VIA UNITED PARCEL SERVICE
In reply, refer to Warning Letter16-NWJ-16
Dr. Mahendra Patel, CEO Navinta, LLC
1499 Lower Ferry Road
Ewing, New Jersey 08618
Dear Dr. Patel:
The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Navinta LLC, located at 1499 Lower Ferry Road, Ewing, NJ 08618, between May 11 and May 16, 2016. The inspection revealed serious violations of the Postmarketing Adverse Drug Experience (PADE) reporting requirements found in section 505(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(k)) and Title 21, Code of Federal Regulations (21 CFR) 314.80 and 314.98. Failure to comply with section 505(k) is a prohibited act under section 301(e) of the Act (21 U.S.C. 331(e)).
At the conclusion of the inspection on May 16, 2016, Investigator Paul L. Bellamy, representing FDA, presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your written response, dated June 6, 2016, to the Form FDA 483, Inspectional Observations.
From our review of the FDA Establishment Inspection Report, the evidence 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 for 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 (ADEs) from any source as required by 21 CFR 314.80(b) and 21 CFR 314.98(a).
As an application holder, your firm is required to develop written procedures for the surveillance, receipt, evaluation, and reporting of post marketing adverse drug experiences (ADEs) to FDA. Your firm does not have written procedures that describe how you comply with PADE regulations. Specifically:
Your firm's Standard Operating Procedure (SOP) SOP QA-GMP-053, "Procedurefor Handling of Market Complaint (Drug Substance and Drug Product)" (effective 12/08/2015), fails to describe how you review, evaluate, and report safety information, including how you: (1) identify the existence of ADEs; (2) assess ADEs for seriousness and expectedness; (3) investigate ADEs for missing data elements; (4) investigate promptly all ADEs that are both serious and unexpected to obtain additional information about the adverse experiences; (5) record all attempts at follow-up; and (6) prepare and report post marketing safety information, individual case safety reports, and the aggregate Periodic Adverse Drug Experience Reports (PADERs) to FDA in electronic format.
During the inspection, your staff provided a written agreement you made with your marketing partner (b)(4) , a distributor of two Navinta products. Although the agreement requires each party (b)(4), there is no procedure between Navinta and (b)(4) describing how you will accomplish this notification. Further, the agreement does not describe how non-serious ADEs will be addressed between your firm and (b)(4). As a result, this agreement fails to ensure that your firm will receive all ADEs, which are necessary both for safety evaluations of your products and for submission to FDA in PADERs.
In your June 6, 2016, written response, your firm: (1) provided a newly established SOP, "Procedure for surveillance, receipt, evaluation and reporting of adverse drug experience (ADEs) for marketed products" (SOP #RA-GDP-004, effective June 2, 2016); (2) committed to hiring an additional employee in regulatory affairs to maintain records associated with ADEs; and (3) included a copy of an executed contract with a third-party service provider to support Navinta with individual case management, aggregate reporting, and literature searches for the firm's marketed products.
Your firm's written response is inadequate because the newly established SOP fails to adequately describe how your firm will (1) receive adverse event information from your non-applicant manufacturers, packers, or distributors, and (2) ensure that all ADEs are evaluated for seriousness and expectedness against the most current U.S. package insert. The new SOP also fails to describe the documentation and investigation of ADEs that are both serious and unexpected, and it fails to include a procedure for the complete and timely reporting of ADE information to FDA in an electronic format that FDA can receive, process, and archive.
The lack of adequate written procedures to ensure the surveillance, receipt, evaluation, and reporting of postmarketing ADEs as required by 21 CFR 314.80(b) and 314.98(a) raises concerns about your firm's ability to assess the safety of your drug products.
2. Failure to submit periodic adverse drug experience reports quarterly for an application which was approved less than three years ago and annually for an application which was approved three or more years ago as requiredby 21 CFR 314.80(c)(2) and 21 CFR314.98(a).
As an application holder of abbreviated new drug applications (ANDAs), you are required to submit PADERs for each application. PADERs are required to include all adverse experience reports not reported as 15-day Alert reports. Your firm did not submit PADERs to FDA for six approved applications. Based on the respective approval dates of your ANDAs, you failed to submit approximately (b)(4) quarterly PADERs and (b)(4) annual PADERs to FDA. Furthermore, you were unaware of this deficiency until an FDA investigator called it to your attention during the inspection.
In your written response, you acknowledged that as of June 6, 2016; Navinta had not submitted any PADERs to FDA. As part of your response to FDA, you submitted your new SOP, "Procedure for Periodic Adverse Drug Experience Reports (PADERs) Submission to FDA"(RAGDP 005, effective June 2, 2016).
In addition to Navinta's new SOP on submission of PADERs, your response included an SOP on PADER preparation from your third-party service provider, (b)(4). However, SOPs from other firms do not compensate for deficiencies in and omissions from your firm's SOP. As an application holder, you are responsible for ensuring that PADERs for all your applications include the required content and are submitted to FDA on time.
Your response is inadequate because your new SOP fails to adequately describe a controlled process for the preparation and timely submission of PADERs to FDA, and because we cannot determine whether you have identified the root causes of these deficiencies and implemented adequate corrective and preventive measures to ensure that they do not recur.
Your failure to establish written procedures, submit PADERs, and identify and assess the root causes of these deficiencies raises concerns about your firm's ability to monitor the safety of your drug products.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your firm. 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, including injunction, without further notice. Federal agencies are advised of the issuance of all Warning Letters about drugs and devices so that they may take this information into account when awarding contracts. FDA may re-inspect your firm to verify corrective actions have been completed.
Within 15 working days of your receipt of this letter, please notify this office in writing of the specific steps you have taken to correct the violations. Include an explanation of each step taken to prevent the recurrence of similar violations, as well as copies of any supporting documentation. If you cannot complete the corrective actions within 15 working days, state the reason for the delay and the time within which you will complete the correction. You may wish to include the dates each corrective action will be fully implemented.
Should questions arise, please contact Liatte Krueger, Acting Compliance Officer, New Jersey District. Address your written response and any pertinent documentation to: U.S. Food and Drug Administration, 10 Waterview Blvd., Parsippany, New Jersey 07054.
Craig W. Swanson
Acting District Director
New Jersey District