for the
BLOOD PRODUCTS
ADVISORY COMMITTEE
82nd Meeting – March 17-18, 2005
The
Committee listened to briefings on the recent activities of the DHHS Advisory
Committee on Blood Safety and Availability by Dr. Jerry Holmberg, and the Transmissible
Spongiform Encephalopathies Advisory Committee by Dr. David Asher. The Committee listened to an update on the
West Nile Virus Guidance by Dr. Alan Williams and a summary of the Critical Path Initiative
Workshop by Drs. Kathryn Carbone, Paul Mied, and Mary Foulkes, FDA
Topic 1. Safety of
Albumin Revisited
Dr. Laurence Landow
introduced this topic and provided the Committee with the regulatory background
for bringing this issue to the Committee.
The FDA had issued a “Dear Doctor” letter in 1998 based on the Cochrane
Injuries Group meta-analysis indicating increased mortality with the use of
albumin. The Committee then listened to
a review of the Cochrane report by Dr. Paul Hebert, Ottawa Health Research
Institute, and a review of the SAFE Study by Dr. Simon Finfer, University of
Sydney.
The
Committee discussed studies on the safety of albumin and some members expressed
concerns about the study design behind the original Cochrane report and its
limited data. Some members stated that
the analysis and conclusions of the study were flawed. Committee members stated that the SAFE study
demonstrated that there was essentially no difference between administration of
albumin and saline. The Committee
requested that more studies should be conducted, so that physicians can make
sound health care decisions on the administration of resuscitation fluids. Members stated that there was a need for
further well-designed studies investigating the risks of administering albumin
to sub groups of patients such as those with trauma and concomitant brain
injury.
During the first open public
hearing portion of the meeting the Dr. Joseph Cervia, Pall Medical, presented
information on removal of infectious prions through filtration. Dr. Joseph Latino, LipidViro Tech presented
information on inactivation of prions in biological fluids. Mr. Jan Bult, Plasma Protein Therapeutics
Association (PPTA) presented industry’s position that albumin is safe and the
FDA warnings given in the 1998 “Dear Doctor” letter are no longer needed. Dr. Gary Haynes, University of South
Carolina reviewed
evidence that albumin and saline are therapeutically equivalent as resuscitative therapy for some
subsets of patients.
The Committee voted on the
following questions:
Have the data from the
SAFE study resolved the safety concerns that were raised in the meta-analysis
by the Cochrane Group for:
a. Critically ill patients in general?
b.
Subgroups of
critically ill patients with burns, hypovloemia or hypoalbuminemia?
On part “a” of this question (Critically ill patients in general), the
Committee voted: 12 yes votes, 0 no votes, and 0 abstained. The industry representative (IR) agreed with
yes votes.
The Committee then
reworded part “b” of this question and broke it down into three separate
components.
Do currently available
data, including those from the SAFE study, resolve safety concerns raised in
the 1998 Cochrane Group meta-analysis for subgroups of:
a. Burns - The Committee voted: 0 yes votes, 11 no votes, 1 abstained with
the IR agreeing with the no votes. Several members commented that their votes
should not be taken to imply that they believed the Cochrane Group
meta-analysis had established a safety concern for use of albumin in burn
patients, given the flaws in the study.
b. Hypovolemia
- The Committee voted: 12 yes votes, 0 no votes, 0, abstained with the IR
agreeing with the yes votes
c. Hypoalbuminemia - The Committee voted: 6 yes
votes, 3 no votes, 3 abstained and the IR agreeing with the yes votes.
The Committee then listened
to an update on international agreements and harmonization by Dr. Mark
Weinstein, FDA, and an update on sharing information with the public by Kathleen Swisher,
FDA.
Topic 2. Review of Standards for Plasma Products for
Transfusion
Dr. Weinstein introduced this
topic and a presented a review of the literature. Next, Dr. Irma Szymanski,
University of Massachusetts, gave a presentation on the clinical use of
plasma.
During
the second open public hearing portion of the meeting Dr. Michael Fitzpatrick, America’s
Blood Centers presented data from surveys of their members on how plasma is
currently stored and frozen and the impact on industry if FDA were to change
the existing procedures. Kay Gregory, AABB presented their position that there
is no current problem with the efficacy of plasma for transfusion and that in
the absence of new data there should not be compelling reasons to require
changes in preparation and storage of plasma components. Mr. Joshua Penrod, PPTA stated his
association’s position that in the absence of science based evidence or a
public health concern that FDA should not implement new standards for plasma
products.
During the Committee discussion, some Committee members expressed a desire to know how efficacious each of the
plasma products are for each of their possible uses. They stated that practicing physicians should be educated in the
appropriate use of these products. They
also stated that there should be a scientific basis for the use of these
products, rather than just continuing established practice. Suggestions were made to form a task group
to recommend future research studies so the decisions on use of plasma products
would be science based. The question
was posed if it was necessary to know the desired clinical effect (or side
effects) of these products before FDA attempts to standardize them. Efforts to standardize these products will
be difficult since the starting material for plasma products is highly variable
and the product itself is different in different places. Some members supported efforts to obtain
more product consistency. Several
members noted the complexity of plasma as an obstacle to fine characterization
relevant to multiple use indications.
Members from industry stated that GMP could be used to standardize the
product. Other members suggested that
plasma products used for transfusion should have to meet certain minimal
requirements. The Committee struggled
with providing recommendations on products without a basis in science to use
for making such decisions. Several BPAC
members and members of the public stated that liquid plasma is no longer being
used and should be deleted from the regulations.
Topic 3. Study Design for Abbreviated Uniform Donor
History Questionnaire
The committee discussed the
design, and intent of the proposed study.
Dr. George Schreiber discussed the statistical difference between
studies designed to demonstrate equivalence and those to demonstrate
discordance. Committee members stated
that there will always be risks that will not be caught by any questionnaire. They discussed the diversity of donor
questionnaires currently used at different centers and encouraged development
of a better questionnaire.
During
the third open public hearing portion of the meeting PPTA supported the
implementation of an abbreviated donor history questionnaire for frequent
donors and encouraged FDA to respond favorably to AABB’s proposal for studying
the abbreviated questionnaire.
The Committee modified the
first question to read, “ Does the committee agree that the proposed study
design (exclusive of sample size) is adequate to demonstrate comparability (or
lack of comparability) between the abbreviated questionnaire and the
full-length questionnaire?
The Committee voted on the
modified question: 3 yes votes, 9 no votes, and 0 abstained. In explaining their votes the committee
members voting either yes or no, did not think that the study was adequately
powered.
Since the Committee voted
“no” on question one, they did not discuss Question 2 regarding sample size.
Question 3: If not, what alternative study design and
/or sample size does the committee propose would be adequate? Several Committee members suggested that FDA
consider allowing the questionnaire to be implemented with a post approval
study with a “stop rule” to reanalyze the study design if needed. Members also requested that consideration
be made to evaluating donor retention in this analysis. The committee requested that a cognitive
analysis of the two new capture questions on the abbreviated donor
questionnaire be performed and that a well designed post implementation study
be preformed.
Topic 4. Review of
Site Visit Report for the Laboratory of Molecular Virology, DETTD
The
Director, Division of Emerging and Transfusion Transmitted Diseases, Dr. Hira
Nakhasi, introduced the research being performed in the Laboratory. Then each
of the investigators gave a short presentation on their research. The following research summaries were
presented:
§
Diagnosis and Pathogenesis of HIV variant: a
progress report by Dr. Indira Hewlett, Chief, Laboratory of Molecular Virology
In
closed session the Committee discussed the site visit report on the above
research programs.
This
summary is provided as an unofficial overview of committee discussions. Please refer to the meeting transcripts for
a detailed account of the meeting.