Ask the FDA and CMS/CLIA
October 26, 2015
AABB 2015 Annual Meeting
- RICHARD DAVEY, MD – Director, Division of Blood Components and Devices (DBCD), Office of Blood Research and Review (OBRR), Center for Biologics and Review (CBER)
- ELLEN LAZARUS, MD, CAPT, USPHS – Director, Division of Human Tissues, Office of Cellular, Tissue and Gene Therapies, CBER
- MARTIN RUTA, PhD, JD – Regulatory Counsel, OBRR
- JENNIFER SCHARPF, MPH – Associate Director for Policy and Communications, OBRR
- ORIEJI ILLOH, MD – Deputy Director, DBCD
- JUDY CIARALDI, BS, MT(ASCP)SBB, CQA(ASQ) – Consumer Safety Officer, Blood and Plasma Branch, DBCD
- DAVID LIEBY, PhD – Chief, Product Review Branch, Division of Emerging and Transfusion Transmitted Diseases, OBRR
- GILLIAM CONLEY, MS, MT (ASCP) SBB – Director, Division of Inspections and Surveillance, Office of Compliance and Biologics Quality, CBER
- PENELOPE MEYERS, MS, MT (ASCP) SBB – Technical Director, Division of Laboratory Services, Survey & Certification Group, Center for Medicaid & State Operations, Center for Medicare and Medicaid Services (CMS)
- ALLENE CARR GREER, MT(ASCP)SBB – Director, Regulatory Affairs, AABB
MODERATOR: Good afternoon. I want to welcome everyone to this year's session of Ask the FDA and CMS/CLIA. My name is Allene Carr-Greer. I am director of Regulatory Affairs at AABB, and moderator for today's program.
DR. DAVEY: Again, welcome to the session today. We always look forward to this at FDA, to hear from you what some of your concerns are about our operations, the way we do things, our interactions, the regulations. It's very useful for us to hear your questions. We learn from it, and I hope you learn a little bit from our responses to your questions.
A couple of announcements I'd like to make. For those of you that interact with the Blood and Plasma Branch or with my division, we have a new branch chief. The position has been vacant for a while, but Richard McBride, who has long experience in the Armed Services Blood Program, is our new branch chief.
We've also, very happily, filled some vacancies in our CSO [consumer safety officer] positions. We've had a number of vacancies for quite a while now, but they've been filled. So, you may have some new CSOs. And the ones you've been dealing with may be a little less stressed because we're going to have more people onboard.
Review of FDA Final Rule
As you know, FDA issued a very important Rule on May 22nd, the rule titled “Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use”, which we often abbreviate as the donor eligibility rule, or the DE rule. I'm sure you're all familiar with this, I imagine, by now. It will be implemented May 23, 2016. And what we would like to do today is spend the first part of this session providing an overview of the Rule, the different sections, the different issues, some of the topic areas of particular interest. There will be a few slides with commentary presented by Martin Ruta, Jennifer Scharpf, and Orieji Illoh.
DR. RUTA: Thank you all for coming. As Dr. Davey said, we issued a final rule in May of this year. It becomes effective May 23rd of next year. And that means that, not only are we training our staff in what's in the rule, we're training our inspectors in what's in the rule. So, it's very important for you to read it, because this is what we're going to live with for a long time to come. I'm just curious. How many of you have actually read the rule?
DR. DAVEY: Whoa.
DR. RUTA: Wow.
DR. DAVEY: That's good.
DR. RUTA: Well, that's good. So, one of the things I did not put on the slide -- and it may not have been necessary -- was the web link. But if you take the title to the rule and you put it into any search engine, it'll take you to the Federal Register notice, which contains the preamble and the final rule. This will appear in next year's Code of Federal Regulations (CFR) as new sections replace many of the old sections that have been found in the 600s.
My talk is going to give some historical background on why we wrote the rule and what the intent was. The rule contains many provisions. For those of you who have read it, you realize that. We can't cover everything in this session. We're going to do abbreviated highlights. That makes it even more important for you to go back and look at the rule in more detail. Because when you do highlights, you tend to make it simpler. And you will want to see it and see what's actually written in it. So, we're going to talk about the provisions; a new one called relevant transfusion-transmitted infection; control of bacterial contamination of platelets; medical supervision; donor acknowledgement; alternative procedures; and donor eligibility. And again, we're going to reiterate that implementation needs to be in effect after May 23rd of next year.
The rule came about over a period of years because of a number of concerns, both our own, FDA's concerns, oversight concerns from the Government Accounting Office (GAO) – the Inspector General, Congress, and industry, too. And one of the concerns -- and this is, I think, a quote from a recommendation from the GAO -- is that the FDA should publish, in the form of regulation, guidelines that FDA deems are essential to ensure the safety of the blood and blood supply. There's been a general concern about the time it takes to write regulations. For example, we approved the test for HTLV in 1989. The regulation for HTLV went into effect in 2001. We recommended testing for West Nile virus (WNV) in 2004. And, thankfully, everyone was doing it, because it helped ensure the safety of the blood supply. But it will go into the regulations in May of 2016. It takes a long time to get changes put into the regulation, even when they've already been implemented by industry. There has been concern about blood safety and the regulations being out of date and concerns about donor safety. And I'm sure you've heard a number of sessions at this meeting about that.
Also, the intent of the rule was to better assure the safety of the blood supply and how to protect donor health, to make donor eligibility and testing requirements more consistent with current practices, i.e., you're already testing for WNV. We're going to put it into the books for Chagas testing [for Trypanosoma cruzi].
To accommodate technological advances, we've put in some place markers for possibly removing screening and testing measures down the road as advances in science and advances in technology come onboard, assuming that the science supports those kind of changes.
And we've put into the regulations a requirement for donor education – which you have been doing for a long time, for some of the history questions, and for donor testing. And this was a lot of effort and took place over many years with many workshops, many BPACs [Blood Product Advisory Committee meetings], and a lot of comments. And much of the work that we've done over the past 10, 15 years or longer have been incorporated into the rule.
I wanted people to see that there are many different parts of the rule. So, I'm going to go through the next few slides quickly and just point out a few of them. But this is for those who in the audience who didn't raise their hands – go back and look at it. There are many different sections. We're not going to cover them today. You should go back on your own and look at them.
[The rule] includes sections on standard operating procedures (SOPs), control of bacterial contamination that we're going to go over, testing requirements, donor deferral, and medical supervision. We're going to talk a little bit about eligibility requirements, but there are a number of exceptions in specific sections that you want to look at. We're going to talk about some exceptions from eligibility requirements for infrequent plasma donors. And you should also look at the sections on requalifying donors and notifying donors. And finally, there is a specific section on platelets, source plasma, and alternative procedures.
That's a quick overview of the whole rule; now, I want to highlight a couple of sections. There's a new concept -- maybe it's not a new concept. It's new to the regulations. But there is a concept that there are relevant transfusion-transmitted infections (RTTIs). Well, what are these?
These are things that we think may be transmitted through blood transfusion. And we've built a regulatory framework to allow for either donor education material, for asking questions, or for testing. So, this concept of RTTIs fits into three parts of the regulation: education, screening, and testing. And it identifies the specific agent, the one for which we've issued guidance documents or have had requirements now. It provides for the addition of new agents if they come along and we think they meet the criteria of the regulation. It allows the potential for removal of either testing or screening down the road as the science evolves and we think it's appropriate to do that. And it incorporates our current recommendations.
I'm not going to read this whole thing. This should look familiar. These are actually some quotes from the regulations. And you can see we define RTTIs to include HIV, HBV, HCV and the other agents for which we've issued guidance documents that say you either should ask donor history questions or you should test for these agents.
Then there's a part two. And part two is what about these other things – new transfusion-transmitted infections (TTIs) – that keep coming along. So, we've put in a section -- and that's 21 CFR 630.3(h)(2) -- that will deal with the TTIs. And if these [described] conditions are met, that there are screening measures, appropriate screening measures have been developed or an appropriate screening test has been licensed or approved by FDA and the agent has sufficient -- may have sufficient incidence -- in the population. Then, under the other provisions, we may call for education material. We may call for asking donor history questions, or we may call for testing.
Our intent is to issue draft guidance, for public comment, to address whether you should do screening, including medical history assessments. And that would be in accordance with the §630.10(e). We may say for this new agent -- and, you know, there are new ones on the horizon like Chikungunya or Babesia. We may say you should do testing, or we may say you should provide educational material in accordance with the different sections here. Our intent is that we'll issue guidance and say we think that this part of the regulation now applies and you should do whatever we said – screening, educational material, testing – to comply with the regulations.
Now, I am going to go more specifically into the testing requirement. And again, this is abbreviated. It's not the actual words, or some of it is not the actual words. So, it's saying if you collect blood for transfusion or further manufacturing, you should test for HIV, HBV, and HCV. Okay, all that's familiar. And for other agents, such as HTLV, syphilis, WNV, Chagas. So, why did I lump them that way? I lumped them that way because later on, when we talk about potentially removing agents, we didn't identify HIV or HBV or HCV as agents to be removed. So, that we think that testing for those would stay in place for a long time. And somewhere down the road, if the next FDA person thinks we should remove those, they're going to have to rewrite the regulations and go through more effort for those. But you'll see we've put in more flexible approaches for possibly removing these other agents.
And I wanted to point out that source plasma doesn't quite follow this paradigm. On Source Plasma, they don't test for HTLV or WNV, and they test for syphilis according to a different scheme. So, we didn't change that.
Okay, this allows a flexible approach to testing. And we provided for alternative schemes. For example, Chagas, we have one-time testing. The regulation allows for one-time testing or alternative schemes, when we think it's appropriate.
And again, as I pointed out, we may allow testing to be discontinued for a specific agent, other than HIV, HBV, or HCV, if we think the science supports that testing is no longer necessary to what we call “adequately and appropriately reduce the risk of transmission”. And we'll take into account the science, epidemiology, the geography, and potentially pathogen reduction.
I'm going to stop there, and I'm going to turn over the next part of the presentation to Jennifer Scharpf. Thank you.
MS. SCHARPF: Hello, everyone. The final rule contains new requirements for the control of bacterial contamination of platelets. And specifically, that blood collection establishments and transfusion services must assure that the risk of bacterial contamination of platelets is adequately controlled using FDA-approved or cleared devices or other adequate and appropriate methods found acceptable for this purpose by FDA. These provisions are contained in §606 of the regulations to really underscore that we consider the control of bacterial contamination of platelets as current good manufacturing practice (cGMP). Transfusion services may rely on the steps taken by the blood collection establishment to meet these requirements. And this is described in the preamble to the final rule.
However, if the blood establishment did not take appropriate steps, the transfusion service must do so. The rule allows for the use of bacterial testing or pathogen reduction technology to control the risk. In an associated requirement, when a platelet is determined to be contaminated, either the blood establishment or the transfusion service must take steps to identify the contaminating organism. If it is determined that the infection is likely to be endogenous to the bloodstream of the donor, then donors must be deferred and notified of the infection.
Section 630.5 of the final rule describes the activities related to the collection of blood components that must be performed by the responsible physician and those activities that may be delegated to a physician substitute or other trained person. In §630.3, the rule provides definitions for responsible physician, physician substitute, and trained person.
And, under the final rule, the responsible physician must ultimately determine the eligibility of a donor of blood or blood components. However, the responsible physician may delegate certain activities to either a physician substitute or other trained person, taking into account the medical expertise that is needed to assess whether the donor's health will permit the collection. Further, this section of the rule describes that, except for during red blood cell immunizations, the responsible physician does not need to be present at the collection site, provided that the requirements in this section are met. And we will address some specific questions related to delegations during the question and answer portion of this session.
The final provision in §630.5 discusses rapid emergency services. Specifically, that blood collection establishments must establish, maintain, and follow SOPs for obtaining rapid emergency medical services for donors when medically necessary. And in addition, establishments must ensure that an individual who is currently certified in CPR is located on the premises whenever collections of blood or blood components are performed. And further, the preamble to the final rule recommends that blood establishments should consider the availability of rapid emergency services and the local response times when determining locations for mobile collections.
In §630.10, there are new provisions regarding obtaining a donor's acknowledgment. Prior to each donation, you must provide information to the donor to address if the donor has reviewed the educational materials regarding relevant RTTIs and that the donor agrees not to donate if there is a potential risk to the recipient as described in the educational materials. You must inform the donor that a sample of their blood will be tested for RTTIs and that the donor will be notified of an unsuitable donation and that the donor's record will then identify the donor as ineligible. You must provide information to the donor regarding the risks and hazards of the donation procedure, and you also must assure that the donor has an opportunity to ask questions and withdraw from the donation procedure.
The final rule describes that the information relevant to the risks and hazards of the donation procedure may be provided in the donor educational materials. The donor acknowledgement must not include exculpatory language through which the donor is made to waive his or her legal rights. You must establish procedures to assure that the donor has reviewed the materials that you have provided and provide for a donor signature or other documented acknowledgement. And we described in the preamble, as well, that an electronic signature would be acceptable for this purpose.
I wanted to highlight that the requirement to obtain a donor's acknowledgement is in addition to the informed consent requirements in §§630.15 and 640.21, with respect to plasmapheresis and plateletpheresis donors, respectively. I'll provide some further information on these sections during the question and answer session.
Finally, I will discuss provisions in the final rule that address alternative procedures. So, largely consistent with the current requirements, FDA may issue an exception or alternative to any requirement to the regulations regarding blood and blood components or blood products in response to a written or oral request from an establishment. But what I would like to highlight is a new provision in the regulation in §640.120(b), which authorizes the director of CBER, in response to a public health need, to issue a notice of exception or alternative procedure if a variance is necessary to assure the availability of blood and blood products. The rule provides that CBER or FDA, on our own initiative, may issue such a notice to either address an urgent and immediate need for blood or to provide for appropriate donor screening and testing. And the second prong, I think, is important as we have recently experienced some shortages of donor tests and this provides for the use of alternative testing algorithms to comply with the requirements in §610.40
This concludes my portion of the presentation and I'll invite Dr. Illoh to conclude.
DR. ILLOH: Good evening. I'm going to talk about donor eligibility as a highlight of §630.10 mainly. And then, I'll also talk about exceptions to donor eligibility. Before I start, for those of you who have read the rule or who intend to read the rule, or want to read it again, you will notice that now we have kind of have two sections, if I can put it that way. We talk about donor eligibility, but also talk about donation suitability. So, just pay attention to that – donor eligibility at the time of donation and then, when you've collected the unit, determining whether the donation is suitable. So, pay attention to that as you look at the rule.
I am going to talk about the factors that determine the eligibility of the donor. That's how that section begins. And basically, like we say currently, the donor must be in good health and free from diseases transmissible by blood as required from this chapter. Martin already highlighted the RTTIs and other TTIs that may come as we put that out in guidance. But that's what you would be looking for. And then, we talk about what factors make the donor not eligible. If the donor is not in good health, they're not eligible. You must also identify factors that might affect the health of the donor or the safety, purity, or potency of the blood or blood component. So, we're looking at donor safety and then also the potency and the safety of the blood component.
We talk about when you must determine the eligibility of the donor. It must be done on the day of donation, except if the component cannot be stored for more than 24 hours. So, this is maybe in cases of collection of granulocytes, for example. You may determine the eligibility no more than two days before donation. So, we recognize that in such situations, you may need to screen your donors ahead of time before collecting.
Incomplete responses regarding the donor's medical history may be clarified within 24 hours of collection. I believe this is consistent with current practice. However, we emphasize that this does not include failure to perform or document part of the physical assessment. So, that must be done at the time that the donor is presenting for donation. So, of course, we can't call a donor back and say “What's your blood pressure?” You know, that's not….
So, how must you determine the eligibility of the donor? You must consult the records of the donor. We go into detail about how to look at the records. If you cannot check the cumulative record prior to collection, you must do so before release of the product. So, once again, your donation suitability comes in there. You must assure that the donation interval is appropriate. You have to assess the donor's medical history and also perform a physical examination of the donor or physical assessment. That's what we call it.
So, talking about the donor's medical history…before collection, you conduct a medical history interview. And during this interview, you want to assess and identify risk for or evidence of relevant transfusion-transmitted infection. So, this way, you ask about questions concerning behavior, high risk factors, behaviors associated with an RTTI, history of receipt of blood components or other medical treatments, asking for signs and symptoms of RTTIs. In addition, you want to ask for a history of institutionalization for 72 hours or more in the last 12 months, intimate contact with the risk for RTTIs, and the history of non-sterile percutaneous inoculation.
So, other factors you will have to look at are factors that may affect the donor's health or the blood product: symptoms of recurrent or recent illness; certain medical treatments or medications; these things we already do; travel to or residence in an area endemic for TTIs and so, the travel history, basically; exposure to accidentally or intentionally released disease or disease agents. We now have pregnancy, even though we ask this question currently. It's now in the regulation – pregnancy at the time of or within six weeks prior to donation.
And you also want to determine that the donor is giving you unreliable answers. This might be a donor under the influence of alcohol or drugs or if you sense that the donor is test seeking. The donor may not be eligible to donate if that happens.
And then, we also have in here, which is new also, history of xenotransplantation product recipients. And these are products with exposure to live, non-human cells, tissues, or organs. So, I will say here that we did get a couple of questions about xenotransplantation. During the question and answer session, we'll address it a little bit more.
Now, in terms of the physical assessment, you want to do that, as I said earlier, on the day of donation. You want to check the temperature. It should not exceed 37.5 C or 99.5 F. And this is oral. If you look at the regulations, we say oral. And then, we -- I think we say something about other -- or something that corresponds to the oral temperature. So, depending on how you're taking the temperatures, it should correspond to this.
Blood pressure -- we now have limits for blood pressure. The blood pressure should be systolic between 90 to 180 millimeters mercury (mm), or the diastolic should be between 50 to 100 mm. The hemoglobin standards, as you've seen, have changed. For males, it should not be less than 13.0 g/dL, or 39% hematocrit. And for females, it remains at 12.5 g/dL or more or at 38 % hematocrit.
Now, what is new is that we allow a provision to collect from females whose hemoglobin levels fall between 12.0 and 12.4 g/dL, basically, or at 36 % hematocrit with FDA approval. I wanted to clarify what I've been hearing about an FDA variance. This is not an FDA variance. We now allow this, but we need to approve your procedure to do this. So, you will submit a protocol to us, and we will determine if the protocol is sufficient for you to collect blood from such donors. Just wanted to clarify that it is not a variance.
Pulse must be regular and between 50 to 100 beats per minute. Donors with measurements outside this range may donate only when the responsible physician has determined and documented that the health of the donor will not be adversely affected by donating. We've already gotten a couple of questions concerning this, you know, especially about athletic donors whose pulse rates may fall below 50 and whether this needs to be done all the time. I'll address this a little bit more when we're going over our questions. But what we're going to allow or what we'll evaluate in your SOPs for licensed facilities is procedures for one-time determination by a responsible physician for athletic donors with a pulse rate less than 50 beats per minute. This may be acceptable. So, the responsible physician will be called one time. If it's determined that the donor is okay to donate, that can be documented. Subsequently, you still need to take a pulse each time they present to donate. But we'll allow the donor to be accepted if the physician has previously documented one time that this is acceptable.
In terms of weight, the weight should be greater than or equal to 110 pounds. And you must perform a skin examination. So, there have also been a couple of questions about weight. And I believe we're going to address this a little more. But when must the donors be weighed versus asking them verbally their weight? Donors who are donating by plasmapheresis must be weighed at each donation. So, this applies to plasmapheresis donors, whether they are collecting plasma alone, whether it's infrequent, whether it's frequent, and when you're also collecting plasma as a co-component with other blood components. A current weight measurement permits the collecting establishment to calculate accurately the plasma volumes to be collected based on the weight-specific nomograms. So, this is the reason why we're requiring that a weight may be obtained.
Now, the exceptions for certain ineligible donors -- we'll permit donation from certain ineligible donors if the donation is for autologous use only as prescribed by the donor's physician. However, if it's for autologous use, the donor must still have a hemoglobin of at least 11 g/dL. The responsible physician determines and documents that the donor's health permits the collection procedure. So, the responsible physician can do this by off-site consultation or by telephonic consultation. We believe that this is necessary because a responsible physician is the best person to determine the donor's health and determine whether it permits a donation procedure.
Finally, the rule, like we've said many times, is going to be implemented by May 23, 2016. There have been questions about whether you can implement the rule earlier or later. Not later -- earlier. But what we're saying is, if a new requirement is more stringent than the current requirement -- so, for example, if you want to start collecting from male donors with hemoglobins of 13, that's acceptable, because it's more stringent than the current rule. You can implement that prior to the effective date.
Now, for licensed blood establishments, we recommend that you send your required submissions as soon as possible to FDA. This will allow us to begin to review the necessary submissions and SOPs and kind of develop an interaction with you earlier than later so we can all reach this May 23rd implementation date. We encourage you to really begin to submit your SOPs to us for review. As you determine what you should submit it as, whether as a PAS or a CBE or a CBE-30, we advise you to refer to the FDA guidance for industry, titled “Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture; Guidance for Industry” or what we just call the 601.12 guidance, to determine what category you should use to submit your SOPs. And we really encourage you to contact us if you have questions so we can all do this in a very systematic manner.
So, if you have any questions, please contact your CSO. Dr. Davey mentioned the fact that [besides] your current CSOs we have new CSOs, and they're all undergoing training. And we're all trying to make sure we're consistent in what we tell our firms. So, please do contact your CSOs, or contact me. Contact Dr. Davey or Richard McBride, who is the branch chief, if you have additional questions.
In summary, we've given you a quick highlight of the rule. We've tried to pick out some specific areas that we think you should be aware of and new changes. And, you know, please enjoy the rule. Read it at night so that -- it's very entertaining. So, now, we'll take the questions.
Questions for the Panel
MODERATOR: Thank you, Martin, Jennifer, and Orieji. Once again, the new rule titled “Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use” has an implementation date of May 23, 2016. For each of the questions we received relating to the rule, I have reprinted relevant language from the rule.
§603.3(j) Suitability of the donation means a determination of whether the donation is acceptable for transfusion or for further manufacturing use.
§630.30 Donation suitability requirements.
(a) When is a donation suitable? …The donor is not currently deferred from donation…donor is in good health and procedures were followed to ensure that the donation would not adversely affect the health of the donor… donor history interview and testing were performed as required and the results indicate that the donor is free from risk factors for, or evidence of, relevant transfusion-transmitted infections and other factors that make the donor ineligible to donate and blood tests are negative or nonreactive.
The hemoglobin requirement for male donors will be increased from 12.5 to 13 g/dL. However, if a product is mistakenly collected from a male donor with a Hgb between 12.5 and 12.9 g/dL:
- Would FDA consider this a product deviation that affects the safety, purity or potency of the product that would require a BPDr or does FDA consider this a donor safety issue that does not require a BPDr?
- If a BPDr is required, can the medical director evaluate the donation and release it as safe for transfusion, as they would manage products from donors who donate too early or do not reveal an underlying donor safety issue that would have disqualified them, had it been known at the time?
- Specifically, we are seeking this clarification because we believe “already collected” products from donors with Hgb between 12.5 and 12.9g/dL are safe, pure, potent, and suitable for transfusion without regard to the sex of the donor.
MR. CONLEY: Beginning May 23, 2016, blood establishments must no longer collect blood from allogeneic male donors with a hematocrit less than 13 g/dL. Section 601.171, which was quoted from defines the regulatory requirements for reporting product deviations. As we described in our 2006 guidance document, “Biological Product Deviation Reporting for Blood and Plasma Establishments,” a report is required if the donor's hemoglobin or hematocrit was unacceptable and the product was distributed. We intend to maintain the same approach once the new regulatory requirements are effective. The deviation code is DS-21-02. The verbiage associated with that code is “Donor screening/Donor did not meet acceptance criteria/Hemoglobin or hematocrit unacceptable, not documented, or testing performed incorrectly.” And that code would be used to report these events. So, yes, it is a BPDR. Please use code DS-21-02.
MODERATOR: Thank you, Gil.
Our next question goes from donation suitability to donor eligibility. And within that section, if you read down through letter (e) and number (2), we get to the requirement now to assess donors to see if the donor is a xenotransplantation product recipient. We have four questions here. I am going to read all four questions, and then, we'll hear the answers.
§630.10 General donor eligibility requirements
(e) How do you assess the donor’s medical history?
(2) Other factors that make the donor ineligible to donate…Your assessment of the donor must include each of the following factors:
(vii) The donor is a xenotransplantation product recipient.
- Does the FDA have or recommend a definition that can be used for xenotransplantation that would allow for a donor to understand what it means?
- If a donor does not understand what this means, is it okay to accept the donor on this basis (similar to vCJD recommendations)?
- Based on the now withdrawn Guidance content (2002 draft), we had a policy established by the Medical Director that a permanent deferral was required if the graft/transplant was of skin, organ, dural or living tissue, but a one-year deferral after graft/transplant of a valve, bone, tendon or ligament. How does the new requirement affect that policy?
- Does the FDA require product retrieval if a donor indicates he/she was a xenotransplantation product recipient?
- What would be the deferral period, if any, for a donor who received a bovine dental implant? Would that be considered a xenotransplant product?
MS. SCHARPF: So, first, I'd like to note that since the 2002 draft guidance has been withdrawn, we do recognize that it would be beneficial to provide a definition of xenotransplantation for the purpose of donor eligibility and guidance. That said, to address the first question, FDA has not provided a recommended definition for xenotransplantation for the purpose of donor questioning or to aid, I guess, in donor understanding of the question.
We will consider, however, proposed donor questions and accompanying materials such as flow charts to address donors who may not understand the questioning regarding receipt of xenotransplantation products in the context of reviewing revised donor history questionnaires. Of note, the 2001 Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation, defines xenotransplantation to include any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a), live cells, tissues, or organs from a non-human animal source or, (b), human body fluids, cells, tissues, or organs that have had ex vivo contact with live, non-human animal cells, tissues, or organs. And this guideline is available on the FDA website.
Consistent with this guideline, FDA's concern is with donor exposure to live cells, tissues, and organs. It is not our intention to require deferral for donors with implants of non-living tissues such as bone, tendon, or heart valves. We do encourage you to contact your CSO if you have any specific questions regarding potential xenotransplantation products. And finally, to address the last question, FDA would expect product retrieval if post-donation information indicates that a donor was a xenotransplantation product recipient.
MODERATOR: Thank you, Jennifer. And I think the Donor History Task Force will give you some material to review.
§630.10 General donor eligibility requirements
(c) When must you determine the eligibility of a donor?
(2) In the event that, upon review, you find that a donor’s responses to the donor questions before collection were incomplete, within 24 hours of the time of collection, you may clarify a donor’s response or obtain omitted information required under paragraph (e) of this section, provided that your standard operating procedures address these activities.
Language in the preamble of the Final Rule “expressly authorizes establishments to clarify donor records after collection under these circumstances, in the event that, upon review, you find that a donor’s responses to the donor questions before collection were incomplete, within 24 hours of the time of collection.”
- If documentation is missing for temperature, pulse or blood pressure, what opportunity exists to obtain this information to establish the suitability of the donation?
DR. RUTA: As was mentioned, the rule provides opportunity for establishments to clarify donor records. In the event that you find that the donor questions were incomplete, within 24 hours of the time of collection -- and I'm quoting, "you may clarify a donor's response or obtain omitted information required under paragraph (e). Those are the risk factors of the section, provided that your standard operating procedures, address these activities."
This applies only to responses to donor questions and not to information that establishments are required to obtain as part of the physical assessment of the donor addressed in Section (f) of that section. The final rule did not provide an opportunity to obtain physical information subsequent to collection, because it's kind of hard to go back and say what was a pulse or blood pressure, the temperature of the donor at the time of the donation. If this is a rare unit or if this is a shortage situation, we'll entertain 640.120s to allow those units to be used.
MODERATOR: Thank you, Martin.
We have two questions about donor consent. I will read both of them and then, someone's going to respond to this.
There is some confusion surrounding the requirements for informed consent for apheresis donors when the donor is an infrequent plasma donor. Considering:
§630.3(e) defines Infrequent plasma donor as a donor who has not donated plasma by plasmapheresis or a co-collection of plasma with another blood component in the preceding 4 weeks; and has not donated more than 12.0 liters of plasma (14.4 liters of plasma for donors weighing more than 175 pounds) in the past year.
§630.15 What additional donor eligibility requirements apply when you… collect blood or blood components, collect Source Plasma or plasma by plasmapheresis? §630.15(b)(2)(ii) states the responsible physician must obtain the informed consent of a plasma donor who does not return within 6 months of the last donation. AND
§630.25 (exceptions for infrequent plasma donors) does not specifically list an exception from §630.15(b)(2)(ii) for infrequent plasma donors.
- Is an infrequent plasmapheresis donor exempt from this requirement to repeat an informed consent if the donor does not return within 6 months of the last donation?
- How often must an infrequent plasmapheresis donor complete an informed consent?
Then the other question has to do with the medical supervision of this donor in §630.5:
§630.5 Medical Supervision outlines responsibilities that the responsible physician may and may not delegate. In reading this section, as well as §630.15 Donor Eligibility Requirements specific to Whole Blood, Red Blood Cells, and Plasma collected by apheresis, it is not clear whether informed consents must be explained (risks and hazards of the procedure) to each donor.
- Must the risks and hazards be explained (e.g., verbally) to whole blood, platelet, red cell apheresis donors and if yes, is that a responsibility that the responsible physician can delegate to trained personnel?
- Must the risks and hazards be explained (e.g., verbally) to plasmapheresis (source and infrequent) donors and if yes, is that a responsibility that the responsible physician can delegate to trained personnel, physician substitute or must only by the physician explain?
- If yes, does that also apply to automated collection procedures that include a plasma component, e.g., platelet-plasma or RBC-plasma?
MS. CIARALDI: I have that one. You probably thought I was just up here for eye candy, but they are going to put me to work.
There's a lot of information that's asked of this. So, I'm going to gradually walk you through the regulations and the requirements to answer all of these questions. They're absolutely right in their question that §630.15(b)(2) requires the responsible physician to obtain informed consent from plasma donors. We state in page 29873 of the preamble to the Federal Register that the informed consent process should be an interactive dialogue that involves the physician explaining -- which means verbally -- the risks and hazards of the procedure to the donor, and the donor has the opportunity to ask questions and, if appropriate, refuse the procedure.
The regulation requires the consent to be obtained initially, annually, and if it has been more than six months since the donor's last donation. Page 29870 of the Federal Register states, "This applies to source plasma donors and all other plasma donors." Page 29873 restates, "If a donor does not return for 6 months, the establishments must obtain informed consent again."
Lastly, as stated on the slides, §630.25, which is the infrequent plasmapheresis regulation, does not exempt infrequent plasma donors from the informed consent requirement. Therefore, the informed consent must be obtained from all plasma donors. The requirement applies to plasmapheresis donors, regardless of the frequency of donation; the intended use of the plasma, transfusion or further manufacture; and whether plasma was collected as a co-component with other apheresis components, such as platelets and red blood cells. So, if an infrequent donor does not return within six months, the informed consent must be obtained again. After that, the informed consent is obtained annually, as long as the donor donates at least every six months.
As to who must obtain the informed consent, first, I'm going to cover plasma donors, then platelet donors, and then, everybody else. According to §630.5(c)(3) "The responsible physician may delegate to a physician substitute the requirement to obtain an informed consent from frequent plasma donors." According to §630.5(c)(4)(i) "The responsible physician may delegate to a trained person the requirement to obtain an informed consent from an infrequent plasma donor." So, if they're frequent, the physician substitute can do the informed consent. If they're an infrequent donor, a trained person can do it.
Now, for a plateletpheresis donors. Section 630.5(b)(1)(iv) says, "The responsible physician may delegate to a physician substitute, or a trained person the requirement to obtain an informed consent from plateletpheresis donors. And as was mentioned on an earlier slide, the informed consent for plateletpheresis donors is discussed in §640.21(g).
The informed consent process described above involves the explanation of the risks and hazards to the donor. Now, there's no requirement to obtain an informed consent from whole blood donors and from apheresis red blood cell donors. We did recommend in our 2001 guidance document, “Recommendations for Collecting Red Blood Cells by Automated Apheresis Methods, that informed consent be obtained from apheresis red cell donors. So, there is a recommendation, but there's no requirement in the reg.
Even though there's no requirement to verbally explain the risks and hazards to these donors, we do require, in §610.30(g)(2)(ii)(E) -- that's the donor acknowledgement regulation -- that all donors be provided with information about the risks and hazards of the donation procedure at each donation. So, for the whole blood donors and the red cell apheresis donors, unless you've incorporated the informed consent for the red call apheresis donors, there is no requirement for the informed consent to be verbally explained. But everybody gets exposure to the risks and hazards of the donation procedure during the donor acknowledgement.
MODERATOR: Thank you, Judy.
MODERATOR: Staying with donor eligibility requirements…
§630.10 General donor eligibility requirements
(g)Are there additional requirements for determining the eligibility of the donor?
(2) Donor’s acknowledgement…prior to each donation…
§640.21 Eligibility of donors
(g) The responsible physician must obtain the informed consent of a plateletpheresis donor on the first day of donation, and at subsequent intervals no longer than 1 year.
I believe a donor acknowledgement is required at each donation, whether whole blood or apheresis, while the informed consent is also required (for apheresis donors only) at the first procedure and then annually.
- Is this a correct summary statement?
The required elements of the informed consent and acknowledgement seem to overlap to a degree.
- If the elements of the informed consent were included in the acknowledgement statement, and signed by the donor, could an acknowledgement at every visit remove the requirement for a separate signed statement called the Informed Consent?
MS. SCHARPF: The requirement to obtain a donor acknowledgement in §630.10(g)(2) applies to every collection of blood and blood components, including apheresis platelet and plasma collections. At each donation, you must provide information to address the required elements to the donor and obtain the donor's acknowledgement that he or she has reviewed the materials provided.
Informed consent, as discussed in the final rule in §640.21(g) for plateletpheresis donors and §630.15(b) for plasmapheresis donors, must occur prior to their first donation and at least annually, as Judy just described. The responsible physician must explain the risks and hazards of the procedure to the donor in such a manner that the donor may give consent and has a clear opportunity to refuse the procedure. As discussed in the preamble to the final rule, the informed consent process involves a dialogue between the donor and the responsible physician. However, as Judy just noted, these requirements may be delegated to the physician substitute or trained person, consistent with §630.5.
We agree that the required elements of the informed consent and the donor acknowledgement overlap with respect to providing the donor with information regarding risks and hazards of the donation procedure. However, the mechanisms by which the risks and hazards are communicated to the donor are different for each provision.
While the donor should be provided an opportunity to ask questions, a dialogue with each donor is not required for obtaining the donor's acknowledgement. However, we continue to expect an interaction or dialogue with the donor as part of the informed consent process. Therefore, obtaining the donor acknowledgement at each donation does not negate the requirement for informed consent.
MODERATOR: It sounds like the issue is that the informed consent requires a verbal conversation.
MS. SCHARPF: Right.
MODERATOR: And the acknowledgement statement is a statement.
MS. SCHARPF: Correct.
MODERATOR: Thank you.
MS. SCHARPF: And you may provide the information in the donor acknowledgement in written materials.
MODERATOR: Thank you, Jennifer.
We are going to look at several slides before we get to the next question concerning therapeutic phlebotomy. So, we start out with the donor eligibility requirements that are specific to whole blood, red blood cells, and plasma that's collected by apheresis. It's where the requirements are found. Then there is letter (a), the additional requirements that apply to whole blood or red blood cells collected by apheresis. And then, item (2), therapeutic phlebotomy.
§630.15 Donor eligibility requirements specific to Whole Blood, Red Blood Cells and Plasma collected by apheresis.
(a) What additional donor eligibility requirements apply when you… collect Whole Blood or Red Blood Cells by apheresis?
(2) Therapeutic phlebotomy. When a donor who is determined to be eligible under § 630.10 undergoes a therapeutic phlebotomy under a prescription to promote the donor’s health, you may collect from the donor more frequently than once in 8 weeks for collections resulting in a single unit of Whole Blood or Red Blood Cells, or once in 16 weeks for apheresis collections resulting in two units of Red Blood Cells, provided that the container label conspicuously states the disease or condition of the donor that necessitated phlebotomy. However, no labeling for the disease or condition is required under this section if:
§630.15 Donor eligibility requirements specific to Whole Blood, Red Blood Cells and Plasma collected by apheresis.
(i) The donor meets all eligibility criteria;
(ii) The donor undergoes a therapeutic phlebotomy as prescribed by a licensed health care provider treating the donor for:
- Hereditary hemochromatosis; or
- Another disease or condition, when the health of a donor with that disease or condition will not be adversely affected by donating, and the donor’s disease or condition will not adversely affect the safety, purity, and potency of the blood and blood components, or any products manufactured from them, and the collection is in accordance with a procedure that has been found acceptable for this purpose by FDA; and
(iii) You perform without charge therapeutic phlebotomies for all individuals with that disease or condition.
§630.15 Donor eligibility requirements specific to Whole Blood, Red Blood Cells and Plasma collected by apheresis.
From the preamble to the rule:
For clarity, the requirements regarding therapeutic phlebotomy have been consolidated in the final rule in §630.15(a)(2). Establishments do not need an exception or alternative under §640.120 to make a collection under this provision if the requirements set forth in §630.15(a)(2) are met.
The new regulations appear in a section specific to products collected by apheresis. Therefore it appears that §630.15(a)(2)(ii)(B) does not apply to therapeutic donations collected by manual methods.
- Will variances still be needed for therapeutic donations collected by manual methods?
MS. CIARALDI: Okay. That's mine again. Thank you. By manual methods, we're assuming that you mean whole blood collections. But we just wanted to put that clarification out there. There is additional clarification about what is in -- what products are covered in §630.15. Specifically, §630.15 includes 3 types of products: whole blood, apheresis red cells, and plasmapheresis.
To break it down where each of these are, § 630.15(a) involves whole blood and apheresis red cells. Section 630.15(b) involves plasmapheresis. Now, as you saw, therapeutic phlebotomy is in §630.15(a). Therefore, whole blood can be collected from therapeutic phlebotomy donors. And I advise you to reference §630.15(a)(2) for the frequency of the whole blood collections for therapeutic phlebotomy donors.
Since the therapeutic phlebotomies are now discussed in more detail in the regulations, you do not need to submit a variance under §640.120 to collect these donors. But there is some submission required. If you are a licensed blood establishment and you want to collect from therapeutic donors, including hemochromatosis donors, -- I'm just going to call them HH donors for brevity -- on a more frequent basis than every eight weeks and to not label the unit with the donor's disease, you must submit a prior approval supplement under §601.12. And what you'll be asking for, what you'll be doing is submitting your procedures for approval to do the steps that are described in §630.15(a)(2).
So, it won't be a variance under §640.120. It'll be a submission under §601.12 to do what's described in §630.15(a)(2). Unlicensed blood establishments do not need to submit variances to collect HH donors on the more frequent basis without the special labeling, provided that the requirements in §630.15(a)(2) are followed. Again, it's no longer a variance.
Both licensed and unlicensed blood establishments would need to submit a request under §630.15(a)(2)(ii)(B) for therapeutic donors other than the HH donors. The licensed blood establishments would need to submit this as a prior approval supplement.
You might ask why do I need to submit something if it's now described in the guidance and it's no longer a variance? For licensed blood establishments that want to ship HH units or units from HH donors in interstate shipment, they would need to submit this as a prior approval supplement.
For licensed and unlicensed blood establishments collecting the other therapeutic donors, they would need to submit their procedures to us for review. That regulation §630.15(a)(2)(ii)(B) requires the collection for the other therapeutic donors to be in accordance with a procedure found acceptable by FDA. Without a guidance document describing acceptable procedures for these types of donations, we must review your procedures to ensure that they are acceptable. As a side question, we didn’t get asked this, but I did get asked this at the booth is that I already have a variance for hereditary hemochromatosis or I already have a variance for the testosterone therapy donors that were done under §640.120. Do I need to resubmit now to get them approved under this new regulation? And the answer would be is that no, you would not need to resubmit those if the original approvals are consistent with the new regulation. And we in our office went ahead and reviewed the variance approval letters for both of those two types of therapeutic phlebotomy. And they are consistent with the new provisions in the new regulations. So, if you already have those approvals on file, even though they were done under a different regulation -- if you have those approvals on file, you're good. And you don't need to resubmit.
MODERATOR: Thank you, Judy.
21 CFR 630.15 Donor eligibility requirements specific to Whole Blood, Red Blood Cells and Plasma collected by apheresis.
(b)What additional donor eligibility requirements apply when you, an establishment that collects blood or blood components, collect Source Plasma or plasma by plasmapheresis?
(3) Weight. You must weigh a donor at each donation.
In the preamble to the final rule Comment 87 and Response 87, found on page 29873, explains this requirement. Included in the explanation is a note that plateletpheresis donors do not have to be weighed unless there is a requirement in the operator’s manual/SOP. The paragraph on co-collection including plasma by apheresis again concentrates on platelets as the co-component.
- What about a co-collection of red cells and FFP, or PF24, by apheresis; would the donor have to be weighed?
MS. CIARALDI: The requirement to actually weigh the donor, as you see over here, is in §630.15 but specifically, §630.15(b)(3). And that requirement is to weigh the donor at each donation. This is the §630.15(b) -- this is the section that covers plasmapheresis donors. So, that's who it applies to, the type of donors it applies to.
Therefore, there is no requirement to weigh donors of other products such as whole blood, red cells by apheresis and platelets by apheresis. As mentioned in the question, page 29873 discusses which donors must be weighed. It says in that response to comment 87, “The weight allows the collection establishments to calculate the accurate volumes of plasma to collect from the donor.” And, that's why it has become a requirement. We were asked in that comment whether co-collections were included in this requirement. And, we responded that the requirement to weigh the donor applies to all plasmapheresis donors, regardless of the intended use, again, for further manufacturing or transfusion, the frequency of donation, frequent or infrequent, and whether the plasma was co-collected with any other product, which would include red blood cells and platelets.
This requirement would also apply, regardless of where the donation was occurring, at a fixed site or at a blood mobile. So, again, if you're collecting whole blood by itself, which you have to, and if you're collecting red cell apheresis by itself or plateletpheresis by itself, you do not have to actually weigh the donor. But the moment you collect a plasmapheresis, either alone or with any other component, then the requirement kicks in to actually weigh the donor at each donation.
MODERATOR: So, this donor of red cells and FFP or red cells and PF24 must be weighed?
MS. CIARALDI: If it's a co-collection with red cells, yes, they must be weighed.
MODERATOR: Thank you.
MS. CIARALDI: Because it's all plasma.
§630.10 General donor eligibility requirements
(f) How do you perform a physical assessment of the donor?
(4) Pulse. The donor’s pulse must be regular and between 50 and 100 beats per minute. A donor with an irregular pulse or measurements outside these limits may be permitted to donate only when the responsible physician determines and documents that the health of the donor would not be adversely affected by donating.
- When the donor explains they are an athlete, can blood centers continue to use their current SOPs to assess these donors, rather than asking them to wait while a medical director is consulted, or come back on another day?
DR. ILLOH: I think I had addressed some of this during my presentation. As mentioned, the final rule provides that a donor with pulse measurements outside the established limits be permitted to donate only when the responsible physician determines and documents that the health of the donor would not be adversely affected by donating. Effective next year when this rule becomes implemented, this is what we are expecting.
Now, we do recognize that healthy athletic donors may present with pulse rates less than 50 beats per minute. For such donors, blood establishments may establish SOPs and specify an initial determination of acceptability by the responsible physician. So, your SOPs can state that a responsible physician can do an initial determination. And this should be documented in the records. This could apply to future donations. Please note that you must continue to assess a donor's pulse at each donation. This does not preclude you from determining donor's pulse, even if they're an athletic donor.
For all other donors with pulse rates outside the acceptable limits or with an irregular pulse, the responsible physician must, at each donation, determine and document that the health of the donor would not be adversely affected by donating. So, even if the donor is on a drug that slows down the pulse rate, they still need to be evaluated by a physician at each visit.
Now, licensed blood establishments must submit these SOPs to FDA as a PAS supplement. SOPs for both licensed and unlicensed blood establishments should describe how the determination of acceptability is made and document it and how the information will be assessed and documented on subsequent donations.
MODERATOR: Thank you.
§630.20 Exceptions for certain ineligible donors. Regarding autologous donors – the new language requires the responsible physician to “determine and document that the donor’s health permits the collection procedure,” and allows for this determination by telephonic or other offsite consultation per §630.5(b)(1)(i)(B).
Autologous donor collections occur at many collection sites on a variety of schedules to meet the needs of the patient/donor. Currently, facilities manage the assessment to ensure the donor’s health permits the collection procedure through use of SOPs reviewed and approved by the responsible physician.
- Will the FDA permit continued use of the SOPs by blood center staff dealing directly with the donor to meet this requirement as an option to telephonic, or other offsite, consultation with a physician?
DR. ILLOH: Once again, the rule as written would require the responsible physician to determine and document that the donor's health permits the collection procedure. It allows this determination to be made by telephonic or other off-site consultation. As I mentioned in my presentation, we put it this way because we believe that a responsible physician is in the best position to determine the donor's health at that time and to permit the collection procedure.
Now, we've heard a couple questions and comments about this. And we really encourage you to discuss with us or we would like to really better understand your procedures as you have it right now or as you intend to modify it to comply with the rule so we can better determine the suitability of your processes. So, please, do talk with us, share your SOPs or any questions that you have concerning this with us. And, we'll be able to maybe discuss it one-on-one on what is acceptable and what is not acceptable.
MODERATOR: Thank you. Now, we have a few questions for Dr. Lazarus.
A stem cell product was collected in March and had reactive results on one of the screening tests, with negative results on the confirmatory/supplementary tests that were performed by the establishment. The donor was determined to be ineligible based on the screening results. The donor was recollected in July. At that time all screening test results were negative.
The product that was collected in March could be infused under “urgent medical need” allowances.
- When the donor returned for the July donation/collection and had negative screen results – what is the donor’s status?
- Is the donor determined to be eligible, based on the negative test results obtained at that time, or is the donor in an ineligible status because of the March results?
DR LAZARUS: According to the donor eligibility rule for human cell and tissue product donors or HCT/P donors -- that regulation is in 21 CFR, Part 1271. There's a regulation at §1271.80(d)(1) that, as this inquirer correctly summarizes, a donor who tested reactive on a donor screening test for a communicable disease agent is considered ineligible with an exception provided for syphilis testing. In the interest of time, I'm not going to talk about syphilis testing.
Other than the syphilis testing exception, if confirmatory tests are performed, a negative result on a confirmatory test does not override the initial reactive donor screening test for the purpose of HCT/P donor eligibility determination. This inquirer is correct for the first cell product that was recovered in March. The donor is considered ineligible because of the reactive screening test, regardless of results of confirmatory testing.
Now, to answer the question -- like I said, I'm assuming that syphilis testing wasn't the issue. For the first product, for the cell product recovered in March, the first product, if the donor had a reactive result for a required donor screening test, then the donor is ineligible. For the cell product recovered four months later -- and this is the heart of the question, all the donor screening tests were non-reactive, and the question is whether the donor must be determined to be ineligible based on the reactive result four months earlier. The answer is yes. And here is why. The donor eligibility determination must be based on the results of donor screening and donor testing. For donor screening, we say that you must review the relevant medical records for risk factors for and clinical evidence of relevant communicable diseases. The relevant medical records include a current donor medical history interview, a current report of the physical assessment, and other available records, such as test results.
The reactive donor screening test result from the first donation is part of the relevant medical record and must be considered when making a subsequent donor eligibility determination. Therefore, this donor must be determined ineligible for the second cell therapy product as well. However, like this inquirer correctly summarizes, there is a regulatory mechanism for use of HCT/Ps from ineligible donors. So, this should not preclude the use of the cell product that is deemed medically necessary.
MODERATOR: Thank you, Ellen.
Does a hospital need to register as a tissue bank with the FDA if hospital surgeons collect autologous bone flaps, preserve them using a kit from an off-site storage center and send the flaps off-site to be stored for potential re-implantation at a later date? The tissue would only be re-implanted at the same hospital.
If they do need to register, is there a reduced burden for testing and screening for autologous bone flaps in this instance?
DR. LAZARUS: This question and the other question that I received -- they both relate to exceptions in the tissue regulations. And, the exceptions are listed at §1271.15. So, first, let's look at this question, which relates to the exception in §1271.15(b) which says that you, the establishment, are not required to comply with the requirements in 21 CFR Part 1271, those are the HCT/P regulations, if you are an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure. So, we refer to that sometimes in shorthand as ‘the same surgical procedure exception.’
As some of you may know, a year ago, almost exactly a year ago, we published
“Draft Guidance for Industry: Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception” that further explains the scope of the same surgical procedure exception, because we get asked that -- get asked about it a lot. And, by the way, this draft guidance specifically addresses removal and temporary storage of autologous bone flaps and also autologous parathyroid tissue. The draft guidance explains that, under very limited, circumstances, -- basically, those two circumstances -- surgical removal and subsequent implantation of the autologous tissue may be considered same surgical procedure, even though the removal and future implantation may be a number of days apart. During this time, the HCT/P may be rinsed, cleansed, temporarily stored after being labeled, pending re-implantation, and still be considered same surgical procedure, provided no other steps beyond labeling and storage are performed.
I should mention that this same surgical procedure exception applies only to those establishments that both remove and implant the autologous HCT/Ps at the same establishment. Therefore -- and again, now I'm going to get to the heart of the question. An establishment cannot qualify for this exception if the establishment ships the autologous HCT/P to another establishment for temporary storage. The establishment where the autologous bone flap was obtained and that ships it to another establishment for temporary storage must, therefore, register as an HCT/P establishment, submit a list with the registration of the HCT/Ps they're manufacturing -- because now they're considered manufacturers -- and follow all other applicable regulations in 21 CFR Part 1271 such as pre-distribution shipment, §1271.265, and requirements for manufacturing arrangements at §1271.150(c). Those seemed like two of the potentially applicable regulations.
Also, I would like to point out that the establishment that receives the autologous tissue, temporarily stores it, and ships it back to the hospital when it is needed for implantation in that same individual -- that establishment must also register, submit a list of HCT/Ps that they are dealing with and follow all other applicable regulations in Part 1271.
And then, quickly, the second part of the question is about how the requirements for donor screening, testing, and donor eligibility apply in this type of situation. I just want to point out that donor eligibility determination is not required for HCT/Ps that are for autologous use. However, establishments must comply with the applicable labeling requirements. And they are found in §1271.90(b).
MODERATOR: Thank you, Ellen; here's your other registration question.
DR. LAZARUS: We get a lot of those.
MODERATOR: Yes. We have them for you every year, I know.
Our establishment has a centralized tissue service and we currently distribute pre-packaged (bought or consigned) HCT/P's within our facility. Next year we will be transferring tissue from our site at the main facility to a remote lab site for use at a new ambulatory surgery center. The remote lab will store and distribute the tissue to the ambulatory surgery center, which will be across the street. The remote lab and ambulatory center are part of organization, but are in different locations. The current HCT/P product list for the main facility contains stem cells, cord blood, pancreatic islet cells, and therapeutic cells, but no products from the tissue service.
- With this change, will we need to update the HCT/P registration at the main facility to include tissue that will be transferred to the remote lab site?
- Does the remote lab also need to have a HCT/P registration since the ambulatory surgery center is across the street?
- If the remote lab does need a HCT/P registration, will it be assigned a different FEI number?
DR. LAZARUS: This question touches on one of the other exceptions from the regulation. To reiterate, the main facility is currently registered with FDA for the cell therapy products that they manufacture: stem cells, cord blood, pancreatic islets, and therapeutic cells. They also currently receive and store other tissues for use at their facility. But they don't list these tissue products in their current registration, because they don't perform any manufacturing steps on those tissue products. They only receive those tissue products and use them within their own facility.
Now, things are changing. They now intend to send the tissue products that they receive to another facility, which they refer to as a remote lab site. This storage facility, or remote lab site, will then provide the tissues to a nearby ambulatory surgery center. The inquirer asks whether they need to list tissue products in their current registration and whether this remote storage facility is required to separately register.
So, I'm going to cut to the chase. I can't answer this question, because I don't have enough information. However, let me walk you through the way I would analyze it, and you'll be able to answer it for your facilities. And if you can't answer it walking through it the way I'm going to describe, then contact your district office; they will help you figure out what registration you have to do. So, first, let's look at the exception in the regulation that relates to this scenario. According to §1271.15(d), you are not required to comply with the requirements in Part 1271 if you only receive and store HCT/Ps solely for use within your own facility as long as you don't perform any other manufacturing steps on those products.
Now, let's look at the definition of establishment in §1271.3(b). An establishment is defined as a place of business under one management at one general physical location that engages in the manufacture of HCT/Ps. Regarding FEI numbers for individual establishments that compose a single corporate entity, in 2007, FDA published “Guidance for Industry: Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - Small Entity Compliance Guide” that includes several questions and answers related to registration requirements. As explained in this guidance, each physical location will generally have only one registration number or FEI number that covers the combination of HCT/Ps and functions, unless the establishments are different corporate entities. Different corporate entities get different FEI numbers.
Regarding physical location, what is that? This small entity guidance further explains that one general physical location could be reasonably construed to include separate buildings within close proximity, provided that the activities in them are closely related, are related to the same business enterprise, they are under the supervision of the same local management, and are capable of being inspected at the same time. That's how we understand general physical location.
So, to the question… It appears that, in this scenario, the main facility, the new storage facility, and the ambulatory surgery centers are all under one management. The new storage facility is across the street from the ambulatory surgery center, but I don't know about the proximity of the new storage facility and the main facility, and the main facility is the one that's currently registered with FDA. That's why I can't definitively answer the question about the registration requirements for these facilities.
One possibility is that the main facility, the new storage facility, and the ambulatory surgery centers are under the same management. They're all in close proximity and, therefore, could be considered to be at one general physical location. Then, separate registration would not be required for the new storage facility and the tissues would not need to be listed under the main facilities registration. But like I said, this may not be the case. The new storage facility may not be close to the main facility and there are other possible variables.
So, even though I'm not able to definitively answer the question, I hope that walking you through it the way we analyze these questions will help you figure out your own registration requirements. Ask us, or ask the district, if you're still uncertain.
MODERATOR: Thank you, Ellen.
The next questions are for Penny, who represents the CLIA program at CMS.
When one of the automated methods used for routine testing in a Transfusion Service is a method like solid phase with increased sensitivity, how do you meet the CLIA standard that requires you to do the 6-month method comparison when your alternate method is much less sensitive? Tube testing has been in use for decades and is still the method of choice in small institutions.
MS. MEYERS: The CLIA regulation -- I'll read this to you quickly -- at 42 CFR, Part 493.1281 states the following: if a laboratory performs the same test using different methodologies or instruments or performs the same test at multiple testing sites, the laboratory must have a system that twice a year evaluates and defines the relationship between test results using the different methodologies, instruments, or testing sites. Now, the regulation does not require that the methods have the same sensitivity. That seemed to be the concern of the person asking the question.
So, the laboratory needs to have a procedure for doing it and follow the procedure. How you do it is up to you. My advice would be to keep it simple. And then, you will be in compliance.
Every six months, clinical labs are required to do parallel testing between instruments used for patient testing to show correlation of quantitative and qualitative results between instruments.
- Is this required for instruments used for complex donor testing that are qualitative tests where performance is far more tightly controlled through an extensive system of quality control, repeated in duplicate if reactive, sent for additional more specific/confirmatory testing when available and uses performance checks such as CAP?
- For instruments such as the Tigris which are only approved for donor testing and cannot be used in the clinical setting for patient testing?
This question arises because any lack of correlation would be identified as a false positive/negative (that is close to the cut off); further testing and actions would be followed as part of a specific and well-established process to evaluate such results that was submitted by the manufacturer and approved by FDA.
MS. MEYERS: This is a similar question to the previous one. The answer to the question is yes, it is required. The same regulation applies.
This regulation applies to all testing that's subject to CLIA, which includes donor infectious disease testing. This questioner seems to be saying that well, the lack of correlation would be identified in a different way. My advice to you would be to write up your SOP that would use the characteristics of your test system to show the relationship between the two different instruments every six months. That's how you would be in compliance. We don't tell you exactly how to do this.
MODERATOR: Thank you Penny
Is there a process to get an explanation for a CLIA regulation that did not apply to manual blood bank testing but now does apply to automated blood bank testing?
MS. MEYERS: Well, unfortunately, the person asking this question didn't specify which regulation they are asking for an explanation to. I’ll just say in general, yes, there is a way you can get an answer to CLIA questions. I'll give you some general guidance. If your laboratory is accredited by one of the CMS-approved accreditation organizations for laboratories, they really are your first source of information for regulations. Remember, as an accredited laboratory, you receive your CLIA certification by virtue of your accreditation. And you have to follow all of the requirements for that accreditation organization, even those that may be more stringent than the CLIA regulation.
In addition, if you would like to ask direct questions of CLIA, you certainly can contact us at any time. And you can direct them to the following mailbox that I'm going to give you. It's called email@example.com and someone will answer your question.
MODERATOR: The last questions are again directed to panelists from OBRR.
There is a lot of conversation going on regarding 7 day platelets.
- What are the current options for a registered or licensed blood establishment to use in order to extend the expiration date of platelets to 7 days?
DR. RUTA: The CFR has dating periods for platelets. One of the provisions in here says that the dating period can be specified in the directions for use for the blood collection processing or such system approved for such use by the Director of CBER. Recently, FDA has approved a couple of storage containers that allow the shelf life of platelets to be extended beyond five days, up to seven days, and they contain specific instructions within the instructions for use of the container. The dating can be extended if they're tested with a cleared bacterial detection test that's labeled as “a safety measure.” So, what I would do is refer you to the instructions for use of the containers and to the bacterial test that is labeled as a safety measure and point out that we would consider this testing to be manufacturing. If there are transfusion services that wish to do this, we would expect them to register with us, if they're not currently registered.
MODERATOR: So, this can be achieved with use of the one test that has the safety measure claim?
DR. RUTA: If more come along…
MODERATOR: Yes, thank you.
On a regular basis we thaw plasma and distribute it immediately [has not been refrigerated]. We know from in-house studies that it takes a plasma unit more than 6 hours to reach 1-60 C.
- If the product is issued to the Operating Room where they have monitored refrigerators, or the products are maintained in [validated] coolers, can they be returned to inventory?
MS. CIARALDI: The requirements for the storage of thawed plasma are described in the Circular of Information and not in the CFR. We recognize the most current one, which is the November 2013 Circular, and a guidance document originally issued in August 2013 and updated in April 2014.
The Circular says thawed plasma should be infused immediately or stored at 1 to 6 C. The storage containers, whether they be refrigerators or coolers, should be qualified to ensure they can maintain the proper temperature for the required timeframe. If the plasma is stored in a qualified storage container or storage device within the timeframes established by the qualification process and is not outdated, it may be returned to inventory.
If the testing tech and a second reviewer (supervisor or appropriately trained designee) perform a final review of all maintenance logs, QC, and test reports and sign off as complete and accurate, is a member of the QA staff also required to review all maintenance logs, QC, and test reports before blood products can be released for labeling and distribution? If so, can you please provide the CFR citation for site for our reference?
MR. CONLEY: The questioner wanted CFR citations. So, I'll give you two that are important on the topic, both in 21 CFR, the first being §211.22. This is the section that discusses the responsibilities of your quality control unit. The second citation is at §606.100(c). This section describes the required review of records, the appropriate investigation, and following up when discrepancies or failures to meet the specifications are identified, and the necessity to keep records. What the regulations do not do is they do not dictate who performs the functions of the quality control unit. So, you must define your processes and personnel responsibilities so that the functions are performed and properly recorded.
MODERATOR: Thank you, Gil. So, I think it's important that the SOP determines who is going to provide that requirement for §211.22.
MR. CONLEY: [agreement noted]
In 2012 the FDA sponsored a workshop on Statistical Process Controls (SPC) for Blood Establishments. Concerns related to massive amounts of continuous product testing continue. Large collections establishments access the services of statisticians; my small blood center is hanging in there with almost 100% testing.
- Has the FDA given more thought to the current requirements for inclusion of testing of products from all equipment at all sites, even though it is the same type equipment and same training materials in use at the sites?
- Also, small centers like mine are still waiting for guidance from the FDA on how to meet the requirements when we do not have large collection volumes.
DR. ILLOH: Yes, we have heard comments about this. And as you said, we did have a workshop, in 2012, to address SPC. Now, at that workshop, we discussed options that could be considered in terms of what we have in our two guidance documents. And I'll just shorten it down. I think you know the guidance documents I'm talking about, the leukocyte reduction guidance and the plateletpheresis guidance. And I believe they offer options for both small and large collections. We do know that people would like us to consider other options. And at this workshop, we did encourage blood industry to propose alternatives to what we have proposed and recommended in guidance. We will welcome such proposals.
But to the inquirer, you should know that you can always submit an alternative to what we have in our guidance, an alternate -- what we call an alternate approach to the guidance for us to consider. We have considered such alternative approaches in the past, and we are open to looking at those.
MODERATOR: Thank you. I believe we've arrived at our last question.
What guidance document provides FDA’s current thinking on the deferral of donors who test repeat reactive for HBsAg (HBsAg not neutralizable, HBcAb: NR, HBV NAT: NR) on one or more occasions that includes the use of the HBV NAT having a sensitivity < or = 2 IU/mL at 95% detection rate?
Is there a limit on the number of times a donor with a reactive, not neutralizable HBsAg, can return to donate when all other testing is negative? Is there an option similar to the HB core re-entry algorithm? Is there current guidance on the use of HBV NAT with such a donor test result scenario?
DR. LIEBY: First of all, for the documents, I think we can suggest two documents, the first being the December 2, 1987 memo about establishments entitled “Recommendation for Management of Donor and Units that are Initial Reactive for Hepatitis B Surface Antigen." And the second one would be the October 2012 guidance, “Use of Nucleic Acid Tests on Pools and Individual Samples from Donors of Whole Blood and Blood Components, Including Source Plasma, to Reduce the Risk of Transmission of Hepatitis B Virus."
Now, as far as the questions regarding number of times the donor may donate, donors with a reactive non-neutralizable HBsAb when all other testing is negative will be deferred and the donations destroyed but, based on medical director's discretion, can return to donate after 56 days. Donors will be tested each time they donate. While they remain reactive for HBsAg screening and assay, and negative for all other tests, they will again be deferred and the product destroyed each time. Medical directors may use their discretion to determine how many times these donors may reasonably return to donate.
MODERATOR: Thank you David.
Thank you audience for your presence and your questions, and our panelists for their endurance.