Inspections, Compliance, Enforcement, and Criminal Investigations

Ignatius P. Godoy, M.D. 10/1/18

 

  

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10903 New Hampshire Avenue
Silver Spring, MD 20993 

 

Warning Letter
 
 
 
CBER-19-01 
October 1, 2018
 
 
 
UPS EXPRESS MAIL & ELECTRONIC MAIL
 
 
Ignatius P. Godoy, M.D.
16660 Paramount Boulevard, Suite 206
Paramount, California 90723-5458
 
Dear Dr. Godoy:
 
This Warning Letter informs you of objectionable conditions observed during a Food and Drug Administration (FDA) inspection conducted between May 29, 2018, and June 8, 2018. An FDA investigator met with you during the inspection to review your conduct as a clinical investigator of the following clinical study:
 
A Phase 3, Randomized, Multicenter, Observer-Blinded, Noninferiority Study to Evaluate the Immunogenicity and Safety of a Quadrivalent Inactivated Influenza Virus Vaccine (Seqirus QIV) with a US-licensed Quadrivalent Inactivated Comparator Influenza Virus Vaccine (Comparator QIV) in a Pediatric Population 6 Months Through 59 Months of Age (CSLCT-QIV-15-03).
The FDA conducted this inspection under the Bioresearch Monitoring Program that includes inspections designed to review the conduct of research involving investigational products. At the end of the inspection a Form FDA 483, Inspectional Observations, was issued and discussed with you.
 
Based on our review of the establishment inspection report, the documents submitted with that report, and your June 22, 2018 response to the Form FDA 483 (“Response Letter”), we have determined that you violated regulations governing the proper conduct of clinical studies involving investigational new drugs, as published in Title 21, Code of Federal Regulations (CFR) Part 312 (available at https://www.gpo.gov/fdsys/pkg/CFR-2018-title21-vol5/pdf/CFR-2018-title21-vol5-part312.pdf), as well as regulations governing protection of human subjects, as published in Title 21, CFR Part 50 (available at https://www.gpo.gov/fdsys/pkg/CFR-2018-title21-vol1/pdf/CFR-2018-title21-vol1-part50.pdf).  The applicable provisions of the CFR are cited for each violation listed below.
 
CLINICAL INVESTIGATOR VIOLATIONS:
 
1.    You failed to obtain the legally effective informed consent of the subject’s legally authorized representative prior to involving them in research [21 CFR § 50.20].
A.  Subjects (b)(6) were both randomized pursuant to the study procedure for randomization on (b)(6) but there is no indication that they provided informed consent, and no other study records for these subjects were available during the inspection, including Informed Consent Forms. Your Response Letter explains that the parents of both subjects refused to participate in the study; however, both subjects were entered into the Interactive Web Response System (IWRS) as randomized. Your letter also states that an effort to have them removed from the IWRS was initiated but you were informed that this would not be possible.
 
However, as the clinical investigator, it was your responsibility to obtain informed consent in accordance with 21 CFR Part 50. Your failure to obtain informed consent in accordance with 21 CFR Part 50 prior to involving these subjects in research raises concerns about your protection of study subjects enrolled at your site.
 
Your corrective action of retraining staff on the consent process appears to be adequate, if implemented as described. Please submit documentation of training provided to staff on obtaining informed consent prior to conducting any research activities, including randomization, as described in your Response Letter.
 
2.  You failed to ensure that the investigation was conducted according to the signed investigator statement, the investigational plan, and the applicable regulations, and to protect the rights, safety, and welfare of subjects under your care [21 CFR § 312.60].
 
A.  Protocol Section 4.1.2 Exclusion Criteria states that a subject will be ineligible if one or more exclusion criteria are met.  Protocol Section 4.1.2, Item 5 excludes subjects with, “Clinical signs of active infection and/or an axillary temperature of ≥ 99.5ºF / ≤37.5ºC on the day of vaccination or within 48 hours preceding vaccination.”
 
The following subjects were enrolled, despite meeting this exclusion criterion. The symptoms and diagnoses at the time of enrollment are shown below:
 
Subject ID#
Date of Vaccination
Symptoms
Diagnosis
(b)(6)
(b)(6)
Sore throat, cold, rash on lip
Pharyngitis, Upper Respiratory Infection, Impetigo
(b)(6)
(b)(6)
Cl cx 4d
Upper Respiratory Infection
(b)(6)
(b)(6)
Mild cold
Mild Upper Respiratory Infection
(b)(6)
(b)(6)
Improved wheezing
Acute Bronchitis
(b)(6)
(b)(6)
Cold, cough
Mild Upper Respiratory Infection, Impetigo
(b)(6)
(b)(6)
Sore throat, mouth blisters
Acute Pharyngitis, Acute Herpangina
(b)(6)
(b)(6)
Cough, mouth blisters, fever
Acute Bronchiolitis, improved
(b)(6)
(b)(6)
Cough w/phlegm, sore throat
Allergic Rhinitis, Left Otitis Media
 
In your Response Letter, you describe updating Exclusion Criteria #5 to “Yes” and notifying the IRB that subjects (b)(6) were ineligible. For subjects (b)(6), your letter states that the diagnoses will be corrected in the study records. The eligibility criteria for each clinical investigation are designed to optimize interpretability of collected data and to minimize foreseeable harm to enrolled subjects.  Enrollment of subjects who do not meet the eligibility criteria jeopardizes subject safety and welfare and raises concern about the validity and integrity of the data collected at your site.
 
Your corrective action plan appears to be adequate, if implemented as described. Please submit documentation of the corrected study records and the IRB notification for these protocol deviations. 
 
Your Response Letter describes consultation with the medical director of (b)(4) regarding eligibility questions. Please be advised that questions about any aspect of the protocol should be directed to the Sponsor or its designee.
 
B.  Protocol Section 8.4.2 Treatment Period states that “subjects would be randomized into a one-dose or two-dose regimen according to the US Advisory Committee on Immunization Practices (ACIP) dosing regulations.” The ACIP recommendations are as follows: “For 2016–17, ACIP recommends that children aged 6 months through 8 years who have previously received ≥2 total doses of trivalent or quadrivalent influenza vaccine before July 1, 2016 require only 1 dose for 2016–17. The two previous doses need not have been given during the same season or consecutive seasons. Children in this age group who have not previously received a total of ≥2 doses of trivalent or quadrivalent influenza vaccine before July 1, 2016 require 2 doses for the 2016–17 season. The interval between the 2 doses should be at least 4 weeks.” 
 
You failed to follow the protocol-specified recommended guidelines and improperly randomized at least three subjects as described below:
 
Subject ID
Date of randomization
Previous history of vaccination
Expected Randomization
Actual Randomization
(b)(6)
(b)(6)
No
Two dose
Single dose
(b)(6)
(b)(6)
Yes
One dose
Two dose
(b)(6)
(b)(6)
Yes
One dose
Two dose
 
Your Response Letter states that you will conduct a thorough review of subjects’ immunization records prior to randomization and that the IRB was notified of these protocol deviations. Failure to adhere to protocol requirements for study drug administration compromises subject safety and welfare significantly and raises concerns about the validity and integrity of the data collected at your site.
 
Your preventive action plan appears to be adequate, if implemented as described. We request you submit documentation of the IRB notification for these protocol deviations.
 
C.  Protocol Section 5.2. Supply and Storage states that: “the Study Vaccines should be stored under temperature monitored conditions (+36ºF to +46ºF [+2ºC to +8ºC]).” On (b)(6), you administered study vaccine to Subject (b)(6) that was stored in a refrigerator that had a temperature excursion to 9.1ºC for at least 30 minutes on 1/9/2017.
 
Your Response Letter states that the site administered the vaccine prior to notifying the Sponsor and placing the affected vaccine into quarantine.  Failure to adhere to protocol requirements for study drug supply and storage compromises subject safety and welfare significantly and raises concerns about the validity and integrity of the data collected at your site.
 
Your preventive action plan to notify the Sponsor prior to administering the improperly stored study vaccine appears to be adequate, if implemented as described.
 
D.  Protocol Section 8.4.3 On-study Period states that Visit 2, Second Vaccination (Two-Dose Schedule) should occur on Day 29+4. You failed to adhere to this timeframe for at least five subjects, as described below:
 
Subject ID
Day 1
Actual Date of Visit 2
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
 
Your Response Letter states that study site staff will review study requirements with parents, document communication with the parents, and notify the clinical investigator when the vaccination schedule is not followed. Failure to adhere to protocol requirements for study drug administration compromises subject safety and welfare significantly and raises concerns about the validity and integrity of the data collected at your site.
 
Your preventive action plan appears to be adequate, if implemented as described. Please notify the IRB of these protocol deviations and submit documentation of this notification.
 
E.  Protocol Section 8.4.3 On-study Period states that Diary Reminder Telephone Calls occur between Days 3 and 5 after vaccination. You failed to adhere to this timeframe and/or to document the Day 3 to 5 telephone calls for at least eleven subjects, as described below:
 
Subject ID
Day 1
Date of Phone Call
(b)(6)
(b)(6)
Not done
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
(b)(6)
Not done
(b)(6)
(b)(6)
Not done
(b)(6)
(b)(6)
Not done
(b)(6)
(b)(6)
Not done
(b)(6)
(b)(6)
Not done
(b)(6)
(b)(6)
Not done
(b)(6)
(b)(6)
Not done
(b)(6)
(b)(6)
(b)(6)
 
Your Response Letter states that study site staff will schedule regular meetings to facilitate communication and clinical investigator oversight. Failure to adhere to protocol requirements for  subject safety follow-up compromises subject safety and welfare significantly.
 
Your preventive action plan appears to be adequate, if implemented as described. Please provide documentation of your notification to the IRB for these protocol deviations.
 
F.  Protocol Section 7.3 Prohibited Therapies includes the following:
Current or recent immunosuppressive or immunomodulatory therapy, as follows:
i)    Chronic (>2 weeks) or long-term systemic corticosteroids: ≥0.125 mg/kg/day of oral prednisolone or equivalent daily;
ii)    Sporadic systemic corticosteroids: ≥0.5 mg/kg/day of oral prednisolone or equivalent for two or more short courses of >3 days in the 3 months preceding vaccination and/or during the active study period.
 
The following subjects received the study vaccine, despite having received prohibited therapy before and/or during the active study period:

Subject ID#
Date of randomization
Prohibited Medication
Treatment Course
Purpose
(b)(6)
(b)(6)
Prelone syrup
(b)(6)
Acute Bronchitis
(b)(6)
(b)(6)
Prelone syrup
(b)(6)
 
Bronchitis
(b)(6)
(b)(6)
Prelone syrup
(b)(6)
Bronchitis

 
Failure to adhere to protocol requirements regarding prohibited therapies compromises subject safety and welfare significantly and raises concerns about the validity and integrity of the data collected at your site.
 
Your Response Letter states that you will update Exclusion Criteria #10 to “Yes” in the source documents and notify the IRB of these protocol deviations. Your corrective and preventive action plans appear to be adequate, if implemented as described. Please submit documentation showing the corrected study records and your IRB notification for these protocol deviations.
 
3.  You failed to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug [21 CFR § 312.62(b)].
 
A.  At least three subjects’ records showed discrepancies between the source documents and Case Report Forms (CRFs) or no source documentation was available regarding the Day 3-5 phone calls.
 
i)  Subject (b)(6): Source record shows the call date and times documented as having occurred on (b)(6) but the ‘Yes’ box is not checked and the rest of the form is blank. According to the eCRF audit trail, dated (b)(6), the entry states that the call was not made. However, the response was changed on the source document on
(b)(6) to ‘Yes’ due to “entry error.”
 
ii)  Subject (b)(6): Source record is blank but was updated on (b)(6) with handwritten notes documenting that the calls took place on (b)(6). According to the eCRF audit trail, dated (b)(6), the entry states that the calls were not made. However, the response was changed on the source document on (b)(6) to ‘Yes’ due to “entry error.”
 
iii)   Subject (b)(6): Source record shows call date and times documented but the ‘Yes’ box is not checked. According to the eCRF audit trail, dated (b)(6), the entry states that the call was not made. However, the response was changed on the source document on (b)(6) to “Yes” due to “entry error.”
 
As a clinical investigator, you are required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Your failure to maintain adequate and accurate case histories raises concerns about the validity and integrity of data captured at your site.
 
Your Response Letter states that staff will review the protocol and have regular meetings to facilitate clinical investigator oversight. Your corrective and preventive action plans appear to be adequate, if implemented as described. However, your Response Letter does not provide any documentation to explain the changes made in the eCRF.
 
B.  At least six subjects’ Informed Consent Forms were not maintained properly or documented appropriately.
 
i)  Subjects (b)(6): The signature pages in the file at the time of the inspection are not original documents.
 
ii)  Subject (b)(6): Times of parent and investigator signatures were changed from 1655 and 1659, respectively, to an earlier time of 1605. Time of vaccination was 1639.
 
iii)  Your signature is documented as occurring prior to that of the parents, as follows:
 
Subject ID#
Time of Investigator Signature
Time of Parent Signature
(b)(6)
1715
5:20 (1720)
(b)(6)
1455
1456
(b)(6)
1510
1531
 
As a clinical investigator, you are required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Your failure to maintain adequate and accurate case histories raises concerns about the validity and integrity of data captured at your site.
 
Your Response Letter states that staff will be re-trained and the clinical investigator will participate in clinical research training programs. Your corrective and preventive action plans appear to be adequate, if implemented as described. Your Response Letter does not provide any documentation to explain the changes made in the eCRF.
 
This letter is not intended to be an all-inclusive list of deficiencies with your clinical studies of investigational new drugs. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations.
 
Within fifteen (15) business days of receipt of this letter, please provide written documentation of the additional actions you have taken or will take to correct these violations and to prevent the recurrence of similar violations in current and future studies for which you are the clinical investigator. Failure to respond to this letter and to take appropriate corrective action could result in FDA taking regulatory action without further notice to you. If you do not believe you are in violation of FDA regulations, include your reasoning and any supporting information for our consideration.
 
Your reply should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., WO71-G112, Silver Spring, MD 20993-0002. If you have any questions regarding this letter, please contact the Division of Inspections and Surveillance, CBER at 240-402-8928.
 
We also request that you send a copy of your response to the FDA Office listed below.
 
Sincerely,
/S/ 
Mary A. Malarkey, Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
 
cc:      
Eric Pittman
Director, FDA ORA-BIMO West
550 West Jackson Street, Suite 1500
Chicago, Illinois 60661
 
(b)(4)

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