- Galena BioPharma Inc
- Issuing Office:
- Seattle District Office
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
22215 26th Avenue SE, Suite 210
Bothell, WA 98021
April 3, 2015
In reply refer to Warning Letter SEA 15-12
Mark W. Schwartz, Ph.D.
President and Chief Executive Officer
Galena Biopharma, Inc.
291 Discovery Bay Boulevard
Discovery Bay, California 94505
Dear Dr. Schwartz:
The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Galena Biopharma, Inc., located at 4640 SW Macadam Avenue, Suite 270, Portland, Oregon, between November 17 and 21, 2014. The inspection focused on your firm’s compliance with Postmarketing Adverse Drug Experience (PADE) reporting requirements and Current Good Manufacturing Practice (CGMP) for Finished Pharmaceuticals relating to Abstral (fentanyl) sublingual tablets, NDA-022510, approved by FDA on January 7, 2011, and acquired by your firm on May 1, 2013; and Zuplenz (ondansetron) oral soluble film, NDA-022524, approved by FDA on July 2, 2010, and acquired by your firm on August 13, 2014.
Our inspection revealed serious violations of FDA’s PADE reporting requirements under 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) Part 314.80. At the conclusion of the inspection, your firm was issued a Form FDA 483, Inspectional Observations, which listed instances where your firm failed to comply with PADE requirements under section 505(k)(1) of the Act [21 U.S.C. § 355(k)(1)] and 21 CFR 314.80. Failure to comply with section 505(k) and its corresponding regulations under 21 CFR 314.80 is a prohibited act under section 301(e) of the Act [21 U.S.C. § 331(e)].
We acknowledge your firm’s December 11, 2014, written response to the Form FDA 483. From our review of the FDA establishment inspection report, the documents submitted with that report, and your firm’s written response, we conclude that your firm did not adhere to the applicable statutory requirements and FDA regulations governing PADE reporting. Specific violations include, but are not limited to, the following:
1. Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences from all sources as required by 21 CFR 314.80(b).
Your firm does not have adequate written procedures to ensure that adverse drug experiences (ADEs) are detected, correctly identified, assessed, and reported to FDA in accordance with postmarketing regulations. Specifically, the draft Standard Operating Procedures (SOPs) provided during the inspection, “Product Complaints” and “Post Marketing Reporting of Serious Adverse Events,” failed to adequately address regulatory requirements to ensure that (1) ADE information obtained from any source is promptly conveyed to the appropriate Galena Biopharma, Inc. personnel for evaluation; (2) ADEs that are evaluated as 15-day Alert reports are promptly investigated and all attempts to obtain follow-up information about the ADEs are recorded, as required by 21 CFR 314.80(c)(1)(ii);and (3) an FDA Form 3500A for each ADE not reported as a 15-day Alert reportunder 21 CFR 314.80(c)(1)(i) is submitted in the correct format and on time.
During the inspection, your staff indicated that the initial receipt of postmarketing ADEs for Abstral is contracted out to a call center, and the call center forwards ADE reports to a centralized (b)(4). Draft SOPs reviewed during the inspection require product complaints to be logged in by Quality Assurance staff for an investigation and cases to be created in the safety database or logged on (b)(4) for special interest reports and adverse events by the pharmacovigilance staff. However, the SOPs do not include: who at your firm is responsible for retrieving reports forwarded to the (b)(4) from the call center; how the responsible person retrieves the reports; how your staff ensures that all ADE information obtained by the call center was forwarded to and received by Galena Biopharma, Inc.; or how your staff ensure any ADE obtained by the Quality Assurance staff during a complaint investigation is forwarded to pharmacovigilance staff.
The draft “Post Marketing Reporting of Serious Adverse Events” SOP generally references obtaining follow-up data from a reporter and documenting follow-up attempts. The SOP does provide vague guidelines for which reports require follow-up (i.e., the report requires additional information, the outcome of the event is unknown). However, the SOP fails to adequately describe the requirement to follow-up on 15-day Alert reports, methods used to obtain follow-up information, the timetable for submitting follow-up information, or how the follow-up information is to be reported to FDA in accordance with 21 CFR 314.80(c)(1)(ii).
In addition, the draft “Post Marketing Reporting of Serious Adverse Events” SOP states that periodic reports will be submitted “as required.” This is inadequate because there is no indication of what “required” means to ensure timely, periodic reporting. We believe the inadequacy of these SOPs have contributed to your firm failing to submit any Periodic Adverse Drug Experience Reports (PADERs) and associated Individual Case Safety Reports (ICSRs) since acquiring the product, Abstral.
In your December 11, 2014, written response to the Form FDA 483, you included revised procedures, QA-03-1 “Product Complaints” and PV 01-1 “Post Marketing Reporting of Adverse Events,” and training records. You noted that the revised procedures include the initial assessment and event disposition of ADEs, the procedure for the Chief Medical Officer evaluation of the events, and the expedited reporting of 15-day Alert reports. In addition, your response notes that the revised procedures include a process for submitting PADERs.
Your response is inadequate. The revised SOP QA-03-1 “Product Complaints,” does not include procedures to follow if an ADE is identified in a product complaint. Therefore, this written procedure fails to ensure your firm obtains ADE reports from any source, which includes product complaints, as required by 21 CFR 314.80(b).
The revised SOP PV 01-1 “Post Marketing Reporting of Adverse Events” received with your December 11, 2014, written response includes a case creation requirement similar to what was included in the draft SOP collected during the inspection. However, the revised SOP does not specify who at your firm is responsible for obtaining reports from the call center, or how the reports are retrieved by the pharmacovigilance staff for case creation. In addition, the revised procedures do not provide any processes for your staff to ensure that all ADE information obtained by the call center was forwarded to and received by Galena Biopharma, Inc.
The revised SOP PV 01-1 “Post Marketing Reporting of Adverse Events” lacks the steps required for the follow-up of 15-day Alert reports. Specifically, it fails to describe what procedures are to be used by your staff to attempt the required follow-up. Also, you do not describe your procedure for submitting Postmarketing 15-day Alert Follow-up reports to FDA in accordance with 21 CFR 314.80(c)(1)(ii).
The revised SOPPV 01-1 “Post Marketing Reporting of Adverse Events” states that periodic reports will be submitted “as required.” This is inadequate as noted previously because there is no indication of what “required” means to ensure timely, periodic reporting. Although you committed to, and submitted, a Periodic Safety Update Report (PSUR) on February 9, 2015, in lieu of a PADER with an approved waiver, the lack of adequate procedures for how to submit the PSUR/PADER and associated ICSRs does not prevent the possible failure to submit these reports in the future.
2. Failure to report each adverse drug experience not reported under 21 CFR 314.80(c)(1)(i) at quarterly intervals as required by 21 CFR 314.80(c)(2)(i).
As the NDA holder of Abstral, you are required to submit PADERs with ICSRs to FDA at quarterly intervals for three years from the NDA approval date, and then at annual intervals. NDA-022510 for Abstral was originally approved on January 7, 2011, and subsequently transferred to your firm on May 1, 2013. You failed to submit ADE reports in a PADER, or otherwise, for the following periods: May 1, 2013, through July 6, 2013; July 7, 2013, through October 6, 2013; and October 7, 2013, through January 6, 2014. There were at least nineteen ADEs reported to your firm for Abstral from May 1, 2013, through January 6, 2014.
In your December 11, 2014, written response you committed to submitting the ADE reports identified as missing, on or before February 9, 2015. However, the written response is inadequate because you failed to identify why you did not submit PADERs with ICSRs within the quarterly intervals required by regulation. We also note that neither the draft SOPs reviewed during the inspection, nor the revised SOP PV 01-1 “Postmarketing Reporting of Adverse Events” submitted in your response, includes any procedures for how the ICSRs are to be submitted to FDA. The revised SOP only states what will be in a PSUR and at what intervals the PSUR will be submitted. Therefore, you have not provided adequate preventative actions to address the timely submission of periodic ICSRs. Failure to report ADEs to FDA at the required intervals raises concerns about your firm’s ability to monitor the safety of drug products, as well as the reliability and integrity of the information submitted to FDA.
On February 9, 2015, you submitted a PSUR covering the period of May 1, 2013, to January 6, 2014. We acknowledge receipt of your PSUR, however the ICSRs included in the PSUR were not submitted in an acceptable format. Please refer to the FDA Adverse Events Reporting System website for instructions on how to submit ICSRs electronically, available online at: http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm115894.htm
. We emphasize our concern about the adequacy of your written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences. Without adequate written procedures, we cannot be assured that you will accurately capture and report important safety information about your drug products to the Agency.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. It is your responsibility to ensure compliance 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, seizure and injunction. Other federal agencies may take this Warning Letter into account when awarding contracts. FDA may re-inspect to verify corrective actions have been completed.
Also, we are concerned about your firm’s fundamental understanding of the overall regulatory expectations for a firm that enters into agreements with contract manufacturers to manufacture its drug products, including CGMP operations under 21 CFR 211. Although you have agreements with other firms that delineate specific responsibilities to each party, you are ultimately responsible for the quality of your products. FDA is aware that many manufacturers of pharmaceutical products utilize extramural independent contract facilities and regard extramural facilities as an extension of the manufacturer's own facility, 21 CFR 200.10(b). Regardless of who performs your operations, or the agreements in place, you are required to ensure your products are made in accordance with section 501(a)(2)(B) of the Act.
Within fifteen working days of your receipt of this letter, please notify this office in writing of the specific actions that you are taking to correct violations. Your response should explain how each action being taken will prevent the recurrence of similar violations, as well as copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which corrective actions will be completed.
Your written response should be sent to Maria P. Kelly-Doggett, Compliance Officer, U.S. Food and Drug Administration, 22215 26th Avenue SE, Suite 210, Bothell, Washington 98021. If you have any questions regarding this letter, please contact Compliance Officer Maria Kelly-Doggett by telephone at 425-302-0427.
Miriam R. Burbach
cc: Margaret A. Kivinski, P.E., Esq., General Counsel
Galena Biopharma, Inc.
4640 SW Macadam Avenue, Suite 270
Portland, Oregon 97239
Patricia A. Murphy, Vice President Regulatory Affairs and Compliance
Galena Biopharma, Inc.
6051 Estates Drive
Oakland, California 94611