Food and Drug Administration

Center for Biologics Evaluation and Research

SUMMARY MINUTES

BLOOD PRODUCTS ADVISORY COMMITTEE

91^st Meeting:  May 1-2, 2008

Hilton Hotel, 1750 Rockville Pike, Rockville, MD

Committee Members FDA Participants

Frederick Siegal, M.D., Chair                         Maria Rios, Ph.D.

Mark Ballow, M.D.                                         Melissa A. Greenwald, M.D.

Henry Cryer, M.D., Ph.D.                              Robert Duncan, Ph.D.

Adrian Di Bisceglie, M.D.                              Dorothy Scott, M.D.

Willarda Edwards, M.D., MBA                     Salim Haddad, M.D.

Maureen Finnegan, M.D.                                Jonathan Goldsmith, M.D.

Simone Glynn, M.D., MSc, M.P.H.               Ruth Solomon, M.D.

Matthew Kuehnert, M.D.                               Ping He, M.D.

Roshni Kulkarni, M.D.                                   Jessica Kim, Ph.D.

Catherine Manno, M.D.                                  Felice D’Agnillo, M.D.

Katherine McComas, Ph.D.                            Basil Golding, M.D.

Francisco Rentas, Ph.D.                                  Carolyn Wilson, Ph.D.

Andrea Troxel, Sc.D.                                      C.D. Atreya, Ph.D.    

Ann Zimrin, M.D.                                           Hira Nakhasi, Ph.D.

Judith Baker, M.H.S.A.*                                Gerardo Kaplan, Ph.D.

Louis Katz, M.D. **

Guest Speakers

Committee Members Absent                          Jerry Holmberg, Ph.D.

Thomas Quinn, M.D.                                      Richard Davey, M.D.

Donald Trunkey, M.D.                                   Larry Dumont, Ph.D., MBA

                                                                        Mark Stafford-Smith, M.D.

Temporary Voting Members

Thomas Atkinson, M.D. ***                          Lev Pharmaceuticals, Inc. Speakers

Andrea Apter, M.D. ***                                Jason Bablak

Thomas Fleming, Ph.D.                                  Michael Frank, M.D.

Larry Borish, M.D. ***                                  Ira Kalfus, M.D.

B. Gail Macik, M.D.                                       Paula Busse, M.D.

Irma Szymanski, M.D.

Committee Management Specialist

Designated Federal Official                           Pearline Muckelvene

Donald Jehn, M.S.

*    Consumer Representative

**  Industry Representative

***Topic II only

These summary minutes for the May 1-2, 2008 Meeting of the Blood Products Advisory Committee were approved on May 15, 2008.

I certify that I participated in the May 1-2, 2008 Meeting of the Blood Products Advisory Committee and that these minutes accurately reflect what transpired.

/// Original Signed ///                                       /// Original Signed ///

______________________________            _________________________________

Donald W. Jehn                                              Frederick Siegal, M.D.

Designated Federal Official                           Chair

Food and Drug Administration

MINUTES

for the

BLOOD PRODUCTS ADVISORY COMMITTEE

91st Meeting, May 1-2, 2008

Committee Updates

Dr. Jerry Holmberg presented to the Committee a summary of the August 22-23, 2007 and January 9-10, 2008 meetings of the DHHS Advisory Committee on Blood Safety and Availability.  The next update presented to the committee was by Dr. Maria Rios on 2007 West Nile Virus (WNV) epidemiology and FDA’s draft guidance on the use of nucleic acid tests (NAT) to reduce the risk of transmission of WNV in blood and blood components for transfusion.  Dr. Melissa Greenwald then presented FDA’s recommendations on the use of NAT to test donors of human cells, tissues and cellular and tissue-based products (HCT/Ps) for WNV.  Next, Dr. Robert Duncan presented an update to the Committee on the implementation on blood donor screening for infection with Trypanosoma cruzi (T.cruzi).  Dr. Duncan and Dr. Greenwald then updated the Committee on FDA’s current considerations related to the use of serological tests to reduce the risk of T. cruzi infection in blood and blood components for transfusion and HCT/Ps, respectively.

The next update was presented by Dr. Dorothy Scott on the regulatory pathway for lowering measles antibody lot release specification in Immune Globulin Intravenous (Human) and Immune Globulin Subcutaneous (Human).  Finally, the Committee was updated on PASSPORT, a post-marketing surveillance study of 7-day platelets: Dr. Larry Dumont presented information on behalf on Gambro and Fenwal; Dr. Louis Katz presented information from an America’s Blood Centers’ member survey and AABB risk assessment related to PASSPORT; and Dr. Salim Haddad presented FDA’s perspective on the study.       

Informational Presentations on CBER Safety Teams

Following the updates, the Committee was provided informational presentations on CBER Safety Teams related to blood and tissue.  Dr. Jonathan Goldsmith, Chair of the CBER Blood Safety Team, presented an overview of the legal framework for FDA regulation of blood and blood products and addressed the overlapping layers of blood safety.  He then discussed the establishment of the Blood Safety Team within CBER and reviewed the goals and objectives, current activities and long terms challenges of the Blood Safety Team.  Dr. Goldsmith then addressed questions from Committee members related to external communication with other government agencies, patient advocacy groups and the media; the broad charge of the Blood Safety Team; and its role in emergency preparedness and potential product shortages.

Dr. Ruth Solomon, Chair of the CBER Tissue Team, presented an overview of FDA’s regulation of human cells, tissues and cellular and tissue-based products (HCT/Ps) and requirements for manufacturer reporting adverse reactions to FDA.  Dr. Solomon discussed the purpose of the Tissue Team and described the processes for tracking and evaluating adverse reactions related to HCT/Ps.  She discussed challenges related to adverse reaction surveillance and provided summary data on adverse reaction reporting and outcomes for 2006-2007.  Dr. Solomon then addressed questions from the Committee related to manufacturer adverse event reporting, including the requirement for communicable disease reporting and 15 day reporting.                    

During the Open Public Hearing, Dr. Laurence Corash of Cerus Corporation and the University of California, San Francisco, commented on pathogen inactivation of platelet components.  In addition, Mr. Scott Brubaker, representing the American Association of Tissue Banks, discussed WNV and Chagas testing for certain donors of HCT/Ps. Additionally, Dr. Susan Stramer, representing AABB, spoke regarding AABB’s West Nile Virus Task Force.  

Topic I:   BEST (Biomedical Excellence for Safer Transfusion) Committee Report on Red Blood Cell Recovery Standards

FDA sought the advice of the Committee on an industry proposal to change the current acceptance criteria for evaluation of red blood cell (RBC) studies based on in vivo radiolabeling recovery trials.  Dr. Ping He introduced the topic to the Committee and discussed FDA’s criteria for evaluation of red blood cell products.  Based on the analysis of the combined BEST and FDA data sets of red blood cell product studies, Dr. He concluded that the overall quality of RBC products approved or cleared by FDA is improving with time and most recent studies submitted to the FDA passed the current, higher standard for recovery standards.  Dr. Richard Davey, of the Methodist Hospital in Houston, then presented the Committee an overview of red cell in vivo recovery and survival studies and discussed the problems associated with the use of older blood.  Next, Dr. Mark Stafford-Smith, of Duke University, presented on the age of stored blood and reviewed data on the short-term mortality and long-term survival after cardiac surgery.  Dr. Larry Dumont, of Dartmouth Medical School, presented the BEST committee’s evaluation of FDA’s proposed criteria for the evaluation of radiolabeled red cell recovery trials.  Finally, Dr. Jessica Kim discussed FDA’s perspective on statistical methods in the evaluation of red blood cell products. 

The following issues were discussed before the Committee formally addressed the questions posed by FDA:

• The Committee asked for clarification on what the acceptance criteria are used to evaluate. 
• The Committee discussed the merits and limitations of studies that conclude the age of red blood cells affect the clinical outcome of patients. Several members commented that large prospective studies are needed. 
• FDA commented that the National Heart, Lung and Blood Institute has published an RFA to examine red blood cell preparation and that the HHS Advisory Committee on Blood Safety and Availability will be discussing the old blood issue at its next meeting on May 29-30, 2008.
• The Committee discussed the inherent limitations with surrogate marker studies.  One Committee member challenged FDA and the blood banking community to examine better surrogates for red blood cell recovery studies. However, it was also discussed that large scale trials are not feasible due to the time and high cost needed to conduct a trial. Further, limiting the number of subjects exposed to radioactivity is an important feature in trial design.         
• Several Committee members asked how existing products would be affected by the proposed acceptance criteria.  FDA commented that products are not de-licensed unless there are serious concerns and practitioners can make informed decisions for use of products.  Additionally, FDA was asked if novel products would be regulated with the same degree of stringency.         
• One Committee member noted that the biological variability in the studies makes it very difficult to have precise acceptance criteria.  Additionally, the member would be interested in survival studies in patients of varying ages.  FDA commented that the biological variability was considered when the current acceptance criteria were instituted.  The current criteria allow for a certain number of individual units to fail in a study. 
• Several Committee members stated that industry must demonstrate that a lower standard does not affect clinical efficacy and safety.  Others commented that while a relaxed standard may increase likelihood of product approval, a lower standard does not spark innovation or improved products over time.       
• One Committee member questioned, based on the in vivo clinical trial data, whether the acceptance criteria should be more stringent than the current FDA criteria and said prospective studies are needed to accumulate data over the next several years. 
• One committee member noted that Dr. Dumont had pointed out that there was no clinical evidence to support FDA’s current criteria.  He asked Dr. Dumont if there was any evidence to support that lowering the FDA threshold would not cause clinical harm. Dr. Dumont answered in the negative.

The Committee then addressed the following question:

1. Does the Committee agree with FDA's proposal to maintain the current criteria?

(The current criteria are: Radiolabeling studies should be performed in at least two separate centers (laboratories) with a total of 20-24 healthy donors.  The mean recovery at 24 hours for each unit should be > 75% with SD < 9%; and the one sided 95% lower confidence limit for the population proportion of successes > 70% .)

The Committee agreed with FDA’s proposal to maintain the current criteria (15 yes votes, 2 no votes).

Question 2 was not posed to the Committee since it voted affirmatively to question 1.    

Topic II:  Lev Pharmaceuticals, Inc. Clinical Trial for the Use of Human Plasma-Derived C1 Esterase Inhibitor (Cinryze) for the Prophylaxis of Hereditary Angioedema Attacks

FDA sought the advice of the Committee on whether the safety and efficacy evidence is sufficient for approval of Cinryze^TM for prophylactic treatment of hereditary angioedema (HAE).  Dr. Felice D’Agnillo introduced the topic to the Committee and provided an overview of C1 esterase inhibitor, the epidemiology and current management of hereditary angioedema, and Cinryze^TM manufacturing. 

Several individuals then presented on behalf of Lev Pharmaceuticals.  Mr. Jason Bablak provided an introduction to the Committee on Cinryze^TM and the clinical development program.  Dr. Michael Frank, of Duke University, reviewed the clinical manifestations and treatment of HAE and discussed data from a published study in his center on the use C1 inhibitor in HAE patients.  Next, Dr. Ira Kalfus presented on the Cinryze^TM clinical program.  He discussed the dosing rationale, inclusion/exclusion criteria, efficacy endpoints and adverse event summary of the double-blind, placebo controlled prophylactic treatment trial.  Dr. Paula Busse, of Mt. Sinai Medical Center, presented clinical considerations for individualized care of patients with HAE.  She discussed the variability of HAE related to type, severity and pattern and frequency of attacks and considerations for prophylactic treatment. 

Finally, Dr. Basil Golding presented FDA’s analysis of the Cinryze^TM clinical study for prophylaxis of HAE.  Dr. Golding summarized that FDA concluded Cinryze^TM has been demonstrated to be effective for prevention of HAE attacks when used for prophylaxis in persons with HAE.  Additionally, Dr. Golding discussed FDA’s conclusion that post-marketing studies may be needed to gather additional information related to the safety, dosing and immunogenicity of the product.    

The following issues were discussed before the Committee formally addressed the questions posed by FDA:

• Committee members questioned how the dosing regimen was established in the clinical trial and if the dosing changed for any patients during the trial.  Additionally, it was discussed if increased dosing would have resulted in more complete responses in some patients.  Committee members also asked if any cases of dose overload were observed.
• Committee members noted that some patients in the treatment arm experienced an increased number of attacks.
• The subjective reporting of attacks by patients in the study was discussed.  One Committee member asked if there was anything in the patient experience that would unblind the study to the patients.    
• One member stated that it would be very helpful to see the efficacy data for both arms of the trial categorized by severity of attacks.  The member noted that while the overall efficacy endpoint was met, a reduction of the number of severe attacks (those that require hospitalization or were life threatening) would be most beneficial.             
• The development of inhibitory antibody was discussed and the Committee asked if a functional antibody assay was available.  It was asked if anything is known about immunogenicity from person to person.
• The Committee asked several questions related to product administration including if a central line was required, if any tissue damage resulted from infiltration and if at home self-infusion or subcutaneous infusion was considered.         
• The Committee discussed whether the product would be indicated for prophylaxis in the pediatric population and what dosing would be considered appropriate.  
• One Committee member asked if the product would be effective in acquired angioedema and if off label use would be likely.
• Regarding safety, Committee members asked if any long term problems associated with prophylaxis have been observed in Europe.  One Committee member expressed concern that the adverse events in the study were not coded as mild, moderate or severe.           
• Members discussed other treatments for HAE.  Specifically they asked about the role of antifibrinolytic therapy and if most patients in the study were able to stop androgen therapy.     
• Committee members discussed the significance of C4 levels and questioned why the C4 levels were not measured during the study.
• The difficulty in conducting dosing studies for males and females was discussed and it was asked if data from the European experience could be helpful. 
• The Committee discussed the existing need for acute therapy for HAE.
• The Committee commented that a public/private partnership, similar to that in the Hemophilia community, may be beneficial in understanding the prevalence of HAE and conducting long term studies.   

During the Open Public Hearing, eight members from the HAE community, including patients, parents, a spouse and physician, commented on the need for prophylaxis and acute treatment for HAE attacks.  Ms. Diane Dorman, of the National Organization for Rare Disorders, commented on the need for treatment of HAE in the context of orphan drug development.  

The Committee then addressed the following questions:

1. Is the safety and efficacy evidence sufficient for approval of Cinryze^TM for prophylactic treatment of HAE?

The Committee unanimously agreed that the safety and efficacy evidence is sufficient for approval of Cinryze^TM for prophylactic treatment of HAE.

2.  If the answer to Question #1 is yes, should post-marketing studies be performed to further evaluate the following:

a) the optimal dose for prophylaxis in males and females

b) immunogenicity

c) long-term safety

The Committee commented that a registry for HAE may be valuable for long term surveillance of the patient population, including health outcomes, social parameters, cost and reimbursement of product.  Members commented that a Congressional mandate established surveillance in the Hemophilia community and an active surveillance system could benefit the HAE patient community. 

One committee member encouraged FDA to work with the sponsor to examine the existing data to determine to what extent severe attacks were prevented.  Additionally, it was recommended that post-marketing studies should be conducted to determine long-term safety (especially rare events) and optimal dosing for children, African Americans and males.  It was stated that although randomized trials would be optimal, another option could be to design a trial utilizing patients on therapy who still experienced attacks.  Another Committee member recommended harmonizing data between the U.S. and Europe to accumulate more data. 

Finally, one member suggested that home therapy options should be explored.   

Topic III:  Review of the Research Programs in the Laboratory of Hepatitis and Related Emerging Agents, Division of Emerging and Transfusion Transmitted Diseases, OBRR, CBER (Site Visit, November 8, 2007)

Dr. Carolyn Wilson provided the Committee with an introduction to CBER research programs.  She explained that research is a critical element in CBER’s approach to regulation and provided an overview of CBER’s FY08 research priorities.  Dr. Wilson then described the Managed Research Initiative at CBER and informed the Committee of the process for internal and external evaluation of individual research programs.  Next, Dr. C.D. Atreya presented an overview of the Managed Research Initiative in the Office of Blood Research and Review (OBRR).  Dr. Atreya discussed OBRR’s current research priority areas and its vision for research in support of FDA’s Critical Path Initiative.   Dr. Hira Nakahai subsequently provided the Committee with an introduction to the mission and organization of the Division of Emerging and Transfusion Transmitted Diseases (DETTD).  He discussed the impact of DETTD’s research as it relates to FDA’s regulatory mission and then reviewed the regulatory and scientific challenges related to blood safety and availability.  Next Dr. Gerardo Kaplan summarized the purpose of the site visit of November 8, 2007 and further discussed the research programs of the Laboratory of Hepatitis and Related Emerging Agents (LHREA) by providing a brief overview of each of the research programs evaluated by the site visit team, including: 

• The Hepatitis A Virus Cellular Receptor 1 (HAVCR1): Role in Viral Cell Entry and Immune Responses by Gerardo Kaplan;

• Determinants of HAV Growth and Development of Ebola Virus reagents for Diagnosis and Vaccine Evaluation by Krishnamurthy Konduru;

• Hepatitis B Virus in Blood Safety and Development of Microarray Multiplex Assay by Chieh Chu Hsia;

• In vitro and in vivo systems for the study of SARS and HCV by Deborah Taylor;

• Persistence of serum-derived HCV in interferon-deficient cells by Erica Silberstein.

Before discussing the Site Visit report in closed session, the Committee asked if LHREA coordinated with other FDA research programs focused on hepatitis and if LHREA had an established research program on Hepatitis E virus.