Advisory Committees

February 12, 2013: Blood Products Advisory Committee Meeting Summary Minutes

February 12, 2013
Building 5630 Fisher Lane, Conference Room 1066, Rockville, MD

Committee Members 
Dr. Jay Brooks Jackson##
Dr. Demetrios Demetriades
Dr. Francisco A. Bonilla
Dr. Ronald O. Gilcher
Dr. Nigel S. Key#
Dr. Donna M. DiMichele#
Dr. Jennifer Kuzma
Dr. Matthew Kuehnert
Dr. Jeanne Linden#
Dr. James H. Maguire
Dr. Toby Simon**
Dr. Steven Pipe#
Dr. Valerie Durkalski-Mauldin
Dr. Peter M. H. Rhee
Dr. Christopher Stowell
Dr. Katherine Schexneider
Mr. Corey Dubin *
Guest Speakers
Dr. Stephen Arnon
Dr. Agam K. Rao
Dr. Gerald R. Kovacs

Dr. Robert W. Fisher
Dr. Carl-Michael Staschen
Dr. Irwin Feuerstein
Temporary Voting Members
Dr. Michael Adler
Dr. Jeremy Sobel 
Dr. Timothy Pruett
Temporary Non-Voting Member
Dr. Ruth E. Stevens
Designated Federal Official
Emery Bryan, R.N., LCDR, USPHS
Committee Management Specialist
Pearline Muckelvene
Rosanna Harvey
Joanne Lipkind
*  Consumer Representative
** Industry Representative
# Did not attend
## Chair

These summary minutes for the February 12, 2013 Meeting of the Blood Products Advisory Committee were approved on April 20, 2013.

I certify that I participated in the February 12, 2013 Meeting of the Blood Products Advisory Committee Meeting that these minutes accurately reflect what transpired.

Emery Bryan, R.N., LCDR, USPHS
Designated Federal Officer
Jay B. Jackson, M.D.

The Chair, Dr. Jay B. Jackson, called the Meeting of the Blood Products Advisory Committee to order at 8:30 a.m. EST on February 12, 2013.  In open session, the Committee discussed Cangene’s Biological License Application for Botulism Antitoxin (Equine), Heptavalent (A, B, C, D, E, F, G)

An Open Public Hearing was announced.  There were no presentations made during the Open Public Hearing.

Following is a summary of the discussion.  Additional information and specific details may be obtained from the transcript of the meeting.  The transcript may be viewed on the World Wide Web at February 12, 2013: Blood Products Advisory Committee Meeting Transcript.

Proceedings were adjourned at approximately 5:00 p.m., on February 12, 2013

Topic I:  Cangene’s Biologics License Application for Botulism Antitoxin (Equine), Heptavalent (A, B, C, D, E, F, G)

FDA sought the advice of the Committee on whether studies performed under the 21 CFR 601 Subpart H “Animal Rule” have provided reasonable evidence that Botulism Antitoxin (Equine), Heptavalent (A, B, C, D, E, F, G) has an acceptable safety profile and is likely to be effective in the patient populations for the indications being sought.

Dr. Robert Fisher introduced the topic to the Committee and provided an overview of the FDA Animal Rule.  Dr. Gerald Kovacs from the Biomedical Advanced Research and Development Authority (BARDA) discussed botulism as a potential bioterrorist agent and outlined the Department of Health and Human Services medical countermeasures strategy to address the public health threat of botulinum exposure, including the requirement for the development of licensed antitoxins.  Next, Dr. Stephen Arnon, Chief of the Infant Botulism Treatment and Prevention Program at the California Department of Health, provided an overview of the botulinum neurotoxin and clinical botulism.  Dr. Agam Rao, Director of the CDC National Botulism Consultation Program described CDC’s response to botulism in the US and provided data on the use of botulism antitoxin products released by CDC, including Cangene’s Botulism Antitoxin (Equine), Heptavalent (A, B, C, D, E, F, G) (BAT).  

Cangene’s Chief Scientific Officer, Dr. Laura Saward, then presented an introduction to Cangene’s BAT development program.  On behalf of Cangene, Dr. Gordon Peterson from Loma Linda University School of Medicine discussed the unmet need for treatment for botulism.  Dr. Andrew Emanual next presented a summary of the guinea pig and rhesus monkey animal model studies conducted to support BAT efficacy. Dr. Chris Sinclair presented Cangene’s translational data on human dosing and Dr. Tim Babinchak provided an overview of the human safety data and a benefit:risk assessment of BAT.   

Finally, FDA presented a summary of its review of Cangene’s BAT biologics license application.  Dr. Robert Fisher provided FDA’s review and assessment of the animal efficacy studies; Dr. Carl-Michael Staschen reviewed the pharmacokinetic studies; and Dr. Irwin Feuerstein presented FDA’s review of the human clinical data in support of safety of BAT.  Dr. Robert Fisher then summarized FDA’s review assessment, noting that FDA’s assessment is that the potential benefits exceed the risks associated with the use of Cangene’s BAT to treat symptomatic botulism.     

No presentations were made during the open public hearing. 

The Committee addressed the following questions: 

  1. Do the results from the efficacy studies of botulinum antitoxin heptavalent (A, B, C, D, E, F, G)-(Equine) in guinea pigs and nonhuman primates provide sufficient evidence that the product is reasonably likely to provide clinical benefit for the treatment of humans with symptomatic botulism?
    The Committee agreed unanimously.  Vote:  14 yes; 0 no


  2. Do the results from safety studies in healthy human volunteers, efficacy studies in animal models, and clinical data from CDC’s use of BAT under IND (Expanded Access Protocol) support an acceptable risk to benefit profile for use of BAT?
    The Committee agreed unanimously.  Vote 14 yes, 0 no
    Committee members did express concern regarding the serious adverse events of bradycardia and asystole, reported in the ten year old boy who received BAT.  The Committee recommended Cangene conduct thorough postmarket safety studies, especially in children.


  3. Do the animal studies and simulation modeling adequately support the proposed dosing in humans
    1. for adults?
      Vote:  14 yes, 0 no
    2. for children (no data) ?
      Vote:  12 yes, 1 no, 1 abstain
      The Committee member who abstained from voting noted that it was not possible to form an opinion without data.
      Other Committee members commented that in the absence of such data, intense monitoring and robust data collection are necessary to help determine appropriate dosing in children.


  4. Based on the limitations of the safety database, FDA intends to require a postmarketing study to monitor safety of BAT.  FDA proposes that Cangene utilize a registry to capture safety data on sporadic cases of botulism for a 3 year period after licensure.  Please comment whether such a registry would be adequate to add to the safety data for use of BAT in patients with botulism. 

    The Committee provided the following comments:

    • Committee members commented that sparse clinical data in humans mandates robust and active postmarket data collection.
    • The Committee discussed the potential value of CDC’s Botulism Consultation Program managing the registry because a public health authority may be more likely to compel submission of data and it would provide continuity since the antitoxin is released by the CDC Program.  However, CDC commented that it has limited resources and the Committee’s industry representative noted that industry has experience conducting such postmarking programs when required by FDA.
    • Committee members commented that a three year surveillance program may not provide sufficient data regarding pediatric use of the product because there are only a few reported pediatric cases annually.
    • One Committee member commented that the most important consideration is that an active surveillance program be conducted and physicians should be required to report to the registry even in the absence of adverse events.


  5. The Animal Rule requires postmarketing studies to monitor safety and efficacy of products approved under the Rule when such studies become ethical and feasible.  To address this requirement the Agency proposes that Cangene reactivate the previously established registry (as indicated in question 4) to capture safety and efficacy data in any mass exposure scenario.  Please comment whether such a registry would be adequate:
    a.   To monitor the effectiveness of the recommended human dose in cases of botulism
    b.   To add to the safety data

    The Committee provided the following comments:

    • One member commented that in a mass exposure situation there would be opportunity to capture efficacy data because some individuals would receive treatment while others would not.
    • Other committee members commented that it would be difficult to measure efficacy in such a situation because you may not know the exposure dose.
    • Some members commented that it may be very challenging or infeasible to capture safety and efficacy data during a mass exposure scenario.  However, most members agreed that it would be worthwhile to collect whatever data were available.
    • One member recommended that a data collection plan should be developed as part of the botulism emergency response planning. 


  6. Please comment on FDA's proposal that Cangene should commit to a postmarket study to determine blood levels of botulinum antitoxin heptavalent (A, B, C, D, E, F, G)-(Equine) after therapeutic dosing in children in order to validate the dosing recommendations in the absence of a pediatric PK study
    • The Committee members agreed that obtaining blood levels of BAT in children after therapeutic dosing would be highly desirable; some members commented that the practicality of conducting such a study may be difficult.  

    The Committee also discussed the following issues: 

    • The Committee discussed that a decrease in mortality following administration of BAT has not been demonstrated, because few individuals die of botulism due to modern intensive care support.  Rather, the clinical benefit is demonstrated by decreased days on mechanical ventilation and reduced length of hospital stays.
    • Several members commented that it would be helpful to have a more sensitive and rapid assay for botulism toxin to aid in diagnosis and dosing.
    • The unique pathophysiology of infant botulism compared with the pathophysiology of botulism in adults and older children was discussed.
    • Committee members commented that the effectiveness of BAT appears dependent on the timing of its administration, with effectiveness greatest when administered early in disease progression. Committee members discussed the need for early recognition of possible botulism by clinicians, and whether availability of BAT for purchase by hospital pharmacies could result in shortened time from diagnosis to treatment since BAT would be more rapidly available.
    • One Committee member recommended that Cangene study the rate of infusion because many adverse events of immune globulin products are related to the infusion rate.

Please read the official transcript for a detailed account of the meeting.

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