DR. DURFOR: Good morning. Today I wish to give you a brief update on the status of revising the guidance for the preparation of a pre-market notification application for processed human dura mater. You can stay on the first slide, please.

This document has not been publicly released yet, and it is completing the final stages at this time of FDA review and sign-off. Hence, my comments today provide the agency's current thinking on this issue with the intent of updating this Advisory Committee and answering related questions.

Next overhead, please.

Before I discuss the key elements of the proposed revision of the guidance, I'd like to begin by defining the product under consideration. Then I will offer some brief regulatory history as to how we got where we are today.

First, the product under discussion is processed human dura mater. Dura mater substitutes are different products and are regulated as Class 2 medical devices.

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A brief regulatory history starts with the understanding that processed human dura mater for implantation was commercially distributed before the medical device amendments to the FD&C Act were enacted in 1976. Thus, this product is regulated as a pre-amendments medical device.

The sensitivity to Creutzfeldt Jakob disease transmission, related to processed human dura mater implantation, was heightened after the report of the first case of CJD in the United States by the CDC, CJD related to dura mater implantation reported by the CDC in February of 1987.

In April of 1987, the FDA issued a "Dear Doctor" letter to alert physicians about the potential risk of transmitted Creutzfeldt Jakob disease through potentially contaminated batches of human dura mater. This alert specifically mentioned the product Lyadura packaged in 1982. It also requested that all CJD cases be reported to the FDA.

In June of 1987, FDA banned the importation of Lyadura into the United States.

On February 2nd, 1990, the Neurological Devices Advisory Committee to the Center for Devices and Radiological Health recommended that processed human dura mater be regulated as a Class 2 medical device, that is, a device whose safety and effectiveness is maintained through compliance with special controls.

FDA did not finalize this classification recommendation, and hence today processed human dura mater remains an unclassified medical device. As such, commercial distribution requires FDA review and clearance of a pre-market notification application.

To provide guidance to FDA reviewers and product manufacturers, FDA published in June of 1990, a guide for the 510(k) review of processed human dura mater.

In 1996, a Japanese survey identified 43 cases of Creutzfeldt Jakob disease associated with the use of processed human dura mater. Most of these cases were associated with the use of Lyadura.

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In March of 1997, the World Health Organization recommended that processed human dura mater grafts no longer be used, especially in neurosurgery, unless no alternative was available.

The following day, an announcement from the Japanese Health and Welfare Ministry banned the use of dura mater in brain surgery. Because FDA had established safeguards and guidelines in 1990 to minimize the possibility of such infections, the agency at that time did not restrict the distribution of dura mater cleared for the United States markets.

While the U.S. distribution of processed human dura mater was not restricted, FDA did, however, feel that further evaluation of these issues and alternative practices was appropriate. Thus, in October of 1997 this Committee considered the risks and benefits of human dura mater implantation through the testimony of manufacturers, neurosurgeons, and other scientific personnel.

At the conclusion of this meeting, the Committee provided FDA with recommendations for improving the safety of processed human dura mater. Based on these recommendations and internal FDA discussions, FDA issued to the processed human dura mater providers regulatory correspondence in March of 1998. These letters offered recommendations for improving the safety of processed human dura mater.

Thank you.

The following month, FDA presented once again to this Committee proposed revisions in the recommendations for improving the safety of processed human dura mater. These FDA proposals were based on previous Committee recommendations, responses from the providers of processed human dura mater, and FDA discussions.

At the end of that April 1998 Committee meeting, additional guidance on these proposed recommendations was offered by this Committee.

Finally, in December of 1998, FDA issued a tracking order for processed human dura mater. This regulation insures the tracking of each device from the manufacturing facility to the patient.

In March of this year, Tutogen Medical Corporation initiated a recall of Tutoplast processed dura mater with expiration dates before April of 1999. This recall was based on a concern that patients may potentially contract CJD from an implanted piece of dura mater contaminated with CJD prions.

Another important in the regulation of human dura mater was the February 1997 publication of the proposed approach to the regulation of cellular and tissue based products. This document, in particular, states that FDA may in the future redesignate human dura mater to the regulation under the human tissue regulation under the legal authority of Section 361 of the Public Health Service Act.

Currently, FDA still believes that human dura mater may be regulated under the human tissue regulation in Section 361 of the PHS Act. However, the transfer of regulatory authority for processed human dura mater may not occur until the rule for human tissue regulation is finalized. Until that time processed human dura mater will remain a medical device, and consistent with other medical products, FDA believes that all guidance documents should be updated as our scientific understanding of specific issues evolves. This is the basis upon which I come before you today.

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Once again, the information I'm presenting reflects FDA's current thinking about issues that would be appropriate for a guidance document. The document has not been publicly released. However, when the guidance has completed FDA review and sign-off, a notice of availability will be published in the Federal Register, and the document will be posted on the FDA Web site.

With this caveat in mind, the next three slides provide a general outline of what a proposed guidance could be. The final slide then provides additional information on specific topics.

It should be noted that this revision of the guidance document largely draws upon existing FDA guidance documents, as well as FDA experience in the regulation of human dura mater, communications with industry, recommendations of this Advisory Committee, and the published scientific literature.

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The general outline of the document includes information or guidance on qualification for donors and device components, device manufacturing methods and manufacturing controls, product sterilization issues.

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There is also guidance provided on product characterization, device packaging and labeling.

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The new major guidance presented in this document, folks, is on the issues on this slide, and I'd like to go through them briefly with you. There is information and guidance provided to manufacturers with regards to donor suitability, with regard to serology testing for infectious disease, evaluating risk factors for and clinical evidence of neurological and infectious diseases through both review of medical records and interviews with next of kin, and a physical assessment of the cadaver.

The guidance also recommends a full autopsy on each donor's brain. This would include gross examination of the entire brain, including multiple cross-sections. Histological examinations of multiple tissue samples from different parts of the brain is also recommended.

Regarding archiving of brain and dura mater tissue, FDA recommends that frozen and fixed samples of both donor brain and dura mater tissue should be archived. The donor brain samples would include at least five grams of the frontotemporal region.

FDA recommends that these samples be retained for ten years. This recommendation is based upon the current state of scientific knowledge regarding the development of Creutzfeldt Jakob disease screening tests and our expectation that as science evolves, screening tests may become available within that time.

Regarding PrP testing, we recognize that this is currently a research and investigational use tool. Because there is no approved or validated test that is marketed for screening of Creutzfeldt Jakob disease in the brain, the FDA is not recommending its use at this time.

However, when either a validated test does become available or evaluations of available data demonstrate the utility of PrP-RES testing, FDA will recommend the use of this test.

Regarding viral inactivation and disinfection, once again, FDA believes that careful control of donor selection and tissue collection procedures constitute critical safety practices for processed human dura mater.

In addition, histological examination of the brain may detect most infected tissues, but it may not identify all infected grafts. Therefore, FDA recommends treatment of each product with a generally accepted disinfection technique, and this will provide an additional level of device safety, assurance for device safety.

This particular Committee has recommended treating processed human dura mater with one normal sodium hydroxide. FDA recommends that sponsors supply information about methods for disinfection with sodium hydroxide or another procedure that has been validated to significantly reduce CJD infectivity.

Such data would also demonstrate that subsequent rinsing steps are sufficient to reduce the concentration of residual disinfection to a noncytotoxic level.

Regarding dura mater processing, FDA recommends that processed human dura mater grafts from different donors not be commingled during tissue collection or product manufacture.

FDA also recommends that manufacturers take all appropriate efforts to eliminate any opportunity for cross-contamination during tissue collection and processing. For example, FDA recommends that manufacturers use only disposable processing material and surgical instruments during the recovery and processing of dura mater allografts.

Regarding record keeping and tissue tracking, this section -- issues of device tracking have already been discussed, but this section also provides guidance on the sort of documentation that should be kept by manufacturers on each donor, and it also requests in the product labeling that information be provided to a graft recipient in writing, that he or she has received a processed human dura mater graft implant.

In conclusion, I wish to thank the panel for their previous scientific input on this issue and also the time at this meeting to present FDA's current thinking on a revision of the guidance for the preparation of a pre-market notification application for processed human dura mater.

We also recognize that rapid scientific and medical advances in this field may require this to be a continually evolving guidance document.

Thank you very much.

CHAIRMAN BROWN: Thank you, Dr. Durfor.

Does the Committee have any questions for Dr. Durfor?


DR. ROHWER: Dr. Durfor, it might be informative and enlightening to know why there was a withdrawal of the Tutoplast product since I thought there was no commingling in U.S. produced dura, and we were using sodium hydroxide.

DR. DURFOR: This sponsor initiated recall, was recalled because patients could potentially contract CJD from an implanted piece of dura mater, and the presence of the CJD could be due to inadequate donor screening or handling by the German manufacturer, Pfirmer-Vigo.

CHAIRMAN BROWN: Does that mean that in your interpretation of this, that is, the company voluntarily withdrew?

DR. DURFOR: Correct.

CHAIRMAN BROWN: On the basis not because of specific knowledge that that particular graft which had caused CJD had, in fact, been batch processed, but because they were concerned that other batches -- other dura processed at the same time, even though they didn't come in contact with this dura, might somehow have escaped adequate screening?


CHAIRMAN BROWN: Was there any -- Peter. I'm sorry. There was a question over here. Linda.

DR. DETWILER: I just had a question. In animals with TACs, mostly sheep and goats and deer, it's been established -- deer and elk -- it's been established that PrP-RES is there prior to clinical signs and histological lesions, and I can understand about this validation and whatnot that's commercially available. However, what would be the incentive in the human public health arena to have anybody validated if it's not mandated?

I mean if you don't mandate it, what other use, other than screening for things like this, would you have to have anybody want? The demand would not be that great, right?

DR. DURFOR: That's why when I discussed this issue I suggested either a validated test or evaluation of current scientific data, and so it's a matter of keeping up with where the science is and how well the screen tests can work in the area of human dura.

DR. DETWILER: Well, I would ask then the Committee because, I mean, the human, is it not there yet for human for detection in the brain?

CHAIRMAN BROWN: We have -- we can answer that. We have two questions. Who wants to go first, Peter or Kiki?"

DR. LURIE: I was sort of back to the recall. So why don't I wait?

CHAIRMAN BROWN: Okay. Okay. Kiki.

I don't think the mic is on, Kiki. Is there anybody operating the microphones?

DR. HELLMAN: Hello? That's better.


DR. HELLMAN: Kiki Hellman, FDA.

I just wanted to follow up on Linda's comment and also a comment that Chuck made.

The PrP-RES testing, and we went into quite a discussion of this with the Committee at our last meeting, we do require a validated test by the FDA, and it is for this reason that we have discussed within the FDA the holding of a workshop on diagnostics. We're hoping that we will convene this either later this year or early next year to look at the status of the different tests that are being developed, with the goal, I might say, to encourage the developers of tests to get their tests validated and to submit to the FDA for approval of that test.

So we are taking a proactive role in this regard.

DR. LURIE: Paul you hinted at this, but unfortunately the presentation did not make clear that the reason for the recall is because there was a case of CJD related to dura mater, and I think that the committee needs to know that, and in fact, the recall was made of a material described. It was a 39 year old woman who had been implanted in 1992 following a duraplasty during a neurosurgical procedure.

She developed CJD in June of 1998, and she died in September of 1998.

The company had been subject to a couple of inspections back in '92 and '93 which revealed problems in donor screening and processing, and in 1994 an import alert, but no recall was announced.

It's true evidently that there was not commingling in the sense of the Lyadura implant, and it also seems to be true that there has been an improvement in the processing of the dura mater in that one normal sodium hydroxide at least in the present version of the company's product is now used.

But for me, this emphasizes again that there is unnecessary risk there; that there are alternatives that have been suggested and alternatives that have been implemented in other countries, and I think that this case -- because that is what caused the recall -- is, again, concerning -- and I think that to me all of this, improvements in the guidance, are really just window dressing as far as I'm concerned. This product needs to be off the market.

CHAIRMAN BROWN: We can discuss that a little bit. I would take a different direction than you suggest. This was, of course, with you present, discussed at the meeting in which the dura was discussed, and one of the options was to recommend banning dura altogether. That was rejected, I think, fairly soundly by the Committee, and the alternative procedural option was taken, and I think that had this donor been subject to the regulations which were recommended by the Committee, this never would have happened.

It's not just a question of sodium hydroxide disinfection. It's a question of non-commingling, which presumably did not occur. It is a question of adequate historical screening. It is a question of a complete neuropathology exam, and it is, finally, a question of, in addition to all of that, sodium hydroxide decontamination.

Had each of these steps been followed, this dura surely never would have been implanted, never would even have been -- well, it would have been collected, but it never would have been distributed.


DR. SCHONBERGER: Yes. I'd like to concur with what you just said and point out that the actual selection of this particular dura for the case that Peter described was in the 1990 period, and then the questions that Peter raised about FDA questioning the adequacy of their screening was actually done in subsequent years and was, as I understood it, corrected by FDA regs and actions as of 1994.

So as Paul has said, the current regs, even since 1994, probably would have stopped this case, and the regs that we're talking about now are even more conservative.

In investigating this case, I can give you an impression that there tended to be perhaps an over reliance, in my opinion, on the efficacy of the sodium hydroxide step, and an under appreciation, in my judgment, of the importance of screening. I think that that situation has now changed, and this case, I think, demonstrates the importance of screening.

CHAIRMAN BROWN: Yes, and in summary, this is history.


CHAIRMAN BROWN: And because of the long incubation period, you only find out about it now after the more recent regulations were put into place, which would certainly -- I think there is absolutely no question that this case never would have occurred under current regulations.

So I don't think we need to further revise what we recommended last year. I think those safeguards are very stringent and will be very effective. I don't expect ever again to see a case of dura mater CJD in this country as a result of having been done since last year. I just can't imagine it.

DR. SCHONBERGER: Just for the record, let me say because I know the company would object in saying that this is not a proven relationship, and CDC would concur that it is not a proven relationship, although in our judgment the association certainly makes it, in our judgment, a probable etiologic relationship.

CHAIRMAN BROWN: The company has no case, period.


DR. ROOS: There's a little bit of a stretch, but I just wonder whether these kinds of regulations should also be implemented for something like corneal transplants. Are we dealing with a different entity there or is it similar?

And if it's similar, would we be consistent about moving over towards comparable regulations?

DR. DURFOR: I think that was the intent of the proposed rule that I mentioned or the proposed approach to regulation of human tissue. The focus of Section 361 of the PHS Act is to provide safe, implantable material through maintaining appropriate storage and disinfection techniques. So yes.


DR. HELLMAN: Yes, and I would just reiterate -- Kiki Hellman, FDA -- that the more we learn about adventitious, potentially infectious agents from animal and human derived material, the more stringent we are becoming and the more attentive we are to these types of problems.

And I think that the dura mater issue is actually a case in point and provides a prototype for the types of things that we're going to be concerned about.

CHAIRMAN BROWN: Yes, it may be that the FDA will want to convene us at some time in the next year or two to consider precisely that question. That will raise a huge whoop and holler from the eye banks, and the situation is a little different and would have to be considered a little differently.

As opposed to more than 80 dura mater CJD cases, there are two certain and one probable corneal case, and I would guess that the number of corneas transplanted exceed by several-fold the number of duras. So it's certainly on the basis of that alone not as risky a matter and deserves separate consideration.

Are there any other questions before we go on to the sheep subject?


DR. SCHONBERGER: I wanted to just put this on the table. To our knowledge, there has not been a confirmed case of -- let's put it this way -- a confirmed relationship, etiologic relationship, between the product that has been used or made, fully processed in the United States that does not use the sodium hydroxide step, that has been very strongly concerned about screening and has been successful in tight screening, and the new regs, our guidelines are saying that they should use sodium hydroxide or something equivalent to it.

Because this is an area of some controversy about whether the sodium hydroxide step is absolutely necessary if one does use the severe screening test, including an autopsy on the donor, I was wondering whether there's any reports that anybody in the audience or others know about of any complications with the sodium hydroxide.

I've been contacted by a W. Guest, M.D., Executive Director of Transplantation Research Foundation, who said, "Dr. Schonberger, I want you to know that we have had at least the strong suspicion that residual sodium hydroxide," quote, "in Tutoplast has led to fulminant postoperative inflammatory reactions that resulted in cortical scarring, meningo cortical adhesions, and epileptic seizures in at least two patients."

I told him that I would at least if I had the opportunity bring that up to the Committee, so at least put that on the table, and I don't think he has convincing evidence that these complications are, in fact, related to the sodium hydroxide step, but if there is evidence that others know about, that there's complications with the sodium hydroxide, I think that should be raised.

CHAIRMAN BROWN: Well, it's on the table. I don't think we have the expertise either in the Committee or in the room to know anything about that kind of reaction.

I haven't heard personally about any, and I imagine a solicitation of neurosurgeons in this country would answer that question very quickly.

Stan, did you have -- I'm anticipating your finger.

DR. PRUSINER: I, just for completeness, since we're having this discussion, will be very brief. I think that we get a false sense from the idea that an autopsy on these patients who are the donors necessarily exclude CJD. We can have people who have very few histologic changes. We've had several cases like that.

You can do PrP scrapie or PrP-RES, whatever you want to call it, determinations. In a big brain, you can find many areas where you see no protease resistant PrP.

So the idea of having a workshop and discussing this and trying to come up with some, I think, better procedures to try to screen for dura from donors who to all one's best information do not have prions in their brains contaminating the dura I think is a good idea because I really don't know a simple way to say this piece of dura does not contain prions.

And I'm not sure even that the sodium hydroxide method as it's used currently is absolutely the best that can be done.

CHAIRMAN BROWN: Yes, I don't think anybody on the Committee would disagree that no single step is adequate to insure total safety. I think most of the Committee would agree that the ensemble of steps, particularly if in the future it includes testing for PrP-RES, will virtually eliminate risk entirely.

But that is a subject for another conference.


DR. ROHWER: I would like to be absolutely clear though about this withdrawal because as I understand the presentation here, the recommendations were made in '97, 10/97, and this case occurred in '98. When was the dura actually implanted?


DR. ROHWER: Oh, '92. I see. Okay. That I had missed.

CHAIRMAN BROWN: Oh, and I forgot. For the purpose of the Congressional Record, it should be stated that Dr. Roos' absence yesterday was because of a phone call, not for any other reason.


DR. ROOS: Thank you, Paul.


Safe sourcing of sheep derived and goat derived materials contained in or used to manufacturer FDA regulated products will be initiated, with a background and introduction presentation by Dr. David Asher, Center for Biologics Evaluation and Research of the FDA.