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Inspections, Compliance, Enforcement, and Criminal Investigations

Continuum Health Partners , Inc. 8/17/09


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

Public Health Service
Food and Drug Administration
 Center for Biologics Evaluation and Research
1401 Rockville Pike
Rockville MD 20852-1448

By Certified Mail - Return Receipt Requested
And By Facsimile Transmission

CBER-09 -07

Warning Letter

August 17, 2009


Saud A. Sadiq, M.D., Director
Multiple Sclerosis Research Center of New York
521 West 5ih Street, 4th Floor
New York, New York 10019

Dear Dr. Sadiq:

This letter describes the results of a Food and Drug Administration (FDA) inspection that concluded on April 29, 2009. The FDA investigators from the New York District Office met with you and members of your staff to review your firm's conduct of studies (b)(4) and (b)(4) performed under the Good Laboratory Practice (GLP) regulations [Title 21, Code of Federal Regulations, (CFR) Part 58]. The inspection was conducted as part of FDA's Bioresearch Monitoring Program, which includes inspections designed to review research involving investigational products.

At the conclusion of the inspection, a Form FDA 483, Inspectional Observations, was issued to and discussed with you and members of your staff. We have reviewed your letter dated July 17, 2009, sent to the New York District Office, written in response to the Form FDA 483.

Based upon the information obtained during the inspection, we conclude that the Multiple Sclerosis Research Center of New York (MSRCNY) has violated GLP regulations governing the proper conduct of nonclinical studies as published under 21 CFR Part 58. The applicable provisions of the CFR are cited for each violation.

1. Failure of the testing facility management to establish a Quality Assurance Unit responsible for monitoring each study. [21 CFR §§ 58.31 (c) and 58.35 (a), (b), (c)].

At the time of the inspection, your firm had not established a quality assurance unit (QAU) responsible for monitoring each study to assure conformance with the regulations, including but not limited to the following:

a. Maintaining a copy of the master schedule sheet of all nonclinical laboratory studies conducted at the testing facility indexed by test article and containing the test system, nature of the study, date study was initiated, current status of each study, identity of the sponsor, and name of the study director.

b. Maintaining copies of all protocols pertaining to all nonclinical laboratory studies for which the unit is responsible.

c. Inspecting each nonclinical laboratory study at intervals adequate to assure the integrity of the study and maintaining written and properly signed records of each periodic inspection.

d. Submitting periodic status reports to the testing facility management and study director, noting any problems and the corrective action taken.

e. Determining that no deviations from approved protocols or standard operating procedures (SOPs) were made without proper authorization and documentation.

f. Reviewing the final study report to assure that the report accurately describes the methods and standard operating procedures, and that the reported results accurately reflect the raw data of the nonclinical laboratory study.

g. Preparing and signing a statement to be included with the final study report that specifies the dates of inspection and findings reported to management and to the study director.

h. Maintaining written procedures covering the responsibilities of the QAU.

In your July 17th letter you state that you have formed an independent QAU that will follow GLP "guidelines" in its inspections. It is important that the QAU staff clearly understand their responsibilities and the functions they are required to perform. The functions listed above are more than just "guidelines," and are not limited to inspections. They are regulatory requirements designed to assure the quality and integrity of the safety data filed in applications for approval of products regulated under the Federal Food, Drug, and Cosmetic Act. 21 CFR 58.1

In your letter you addressed only a few of these responsibilities and functions. The document titled "Quality Assurance Services" provides a list of things to be inspected, such as facilities, equipment, storage, and methods and practices, but does not state what the QAU will actually look at, what criteria they will use to ascertain compliance, what actions they will take when errors or problems are found, and how they will document and report their findings, all of which are required by the regulations. You state that studies will be inspected every (b)(4)months, which should be described in the QAU SOPs, along with the dates of inspection, who performed the inspection, and the phase or segment of the study that was inspected. You also state that QAU personnel will not be involved with the current IND related application. The QAU written procedures should describe how you will ensure that QAU staff will not be otherwise involved in any nonclinical study that they will inspect.

Please prepare written SOPs for the QAU, and provide a copy with your response to this letter.

2. Failure of the study director to ensure that all applicable good laboratory practice regulations are followed. [21 CFR § 58.33(e)].

The study director failed to follow all good laboratory practice regulations (GLPs) for the nonclinical laboratory study being conducted at your facility.

This violation was not cited on the Form FDA-483. However, the failures cited in this Warning Letter are all violations of the GLP regulations.

The study director is responsible for assuring that all applicable GLP regulations are followed.

3. Failure to ensure that there is a dedicated storage area for animal feed that is separate from areas housing the test systems. [21 CFR § 58.45].

The regulations define test system as "any animal ... to which the test or control is administered or added for study. 21 CFR 58.3(i). The FDA inspection found that animal feed was stored in the animal housing area.

In your July 17th letter, you state this violation was corrected during the inspection. The FDA investigators were not apprised of this correction. You do not state in your letter how this violation was corrected. The storage of animal feed, bedding, supplies and equipment should be covered in detail in your written procedures. Please provide the revised SOP as part of your response to this letter.

In your letter you state that the responsibility for ensuring compliance for this GLP requirement is primarily with the animal facility staff. However, the GLP regulations require that the study director be the single point of study control, who maintains overall responsibility for the nonclinical laboratory study.

4. Failure to adequately test, calibrate and standardize equipment used for the generation, measurement, or assessment of data. [21 CFR § 58.63].

a. Adequate written records are not maintained of all equipment inspection, maintenance, testing, calibration and/or standardization operations. Specifically, there are no maintenance records for the equipment in the Histopathology - Pathology Laboratory or the Cell Culture Laboratory that were used for the inspected nonclinical laboratory study.

You state in your July 17th letter that a binder has been placed in the laboratory to hold all written records of equipment inspection, maintenance, testing, and calibration. You state that temperatures of freezers and refrigerators will be manually recorded, and that each researcher will be responsible for checking the temperature on the refrigerator near his or her bench. The cell culture manager will record temperatures in the cell culture room, and a research assistant will check to ensure that all laboratory personnel are recording daily temperatures. You state these changes will ensure that there are adequate maintenance records.

Your proposed corrective actions are incomplete. This violation does not concern only the recording of temperatures of freezers and refrigerators. It concerns maintaining records that document equipment maintenance, calibration, standardization, and cleaning, and whether maintenance is routine and follows standard operating procedures.

In your response to this letter, please explain your complete corrective actions and provide revised written procedures.

b. The animal cage washer in the Animal Care Facility is rated to be run at (b)(4)°F. A review of the time-temperature recording chart for this cage washer found the chart to be dated 9/2/2002. The time-temperature recording device was found to be broken, and the digital display does not display the temperature. The (b)(4) you are using has a range of (b)(4)°F, but the SOPs for the cage washer do not list the temperature at which the cage washer is to be run.

Your July 17th letter includes a revised cage washer SOP that adds a requirement for temperature (b)(4) "to validate that a temperature of (b)(4) degrees Fahrenheit has been reached." You did not address the fact that the time-temperature recording device was found broken, that the digital display does not display the temperature, and that the last recording chart on file was dated 9/2/2002.

The SOP lists (b)(4) different items that are run through the cage washer, plus a maintenance cycle; the SOP lists the use of (b)(4) different unspecified formulas used to clean the cages and bottles,(b)(4) different wash-time cycles, but no required temperature threshold that must be met. The SOP states that a temperature (b)(4) is to be used only on the (b)(4) load of each day, which does not ensure that the load or any subsequent runs achieved the unspecified required temperature.

Please provide a more complete response and submit a revised SOP. As an alternative to the temperature (b)(4) your firm should consider repairing or replacing the broken time-temperature recording and the digital display devices, having an outside firm perform a time/temperature validation on the cage washer and putting it on a routine maintenance/calibration schedule.

5. Failure to establish required written standard operating procedures (SOPs). [21 CFR § 58.81(b)(11)].

There are no SOPs for the maintenance of equipment in the Histo-Pathology Laboratory or the Cell Culture Laboratory.

You state in your July 17th letter that a binder has been put in place to hold all SOPs.This is inadequate to ensure that required SOPs are actually established.

The SOPs that were submitted with your July 17th response are inadequate. The SOPs that describe equipment maintenance should include among other things; calibration, standardization, maintenance and cleaning schedules, who performs these functions, and whether maintenance is routine or a result of equipment defect. The SOPs should address documenting the nature of an equipment defect, how and when the defect was discovered, and any remedial action taken to correct the defect.

For example, the SOP for the (b)(4) incubators only states the requirement to maintain clean incubators, but does not state how they are to be cleaned, what to clean them with, how often, and who performs the cleaning. The same is true for the pipettes and balance scales. The SOP for the laboratory refrigerators and freezers states the equipment will be defrosted periodically or when deemed necessary, instead of setting a defrosting schedule or criteria for determining such a schedule. The SOP also states that refrigerators and freezers without a digital temperature read-out will use a thermometer, but it does not require the use of a calibrated thermometer. These are just a few of the things the SOPs should address It is not an exhaustive list. 

Please revise the current SOPs and submit them with your written response to this Warning Letter.

6. Failure to ensure that all reagents and solutions used in the conduct of the study are suitable for use. [21 CFR § 58.83].

The inspection of the reagents and solutions stored in the Histopathology Pathology Laboratory found numerous reagents and solutions to have passed their expiration dates for periods of between one and four years.

Your July 17th letter states that laboratory research assistants will check the expiration dates and any outdated reagents will be disposed of. The SOP provided with your letter only states: "Check expiration dates of chemicals. Discard and reorder if expired." This is insufficient, because your SOP does not address how you will document that these checks are being done. For example, implementing a "use log" where lot numbers and expiration dates are recorded. The SOP also does not state who will be responsible for conducting this check or for the disposal of out of date reagents and solutions. The inspection of reagents and solutions should also be covered in the QAU's SOPs.

Please revise the current SOPs and submit them with your written response to this Warning Letter.

7. Failure to conduct nonclinical laboratory studies in accordance with the protocol. [21 CFR § 58.130(a), (c), and (d)].

a. The weight and clinical scoring data for animals identified as (b)(4) and (b)(4) in Group (b)(4) of study (b)(4) for days (b)(4) were attributed to the incorrect source animals.

In your letter of July 17th, you admitted that the EAE scores for the above referenced animals were incorrectly transcribed during days (b)(4) of the experiment.

b. Protocol (b)(4) required that the animals be evaluated on a scale of (b)(4). However, our review of the data for Group (b)(4) found that a scale of (b)(4) was used with increments of (b)(4). Another document showed an additional scoring system of (b)(4) with plus/minus scoring, (b)(4) increments and one (b)(4) value.

In your July 17th letter you acknowledge that you modified the protocol without proper authorization and documentation, and state that, in the future, you will obtain prior authorization for any amendments to a protocol, and fully document the amendment process in all future experiments.

c. Animal (b)(4) from the Group (b)(4) animals in study (b)(4) died during the experiment. Subsequently all other animals reassigned new numbers to fill the void, resulting in (b)(4) becoming (b)(4), and so on.

In your July 17th letter you acknowledged that the animal IDs were reassigned upon the death of animal (b)(4) and you state that you will not reassign identification numbers in the future.

You claim that the errors cited in items 7a to 7c, above, did not compromise the integrity of the study data. We disagree. The regulations state the nonclinical laboratory study shall be conducted in accordance with the protocol. You did not conduct the study in accordance with the protocol. You changed the grading scale that was listed in the protocol without submitting or obtaining approval for a protocol amendment. Data were incorrectly recorded, and animals were assigned new identification numbers. These actions and regulatory violations directly affect the integrity of the study. 

8. Failure to periodically analyze feed and water used for test animals. [21 CFR § 58.90(g)].

Inspection of the Animal Care Facility found that neither feed nor water for the test systems used for Protocol (b)(4) housed in Animal Room (b)(4) are analyzed to ensure that contaminants known to be capable of interfering with the study and reasonably expected to be present in such feed and water are not present at levels above those specified in the protocol.

You indicate in your July 17th letter that all feed manufacturers are GMP compliant. At the end of the inspection you stated that you will request certificates of analysis from the feed manufacturers. Please revise your firm's SOPs to specify how you will ensure compliance with these regulatory requirements.

The analytical data you provided in your July 17th letter for the water used for the (b)(4) appears to be adequate. Please revise your SOP to define how often the water will be checked, i.e., monthly, quarterly, etc. The procedures should also list the contaminants which are to be checked.

You also state that you had sent a number of documents to the New York District Office, including: (1) the IACUC SOP; (2) training records for one staff member; (3) activity logs for (b)(4) and (b)(4); (4) microbiology swabs of cages report; (5) IACUC minutes in reference to (b)(4) and (b)(4) dated 5/15/07, 9/17/07, 2/20/08 and 9/9/08; and (6) a report on rodent diet contamination check. Neither the New York District Office nor our office received these referenced documents. Please provide a copy of these documents with your response to this Warning Letter.

The deviations listed above are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment is in compliance with all requirements of the law and applicable federal regulations. You are responsible for investigating, determining causes of, and correcting violations identified by the FDA, and for reviewing your firm's operations as a whole to ensure that you are in compliance with the regulatory requirements applicable to nonclinical laboratory studies. You should take prompt action to correct these deviations and prevent their recurrence. Failure to do so may result in FDA initiating regulatory action without further notice.

We request that you notify this office in writing, within fifteen (15) working days of receipt of this letter, of the specific steps you have taken to correct the noted violations and to prevent their recurrence. If you cannot complete all of the corrections before you respond, please state the reason for your delay and the time frame within which the corrections will be completed.

Please send your response and the requested documentation to:


Robert L. Wesley
Division of Inspections and Surveillance (HFM-664)
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
1401 Rockville Pike, Suite 200N
Rockville, Maryland 20852-1448
Telephone (301) 827-6338

We also request that you send a copy of your response to the FDA District Office listed below.



Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

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