Our STN: BL 125296/0
Duramed Research, Inc.
Attention: Joseph A. Carrado
One Belmont Avenue, 11th Floor
Bala Cynwyd, PA 19004
Dear Mr. Carrado:
This letter is in regard to your biologics license application (BLA) for Adenovirus
Type 4 and Type 7 Vaccine, Live, Oral manufactured at ----------------(b)(4)--------------------------------- and at Barr Laboratories in Forest, Virginia and submitted under section 351 of the Public Health Service Act (42 U.S.C. 262).
We have completed our review of all submissions you have made relating to this BLA up to the information in the amendment dated June 25, 2009. After our complete review, we have concluded that we cannot grant final approval because of the deficiencies outlined below.
- The following inspectional issues from the Barr Laboratories pre-license inspection (PLI) conducted on April 20 – 24, 2009, have not been completely resolved:
- Equipment cleaning validation studies for the -------------(b)(4)-------------------Tablet Press have not been completed and the final report on cleaning validations for all equipment have not been submitted for evaluation.
- The cleaning efficacy study of ---------((b)(4)-------------------- to remove Adenovirus 4 (ADV-4) and Adenovirus 7 (ADV-7) residues from product-contact surfaces has not been validated.
- The clean hold time for equipment and facility has not been validated.
- The viral inactivation study by (b)(4) at the adenovirus facility has not been validated.
- The following items pertaining to Barr Laboratories have not been submitted. Please submit the following:
- Barr Laboratory’s overall approach or plan to control and prevent contamination and cross-contamination.
- An updated Site Master Plan for the room classification of the adenovirus facility.
- Complete testing results of the “trial batch” manufactured during the PLI.
- Investigation report of the two “hissing” bottles of discolored Formulated Virus.
- We agreed to allow the use of six clinical batches, three for ADV-4 and three for ADV-7, as consistency lots for your BLA. Samples from the six clinical batches were submitted for in- support testing. Since these batches expired in 2008, we requested that additional samples from the ADV-4 batch, manufactured during the April 20 – 24, 2009 PLI, be submitted for the completion of in-support testing. The ADV-4 batch manufactured during the April 2009 PLI was not considered a CGMP batch because of a manufacturing deviation. However, manufacturing proceeded as a trial batch. As a consequence, you have not demonstrated the ability to manufacture the product according to CGMP since the production of clinical batches in 2006. Please submit batch records showing complete testing results for one batch of ADV-4 and one batch of ADV-7 manufactured according to CGMP subsequent to the batch made during the April 20 – 24, 2009 PLI. Please submit 100 tablets from each batch. We may require additional batches for testing if our in-support testing results for the six clinical batches are out of specification.
- Since “Enteric Coated Tablets” is the dosage form and “for Oral Administration” is the route of administration, “Enteric Coated Tablets for Oral Administration” should not be presented as part of the product name. Please separate the dosage form and route of administration from the proper name and submit revised cartons and containers.
- Should additional information relating to the safety and effectiveness of this drug product become available before our receipt of the final printed labeling, revision of that labeling, may be required.
- In 1.16 Risk Management Plans in the original BLA, you indicated that periodic safety update reports (PSUR) will be submitted to meet your post-marketing periodic safety reporting requirements. On May 15, 2009, you requested that your periodic safety reports be prepared according to 21 CFR 600.80 rather than PSUR per ICH E2C guidelines. We request that you submit a detailed plan of post-marketing safety reporting per, 21 CFR 600.80, for each of the three post-marketing surveillance studies including the Sentinel Surveillance Plan, the viral shedding evaluation using the Naval Health Research Center Febrile Respiratory Surveillance Program, and the Pregnancy Registry.
We stopped the review clock with the issuance of this letter. We will reset and start the review clock when we receive your complete response.
Within 10 days after the date of this letter, you should take one of the following actions: (1) amend the application; (2) notify us of your intent to file an amendment; or (3) withdraw the application.
You may request a meeting or teleconference with us to discuss the steps necessary for approval. Please submit your meeting request as described in our “Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products,” dated February 2000. This document is available on the internet at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM079744.pdf or may be requested from the Office of Communication, Outreach, and Development, at (301) 827-1800. For details, please also follow the instructions described in CBER’s SOPP 8101.1: Scheduling and Conduct of Regulatory Review Meetings with Sponsors and Applicants. This document is also available on the internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
ProceduresSOPPs/ucm079448.htm, or may be requested from the Office of Communication, Outreach, and Development.
Please be advised that, as stated in 21 CFR 601.3(c), if we do not receive your complete response within one year of the date of this letter, we may consider your failure to resubmit to be a request to withdraw the application. Reasonable requests for an extension of time in which to resubmit will be granted. However, failure to resubmit the application within the extended time period may also be considered a request for withdrawal of the application.
We acknowledge receipt of your amendment dated June 25, 2009. You may cross reference applicable sections of the amendment dated June 25, 2009, in your complete response to this letter and we will review those sections as a part of your complete response.
If you have any questions regarding the above, please contact the Regulatory Project Manager, Ms. Darlene Hithe, at (301) 827-3070.
Wellington Sun, M.D.
Division of Vaccines and
Related Products Applications
Office of Vaccine
Research and Review
Center for Biologics
Evaluation and Research