Inspections, Compliance, Enforcement, and Criminal Investigations
Pfizer, Inc. 5/26/10
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
May 26, 2010
WARNING LETTER NYK 2010-19
Jeffrey B. Kindler
Chairman and Chief Executive Officer
235 East 42nd Street
New York, NY 10017
Dear Mr. Kindler:
During the period from June 29, 2009 through August 10, 2009, an inspection was conducted by investigators of the U.S. Food and Drug Administration (FDA or Agency) of your firm located at 235 East 42nd Street, New York, NY to determine your firm's compliance with the Postmarketing Adverse Drug Experience (PADE) reporting requirements of Section 505(k) of the Federal Food, Drug, and Cosmetic Act (the Act)) [21 U.S.C. § 355(k)], and Title 21, Code of Federal Regulations (21 CFR) 314.80 and 314.81.
Section 505(k)(1) of the Act [21 U.S.C. § 355(k)(1)] and 21 CFR 314.80 and 314.81 require an applicant to establish and maintain records and to report data relating to clinical experience, along with other data or information, for drugs for which an approved application is in effect. Failure to comply with Section 505(k) is a prohibited act under Section 301(e) of the Act [21 U.S.C. § 331(e)].
I. Deviations from 21 CFR 314.80 and 21 CFR 314.81 include the following:
1. Failure to submit Adverse Drug Experience (ADE) reports to FDA as required by 21 CFR 314.80(c). Specifically:
(a) The following are examples of ADEs and information regarding ADEs that were not submitted to the FDA:
|Report #||Mfg. Report #||Product||Pfizer's Seriousness/Expectedness Determination||Date Received by Pfizer|
|1.||2009236922||Dalacin (Clindamycin HCI)||Serious outcome and failure to assess expectedness||05/04/09|
|3.||2009221607||Lyrica||Serious outcome and failure to assess expectedness||06/01/09|
We have reviewed your firm's response dated September 9, 2009, and have determined that it is inadequate. The response acknowledges that the above-listed reports contained serious and unexpected adverse events which were not submitted within 15 days to FDA. These reports were not submitted until they were identified during the FDA inspection. Your firm's rationale for the failure to submit these reports included a lack of file tracking control as well as a lack of adequate training in utilizing the (b)(4) system. Your firm received FDA Forms 483 on July 29, 2004 and April 18, 2006 for similar postmarketing adverse drug experience violations and your corrective actions for these observations, including training, have been shown to be ineffective. FDA expects drug manufacturers to establish and implement reasonable mechanisms to assure that all serious and unexpected experiences are promptly recorded and investigated to determine whether or not 15-day Alert reports should be submitted to FDA.
(b) FDA's Center for Drug Evaluation and Research, Division of Reproductive and Urologic Drug Products, sent you a letter dated July 14, 2005, requesting that "all manufacturers of PDE5 inhibitors for treatment of erectile dysfunction (ED) continue to submit serious reports of postmarketing ophthalmologic adverse events that might reflect non-arteritic ischemic optic neuropathy (NAION) as 15-day Alert reports." In your letter to FDA dated October 18, 2005, your firm committed to provide 15-day Alert reports for these reported outcomes.
Your firm failed to submit 15-day Alert reports for the following serious visual adverse events that met the postmarketing reporting requirement for Viagra (sildenafil citrate) by misclassifying and/or downgrading reports to non-serious without reasonable justification:
|Mfg. Report No.||Serious Outcome||Date Received|
|1.||2009230915||"Lost right eye vision"||06/22/09|
|3.||2009193299||"Blind in right eye"||03/27/09|
|7.||2009179071||"Visual acuity loss"||02/26/09|
|8.||2008063424||"Visual acuity reduced"||07/24/08|
We have reviewed your firm's response dated September 9, 2009 and have concluded that it is inadequate. Your response indicates that only four of the above reports contained serious and/or expected reports of postmarketing ophthalmologic adverse events requiring a 15-day Alert report. However, the remaining seven adverse events were deemed as non-serious although serious outcomes such as "visual acuity loss/reduction" were noted.
2. Inadequate written procedures for the surveillance, receipt, evaluation, and reporting of adverse events as required by 21 CFR 314.80(b). Specifically:
Your firm does not have adequate written procedures in place to ensure that adverse drug experiences are correctly identified, assessed, and reported to FDA in accordance with postmarketing commitments.
For fosphenytoin, in your firm's letter to FDA dated February 13, 2009, your firm agreed to develop and implement an effective plan which would include criteria to correctly identify, assess, and report cases that are not labeled as Purple Glove Syndrome (PGS), but that are suggestive of this syndrome in association with fosphenytoin sodium use. However, your firm failed to do so.
Your firm also agreed to train all pharmacovigilance staff in the worldwide affiliates by February 15, 2009. Training was to include an overview of PGS and specific directions regarding the process for expediting any adverse event reports involving fosphenytoin use to Drug Safety Surveillance (DSS).
Despite your agreement, only six out of the required sixty-three country offices worldwide were trained and some of the offices that were trained were not trained on time, including the core DSS offices. 1
Your firm's response dated September 9, 2009 remains inadequate because it fails to include an effective plan to identify cases suggestive of PGS and fails to require medical evaluation of reports suggestive of PGS. Additionally, provisions for adequate training and documentation of training were not provided.
3. Failure to submit adverse drug experiences that are both serious and unexpected to FDA 'within 15 calendar days of initial receipt of the information as required by 21 CFR 314.80(c) (1)(i). Specifically:
(a) During the time period of approximately March 1, 2006 through December 7, 2008, there were 80,560 15-day Alert Reports submitted to FDA by your firm, of which 3558 (4%) were late. Between December 8, 2008 through June 28, 2009, approximately 1508 (9%) were submitted late, a further decline in the timeliness of reporting.
The following are examples of ADE reports that contained serious and unexpected events, but were submitted late to FDA:
|Mfg. Report No.||Product||Reason Late||No. of Days Late|
|1.||2007039077||Lipitor||Delay due to case processing/other||1141|
|2.||2007039077||Lipitor||Delay due to resubmission||1102|
|3.||2007048456||Azithromycin||Delay forwarding to safety site||687|
|4.||2008037900||Azithromycin||Delay due to case revision||393|
|5.||2009229922||Amlodipine Besilate||Delay due to clerical/data entry issue||438|
|6.||2008040787||Prostin VR||Delay due to resubmission||285|
|7.||2009231444||Atorvastatin Calcium||Delay forwarding to safety site||274|
|8.||2009212979||Epirubicin HCI||Delay forwarding to safety site||728|
|9.||2009195911||Eplerenone||Delay due to clerical/data entry issue||356|
According to your firm's response, implementation of (b)(4) created problems for the timely submission of 15-day Alert reports. A review of the explanations for the late reports indicates reasons such as cases being initially identified as non-serious then upgraded to serious, user error in routing cases within the safety system, case distribution errors, case processing issues, and technical errors. The firm purports to have addressed these problems by updating user manuals, reinforcing training, additional prospective and retrospective quality review of cases, updating system configuration errors, and other unspecified corrective actions with supplying organizations and partners. Your response indicates reporting improved after May 2009 and that errors significantly declined once colleagues became more experienced with the new safety system. However, your firm's response did not include comparable metrics for the post-May 2009 time period. Although the Agency recognizes the benefits to implementing a new and improved computerized tracking system, such a system can only be an improvement if there is adequate staff to make accurate data entries and if the users are adequately trained in its implementation. Your firm's response also fails to address other factors that possibly contributed to the tardiness of the reports, including personnel training in the categorization of serious versus non-serious reports, training in use of the new (b)(4) system, development of SOPs, development of standardized documentation practices, and development of compliance metrics. A signed copy of your revised corrective action plan should be included in your response to this Warning Letter.
(b) On November 8, 2004, FDA granted a waiver to your firm allowing for serious and unexpected suspected adverse drug reactions for NDA 11-839 (Provera and medroxyprogesterone acetate) to be submitted no later than 30 calendar days of initial receipt of the information, instead of within 15 calendar days of receipt of the information. However, between June 8, 2005 and March 16, 2009, your firm failed to submit approximately 25 reports within 30 days. The following are examples of these late reports:
|Mfg. Report No.||No. of Days Late|
The response comments addressed for item 3(a) also apply to this point.
(c) On August 28, 2006, FDA granted a waiver to your firm allowing for serious and unexpected suspected adverse drug reactions for Bextra (valdecoxib) to be submitted no later than 60 calendar days of initial receipt of the information, instead of within 15 calendar days of receipt of the information. The firm, however, failed to submit approximately 220 of these reports within 60 days. The following are examples of the late reports:
|Mfg. report No.||No. of Days Late|
The response comments addressed for item 3(a) also apply to this point.
4. Failure to submit a 15-day Alert report for adverse drug experiences obtained from postmarketing studies in which the applicant concludes that there is a reasonable possibility that the drug caused the adverse experience, as required by 21 CFR 314.80(e)(1). Specifically:
Fifteen-day Alert reports have not been submitted for all adverse drug experiences during postmarketing studies where there is a reasonable possibility that the drug caused the adverse experience. In your firm's letter dated March 18, 2008, your firm committed to submit 15-day Alert reports for Selzentry (Maraviroc) for the following events during the postmarketing period: liver-related deaths and liver failure, fatal and non-fatal myocardial infarctions, and all non-AIDS defining malignancies. The following ADE reports for Selzentry (Maraviroc) from postmarketing studies were required to be submitted to FDA as 15-day Alert reports, because they either met these criteria described in the March 18, 2008 letter, or they otherwise contain serious and unexpected events in which there is a reasonable possibility that the drug caused the event.
|Mfg. Report No.|
Your response has been reviewed and found inadequate. In a letter to the Agency dated March 18, 2008, your firm acknowledged expedited 15-day reporting for liver-related deaths, liver failure, fatal and non-fatal myocardial infarctions and all non-AIDS defining malignancies from spontaneous and clinical trial sources. No reasons for late submission of reports 2006136607 and 2008003965 were provided in your response. Your response states that reports 2009154994, 2009187951, and 2005162672 were incorrectly not submitted due to errors in distribution. Your response further states that reports 2007067649 and 2007076241 were not submitted because they were received by the firm before clarification from the Agency advising that clinical trial cases were subject to special reporting requirements. However, after receipt of clarification that cases 2007067649 and 2007076241 were subject to reporting, your firm did not submit them to the Agency.
5. Serious and unexpected ADE reports are not promptly investigated as required by 21 CFR 314.80(c)(1)(ii). Specifically:
Adverse drug experiences that were the subject of postmarketing 15-day Alert reports were not investigated and/or documented. Specifically, in your firm's letter dated August 18, 2005, your firm submitted revised procedures to investigate all cases of postmarketing ophthalmologic ADEs that might reflect NAION involving Viagra. Your firm committed in these procedures to submit a pre-specified list of questions to reporters in order to obtain clinical and diagnostic information concerning visual symptoms and risk factors for the event. However, in cases reviewed during the inspection, your firm failed to provide documentation that adequate follow-up information had been requested. In addition, during the inspection, it was observed that some reports were either misclassified or downgraded in severity to non-serious without a reasonable justification.
Your response acknowledges that documentation of follow-up calls and the use of the questions during the calls were not handled consistently. Although the FDA does not mandate a particular method of requesting follow-up information, documentation that all postmarketing ophthalmologic events that might reflect NAION were investigated should be maintained.
6. Failure to submit 15-day Alert reports for serious adverse drug experiences as a non-applicant to the applicant within 5 calendar days of receipt as required by 21 CFR 314.80(c)(1) (iii).
Pfizer, as a non-applicant, elected to submit to the applicant (rather than to FDA) all reports of serious adverse drug experiences. However, you did not submit each report to the applicant within five calendar days of your receipt of the information.
Specifically, your firm's name is on the label of at least ten products (amoxicillin, finasteride, ondansetron, lamotrigine, metformin, penicillin V potassium, stavudine, tiotropium bromide, donepezil, interferon beta-la) for which you are required to submit serious ADE reports to the applicant within five calendar days. Of the 398 reports received by your firm for these products, 132 (33%) were sent to the applicants more than five calendar days after your receipt of them.
Your response acknowledged a need to improve on the timeliness of your submission of serious ADE reports to the applicants for products for which Pfizer does not hold the NDA or ANDA, but appears on the label as a distributor. Your response stated that activities such as targeted training and presentations have resulted in reporting timeframe improvement. However, a review of the overall time reporting for 5-day rule products in a time table provided to the investigators on July 9, 2009, for the period from December 8, 2008 to June 30, 2009, shows the contrary. As demonstrated by your report compiled for inspection entitled "5-Day Rule Products Sent to License Party between 08 Dec 2008 and 30 Jun 2009", there was a decline in the timeliness of reporting during this period.
7. Failure to promptly review all adverse drug experience information obtained or otherwise received by the applicant from any source as required by 21 CFR 314.80(b). Specifically:
Adverse drug experience information obtained or otherwise received from any source was not promptly reviewed, including information from commercial marketing experience and postmarketing epidemiological/surveillance activities.
The following are examples of serious ADEs that wvere not forwarded for case processing within 2-4 business days as required by your SOP AEM-01-02, dated July 14, 2008, pages 3 - 5:
|Mfg. Report No.||No. of Days Received Late|
Your response provided an explanation for the lateness of these reports and stated that the firm has "robust quality processes in place to oversee performance ..." This response is deemed inadequate because your affiliates failed to comply with defined time fines for case processing as required by SOP AEM-01.
Your response commits the firm to implement "additional enhancements to tools enabling enhanced proactive management of case workload" to mitigate late reporting. A signed copy of your revised corrective action plan should be included in your response to this Warning Letter. Adequacy of the corrective action will be determined during subsequent inspection(s).
8. Failure to submit periodic adverse drug experience reports at quarterly intervals for each adverse drug experience which is not reported as a I5-day Alert report, for 3 years from the date of approval of the application, and then at annual intervals submitted within 60 days of the anniversary date of approval of the application as required by 21 CFR 314.80(c)(2). Specifically:
Individual ADEs which were not reported to FDA in a postmarketing IS-day Alert report have not been included in a periodic safety report.
Specifically, the following ADEs were not reported to FDA in a periodic safety report:
|Mfg. Report No.|
Your response to this observation reports a short term corrective action of nightly sweeps of the (b)(4) System with a permanent system correction to be implemented by the fourth quarter of 2009. Adequacy of the corrective action will be determined during subsequent follow-up inspection(s).
II. Deviations from 21 U.S.C. § 353(d) include the following:
In addition to the above violations of Postmarketing Adverse Drug Experience (PADE) reporting requirements, you have significant deviations from the requirements of Section 503(d) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 353(d)] and Title 21, Code of Federal Regulations, Part 203. Based on the information collected during the inspection, non-compliance with the requirements of the Prescription Drug Marketing Act (PDMA), include:
1. Failure to conduct an immediate investigation, to notify FDA within 5 working days, and provide written investigation reports within 30 days of initial notification of prescription drug sample thefts, significant losses, and falsification of prescription drug sample records as required by 21 CFR 203.37(a)(1),(2), and (3) and (b)(1), (2), and (3).
21 CFR 203.37(a)(1) and (b)(1) requires a manufacturer or authorized distributor of record to notify FDA within five working days of becoming aware of a significant loss, any known theft, or suspected falsification involving drug samples. 21 CFR 203.37(a)(2) and (b)(2) requires an immediate initiation of an investigation of a suspected significant loss, any known theft, or suspected falsification. 21 CFR 203.37(a)(3) and (b)(3) requires that FDA be provided with a complete written report, including the reason for and the results of the investigation, not later than 30 days after the date of the initial notification.
The FDA 483 observations concern Pfizer's failure to notify and follow up with FDA regarding significant losses, known thefts, or suspected falsifications in accordance with these PDMA legal requirements. Pfizer's response to the FDA 483 in this regard does not address how Pfizer will meet the Section 203.37 requirements. We recognize your intent to reduce the inventory period, but the reduction you describe would still not meet the five working day reporting requirement.
Examples of incidents of significant losses and confirmed variances in drug sample annual inventory reconciliation re orts that exceeded the established threshold for significant loss in Pfizer's SOP 010 (b)(4) that were not reported to FDA are as follows:
• Employee ID (b)(6) had a total inventory loss of approximately (b)(4) on July 17, 2009. At the time of inspection, FDA had not been notified.
• Employee ID (b)(6) had a possible theft of (b)(4) totaling a loss of (b)(4) on March 11, 2008. A police report was filed on May 13, 2008, yet Pfizer did not notify FDA until May 30, 2008.
• Employee ID (b)(6) had a variance of (b)(4) on Aug 19, 2008. FDA was not notified until approximately two months later.
2. Failure to conduct, at least annually, a complete and accurate physical inventory of all drug samples distributed and to record the results of such inventory as required by 21 CFR 203.31(d).
21 CFR 203.31 (d) requires that each drug manufacturer or authorized distributor of record that distributes drug samples by means of representatives shall conduct, at least annually, a complete and accurate physical inventory of all drug samples. All drug samples in the possession or control of each manufacturer's and distributor's representatives are required to be inventoried and the results of the inventory are required to be recorded in an inventory record. In addition, manufacturers and distributors shall reconcile the results of the physical inventory with the most recently completed prior physical inventory and create a report documenting the reconciliation process.
Annual inventory reconciliations are not conducted once a year as per your SOP 010. Specifically, out of 35 inventories reviewed by FDA, the following employees did not have their inventories taken annually:
Your response relays the intent to revise SOP 010 to assure that all future employee inventories are performed within 12 months from the initial inventory review rather than once each calendar year. However, we have not yet received your revised SOP and you have not addressed the status of inventories for the above employees. Therefore, the adequacy of your response cannot be determined.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your firm. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, prosecution or injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug applications, listing your facility as a supplier or manufacturer until the above violations are corrected. A reinspection may be necessary.
You should notify this office upon receipt of this letter to arrange for a meeting to discuss the specific steps you have taken to correct the noted violations, including an explanation of each step being taken to prevent the recurrence of similar violations. If corrective action cannot be completed within 15 working days, state the reason for delay and the time within which corrections will be completed.
Your reply should be sent to Compliance Branch, Food and Drug Administration, 158-15 Liberty Avenue, Jamaica, NY 11433 Attention: Lillian C. Aveta, Compliance Officer.
Ronald M. Pace
New York District
1 The Milan office, which is one of the core DSS offices, was not trained until July 2009.
Enclosure: Form FDA 483 dated August 10, 2009