DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Date: December 12, 2012
From: Nannette Cagungun CBER/OBRR/DBA, HFM-380
Subject: Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - Equine BLA
Robert Fisher reminded the team about the review timelines. He asked that all requests for information be sent to him by December 19, 2012 in order to meet the internal target date of December 21, 2012. He will draft an issue summary for the BPAC meeting scheduled for February 12, 2013. As a condition for approval under the Animal Rule, Cangene must conduct a Phase 4 study to verify and describe the product’s clinical benefit and to assess its safety when used as indicated when such studies are feasible and ethical (for example, during a Bioterrorism event). The review committee will meet in January 2013 to discuss the labeling.
The review committee provided an update on the status of their review:
There are no process validation issues; however, Cangene has to identify which process scale it plans to license and provide a complete list of all deviations which occurred during the manufacturing process. The CMC reviewers will examine the release specifications for potency.
The stability data submitted seem acceptable. Cangene should clarify the storage condition it is requesting.
An issue was identified about how the viral clearance numbers were calculated.
BIMO inspection assignments were issued for four studies. Two inspections have been completed; the contract research organization that performed the pivotal guinea pig efficacy study (Battelle Biomedical Research Institute in Columbus, OH) and the clinical study site (Loma Linda, CA). The guinea pig study site did not receive an FDA Form 483.The inspected clinical study site received an FDA Form 483 because the investigator did not report protocol deviations within the timeframe specified by the IRB. The investigator also failed to list information on a testing lab that was used throughout the study on the Form 1572 until after the study was completed. Two other sites are pending BIMO inspections; one human study and one non-human primate study.
One protocol deviation has been identified in which one subject who was supposedly blinded knew what drug they were taking. An information request will be sent to Cangene for clarification.
The benefits of this product seem to outweigh the risks. Adverse events reported include two moderate allergic reactions and numerous instances of tonsillar hypertrophy. There was a question regarding the dose and product concentration in the 2 vial sizes. It was explained that the vial fill amount is based on potency so the volume can change. The more product one is giving the patient, the more equine protein the patient is getting.
No statistical issues have been identified.
Animal Efficacy Studies
It is not clear why some guinea pigs were euthanized because they did not appear to meet any of the prespecified criteria stated in the study protocol. This issue will be included in the information request.
Cangene submitted a pharmacovigilence plan (PVP) which includes routine pharmacovigilence and a plan to conduct a study in case of mass exposure to botulism toxin. There were no reports of deaths and cases of serum sickness in the clinical trials that can be attributed to the product. No subject experienced anaphylactic reaction in the CDC Expanded Access Program. One 10 year old male subject who was diagnosed with food-borne botulism experienced bradycardia following infusion of the product. He experienced a second episode of bradycardia following resumption of product administration. The infusion of the product was discontinued and the subject recovered from the event. This serious and unexpected adverse event was possibly related to the product. Cangene did not identify this event as a safety concern.
OBE recommended that Cangene establishes and maintains a registry on all BAT recipients and report all serious events, labeled and unlabeled, related or unrelated to BAT, as well as all non-serious adverse events reactions related to hypersensitivity/allergic reactions and bradycardia as 15-days reports. Cangene should also conduct a postmarketing study that will include patients treated with BAT outside a mass exposure. This would require that the applicant collect information on all patients treated with H-BAT as soon as the product is licensed. These proposals might be good discussion for BPAC.
OBRR asked OBE to prepare a narrative for adverse event signals to determine if postmarketing studies are indeed needed.
Pharmacology and Toxicology
There were no major issues from a pharmacology perspective. No toxicity studies were conducted to support the BLA. However, risk analysis of impurities and excipients was performed and did not reveal any potential toxicity issues. Cangene should provide the acceptance criteria for impurities and phosphate in the release specifications table.
Lot Release Testing Plan
The reviewer did not find any issues and only has comments on the draft lot release testing plan. The review committee will discuss the release specifications for the SNS so the product can be released without going through the CDC.
The pre-license inspection will be waived, since the 2012 TeamBio inspection was favorable and the bulk manufacturing equipment is not currently installed in Building -(b)(4)-. However, ------------------------------------------------------(b)(7)--------------------------------------------------------.
The reviewers have not identified any major issues. The proposed dose is acceptable from a clinical pharmacology perspective.
The meeting adjourned.