FDA Liaison Meeting

Advanced

Home

Members Area

About AABB

Join AABB

Accreditation

About Blood and Cellular Therapies

Donate Blood

Programs and Services

Professional Development

Bookstore

Newsletters and Journal

Meetings and Events

News and Media

FDA Liaison Meeting - 3/11/08

On March 11, 2008, Food and Drug Administration staff met with AABB’s FDA Liaison Committee in Bethesda, Md., to discuss topics of mutual concern in the areas of donor and patient safety. The committee includes liaisons from AABB, the American Red Cross, America’s Blood Centers, Advanced Medical Technology Association (AdvaMed), the College of American Pathologists and the U.S. Department of Defense.

Current FDA Priorities and Initiatives

FDA indicated that it is focusing on a number of priorities and initiatives in 2008.

One of the priorities identified by the agency during the meeting was implementation of the FDA Amendments Act of 2007 (FDAAA). FDAAA, which was enacted through congressional legislation on Sept. 27, 2007, is made up of 11 provisions that amend the Food, Drug and Cosmetics Act. Some of the 11 provisions affect blood and blood products and were reviewed by FDA. While blood products are not covered by user fees, it was noted that reauthorization of Prescription Drug User Fee Amendments has resulted in funding for 35 new FTEs for CBER. Medical Device User Fee Amendments reauthorizes device fees for FY 2008-FY 2012 and requires electronic device registration and listing along with unique device identification systems. In addition, interactive reviews are an option when secure e-mail systems can be used; authorization certificates have to be exchanged between FDA and the sponsor when the file is opened. The Pediatric Medical Device Safety and Improvement Act is not triggered by biologics license applications, but the Pediatric Research Equity Act (PREA) does apply to new drugs and biologics. Pediatric studies are required under PREA when submitting an application or supplement for a new active ingredient, indication, dosage form, dosing regimen or route of administration. In addition, applicants must assess safety and effectiveness for the indication in relevant pediatric populations using age-appropriate formulations. Previously, PREA has been applied to plasma derivatives, and it is not entirely clear what the impact would be on new products such as pathogen reduction processes. The Clinical Trial Database is an expansion of the clinical trial registry, which would impact all trials that are beyond Phase I, and has requirements for basic and expanded results databases. A current requirement of this provision of the FDAAA is that every regulatory submission to FDA must have a Form FDA 3674 (Certification Form) appended. This may change in the near future as a technical amendment has been submitted by CBER seeking to clarify the requirements for use of the certification form.

Continuation of Critical Path Initiative progress also was identified as a main concern for FDA this year. The Office of Blood Research and Review uses research to address scientific issues that are critical to regulation. Priority research areas include the following:

· Novel methods of pathogen reduction and inactivation in blood and blood products.

· Multiplex platforms and high-sensitivity methods for pathogen detection, including genetic variants, emerging infectious disease (EID) and bioterrorism (BT) agents.

· Development of infectious agent panels for assay standardization, and standards and reagents for product lot release testing.

· Development and evaluation of proteomics- and genomics-based biomarkers for efficacy, quality, toxicity and consistency of blood components, blood derived products, and their analogues, including blood substitutes.

· Development of predictive models for preclinical evaluation of blood components, blood derivatives and their analogues, including blood substitutes, and to study pathogenesis of blood-borne EID agents.

· Development of methods to evaluate efficacy of immune globulins of pandemic and BT importance.

FDA is working with the blood community on a number of other initiatives in 2008. The safety of hemoglobin-based oxygen carriers (HBOCs) will be discussed at a workshop to be held April 29-30 on the NIH campus. The agency also is collaborating with ABC, AABB, AdvaMed, Alliance of Blood Operators and ARC on a workshop titled “Regulation of Blood Establishment Computer Software (BECS): Future Directions,” which will focus on industry and FDA concerns; a specific location for this event has not been determined, but it is expected to be held July 10-11 in the Washington, D.C., area. A one-day workshop on babesia is planned for Sept. 12.

AABB Initiatives and Current Priorities

AABB President Dan Connor reminded FDA that blood centers are still concerned about their ability to be health care entities as well as distributors of blood derivatives. Joint comments from the blood community were submitted to a proposed rule issued in February 2006 asking that the exemption contained in the proposed rule — to allow registered blood establishments that qualify as health care entities to distribute blood derivatives — be broadened to include any product “used in transfusion medicine and cellular and related biological therapies (e.g., recombinants).” The final rule has not yet been issued, and the current postponement expires Dec. 1, 2008. FDA acknowledged the importance of this issue to the blood community and said that it has priority within the agency.

FDA policy on blood donations from men who have had sex with other men (MSM) was raised as an issue again in light of the recent decision by the president of San Jose State University in California to suspend all blood drives on campus. The stimulus for this action was the requirement of a lifetime deferral for men who have had sex with another man even once since 1977 — a policy the university considers discriminatory. The university’s action generated considerable publicity locally and nationally, and has caused concern among blood collectors who fear that more widespread adoption of this policy by other institutions could have a negative impact on blood collection. FDA responded that transfusion-transmitted diseases risks such as HIV and hepatitis B are notably higher in this population of potential donors, and the agency continues to be concerned about increased risk to patient safety with a change in the deferral policy. Donor questioning and screening tests have improved, but the possibility of an erroneous release of a product from an infected donor is a serious consideration for the FDA. A change to the policy should be science-based, according to the FDA. FDA noted one study under way looking at an option for a five-year deferral with subsequent negative viral marker tests and indicated that it would welcome data to support such a change. Other potential mitigations suggested by FDA include additional prescreening of the donor, universal adoption of validated software to prevent erroneous releases of positive units and pathogen inactivation of blood components. Committee members noted that information currently posted on the agency’s Web site does not explain the basis for the deferral policy and why it is much more stringent than other similar risks, such as sex with someone who is positive for HIV. Blood collectors are left to try and interpret the policy to a number of public audiences, including media, prospective donor groups, and institutions and agencies that are reviewing their own positions on discrimination and donation. FDA was asked to revise public information materials on the MSM policy so that its scientific basis and rationale are clear and accessible to all.

NOTE: AABB, ABC and ARC issued a joint statement at the Blood Products Advisory Committee in March 2006 indicating that they believe the current lifetime deferral for men who have had sex with other men is medically and scientifically unwarranted. They recommended that deferral criteria be modified and made comparable with criteria for other groups at increased risk for sexual transmission of transfusion-transmitted infections. Read the complete statement,

The AABB Interorganizational Task Force on Pandemic Influenza and the Blood Supply has provided a letter and draft variance to FDA for a request to modify the interdonation interval in the event of a pandemic. FDA responded that they received the variance, and it is currently under active consideration; however, an issue still to be explored is when to “trigger” such an event. It was also noted that the blood organizations (ABC, ARC and BCA) are coordinating inventory data through AABB and reporting to HHS on a weekly basis.

FDA was provided with an update from AABB on the U.S. Biovigilance Network. The network was identified as a priority in AABB’s 2007 strategic plan and is being developed through a public-private partnership with CDC. AABB is in the first phase of the program and gearing up to begin pilot/beta trials in 2008. FDA asked if the system could include regulatory reporting and was informed that, although the network could be adapted for this purpose, it will not be the initial focus of the system.

The blood community is concerned with many of the proposals for donor eligibility and donation suitability contained in “Requirements for Human Blood and Blood Components Intended for Transfusion or for Further manufacturing Use; Proposed Rule” that was published November 2007. AABB has formed working groups to address the many proposals and requests for data. A number of concerns were highlighted for FDA:

· Several issues are out of step with the donor history questionnaire that recently has been accepted by the FDA through a guidance document.

o Questions about dental treatment and whether a health care practitioner has advised the donor not to donate have been determined to be of little value.

o Specific questions concerning major surgery and weight loss are not necessary; relevant information would be captured by other questions.

o As proposed, intimate contact covering any saliva exchange, include kissing, would be too restrictive without any apparent benefit.

o A requirement to review the donor’s medications implies that all medications taken by a donor must be documented, as opposed to the specific medications recommended for evaluation by the FDA that are contained on the DHQ Medication Deferral List.

· Requiring a single donor deferral registry for all establishments under the same license or use of a national system is not feasible. Compliance with this proposal would require establishments to have real-time access to the database at all collection sites. This is impossible on a national basis because all blood center computer systems do not communicate with each other.

· The blood community continues to believe that an upper and lower limit for blood pressure and pulse is not necessary. However, if upper and lower limits are to be set, they should be determined by each establishment and not by regulation.

· Creutzfeldt-Jakob disease is listed as a relevant transfusion-transmitted infection even though it has not been transmitted by transfusion.

· Proposed CFR language for “other factors” that make a donor ineligible to donate — covered in 630.10(g)(4) — implies that a donor who travels to a country endemic for almost any infection deemed potentially transmissible by blood would be ineligible.

· Proposed language for determining donation suitability would require holding a platelet product at the blood center until a negative bacterial test result is achieved, rather than the currently accepted result of “negative to date.”

· The proposed supplemental and confirmatory testing and re-entry algorithms do not adequately address the needs for donor counseling and re-entry.

· The broad deferral for history of hepatitis after age 11 was not removed.

· Concurrent plasma for use in further manufacturing was not included.

Discussion of Agenda Items

Bacterial Contamination Testing of Platelets: From a technical perspective, automated bacterial culture tests can only provide a result that is known to be negative at the time of issue of the product — a result that does not necessarily assure sterility for the remaining shelf life of the component. From a regulatory perspective, FDA has presented a framework for the approval of tests intended to be used to issue a bacterially safe product. According to the committee, the requirements for such approval appear to be unduly burdensome and perhaps not even achievable, particularly for point-of-use methods. The committee asked if FDA could clarify the ways in which it would expect to see bacterially safe platelet products provided for patient use.

Approval of a bacterial detection device with quality control claim is based on in vitro testing that does not answer questions regarding clinical sensitivity, specificity and predictive value of the test. In comparison, approval for a bacterial detection device with a release test claim would include all the requirements of a QC test and clinical studies to determine sensitivity, specificity and predictive value of the test. One test with a QC claim has been approved for point-of-use with apheresis platelets as an adjunct to culture-based testing. FDA understands that the blood community wants a stand-alone point-of-use test for products such as whole blood-derived platelets that are not so easily tested with a culture-based test system. FDA indicated its willingness to work with sponsors to design appropriate trials for approval.

Seven-Day Apheresis Platelets: The committee requested an update on FDA’s current considerations for seven-day apheresis platelets. The PASSPORT study was designed and sponsored by Gambro with FDA input and later co-sponsored with Fenwal. The post-market study was designed to validate clinical performance of BacT/ALERT when used to extend shelf life of platelets to seven days. Based on analysis of early data from the study, the sponsors (Gambro and Fenwal), with the support of FDA, decided to terminate the study. The study was stopped with a phaseout period of 28 days. The early termination of the PASSPORT study caught many collection centers that relied on seven-day platelets for inventory management by surprise. Major concerns expressed by PASSPORT participants revolved around avoidance of acute platelet shortages and insufficient time to convert to five-day platelets while remaining in compliance with GMP requirements. In response to these concerns, Gambro requested an extension of the phaseout period for 90 days, Fenwal followed and the FDA did not object. (The new phaseout date is April 26, 2008.) FDA will work with sponsors and AABB to redesign the study with additional safeguards to reduce and document the septic and contamination rates of seven-day platelets.

Pathogen Reduction: The committee asked FDA how they prioritize their activities related to the development of tests for emerging infectious diseases and pathogen reduction of blood components. OBRR programs are more invested right now in detection technologies because they are funded by bioterrorism initiatives, e.g., nanotechnology and multiplex assays. Pathogen reduction technologies had more activity within the agency approximately 15 years ago and are dependent at this time on funding and recruitment of appropriate expertise. There was general agreement that inadequate reimbursement, to some degree, results in a weak business case for the development of additional testing and new technologies.

Nonconforming Materials: Collection facilities have internal processes for the review of nonconforming materials, including blood products, testing services and reagents, by qualified personnel. The personnel follow detailed SOPs and have the authority and responsibility to ensure adequacy of the investigation, determine the nonconformance, evaluate product scope and impact, and determine disposition of the materials in question. The evaluation and decision are documented, and the file is available to FDA investigators at the time of their inspections. However, facilities have received conflicting messages about the process — in some cases, the message is that every nonconformance must be reported to FDA, and disposition needs to include a request for a variance, while in other cases a thorough review by designated facility personnel is acceptable, and product release could occur if the nonconformance is determined not to affect the safety, purity and potency of the product. Timelines can be critical (e.g., platelet products collected on Friday evening at the beginning of a holiday weekend). The committee inquired about instructions given to field investigators to evaluate these decisions.

FDA acknowledged the importance of having qualified blood establishment personnel make decisions on how to handle nonconformances. Furthermore, the committee was reminded that good manufacturing practices require a process for performing the evaluation on a routine basis and in case of emergencies, with an emphasis on documentation of the rationale and decision. Field investigators are expected to review the files. The Inspectors Operations Manual (IOM), specifically chapter five, was mentioned as a resource for these types of situations. (This document is available to the public on the FDA Web site.) If trends that indicate noncompliance with GMPs are observed, these may appear as 483 observations, and the facility has an opportunity to respond with additional information supporting the process that was used and the decision that was made. When a facility has a recurring process that is not in agreement with the regulations, it is recommended that a pro-active request for an alternate procedure be submitted to the FDA in accordance with 21 CFR 640.120.

HIV Group O: A recently issued guidance, which was quickly withdrawn, allowed the discontinuation of donor history questions when a serological assay for antibodies to HIV-1/2 with a claim for detection of HIV-1 group O is implemented. The guidance recommended a re-entry algorithm for individuals who had indicated at prior donations that they were born in specified risk countries, or lived with or had sexual contact with someone considered at risk. However, there is no apparent difference in risk of exposure between donors who were asked the questions and were deferred and donors who have never been asked the questions. Considering the extremely low risk represented by HIV-1 group O in the U.S., the committee inquired if FDA would consider reissuing the guidance without a requirement for re-entry testing other than application of a screening assay with a HIV-1 group O claim at the time of donation. Donors that are deferred because of the questions would be eligible to donate when the collecting facility implements an HIV-1/2 screening assay with a claim for detection of HIV-1 group O. FDA responded that the guidance, “Recommendations for Management of Donors at Increased Risk for Human Immunodeficiency Virus Type 1 (HIV-1) Group O Infection,” was published on Dec. 10, 2007, and was withdrawn shortly thereafter. This Level II guidance for immediate implementation did three things: 1) Updated the list of countries to include Senegal, Togo and Zambia and clarified that the Democratic Republic of Congo, formerly Zaire, has not had an HIV-1 group O case identified, as opposed to the country of Congo, which has had cases; 2) Explained the discontinuation of West Africa exposure questions upon implementation of a licensed HIV 1/2 group O screening assay; and 3) Allowed re-entry of donors previously deferred on the basis of a response to HIV-1 group O risk questions using a one-year follow-up sample that tested nonreactive on a licensed HIV-1/2 Group O test and nonreactive on a licensed individual donation HIV-1 NAT. The guidance was withdrawn because: 1) For sites that had implemented HIV-1/2 group O testing, the recommendation for a one-year delay and use of HIV-1 NAT on pre-donation re-entry sample (to rule out window period infection) is inconsistent with treatment of donors who are not asked the West Africa exposure questions; 2) Individual donation HIV-1 NAT is not licensed for group O detection and is not approved for HIV-1/2 reentry; 3) There is no rationale provided for recommended re-entry testing; and 4) An attempt to prevent HIV-1 group O window period infection by NAT testing was unnecessary due to one-year malaria deferral. Currently, the revised HIV-1/2 group O country list has been incorporated into AABB’s donor history questionnaire (v1.3) that is under FDA review. The discontinuation of the Africa questions when an establishment implements an FDA-licensed HIV 1/2 assay that detects group O is occurring as evidenced by FDA’s approval of variance requests and annual reports submitted by blood establishments. Establishments are actively requesting re-entry protocols via CBE-30 supplements, which are granted on a case-by-case basis. The re-entry request is based on nonreactive results to an HIV-1/2 group O EIA on a pre-donation sample. The topic of re-entry without having to perform off-line testing was discussed. The point was made that if an establishment utilizes an FDA-licensed HIV 1/2 assay that detects group O, there is no benefit to require off-line testing of donors because they have been concurrently deferred for one year due to malaria risk. FDA indicated that it heard the concern and would consider such an option.

Plasma Inventories: Blood centers seek the same flexibility in managing apheresis-derived plasma inventories for transfusion and manufacturing that they have with manual collections. Blood centers are making changes in their plasma inventories in an effort to mitigate the risk of TRALI in transfusion recipients, a complicated issue at best that has been further complicated by the lack of options for using plasma collected with automated platforms. AABB’s interorganizational task force has submitted a proposal to FDA for licensure of plasma for further manufacture (collected via manual or automated methods) and requested that changes to the regulations be initiated to make this a reality. In a previous FDA liaison meeting on Oct. 4, 2007, FDA explained the process the agency is considering to respond to the need for a regulatory pathway for the one-way conversion of apheresis FFP (prior to expiration) to a licensed, concurrently collected plasma product for further manufacture. FDA is considering the standards for the new plasma product and is working on a framework for the necessary regulatory revisions. While the new regulations are under development, FDA could consider the use of variances to existing regulations, providing an interim regulatory pathway for conversion of apheresis FFP to concurrent plasma for further manufacture. Any such pathway would be made publicly available through issuance of a guidance document. The committee requested an updated status on this initiative. FDA explained that this is an area of very active work within the agency, and there is the potential to review the strategy at a future BPAC meeting, although nothing has been planned as of yet.

Circular of Information: The proposed Circular of Information for the Use of Human Blood and Blood Components was submitted to FDA in August 2007 for review and approval. This revision would replace the one approved in 2002 and currently in use. FDA review comments were recently forwarded to the Circular of Information Task Force. FDA liaisons and the task force will discuss additional revisions and move forward with a final version.

Donor History Questionnaire: Version 1.1 of the full-length Donor History Questionnaire materials has been officially recognized by FDA. Version 1.2, to include deferral for transfusion in France, was submitted in April 2007 to the docket for “Draft Guidance for Industry: Amendment (Donor Deferral for Transfusion in France Since 1980) to ‘Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products’ – August 2006.” (The guidance document has not been finalized.) The latest version of the DHQ (v 1.3) was submitted to FDA in March 2008 for review. FDA provided an overview of all the revisions to the DHQ since version 1.1 was officially recognized and noted that recognition of version 1.3 is linked to the release of the amended guidance document on vCJD, which is currently in process.

Abbreviated Donor History Questionnaire: FDA was asked to provide an update on FDA’s current consideration of the aDHQ and publication of a guidance document officially acknowledging the aDHQ. FDA’s longtime interest in a properly validated aDHQ was noted. The three capture questions on the aDHQ adequately solicit the required donor’s history information (the three capture questions replace 17 questions from the full-length DHQ); however, FDA considers collection of post-implementation data to be a necessary part of implementing the aDHQ. Guidance recognizing the acceptability of the aDHQ has been initiated. FDA has reviewed the latest revision to the post-implementation study and has deemed it appropriate, with a few comments: 1) All blood centers that implement the aDHQ should be encouraged to contribute data to the study (beyond the five facilities listed in the protocol); 2) Predefined stopping criteria for the study need to be added; and 3) There should be agreement for the type of data that will be shared with the FDA. FDA is interested in having the full-length DHQ administered to any donor who consecutively uses the aDHQ for three years.

West Nile Virus: An update was requested on current considerations related to recommendations for WNV testing of blood donors. The West Nile Virus guidance is undergoing internal review at FDA and it is close to being completed. FDA thanked the AABB WNV Task Force for its interactive oversight and especially the ARC for validation of the trigger criteria used during the last WNV season. Data from the validation will be used to update the AABB Association Bulletin regarding trigger criteria that are used to implement individual donation testing.

Chagas’ Disease: FDA considers development of a draft Chagas’ disease guidance document for testing of blood donors a priority and anticipates a draft to be released in the near future. Considerations for selective screening have not changed from what has been discussed publicly at BPAC. Data to support selective screening strategies may be generated from current testing strategies. If so, FDA would welcome a public discussion of the data.

vCJD: FDA performs regular review of issues related to vCJD and blood donation — approximately every six months with the Centers for Disease Control and Prevention. CDC recently revised its Web content on CJD/vCJD, changing the main focus to food safety rather than blood safety. The 2006 draft guidance document — focused on vCJD transmission in France — has undergone some revisions and is currently in internal review.