reviews and discusses documentation items one on one with the Clinical Research Coordinator.


• Ongoing – Regular review of source documentation and clinical trial conduct by Director Clinical Operations, Director Clinical Services or Associate Lead Coordinator.


• Ongoing - Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of reviews.


Observation 4 Section A4 Addressed the documentation of dosing versus dispensing. The following has been done to address this finding:


• In July 2008 - Clinical Operations Guidelines Version 1.5 Double check of IP by two clinical staff members prior to dosing or dispensing to subjects


• Draft - SOP # CLI-210 “Preparation of Drug for Administration or Distribution to Subject”.


• Ongoing - Dosing and dispensing review by the Principal Investigator or Sub-Investigator at their review of source documentation for each appropriate visit.


• Ongoing – Regular review of adherence to SOP #CLI-210 and source documentation by Director Clinical Operations, Director Clinical Services or Associate Lead Coordinator.


• Ongoing – Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of reviews.


Observation 4 Section B - Findings resultant of the review of Protocol (b)(4)


Observation 4 Section B1 addressed late entries in source documentation. The following has been done to address this finding:


• Initial Response – Documentation is a standing agenda item at regular monthly staff meetings


• Initial Response –Director Clinical Services conducts review sessions with Clinical Research Coordinators regarding source documentation.


• Current - Two 4 hour training programs taught by (b)(4) completed at the offices of FPA Clinical Research on February 9, 2009 and February 23, 2009.The primary focus was on GCP parameters with modules on Overview of GCP, Role of the Principal Investigator, Human Subject Protection, Drug Development Process, Clinical Research in Phase I, Adverse Events, Serious Adverse Events, Concomitant Medications, Source Documentation.


• Ongoing – Principal Investigator or Sub-Investigator reviews and discusses documentation items one on one with the Clinical Research Coordinator.


• Ongoing – Regular review of source documentation by Director Clinical Operations, Director Clinical Services or Associate Lead Coordinator.


• Ongoing – Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of review of source documentation.


• Ongoing – Principal Investigator reviews source documents and CRF’s upon completion of study.


Observation 4 Section B2 addresses missing documentation for Concomitant medication assessments.
The following has been done to address this finding:


• In January 2008 -implemented new standardized chart to be utilized for all trials to eliminate the problems noted in this section concerning Concomitant medication assessments and documentation of same


• Draft – Implementation of standardized Concomitant Medication


• Ongoing – Regular review of source documentation by Director Clinical Operations, Director Clinical Services or Associate Lead Coordinator.


• Ongoing - Regular Bi-monthly meetings with Director Clinical Services and all Clinical Research Coordinators to discuss results of review of source documentation


OBSERVATION #5 “You failed to maintain investigational drug disposition records with respect to use by subjects [21 CFR 312.62(a)]. The Warning Letter states that past communications and corrective actions taken in this area appear appropriate and no additional action needs to be addressed.

OBSERVATION #6 “You failed to promptly report to the IRB all unanticipated problems involving risk to human subjects or others [21 CFR 312.66]. The following has been done to address this finding:

• In January 2007 - Clinical Operations Guidelines Version 1- IRB reporting and its significance to the safety of human subjects.


• In January 2008 - Regular monthly staff meeting discussed IRB communications, Protocol/Consent submissions, safety events or IND Safety updates and annual updates and record-keeping of all communications within the Regulatory Binder.


• Current - SOP # REG-501 “Management of Regulatory Files”


• Current - SOP # CLI-203 “Adverse Events”


• Current - - Two in –depth 4 hour trainings by (b)(4) to be completed at the offices of FPA Clinical Research on February 9, 2009 and February 23, 2009 – training focused on GCP parameters with modules on Overview of GCP, Role of the Principal Investigator, Human Subject Protection, Drug Development Process, Clinical Research in Phase I, Adverse Events, Serious Adverse Events, Concomitant Medications, Source Documentation.


• Current – Two hour Regulatory Training of Essential Study Documents by (b)(4) completed at the offices of FPA Clinical Research on February 9, 2009.


• Ongoing – Regular review of Regulatory Binder by Regulatory Coordinator, Director Clinical Services or Associate Lead Coordinator.


In closing, I would like to take a few moments to recap the progress that we here at FPA Clinical Research have made over the past 32 months. In November 2006 I became aware of problems in processes and procedures, oversight, delegation and supervision as it related to the conduct of clinical research within our facility. I took immediate action as follows; personnel issues were addressed, eliminating some employees as well as adding some into new positions within our company. Operational Guidelines were developed and implemented to address issues that had arisen as well as to prevent them in the future. Those Operational Guidelines were revised five times over the course of the 17 months from January 2007 through August 2008. I take full responsibility for errors made in the months leading up to November 2006 within FPA Clinical Research. I wish we could go back and change the past, but we can’t. What we can do is assure you that FPA Clinical Research is dedicated to the provision of quality, regulatory-based, GCP driven research that is conducted within all Federal regulations and guidance’s.


Recent evidence supports my position that the changes we have worked so hard to implement have proven themselves in our facility. It was with much pride and confidence that I was able to meet with Mr. Ronnie E. Jackson, an FDA Auditor, upon his completion of an audit here at FPA Clinical Research. This audit occurred from November 17, 2008 through November 19, 2008 and was a full audit of Protocol ALO-KNT-302. During his exit interview, Mr. Jackson stated that he had no significant findings for our site and that he felt that the study had been conducted well within all parameters of GCP, all Federal Regulations and FDA Guidance’s.


As a company, everyone at FPA Clinical Research is dedicated to strictly follow our Standard Operating Procedures which will keep us in full compliance with all Federal regulations, FDA guidance’s and GCP standards. We are proud of our progress, our facility and our ability and commitment to excellence.


Respectfully,
Christopher M. Chappel, MD
Principal Investigator
FPA Clinical Research