2014 Ask the FDA and CLIA Transcript

Ask the FDA and CMS/CLIA
October 27, 2014
AABB 2014 Annual Meeting
Philadelphia, PA


  • JAY EPSTEIN, MD – Director, Office of Blood Research and Review, (OBRR), Center for Biologics Evaluation and Research (CBER)
  • ELLEN LAZARUS, MD, CAPT, USPHS – Director, Division of Human Tissues, Office of Cellular, Tissue and Gene Therapies, CBER
  • ALAN WILLIAMS, PHD – Associate Director for Regulatory Affairs, OBRR
  • PAUL MINTZ, MD – Director, Division of Hematology Clinical Review, OBRR
  • PAUL MIED, PhD – Deputy Director, Division of Emerging and Transfusion Transmitted Diseases, OBRR
  • ORIEJI ILLOH, MD – Deputy Director, Division of Blood Components and Devices (DBCD), OBRR
  • JENNIFER JONES, MBA, CMQ/OE(ASQ) – CSO, Blood and Plasma Branch, DBCD
  • TERESITA MERCADO – Chief, Devices Review Branch (DRB), DBCD
  • DARCEL BIGELOW – Consumer Safety Officer (CSO), DRB


  • PENELOPE MEYERS, MA, MT(ASCP)SBB – Technical Director, Division of Laboratory Services, Survey & Certification Group, Center for Medicaid & State Operations, Center for Medicare and Medicaid Services (CMS)
  • DARALYN HASSAN, MS, MT(ASCP) – Division of Laboratory Services, Survey & Certification Group, Center for Medicaid & State Operations at CMS


  • M. ALLENE CARR-GREER, MT(ASCP)SBB – Director, Regulatory Affairs, AABB

MODERATOR: Good afternoon. My name is Allene Carr-Greer, I am the Director of Regulatory Affairs for AABB.

DR. EPSTEIN: Thank you very much Allene. It is a pleasure to be here again this year. Of course last year was a little disruptive with a budgetary crisis in the federal government. This is of course a collaborative effort between FDA and CMS. FDA is represented here by several different groups – my own Office of Blood Research and Review, the Office of Cellular, Tissue, and Gene Therapies, and the District Office for Philadelphia Office of Regulatory Affairs.

MODERATOR: Thank you. And I would also like to introduce Anne Johnson who is the Acting District Director in the Philadelphia office out of the Office of Regulatory Affairs, FDA. Anne did not draw a question in this year's session, however she is here, and if any of you would like to come meet her or have questions you would normally direct to the Office of Regulatory Affairs she is available after today's session. Thank you, Anne.

Also, several of you directed questions to the office of CMS, CLIA regulations. Penny Meyers and Daralyn Hassan did not get cleared to travel, however they have provided responses to your questions and I will provide the responses as we roll through those questions.

Question 1: Our blood collection facility has an alternative procedure approval to 21 CFR 640.3(d) to distribute ONLY the Red Blood Cells collected from individuals on prescription testosterone. It lists the following condition: "Plasma and platelet components prepared from Whole Blood collections or collected during apheresis procedures from these donors should NOT be distributed for transfusion."

We asked for a clarification concerning donors who are on topical versus injectable and long-time platelet donors who are not "seeking" phlebotomy to reduce their red cell mass. The response from the FDA was: "The alternative procedure approval requires you collect ONLY red blood cells from any donor who provides the information that they are on prescription testosterone. If the donors are on testosterone, platelet and plasma products from these donors should NOT be distributed for transfusions."

In order to prevent the manufacture and distribution of any plasma product from a donor on testosterone therapy we elected to add Testosterone to the end of our Medications Deferral List. Our logic is if we don't ask the donor if they are on testosterone therapy we may not obtain the information from them especially if they are on topical or oral form of treatment. If other blood centers either don't have the alternative procedure approval or don't specifically ask them about testosterone therapy they are most likely routinely collecting and distributing plasma and platelet products from these donors.

Is the FDA considering a Guidance Document in the future to address these inconsistencies?

DR. ILLOH – I will take this one. I recognize the confusion concerning this topic, and it took us awhile to really try to dissect the topic and come up with what we will be granting variances to. What I would like to do today to clarify the scope of our alternative procedure approvals for 640.3(d). This approval is to distribute red cells collected from individuals on prescription testosterone only. Basically, 21 CFR 640.3(d) states for therapeutic bleedings, "Blood withdrawn in order to promote the health of the donor otherwise qualified under provisions of this section, shall not be used as a source of whole blood unless a container label conspicuously indicates the donor's disease that necessitated withdrawal of blood." So typically if you collect blood from a person who presents for therapeutic phlebotomy you would have to put the person's disease on the label. This variance – this alternative procedure to 21 CFR 640.3(d) - in this case applies to a donor who is on testosterone and who is having blood withdrawn in order to promote their health. In other words, they have been advised by their doctor to have blood withdrawn to promote their health. Typically, these are donors who have developed secondary polycythemia due to testosterone therapy. The variance allows you to distribute their units without labeling it with the donor's disease. That is the clarification of the regulation.

Now, I will explain briefly why we have limited it for now to red cells. We have limited it to red blood cells only because the plasma testosterone levels in these men with testosterone-induced polycythemia who are presenting for donation have not been studied. In other words, it is not clear whether they have normal testosterone levels or whether their testosterone levels are high. There is just no data available at this time to inform us on this issue. We do know that testosterone at high levels could affect some select patient populations, for example, female neonates who may receive multiple transfusions from the same donor. So we decided to limit the collections from such people to red cells only at this time until we get additional data to clarify this concern.

For those donors who are not presenting to have blood [drawn] in order to promote their health, but are on testosterone medications, FDA has not recommended questioning such donors or restricting components collected from these donors. We advise individual blood centers to consult with their medical directors and come up with decisions they would like to make concerning these scenarios.

We do recognize that there – if I can put it this way – [are] probably two different scenarios and some confusion sometimes, but I want to emphasize that our variance approvals is limited to donors who present to promote their health – basically they are on testosterone, they are polycythemic, and their doctors have advised them to have blood withdrawn to promote their health. If you need further clarification, feel free to contact FDA or your CSO [Consumer Safety Officer] to provide additional information.

MODERATOR: Thank you Orieji. So the variance is all about the donor who presents with a prescription for therapeutic phlebotomy because of polycythemia from the prescribed testosterone.

DR. ILLOH: Correct.

MODERATOR: Thank you. And so for all other questions that need clarification, a phone call back to FDA should help.

Question 2: Qualifications of a Technical Consultant vs a General Supervisor under CLIA, subpart M: moderate/high complexity testing

  1. Scenario 1: The blood center product QC lab performs white blood cell, hematocrit, and platelet counts on a Sysmex analyzer. This testing is considered moderate under CLIA. The manager of the department holds an Associate degree and certification as an MLT with over 25 years of experience performing this testing AND has been a General Supervisor in a high complexity laboratory prior to Sept 1, 1992. Yet - under moderate complexity testing - this supervisor would NOT qualify as a Technical Consultant (no bachelor's degree) and could not be delegated responsibility from the CLIA Lab Director for tasks related to competency such as direct observation of staff, result review, etc. However - in the area of high complexity - this individual WOULD qualify as a General Supervisor using 493.1461(c)(5) due to having served as a General Supervisor of a high complexity lab on or before Sept 1, 1992. How can a facility satisfy the CLIA requirements and qualify individuals such as this to be Technical Consultants?

CMS: Blood product QC testing is not generally subject to CLIA, and therefore the CLIA personnel requirements do not apply. A Survey and Certification (S&C) policy memo was issued that addresses CLIA applicability for laboratory testing associated with blood, cells, tissues, and organs. The link to S&C Letter 11-08 is: http://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/Downloads/SCLetter11_08.pdf.

If the Product QC Lab is performing any additional testing that is subject to CLIA, then the facility must have someone who meets the TC requirements to perform competency assessments.

  1. Scenario 2: Platelet counts performed prior to/concurrently with collection are used in the algorithm on automated collection instruments to determine the volume and estimate time of Pheresis Platelets collections. The counts are performed on testing equipment such as CellDyn counters and the test is considered moderate complexity testing under CLIA. Based on our understanding of the CLIA regulations regarding delegation of CLIA competency tasks, facilities must have an individual who has, at minimum, a bachelor's degree and 1 year of experience with the testing. However, we also believe that it is not uncommon for automated collection departments to be managed by RNs who do not have bachelor degrees. These individuals have many years of experience managing the collection areas and also performing the cell counts. How can facilities satisfy the CLIA requirements and qualify such department manager RNs to be a delegate of the CLIA Lab Director as it relates to the tasks for competency such as direct observation, etc.?

CMS: For moderate complexity testing, the facility must have personnel who meet the TC qualifications. According to 42 CFR §493.1411(b)(4)(i)(ii), the minimum qualifications for TC are a bachelor's degree in an applicable science and 2 years' experience. The personnel who meet the TC qualifications are eligible to perform competency assessments; they do not have to be identified as the TC. If the facility is accredited, it must meet the accreditation organization's requirements for competency assessment.

Question 3: The 2007 FDA Guidance document states: "the interval between collection of a double or triple Platelets, Pheresis should be at least 7 days." Does that interval include the day of collection? For example, if a donor donates a double Apheresis Platelets on Monday the 7th, are they eligible to donate again on Monday the 14th or are they required to wait until Tuesday the 15th? This is assuming they have not donated any other concurrent products during that timeframe and are otherwise eligible.

MS. JONES: We interpret the policy to mean the day of collection is considered to be Day 0. In the example provided in the question, if the donor donated on Monday the 7th, they would then be eligible to donate again on Monday the 14th.

MODERATOR: Thank you Jennifer.

Question 4: How long should the deferral period be for a donor of Apheresis Platelets if the collection is intended to be a single unit with a target yield of 5.0 (using a historical platelet count), yet during processing the collection is split into 2 products based on acceptable volume and platelet count? Should the donor be deferred for an interval of seven days because you have actually collected a double product?

MS. JONES: Yes, in this case the donor should be deferred for seven days since you collected a double product.

MODERATOR: Thank you.

Question 5: CLIA regulations require laboratory personnel to undergo annual competency assessment using six specified elements. Is it required that all six elements of competency be performed each year or can you choose to use different ones each year and rotate them?

CMS: Each year, all six elements must be included for personnel performing testing for all tests performed.

Question 6: Timing of competency Assessments –When is the six-month competency due? Is it six months after the employee's start date or six months from the end of training/training competency? This assumes that the trainee is testing patients' samples during training, while being taught and observed by the trainer.

CMS: The regulation requires testing at least semiannually during the first year the individual tests patient specimens. The laboratory must follow its own policy for determining when the year begins.

Question 7: Competency algorithms for transfusion services that employ tube, gel and solid phase methods are complex, even before the employ mix is factored in. To accomplish what the regulations require one must keep a running log of tests/methods versus staff members versus date of completion of training for each test/method. It seems to me that CMS/CLIA has a renewed focus on this issue and I would be interested to hear any and all concrete suggestions for meeting these complex requirements.

CMS: Because the size and complexity of laboratories varies so greatly, the Technical Supervisor or Technical Consultant must determine the optimal approach for tracking competency assessment in their facilities. CMS offers the following suggestions for competency assessment:

  • Competency assessment can be done throughout the entire year. The laboratory may coordinate the competency assessment with its routine practices and procedures to minimize impact on workload.
  • PT performance may be used as part of competency assessment; however use of PT performance alone is not sufficient to meet all six required procedures.
  • In general, competency testing for all tests performed simultaneously on the same testing platform may be combined. However, any test with unique aspects, problems or procedures within the same testing platform should be assessed separately to ensure that staff maintain their competency to report test results promptly, accurately and proficiently.

Question 8: Regarding the June 20, 2014, "Draft Guidance for Industry and Food and Drug Administration Staff: Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices" issued by CDRH.

If the recommendations are finalized as drafted such that "…the Agency does not intend to enforce compliance with the regulatory controls that apply to MDDS…"

  1. Would it mean that CBER would not enforce compliance with the regulatory controls that apply to software that meets the definition of MDDS?
  2. Similarly, would blood centers cease to need to register with the FDA if they ‘manufacture' a MDDS?
  3. If the blood center has already registered with the FDA as a MDDS 'manufacturer' – what action should the blood center take (i.e. withdraw their request/registration)?

MS. BIGELOW: This question focuses on MDDS, but it does not identify the specific software device that the questioner considers to be an MDDS. In the past, FDA has received questions regarding Blood Establishment Computer Software (BECS and BECS Accessories) – specifically, whether BECS Accessories are MDDS. FDA believes that BECS Accessories that control or alter the functions or parameters of the BECS are not MDDS. BECS and BECS Accessories are currently subject to the Premarket Notification provisions of the Federal Food, Drug, and Cosmetic Act, and on December 3, 2014, the Blood Products Advisory Committee [BPAC] will convene to discuss the appropriate classification of BECS and BECS Accessories.

MODERATOR: Darcel, you looked at this question and are just responding to each of these bullets as being a BECS or BECS Accessories.

MS. BIGELOW: Basically we do not have the software device identified that the questioner is considering an MDDS. In order to answer the question, I would like to know what they are considering an MDDS in relation to the BECS or BECS Accessory.

MODERATOR: And all I have here is their statement that it meets the definition of MDDS, so I cannot go farther than that.

DR. EPSTEIN: Yes, if their software meets the definition of MDDS, then the paradigm of the draft guidance, when finalized, and if finalized as drafted, would apply. So that is not the thing in question. The thing in question is what BECS or BECS accessories do or do not meet that definition, and that will be the subject of our discussion at the BPAC along with a classification exercise.

MODERATOR: Thank you.

Question 9: According to package inserts, Dextran is required for thawing and reconstituting frozen cord blood products prior to infusion. Dextran has been in a shortage status since June 2013. Cord blood product manufacturers are in various stages of evaluating substitute solutions. In the interim, how should cord blood manufacturers advise customers to prepare these products?

DR. LAZARUS: I will answer this one. So our understanding is that there is Dextran available despite the shortage, and also that a manufacturer of Dextran is working to release additional Dextran lots. This question is relating to cord blood products that are under IND or that are approved biologic drugs because those are the ones that have package inserts. If the cord blood banks have specific questions about the use of Dextran for the manufacture of their product, or their instructions for administrations of their products, then they should contact CBER. They can contact the regulatory project management branch in the Office of Cellular, Tissue and Gene Therapies and discuss their questions about the use of Dextran.

MODERATOR: Thank you, Ellen.

Question 10: Licensed cord blood manufacturers may not inherently recognize when a change made to a process requires a supplement. While it's fairly clear that a final product container, excipient reagent or processing method require supplements, other changes such as analyzers that characterize product potency or modifications to instructions in the package insert (such as a Dextran substitute) may not be as clear. Is it possible to develop a list of critical changes or items that in every case require a supplement and others that would not be considered critical and therefore not require a supplement?

When a supplement is required, manufacturers acknowledge that they cannot implement a new method until the BLA supplement is approved by the agency. What is the estimated time it takes to get approval? This is a new area for cord blood manufacturers who may desire innovation, and planning for such improvements is critical.

DR. LAZARUS: Changes to an approved biologics license must be reported to the FDA and the relevant regulation is in 21 CFR 601.12. The changes are reported by submitting supplements to the license application. So the questioner asks about what types of changes require reporting. Those include changes to the product, production process, quality controls, equipment, facilities, responsible personnel, or changes to the labeling that was established in the approved license application. So that would include certain changes to the package insert. There are different reporting categories, as the questioner alludes to, for different types of changes. Each of those categories has a corresponding review clock, to put it in shorthand, a different length of time that the agency takes to review those supplements and respond to them. Rather than go through them all, I suggest you refer to the regulation, 601.12, to give you all that information, and if you still have specific questions about this or about a particular change that you intend to make to your product, then you can contact the OCTGT, the Regulatory Project Management branch, talk to your regulatory project manager, and that person can give you specific information.

MODERATOR: Thank you.

Question 11: It seems that not all CLIA deemed accrediting bodies for laboratories are consistent in their approach or focus on the CLIA regulations - especially as it relates to the six elements of competency. Can the CMS/CLIA representative on the panel comment about this inconsistency?

CMS: In order to be granted deemed status under CLIA, accreditation organizations are required to have standards for laboratories that are equal to or more stringent than CLIA condition-level requirements. It is not necessary that the standards be worded or organized in the same manner as CLIA regulations (see the definition of "Equivalency" under 42 CFR 493.2). If an organization has requirements that are more stringent than CLIA, then those requirements may be different from another organization's requirements. Finally, some laboratories, particularly transfusion services, may be accredited by more than one accreditation organization. In those situations, the accreditation organization selected by the laboratory as its "CLIA provider" is the one that is responsible for those laboratories' regulatory compliance.

Question 12: Our lab currently processes platelet bacterial cultures for the local blood services using a blood culture system that is FDA cleared for quality control testing of apheresis platelets (BacT/ALERT). Our lab would like to change to a different blood culture system. It does not have the label indication for quality control testing of Apheresis Platelets (BD BACTEC FX) and the local blood services do not want to validate the new instrumentation for use with their platelets because it has not been documented as FDA-cleared for this use. We have documentation that platelet bacterial cultures are being performed on the new system at other sites, after a proper validation was performed. What are FDA considerations on this issue?

DR. MINTZ: At the present time, the use of the test not cleared by FDA but validated by the user to detect bacterial in platelets is acceptable. However, an FDA guidance addressing bacterial detection in platelets is currently being developed and will likely address the use of FDA-cleared tests for the detection of bacteria in platelet components.

MODERATOR: Ok. There is guidance in development that will speak to laboratory testing…

DR. MINTZ: …will likely address…

MODERATOR: … this situation. Thank you, Paul.

Question 13: The FDA has recently released two draft guidance documents on laboratory developed tests (LDTs) for comment. CDRH has hosted information sessions and presentations related to the content of this guidance. Will you please explain the active role CBER will take in communicating CBER's intentions regarding LDTs regulated under its jurisdiction? LDTs of interest include those used for investigating patient problems such as potential maternal-fetal antibody complications, platelet serology testing, IgA deficient/anti-IgA testing, Human Erythrocyte Antigen (HEA) or Human Platelet Antigen (HPA) beadchip testing, and neutrophil serology testing for investigation of suspected TRALI. Key areas of concern include blood centers' abilities to submit premarket authorization, pay user fees, and fully comply with manufacturer MDR (medical device reporting) requirements.

MS. MERCADO: I will take the question. The guidance documents on LDTs are joint guidance documents issued by CBER as well as the Center for Devices and Radiological Health. CBER has been, and will continue to work with, CDRH on LDTs, including considering what other communications might be helpful. We will also work with manufacturers to address their questions. With regard to the specific concern about PMAs, user fees, and MDRs, we encourage you to describe those concerns in detail in your comments on the guidance document.

MODERATOR: Thank you, Teresita. So really, reviewing the comments to the draft document is what CBER has lined up for understanding and communicating the concerns.

MS. MERCADO: That is right.

MODERATOR: Thank you.

Question 14: Please outline the process, in addition to a discussion by the BPAC, FDA plans to utilize to develop testing recommendations or regulations for Babesia microti once a licensed test/tests is/are available. How does the FDA plan to determine where, when and what tests to use and how often to review this process?

DR. MIED: As you know, on July 18, 2014, AABB issued Association Bulletin #14-05 on Babesiosis to provide educational materials and recommendations regarding managing potential transfusion-transmitted Babesiosis – or TTB – and measures to mitigate the risks of TTB. The September issue of TRANSFUSION contains a series of articles on blood donor screening for Babesia, so there are a lot of data in the public domain already regarding testing for Babesia. Now we understand that Babesia microti is the foremost infectious risk to the U.S. blood supply for which licensed testing is currently unavailable. FDA is currently conducting a risk assessment for Babesia infection in U.S. blood donors based on the published data, and of geographical and seasonal transmission of Babesia infections, to determine which areas of the U.S. and which months of the year testing is warranted. It is our current consideration that we may bring the current topic of testing for Babesia to a BPAC meeting for discussion of the published data. And we expect to issue a guidance document, for comment only, that addresses the question of what types of tests should be performed once Babesia tests are licensed, and where in the US and what times throughout the year testing would have value. The recommendations in that draft guidance could be subject to periodic modifications as a result of data obtained on the effectiveness of testing as testing is performed. We are really looking forward to being able to take steps such as these to more effectively mitigate the risk of TTB.

MODERATOR: Paul, do you suppose the matter coming to BPAC would be after vendors have brought products to the agency for review?

DR. MIED: Not necessarily, but it is really hard to say when exactly it would be scheduled for BPAC.

MODERATOR: Ok, thank you.

QUESTION 15: Minimally manipulated bone marrow cells are specifically excluded from FDA regulated HCT/Ps under 21 CFR 1271.3(d)(4). FDA information indicates that they are regulated by the Health Resources and Services Administration (HRSA), but that body does not appear to address common cellular transplantation issues such as donor history and product infectious disease screening. Could you please direct us to relevant regulations for these issues?

DR. LAZARUS: As the inquirer nicely explained, unrelated donor minimally manipulated bone marrow that is for homologous use and that is not combined with another article (with some exceptions) falls under the purview of HRSA under Section 371 of the PHS Act – for those of you who keep track of such things – and that product is excluded from regulation as an HCT/P under the tissue rules – 21 CFR part 1271. As a practical matter for bone marrow donors, the donor registry, such as the National Marrow Donor Program, and the accrediting organizations, such as AABB and FACT, generally follow the donor eligibility requirements that are applicable to other cell therapy products.

MODERATOR: Ellen, as I hear you say, there are not any federal guidelines, specific to [minimally manipulated bone marrow cells], so inasmuch as accrediting organizations have set standards that are in line with HCT/Ps, those seem to be good guidelines to use.

DR. LAZARUS: Right and as for federal oversight, the National Marrow Donor Program operates the Registry under contract with HRSA, so the NMDP has standards that would cover bone marrow. They are effectively the same as the standards for donor eligibility determination for the PBSC and cord blood donors.

MODERATOR: Thank you.

QUESTION 16: What are FDA's current considerations on the prohibitions on donation by individuals with a history of hepatitis regardless of the type of viral hepatitis? Currently available testing can specifically identify patients who have hepatitis A (HAV); these individuals should be able to donate after recovery.

MIED: The guidance that FDA issued in December 1993 says that an isolated laboratory test result for anti-HAV should not be considered equivalent to a history of viral hepatitis and need not be cause to defer the donor. However, if by "patients who have HAV" you mean patients who had clinical Hepatitis A with symptoms, as well as perhaps positive diagnostic test results after the age of 11, then according to the current regulations, 640.3(c)1 and 640.6(c)11, that donor must be deferred. And all other donors with the history of hepatitis after the age of 11, regardless of the type of hepatitis, must be deferred. You may remember that FDA did propose to remove "history of hepatitis" in the proposed rule in November 2007, titled "Requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use." Until that proposed rule is finalized, and if that requirement to defer that donor is changed in that final rule, such a donor must be indefinitely deferred.

MODERATOR: I think that is probably the basis of the question in asking what the current considerations are because it was proposed in 2007 – so you say we must be patient.

DR. MIED: Yes, it is still a proposed rule, but one day it will be a final rule.

Question 17: When assessing employee records, should the facility have copies of diplomas or transcripts? What other documentation could suffice, such as a copy of the ASCP certificate or an attestation sheet from the medical director that states the employee meets the requirements for testing personnel?

We continue to receive inquiries as to whether the laboratory can present the surveyor an individual's professional certification, such as MT (ASCP) or nursing licenses, as the only type of documentation to meet the CLIA requirements. This information is not considered sufficient evidence. Therefore, more detailed information, like degrees and transcripts, is required.

When the CLIA regulation specifies that the individual must possess a license, if required by the State, such as a physician (Doctor of Medicine: MD, Doctor of Osteopathy: DO, Doctor of Podiatric Medicine: DPM, Doctor of Dental Surgery: DDS), Midlevel practitioner (as defined at 42 CFR §493.2), testing personnel or otherwise, the laboratory need only produce a copy of the individual's State license as proof of academic achievement. No further academic documentation is required.

We suggest consulting S&C-10-07-CLIA, Consolidation of Personnel Policies for Individuals Directing or Performing Non-waived Tests under the Clinical Laboratory Improvement Amendments (CLIA), for more detail.


Question 18: Referencing the syphilis guidance released in September of 2014, if a donation is reactive on initial screening using a nontreponemal test and then found to be nonreactive when the index donation is further tested using a treponemal test, is the donor considered to have been deferred, and is the facility still obligated under 21 CFR 630.6 to notify the donor of the deferral?

DR. MIED: You must defer the donor according to 21 CFR 610.41(a), and you must make reasonable attempts to notify the donor within eight weeks, according to 630.6(a). The syphilis guidance that was issued in September, 2014 recommends that you defer the donor indefinitely for a reactive nontreponemal test and that you may perform a treponemal test using a follow up sample collected from the donor at a later date or a sample from the index donation. If you run the treponemal test within eight weeks and it is negative, you may reenter the donor. If you collect a follow-up sample from the donor, to run the treponemal test, obviously you will need to notify the donor of the deferral. But the question is if you use a sample from the index donation to run the treponemal test, and you get the result within eight weeks and it is negative, do you have to notify the donor of their deferral and their reentry? If the treponemal test is negative, it means that the initial reactive result on the nontreponemal test was a biological false positive. If you do the treponemal test within eight weeks and it is negative, you do not have to notify the donor. But, there may be value in notifying the donor that they were deferred, and you may consider counseling the donor about the potential medical significance of a biological false positive screening test, and that now with a negative treponemal test they may be reentered, or eligible to donate again. So the decision of whether to notify and counsel the donor in this case may be best left to the medical director.

MODERATOR: So the donor has to go through a deferral and reentry based on the initial [result]. The requirement to notify [the donor] is not there if all of this occurs within the eight weeks using the index donation sample, but the medical director should probably take a look at this and make a decision about doing some donor counseling. This is a medical director decision.

DR. MIED: That is correct. We are saying that you really do not need to notify the medical director but there might be value in notifying that they had a biological false positive. It is up to the medical director.

DR. EPSTEIN: It is also the case that the blood center continues to screen with the nontreponemal test that this pattern is just going to keep getting repeated because the biological false positives tend to be reproducible. That is another reason to inform the donor. The alternative of course is that the donor may be screened primarily with a treponemal test.

MODERATOR: Thank you.

Question 18: Is establishment registration required under an IND?

DR. ILLOH: This is a good question. Generally – no, blood establishments do not need to register or update their registration if they are performing a blood collection procedure or manufacturing strictly under an IND. I know some of these scenarios can be complicated, so if you do have questions, concerns or are not sure, feel free to contact us and we will be able to help you with that. I also want to mention that there is abundant information on the FDA website about IND requirements if you want to look at that too.

Question 19: What are the agency's current considerations for providing recommendations for HPC, Apheresis products, both as licensed products and for use under IND?

DR. LAZARUS: The first step is to think about the regulatory framework and where the particular PBSC or HCT/P apheresis product falls within the HCT/P regulatory framework. The HPC apheresis products that are for autologous use or administration to a first or second degree blood relative and meet all the other criteria in part 1271.10(a) – those are the HPC apheresis products that are regulated solely under Section 361 of the PHS Act and the tissue rules in 21 CFR Part 1271. So premarket review and approval are not required for those products and the manufacturer follows applicable regulations such as good tissue practices (GTP) and donor eligibility where applicable.

If you are talking about unrelated donor HPC apheresis products or PBSC products or those HPC apheresis products that do not meet the other criteria in 1271.10(a), those are the ones that are not regulated solely under Section 361 of the PHS Act and the tissue rules – they are subject to regulation under Section 351 of the PHS Act. But as many of you know, and as the inquirer probably knows, we are in a period of delayed implementation of IND and BLA requirements for those particular unrelated donor PBSCs, most of which are facilitated by NMDP.

MODERATOR: Thank you, Ellen.

Question 20: HPC donor eligibility - If a product is available to be imported into the US, and is missing infectious disease marker testing required by the FDA, we would determine the donor eligibility to be both "ineligible" and "incomplete." Is one status more critical than the other? What should we do in response to this situation?

DR. LAZARUS: Before I launch into what I promise to be a very brief discussion of those terms "ineligible" and "incomplete", I just want to emphasize the main point which is there are provisions within the HCT/P regulations for use of HCT/Ps under conditions of urgent medical need, as defined in the regulations. So that is regardless of which of those two situations pertain. But to get to the regulatory and labeling point…there is a donor eligibility guidance document that explains that the donor eligibility determination is the conclusion that the donor is either eligible or ineligible based on the results of required donor screening and testing. If the donor screening and testing has not been performed in accordance with all of the requirements – such as in the example the inquirer provided the FDA required donor tests were not performed – or all of them were not performed – then the donor eligibility determination cannot be completed. So that is an incomplete donor eligibility determination. But like I said, the donor eligibility regulations allow limited uses of HCT/Ps from ineligible donors, for example if there is a documented urgent medical need or if the HCT/P is for allogeneic use in a first or second degree blood relative, or if it is reproductive cells or tissues from a directed donor. And note that there are specific labeling requirements that are described in 1271.65 that relate to this particular situation.

Now if there is a documented urgent medical need for use of an HCT/P from a donor for whom the DE determination has not been completed, then you need to document the attempt, and the reason for the inability to complete the DE determination, and you must label the HCT/P with a statement "Not evaluated for infectious substances" and follow all other labeling and accompanying records requirements in 1271.60.

MODERATOR: Thank you.

QUESTION 21: Per 42 CFR 493.1281, if a facility performs the same test using different methods or instruments they should have a system that twice a year evaluates the relationship between them. Does this include different reagents such as low ionic-strength saline (LISS) and polyethylene glycol (PEG)?

CMS: Using different enhancement media in this manner in order to enhance reactivity does not constitute a different methodology or instrument; therefore, the requirement at 42 CFR § 493.1281(a) does not apply.

QUESTION 22: Is it necessary for a blood center to do proficiency testing for eluates? We have received conflicting advice about the necessity for performing this proficiency testing. Please advise as we will only do the survey if it is required.

CMS: The preparation of an eluate does not require proficiency testing. However, accreditation organizations may have more stringent requirements than CLIA and laboratories must follow them if they receive their CLIA certification by virtue of accreditation by a CMS-approved accreditation organization.

Question 23: Please comment on FDA's current considerations regarding the use of rapid bacterial tests to permit the extension of platelet storage to 7 days?

Some centers have submitted variance requests to extend platelet shelf life to 7 days. Does the FDA view these variance requests as independent of guidance development?

DR. MINTZ: The aforementioned FDA guidance may discuss bacterial testing modalities that could enable the extension of platelet dating to seven days.

MODERATOR: Thank you. Regarding the variance requests…?

DR. EPSTEIN: We have not been acting on variance re quests pending guidance, which we do intend to issue.

Question 24: What is the basis for the minimum requirement of 3 x 1011 platelet count for an apheresis platelet unit? Was it based on a study which determined the effective adult platelet dose? I have read in one article that the definition of a platelet dose as 3 x 1011 was based more on the capability of the technology rather than data that demonstrated the minimum effective dose for patients needing platelet therapy (Transfusion and Apheresis Science 32 (2005) 299–304)

DR. MINTZ: I like this question. I think it is interesting and pertinent. The requirement of a minimal platelet dose was associated originally with the preparation of single units of whole blood derived platelets, which preceded the advent of apheresis platelets of course. The minimal yield for the single unit was set at 5.5x 1010 platelets, so considering that a transfusion dose was composed on average – often – of a pool of 6 single units of whole blood derived platelets, the minimal transfusion dose translated into 5.5x 1010 x 6 which is 3 x 1011. That same dose was carried over to apheresis platelets on the development of this collection technology. So the minimum dose for single units at 5.5 x 1010 was actually defined in 1975 and it is believed to be the average minimal dose for single units of whole blood derived platelets as prepared by the collection centers at that time. That is a succinct history of this empiric development.

MODERATOR: Thank you Paul.

Question 25: As shown below regulations require a physician signature on emergency release paperwork. Physician Assistants and Nurse Practitioners are considered independent licensed practitioners in our system and allowed to independently order blood products. In some trauma cases they are ordering the emergency release blood products. Can they sign the emergency release forms if they are the ordering independent licensed provider?

§ 606.151 Compatibility testing. (e) Procedures to expedite transfusion in life-threatening emergencies. Records of all such incidents shall be maintained, including complete documentation justifying the emergency action, which shall be signed by a physician.

§ 606.160 Records. (v) Emergency release of blood, including signature of requesting physician obtained before or after release.

DR. ILLOH: I think that basically the regulations are clear. I do recognize that some states may allow nurse practitioners or physician assistants to request or sign off on prescriptions for patients, but our regulations trump those laws and right now we state that the physician's signature is required. Now we do allow accommodations: we do say this can be done before or after release of the products, so we advise that you obtain the physician's signature either before or after release of the products, but also probably have something in place to determine how long you want to have that period elapse before you obtain that signature.

MODERATOR: Thank you, Orieji.

Question 26: Is the FDA considering further interventions for chikungunya (CHIKV) and dengue? If so, what factors are likely to influence the decision for a given intervention?

DR. MIED: FDA is closely monitoring CHIKV and dengue transmissions in the Americas and globally and assessing their potential impact on the U.S. blood supply. The situation is continuing to evolve. There is an ongoing outbreak of autochthonous transmission and imported cases of CHIKV in 36 countries and U.S. territories in the Americas. It started in the Caribbean Islands and has spread to countries in North, South, and Central America, causing over 770,000 cases, including over 1,400 travel-associated cases in the U.S., and 11 locally-acquired cases in Florida. CDC expects dengue virus-like transmission of CHIKV to occur in the US, with the same impact as dengue, with only localized outbreaks. Transmission of CHIKV infection by blood transfusion has not been demonstrated but it remains a possibility. We are having ongoing discussions with CDC, NIH, and other PHS agencies, as well as the blood organizations regarding possible interventions for CHIKV and dengue to protect the safety of the blood supply. On June 6, 2014, AABB issued Association Bulletin #14-03 in response to the outbreak in the Caribbean Islands. This bulletin provides information about the potential for transfusion-transmitted CHIKV, educational post-donation information (PDI) materials for use by blood-collecting establishments and considerations for the collecting facility in response to PDI reports.

I need to tell you about some other measures that have been voluntarily taken to protect blood safety. The American Red Cross has ceased blood collection in Puerto Rico and is currently importing blood components from the U.S. mainland. For all blood establishments the Puerto Rico Department of Health has recommended predonation screening questions regarding symptoms or contact with symptomatic individuals in the last seven days. If there is an affirmative answer, the donor is deferred for 28 days. They quarantine products for 72 hours to allow the donor to report postdonation information (PDI), and if the donor reports symptoms, they discard in-date products beginning seven days from the onset of symptoms and the donor is deferred for 28 days. In response to local transmissions of CHIKV, OneBlood in Florida has voluntarily implemented a tiered safety strategy to prevent transmission by transfusion. OneBlood is using a four color model which is applied to defined areas represented by zip codes. The area is green if there is no arbovirus threat and they follow the AABB recommendations; yellow if they have travel acquired cases and they defer travelers from the Caribbean for 21 days; orange if there are 1-5 locally acquired cases with a rolling thirty day period – they activate a scripted proactive callback system; and red if there are six or more locally acquired cases within a rolling 30 day period. They cease platelet collections in the affected area and they place a seven day hold on red cells prior to release (combined with proactive scripted callbacks).

Now FDA has also had discussions with test manufacturers who are interested in developing tests for donor screening for these viruses about the possibility of making these tests available under IND with the goal of licensure of those tests. FDA has developed a reference reagent for CHIKV with analyzed testing data for that reference reagent and that reagent is available to assist in assessing the performance of NAT assays that are being developed. The availability of tests for CHIKV and dengue would be an effective invention, but if tests are not available, other interventions may have value. And it is our current thinking to develop a draft guidance document for comment that would include recommendations for blood establishments on possible interventions to reduce the risk of transfusion transmission of these viruses.

MODERATOR: Thank you, Paul.

Question 27: Recognizing that this is an evolving situation, what role does the FDA believe they will play should further action be needed regarding Ebola virus disease? What events may trigger further actions? What actions could the FDA take?

DR. MIED: FDA is closely monitoring the Ebola virus outbreak in Western Africa. With regard to its impact on blood safety in the U.S., FDA is in discussions with other PHS agencies as well as blood organizations for possible interventions. We recognize the voluntary efforts initiated by AABB and other blood organizations to ensure blood safety in response to Ebola risk. Towards that end, FDA is considering developing guidance in this area. We also note that there has been interest in the issue of convalescent plasma. To the extent that a blood establishment is interested in an IND for convalescent plasma, we encourage you to contact us.

MODERATOR: Thank you.

Question 28: Could the FDA share current considerations for changes to the MSM deferral and current considerations for bacterial testing of platelets?

DR. WILLIAMS: FDA has been an active participant in an HHS-level working group that was assembled by the Assistant Secretary for Health following the June 2010 meeting of the Advisory Committee for Blood and Tissue Safety and Availability. As you recall, they made some specific recommendations with respect to data collection activities they felt should occur prior to continuing policy deliberation. There has been a lot of consideration by the working group including coordination and in some cases design of studies that are now complete or very nearly complete. These will be considered by two public meetings that have been included in the Federal Register for this year. On November 18 there will be a meeting of the ACBTSA in Crystal City. That has an agenda item regarding eligibility of MSM for blood donation. Then on December 2, there is a Federal Register Notice that also includes the topic for the BPAC.

DR. MINTZ: Regarding the second part of the question dealing with bacterial testing of platelets: I think it is evident that we are prohibited from discussing the content of a guidance that is being actively developed. We have stated that it is a high priority for the Office of Blood Research and Review and for CBER.

MODERATOR: I thought I was being clever here. I changed the words from "current thinking" to "current considerations" so you could share. Didn't work!

Question 29: Does a Transfusion Service that rarely prepares a Red Blood Cells Plasma Added unit for patient exchange transfusion, need to be FDA Registered? The unit is prepared using an O Negative Red Blood Cells and AB Plasma. Staff are trained and annual competencies are completed. To date there have been no actual patient-exchange transfusions performed. The product is prepared for internal use only.

MS. JONES: In this situation if the facility has developed a written Standard Operating Procedure for the manufacturing process then they have shown an intent to make the product and if they use SOPs to make reconstituted whole blood, then they must register.

MODERATOR: Thank you, Jennifer.

Question 30: What should the product expiration date be if the ACDA solution used in the collection of Apheresis Platelets expires less than 5 days from the day of collection? Would you use the expiration date of solution or do the platelets expire as normal 5 days after collection?

MS. JONES: The expiration date of the platelets would be based on the shortest expiration date of the supplies used and on the manufacturing process. So in this situation, the expiration date of the platelets would be based on the expiration date of the ACDA solution if there were no other manufacturing processing performed on the platelets that would thus impact the expiration date further.

MODERATOR: Thank you, and this brings us to the conclusion of the 2014 session.

Thank you to the audience and to the panel.