FOOD AND DRUG ADMINISTRATION
ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE
Conference Room
Food and Drug Administration
ATTENDEES
COMMITTEE MEMBERS:
ARTHUR H. KIBBE, PH.D., Acting Chair
Chair and Professor
Department of Pharmaceutical Sciences
KATHLEEN REEDY, R.D.H., M.S., Executive Secretary
Advisors and Consultants Staff
Center for Drug Evaluation and Research
Food and Drug Administration (HFD-21)
JOSEPH BLOOM, PH.D.
4th Floor, Office 416
PATRICK P. DeLUCA, PH.D.
Professor, Faculty of Pharmaceutical Science
327-H
MARVIN C. MEYER, PH.D.
LEMUEL MOYE, M.D., M.D., PH.D.
Associate Professor
University of
at
ATTENDEES (Continued)
COMMITTEE MEMBERS: (Continued)
NAIR RODRIGUEZ-HORNEDO, PH.D.
Associate Professor of Pharmaceutical Sciences
The
CONSULTANTS:
(ROBERT) GARY HOLLENBECK, PH.D.
Associate Professor of Ppharmaceutical Science
University of
20 North Pine Stret
MERYL H. KAROL, PH.D.
Department of Environmental and Occupational Health
MICHAEL S. KORCZYNSKI, PH.D.
Senior Vice President/General Manager
Mikkor Enterprises, Inc.
THOMAS LAYLOFF, PH.D.
Principal Program Associate
Center for Ppharmaceutical Management
Management Sciences for Health
WOLFGANG SADEE, DR.RER.NAT.
Chair, Department of Pharmacology
5072 Graves Hall,
ATTENDEES (Continued)
CONSULTANTS: (Continued)
CYNTHIA R.D. SELASSIE, PH.D.
Professor of Chemistry
Department of Chemistry
Seaver North, Room 219
MARC SWADENER, ED.D.
JURGEN VENITZ, M.D., PH.D.
Department of Pharmaceutics
Medical
Room 340,
INDUSTRY REPRESENTATIVES:
LEON SHARGEL, PH.D., R.PH.
Vice President, Biopharmaceutics
Eon Labs Manufacturing, Inc.
EFRAIM SHEK, PH.D.
Divisional Vice President
Pharmaceutical and Analytical Research and Development
Abbott Laboratories
Dept. 04R-1, Building NCA4-4
ATTENDEES (Continued)
GUEST SPEAKER:
HERB CARLIN, D.SC.
FOOD AND DRUG ADMINISTRATION STAFF:
LUCINDA BUHSE, PH.D.
CHI-WAN CHEN, PH.D.
YUAN-YUAN CHIU, PH.D.
PETER COONEY, PH.D.
DALE CONNER, PHARM.D.
DENA HIXON, M.D.
AJAZ S. HUSSAIN, PH.D.
STEPHEN MOORE, PH.D.
ROBERT OSTERBERG, PH.D.
JONATHAN WILKIN, M.D.
HELEN N. WINKLE
ALSO PRESENT:
THOMAS J. FRANZ, M.D.
Dermtech International
C O N T E N T S
AGENDA ITEM PAGE
MEETING STATEMENT
by Ms. Kathleen Reedy 7
INTRODUCTION TO THE MEETING
by Ms. Helen Winkle 12
SUBCOMMITTEE UPDATES
Process Analytical Technology - by Dr. Tom Layloff 22
Manufacturing - by Dr. Ajaz Hussain 31
Clinical Pharmacology - by Dr. Jurgen Venitz 33
FUTURE SUBCOMMITTEES
Pharmacology-Toxicology - by Dr. Robert Osterberg 38
Microbiology - by Dr. Peter Cooney 44
Biopharmaceutics - by Dr. Ajaz Hussain 47
TOPICAL DERMATOLOGICAL DRUG PRODUCT NOMENCLATURE
by Dr. Yuan-Yuan Chiu 61
by Dr. Jonathan Wilkin 64
by Dr. Lucinda Buhse 79
by Dr. Chi-wan Chen 91
by Dr. Herb Carlin 103
OPEN PUBLIC HEARING PRESENTATION
by Dr. Thomas Franz 149
TOPICAL DERMATOLOGICAL BIOEQUIVALENCE -
METHODS DEVELOPMENT
by Dr. Ajaz Hussain 164
by Dr. Dale Conner 166
by Dr. Dena Hixon 187
by Dr. Jonathan Wilkin 205
COMPARABILITY PROTOCOLS
by Ms. Nancy Sager 221
by Dr. Stephen Moore 227
P R O C E E D I N G S
(
DR. KIBBE: I see by the clock on the wall that we are at
My name is Art Kibbe and I'm acting Chair. The agency always let's people act, but never gives them a permanent position. Helen has been acting Director for three years now. At my school that would allow her to go up for tenure. I don't know what that means.
The first thing we have to do is get Kathleen Reedy to read from a list of important information about conflict of interest. After that, I will ask everyone at the table to go around and introduce themselves, and please use the mike so we can be officially recorded for posterity.
MS. REEDY: Acknowledgement related to general matters
waivers, Advisory Committee for Pharmaceutical Science,
The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
The topics of this meeting are issues of broad applicability. Unlike issues before a committee in which a particular product is discussed, issues of broader applicability involve many industrial sponsors and academic institutions.
All special government employees have been screened for their financial interests as they may apply to the general topics at hand. Because they have reported interests in pharmaceutical companies, the Food and Drug Administration has granted general matters waivers to the following SGEs which permits them to participate in these discussions: Dr. Joseph Bloom, Dr. Charles Cooney, Dr. Patrick DeLuca, Dr. Gary Hollenbeck, Dr. Meryl Karol, Dr. Arthur Kibbe, Dr. Michael Korczynski, Dr. Thomas Layloff, Dr. Marvin Meyer, Dr. Samuel Moye, Dr. Nair Rodriguez-Hornedo, Dr. Wolfgang Sadee, Dr. Jurgen Venitz.
A copy of the waiver statements may
be obtained by submitting a written request to the agency's Freedom of
Information Office, room 12A-30 of the
In addition, Drs. Cynthia Selassie and Marc Swadener do not require general matters waivers because they do not have any personal or imputed financial interests in any pharmaceutical firms.
Because general topics impact so many institutions, it is not prudent to recite all potential conflicts of interest as they apply to each member and consultant.
FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussion before the committee, these potential conflicts are mitigated.
With respect to FDA's invited guests, Dr. Herb Carlin reports that he does not have a financial interest in or professional relationship with any pharmaceutical company.
We would also like to disclose that Dr. Leon Shargel and Dr. Efraim Shek are participating in this meeting as acting industry representatives, acting on behalf of regulated industry.
Dr. Shargel reports he is employed full-time by Eon Laboratories, Incorporated as Vice President, Biopharmaceutics.
Dr. Shek reports holding stock in Abbott Labs and Cephalon, Incorporated, and that he is employed full-time as Divisional Vice President for Abbott Labs.
In the event that the discussions involve any other products or firms not already on the agenda for which FDA participants have a financial interest, the participants' involvement and their exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon.
DR. KIBBE: Thank you.
And now, if we would start perhaps with Ajaz and introduce everybody. Thank you.
DR. HUSSAIN: Good morning. Ajaz Hussain, Deputy Director, Office of Pharmaceutical Science.
MS. WINKLE: Hi. Helen Winkle, acting Director, as Art has already pointed out, of the Office of Pharmaceutical Science.
DR. VENITZ: I'm
DR. KAROL: I'm Meryl Karol from the
DR. SADEE: I'm Wolfgang Sadee. I'm at the
DR. MOYE: Good morning.
Lem Moye,
DR. RODRIGUEZ-HORNEDO: Nair Rodriguez-Hornedo from the
DR. SWADENER: Marc Swadener, retired from the
DR. MEYER: I'm Marvin Meyer, Emeritus Professor,
DR. KORCZYNSKI: Michael Korczynski, consultant.
DR. BLOOM: Joseph Bloom,
DR. SELASSIE: Cynthia Selassie, Chemistry Department,
DR. HOLLENBECK: Hi.
I'm Gary Hollenbeck, Associate Dean and Professor of Pharmaceutical
Sciences at the
DR. DeLUCA: Pat DeLuca,
DR. SHARGEL: I'm Leon Shargel, Vice President, Biopharmaceutics, Eon Labs, a generic manufacturer.
DR. SHEK: Efraim Shek, Abbott Laboratories, industrial representative.
DR. LAYLOFF: Tom Layloff, Management Sciences for Health, a non-for-profit health sector organization working in developing countries setting up health systems.
DR. KIBBE: Thank you.
Now, Helen, do you want to introduce us to the meeting?
MS. WINKLE: Good morning, everyone. It's really my pleasure to welcome you all here for this advisory committee meeting on behalf of the whole Office of Pharmaceutical Science.
I think all of you understand that this advisory committee really provides an important role to the Office of Pharmaceutical Science in really helping us vet the significant science that underpins our complex regulatory processes. This committee continues to provide scientific evaluation and recommendation on broad scientific issues that really help us make our day-to-day regulatory decisions in OPS, as well as in the center. And the committee's scientific input has helped us strengthen and confirm and validate many of our own internal scientific decisions and our scientific knowledge and expertise. So the committee is really valuable, and I think this is a thing I want to especially express today with so many new committee members here, the value that you all bring to us in the Office of Pharmaceutical Science.
I'm going to start off this morning just talking a little bit about what I see as really a significant juncture in the advisory committee. This committee has been in existence for a number of years, but I think we're starting to change some in structure of the committee and the focus of the committee. I wanted to talk first about this before I talked about what we're going to do for the next two days.
The first notable change is Dr. Kibbe. Dr. Kibbe said he is acting now but he will be serving as the full Chair of this committee. Art has already been very invaluable to us as a committee member. His academic experience and his knowledge on the complicated regulatory world of FDA has helped us in clarifying and understanding a number of significant issues in the past. I think many of you know that Art goes back a long way with FDA, and that's actually how I met him, in his past life with FDA. He also brings a keen sense of what FDA needs to do in enhancing its science and technical processes for the 21st century. So we're definitely fortunate to have Art not only as a member of the committee but as its Chair.
Secondly, as I said, we have a number of new committee members. I really appreciate your being willing to serve for us here at OPS and being part of this committee. With new and important questions coming before the agency at a frenetic rate, I think it's really important that the committee members have the scientific knowledge and expertise to address the various subject matters that will come before us and provide us with the wisdom that will help us in serving the public better. We have been really trying to balance off this committee so we can address issues in a variety of ways. We feel honored to have each of you as a member of the committee, and I personally look forward to working with each one of you.
Thirdly, I think there have been a lot of changes in the advisory committee structure. I have talked numerous times about the subcommittee structure, and I think that the structure is going to be extremely important to us in helping better understand some of the questions and some of the science that really underpins coming to the right answer to these questions.
It's difficult when we have a committee that has so many various disciplines on it to really have the knowledge and the expertise to hone in on a specific answer. So with the subcommittees being able to do some of the background for the questions, being able to discuss the questions, and come back with recommendations to the committee, I think this will help the committee better meet its obligations.
Lastly, I think we are in a time of significant changes in the agency. All we have to do is step back and look at the cGMP initiative for the 21st century and the consolidation of some of CBER with CDER, and we know that there are many changes on the horizon for FDA. And these new and exciting initiatives will affect how we in FDA do our business now and in the future. I think that you all are an important part of helping us better understand what our obligations will be as we move to the future and help us address many of the scientific questions that will come up. So I think we're really looking at a whole new era, and you all can be a very active part of that.
I hope you all share my enthusiasm in working on these initiatives, addressing the scientific questions which will arise because of the changes in our processes and our day-to-day operations, and I hope that you will share my enthusiasm in taking on the challenges of this changing regulatory environment. It's really an exciting time.
For the next few days, we're probably going to overload you, as Art has already said, with massive amounts of information. We've got a lot packed into two days, and I sort of want to apologize. But I think the reason for this is we have a lot of what we will call awareness topics. I think with the membership of the committee changing, we need to lay the groundwork of many of the topics that we're going to be bringing up in the future. So it will be fast. Art says you need to listen carefully, but I think there will be some real good discussions.
This morning we're going to start off with a discussion of the subcommittee structure. We've talked about this in the past. I think that structure is really pretty much finalized, and we're moving and setting up a number of subcommittee meetings. We've talked about it, as I have said, in the past. Today we're going to give you a little bit of update on the existing subcommittees and then provide you with where we're going with the future subcommittees. Most of these will be meeting in the next couple of months. So I want you all to be aware of where we are and how we're developing these particular subcommittees.
I do want to publicly, though, thank all of the people in FDA who have worked hard on getting these subcommittees up. As you see, when we start talking about it ‑‑ we have, I think, five, six subcommittees ‑‑ there's a lot of work here, a lot looking for membership, getting the people in. And we've really had to work hard on it. So I really want to thank the people on my staff and others within the agency for working on this.
After the subcommittee discussion today, we'll discuss topical dermatological drug product nomenclature. There are a number of questions which exist regarding the classification of dosage forms, including definitions of ointments, paste, lotions, creams, and gels. Dr. Yuan-Yuan Chiu will lead us in a discussion of the issues and the internal working group's recommendations on how to address various questions.
Dr. Herb Carlin is here representing USP's Nomenclature and Labeling Expert Committee, and he will also present some of his observations and also present us with the direction USP has been going in this area.
Dr. Jonathan Wilkin, who is the Director of the Division of Dermatological and Dental Drug Products in the Office of New Drugs in CDER, will also join OPS's staff in this discussion.
After lunch, we want to continue our previous theme of just talking about topical products, and we're going to be discussing topical dermatological bioequivalence methods development. We've presented several times to the advisory committee on this topic, specifically talking about DPK, dermatopharmacokinetics, and we really want to continue that discussion. At the last meeting we sort of agreed that we needed to back off of our position on DPK to have it as the only method for doing BE for topical products. We took the committee's recommendation to withdraw the draft guidance on DPK and determined that we would take a fresh look at the whole subject of topical dermatological products and the bioequivalence for those.
So today Dale Conner, who is the Director of the Division of Bioequivalence in our Office of Generic Drugs, will begin to reinvigorate the whole topic of BE methods for derm products and will help enhance the committee's understanding of the issues. Dr. Dena Hixon, who is our Associate Director for Medical Affairs in OGD, and Dr. Jonathan Wilkin from OND will talk about the clinical perspective on therapeutic equivalence, and then Dr. Hussain will discuss how we plan to address the topic in the future and will actually solicit the advice of the committee on developing a comprehensive research plan for doing future research in the area of topical bioequivalence.
The next agenda item and the last for the day is on also an awareness topic. Nancy Sager and Steve Moore will discuss the comparability protocol process and its specific principles. I think it will be a very interesting subject for you to hear where we're going with comparability protocols.
Tomorrow we're going to start off with an update of the cGMP initiative for the 21st century. I think all of you are familiar or have at least seen some information on this initiative. We're now starting to call it the drug product quality initiative for the 21st century. I think it's somewhat misleading to call it GMP because it's really focused on the entire quality process from review through the GMP process.
You're probably going to think that we're a little schizophrenic or out of order talking about it tomorrow, but we didn't want to squeeze it on the agenda today because we had so much going on.
We think, though, it's really important that you have a better understanding as the advisory committee of the initiative because I think there will be a lot of things over the next few years that will relate to some of the scientific decisions that will come out of the changes in this whole, entire quality process that we'll want to bring to the committee. So Ajaz and I will talk a little bit about that tomorrow with you.
After plowing through this initiative, we're going to shift gears. We'll discuss the recommendation from the International Pharmaceutical Aerosol Consortium on Regulation and Science, IPAC-RS, on dose content uniformity. IPAC submitted this proposal to us a while back, and conceptually the agency agrees with the recommendations as presented in the proposal, but we feel that there are still a number of questions that need to be answered before we can incorporate that recommendation into our guidance. So tomorrow we'd like to make the committee aware of those questions, have some future discussions at one of the next advisory committees on the recommendation. So basically what we'd like to do is familiarize you with the recommendations, familiarize you with some of our questions, and then go from there at a future meeting.
Bo Olsson from AstraZeneca will present the recommendation on behalf of IPAC-RS, and Dr. Walter Hauck, who has been working with FDA for a number of years and providing statistical support to us as a special government employee, will provide an assessment of the proposal. So it should be a very interesting topic. Wally Adams, who is on the OPS staff, will lead that presentation.
After the open session tomorrow and lunch, we'll present another awareness topic on bioavailability and bioequivalence of endogenous drugs. Approving such drugs continues to be a challenge here in the agency because of the different characteristics of endogenous products. Although we feel that we have made some strong scientific decisions in the past with respect to these products, we think we can continue to enhance the science and provide more complete understanding and information to help better guide the sponsors with regard to what are the correct bioavailability and bioequivalence studies to do for these products.
We have two case studies we'll present, one on levothyroxine sodium tablets and one on potassium chloride modified-release tablets and capsules. In advance I want to thank Abbott Laboratories who has been willing to work with us and to present some of their study data on levothyroxine sodium at this meeting relating to the approaches for baseline corrections.
Dale Conner will lead the overall discussion tomorrow, and Dr. Steven Johnson and Dr. Barbara Davit will present the case studies. It will be an interesting discussion and I look forward to your input.
Lastly, we will provide an update on our research program. We're specifically going to focus on the rapid response program. Dr. Nakissa Sadrieh, who heads up the Rapid Response Team in OPS, will give you an overview of some of the projects we've been working on under rapid response. We feel that it's really important for the committee to have an understanding of the research capabilities that we have available in OPS so as different issues and questions come up before the committee, you know what we might be able to utilize internally to answer some of those questions from a research standpoint.
So as I said earlier, it's definitely a very packed meeting, but I think they will be very interesting topics. I thank you for your participation in advance, and I will turn it back over to Dr. Kibbe. Thank you.
DR. KIBBE: Thank you, Helen.
A couple of points just for everyone's information. There is open public hearing time on both days. Individuals who wanted to make presentations had to have gotten their request in by March 3rd. So we have 1 person on today's agenda and 12 on tomorrow's. So the hour tomorrow will be jam-packed and filled with entertaining presentations.
The next speaker will be the beginning of our reports on the subcommittee updates. Tom Layloff for PAT.
DR. LAYLOFF: Good morning. It's a pleasure to be here in front of the committee again. An unusual event: this is a closing report. The committee is sunsetting. We have completed our objectives and we'll be moving on.
The interest in process analytical technology goes, I think, all the way back to the formulation. If we look at formulating a 50 milligram tablet, we can weigh out the quantities for active diluents and disintegrants of lubricants, and the only issue after the accurate weighing is achieving a uniform product. So it's relatively straightforward. You weigh this out very accurately. You throw it in a bucket, and you get to a uniform, consistent mix. Unfortunately, it's not quite that easy.
Traditionally, the manufacturers follow the active pharmaceutical ingredient as a measure of uniformity throughout the whole process. So the univariate handle is applied to a polyvariate process where you have excipients, diluents, and other materials. And in some cases it is a poor surrogate marker for many of the components in the process.
Process analytical technology is an optimum application of process analytical chemistry tools. It's a feedback process with control strategies. It involves information management tools and/or product/process optimization strategies to manufacture pharmaceuticals. So pharmaceutical design is a critical factor as is information acquired during the process.
The 1978 preamble to the GMPs says, "There is no prohibition in the regulations against the manufacturing of drug products using better, more efficient, and innovative methods." Further, the USP in the general notices says, "Compliance may be determined also by the use of alternative methods chosen for advantages in accuracy, sensitivity, precision, selectivity, or adaptability to automation or computerized data reduction or in other special circumstances." So neither the GMPs nor the USP restrict how you make the assessments of product process streams or product assessments anywhere.
The charges to the Process Analytical Subcommittee were: What is to be gained by embracing the technology? What is the state of the art? What are the problems, hurdles, and solutions? How should the new technologies be regulated? How should FDA be prepared to adapt to dealing with the new technologies? And what are the staff educational issues and how should these competencies be assessed?
Our subcommittee had three meetings. We did applications and benefits. At those sessions we observed that there were, in fact, assessment tools which could be adapted for monitoring the process stream on a continuing basis. Those tools could be validated or qualified, and that there were chemometric tools which could monitor the process.
We went on in our June 12-13 session. At that session I think we made a very significant contribution with a group of individuals getting together and defining the competencies that would be expected for reviewers and inspectors to deal with process analytical technologies and to define a curriculum to achieve those competencies. That was done.
Our October meeting was an add-on, and it was added on because of the perception that there would be problems with the implementation of PAT technologies with the interpretation at the time of 21 C.F.R. 11. Because the PAT is inherently computerized very heavily, the concept of validating software independent of the data acquisition units poses a very severe burden. CDER has moved 21 C.F.R., part 11 into its compliance operations to better bring scientific knowledge of PAT to bear on those assessments.
We also dealt with rapid microbiology testing at that 23rd meeting. How should the FDA respond? Well, the FDA should develop a general guidance, a conceptual framework, and establish regulatory positions on this. The FDA has established ‑‑ I like this ‑‑ PATRIOT. Who came up with this, Ajaz? Process Analytical Technologies Review and Investigation, Office of Pharmaceutical Sciences ‑‑ you've got to say that quickly because it fits in the "O" ‑‑ Team.
(Laughter.)
DR. LAYLOFF: And it's a science and risk-based approach, integrated systems approach.
Now, that PATRIOT initiative is probably, I feel, one of the most important outcomes of the meeting because reviewers and investigators are trained and work as a team to assess compliance in the industry, and I think this is going to be a great boon because if you're not familiar with the technologies, it's going to be very difficult to review the material and very difficult to inspect it. It will be eventually stifled if it's not handled well. CDER, Office of Pharmaceutical Science has moved very quickly and properly to develop the individuals to help deal with these issues.
There is a proposed draft, a guidance on applications with PAT.
A summary of our observations, tools. The assessment tools, data support systems, and technologies are available to improve product consistency and reduce bad production and recalls. We have had many presentations from individuals in the industry and from academia describing those tools and their ability to make those measures.
If we look at one of the problem areas that occurs, we look at the USP content uniformity test issues, the USP allows an RSD of 6 percent. If we have a normal population at 100 percent, there will be 30 tablets in a million out of 75 to 125. The USP allows only 1. So statistically no batch of a million could pass the test because there are more than 1 in 30. There are more than ‑‑ I mean, 1 in 30. We have 30 total. So the PAT initiative will have to have statistical interpretations science-based rather than these hard numbers to deal with, but that's another issue.
The agency's perspective. CDER has assumed a very strong, I think, good position. They're going to use the knowledge, experience, and guidance from other FDA components, NIST, ASTM, and ANSI and do those by reference rather than attempting to develop guidances independently. They will reach out to those existing bodies where many people have put a lot of effort in developing guidances, such as the Design Control Guidance for Medical Device Manufacturers.
Also, they will provide a framework to manufacturers with the flexibility needed to develop design controls to comply with regulations and also appropriate for their own design and development of processes and SOPs.
Future issues. These will be left for other committees. Validation of data and retention of data. In-process endpoint detection and data acquisition and storage. Documentation and E-sig closure of decision points. Incoming material stream consistency of robustness assessments.
Regulatory incentives. The FDA has said PAT is not a requirement. It's an option for those that want to implement it. Regulatory support and flexibility during the development and implementation by meeting with FDA will eliminate the fear of delayed approval and dispute avoidance and resolution in the future. So FDA is willing to work with people, work with the industry.
It's a science and risk-based regulatory approach. Low risk categorization based on a higher level of process understanding. Continuous monitoring on stream will assure a higher quality product. There will be a research exemption so that continuous improvement can occur without fear of being noncompliant. So you can do PAT development work in parallel with your current process stream as a research tool rather than an implementation tool and implement it when you're confident in this thing. Until the FDA has approved a new process approach, the one that is currently approved will stay in force, which is not unreasonable.
What's missing? I believe ‑‑ this is personal ‑‑ industry political will is missing. I think FDA has bent over backwards to take this initiative and have these meetings bringing people together. The ball is now in the industry's court. FDA is waiting.
How to move forward. I think the way to move forward is not to try to eat the elephant in one bite, evolution rather than revolution. Bring on stream validated or qualified PAT systems piecemeal, incoming materials ID, wherever they best fit. But piecemeal.
Acknowledgements. I'd like to acknowledge the leadership of Ajaz Hussain. He has been a greater leader in this business. And Raj Uppoor developing guidances. My former colleagues at the DPA, Division of Pharmaceutical Analysis, and Division of Product Quality Research. The colleagues on and presenters to the Process Analytical Technology Subcommittee.
There's a compilation of reports on the FDA website, and I've given that. And comments and suggestions can be sent to: PAT@cder.fda.gov. Thank you.
DR. KIBBE: Thank you, Tom.
I think we have time for a couple of brief questions, if anyone on the full committee has any questions of Tom.
DR. HUSSAIN: Just sort of an update to all the recommendations that we have received on the PAT Subcommittee. I think this committee was amazingly efficient and effective in getting these recommendations to us. We have actually progressed quite well.
Tom mentioned the PATRIOT team. It's undergoing training and certification
programs as we speak. In fact, next week
they will be going to the
So the training program was brought
together by three schools, the
A guidance is floating around inside OPS right now, and I think we will plan to get the guidance out as soon as possible. The reason we held back the guidance is we wanted to see the evolution of the drug quality system for the 21st century, the GMP initiative, and make sure that PAT becomes a model for that. As that has evolved, the part 11 draft guidance is out, so I think we are now ready to move the general guidance forward which will actually provide not only the regulatory process for implementing PAT, but actually address many of the issues and concerns that industry has expressed to us. So it removes all perceived and real regulatory hurdles for bringing innovative technology into the manufacturing sector.
So I think what was best was, at the final meeting of the subcommittee, industry representatives at that subcommittee were very clear, saying that FDA is no longer the hurdle. The hurdle is within the companies. So I don't want to see FDA being blamed as being a hurdle anymore.
I just want to thank Tom and his leadership. In fact, if you really look at it, the proposal on PAT started in '93 with what Tom had led, but it had subsided. What I have done is brought it back and added my pharmaceutical angle to it. So the FDA initiative actually started in 1993, and I thank Tom for that.
DR. LAYLOFF: I think I'd like to say the PAT strategy that has been implemented in OPS is basically a design strategy for a regulatory action. So it's a quality system approach on how do you regulate because it defines competencies, certification of individuals for training, and the guidance documents are all converging at once. So it's really an excellent example of a quality system approach to setting up a regulatory strategy.
DR. KIBBE: Thank you, Tom. And I'd like to add my congratulations. I think the subcommittee did excellent work. We were very fortunate to be able to bring to the table with us some knowledgeable individuals from industry who came and shared quite openly, and I think that was a good model for moving forward on things like that. You did a wonderful job.
I understand that there's training going on, and I'm sure there will be a manual or something that comes from it. And we could call that the PATRIOT missile?
(Laughter.)
DR. KIBBE: I'm sorry.
Ajaz now is going to talk about the Manufacturing Subcommittee.
DR. HUSSAIN: Well, I think the credit for naming that goes to Karen Bernard, and it was her idea to name it that way, so I sort of accepted that.
I wanted to give you a quick update on the Manufacturing Subcommittee. On October 22nd when we met at the previous advisory committee, we had made the proposal on sunsetting the PAT Subcommittee and in its place establishing a broad, general Manufacturing Subcommittee. The progress I would like to report back to you is that now we have formed the committee. Judy Boehlert from this committee will be the chair of that. The first meeting of this committee is on the 21st of March.
Now, I would like to go back and sort of refresh your memory in terms of why we wanted this committee and what the goals and objectives are. To a large degree, we will use this subcommittee to give us advice to move forward on the drug quality system for the 21st century initiative.
The first meeting of this committee will essentially be to go back and look at the desired state of manufacturing that we have outlined in our announcement on February 20th with respect to what that is and how do we get there and essentially create a framework for the future activities of the subcommittee.
In addition to that, I think there are a number of issues which have already started, the aseptic guidance and a draft guidance that we are working on. Some of that will be discussed here.
Also, I'll remind you this is a team effort. We are partnering with our Office of Compliance and Office of Regulatory Affairs, and we will bring the combined effort on managing the process of the subcommittee.
So I don't have much else to report on this except that now we have formed the committee and the first meeting is on the 21st of March.
DR. KIBBE: Here?
DR. HUSSAIN: Yes, the same room.
DR. KIBBE: Joe?
DR. HUSSAIN: I'm speaking for Joe and myself.
DR. KIBBE: Oh, that's good. We're gaining time. I like it.
(Laughter.)
DR. KIBBE: Thank you, Ajaz.
Jurgen.
DR. VENITZ: Good morning and thank you, Art.
I'm here to represent the Clinical Pharmacology Subcommittee. As most of the members of the committee know, this was a committee that was recommended and endorsed by the parent, the Advisory Committee for Pharmaceutical Science, about a year or so ago.
The intent of this committee is to provide feedback in three different areas, feedback to this parent committee, in the areas of: exposure response, relationship between doses, drug levels, and effect; pediatric clinical pharmacology; and pharmacogenetics. FDA believes ‑‑ and I think this committee agreed with that ‑‑ that those are areas where the science is emerging rather quickly.
We put together the committee membership the second half of last year, and I've listed the members for you. As I said, three areas, pharmacometrics, pediatric clinical pharmacology, and pharmacogenomics. Bill Jusko was kind enough to be the acting chair at our very first inaugural meeting last year. He at that time was also a member of this current committee. You see we had two industry representatives, Michael Hale and Rich Lalonde from Pfizer and Glaxo, respectively, both of them with very extensive experience in exposure response. Myself, I was not on the committee at that time since I was on a sabbatical with the FDA. We have three experts in the area of pediatrics: Ed Capparelli, Greg Kearns, and Mary Relling. And then we have three individuals, Dave Flockhart, Howard McCleod, and Wolfgang Sadee, who is a current member of the parent committee.
We had our first meeting in October of last year, and I've listed for you the topics that we discussed as part of this meeting. Most of those are what Helen would call awareness topics. So this was the first meeting, and we wanted to make sure that the committee members had an idea of what's going to come down the line.
So the first topic was using exposure response information to individualize dose. How can we use information from premarketing studies, from clinical pharmacology studies to optimize dosing regimens and to label new drug products accordingly? What are the data sets that we can use to make that decision in terms of how to label drugs appropriately?
Peter Lee, the Associate Director of OCPB, presented an approach that is currently used that uses kinetic information from usually a special population or drug-drug interaction studies, combines it with exposure-response relationships to predict clinical outcomes. For a given dose, what is the likelihood that we have certain outcomes? And are those outcomes acceptable? If they are not, well, that would lead to a dose adjustment.
We had feedback from the committee members. Rich Lalonde and Lew Sheiner gave an endorsement to the method in general, but discussed specific potential issues with it. In general, the committee requested to get specific case examples to get a better sense for how much this approach could be generalized.
I went on to discuss and introduce a new term called "utility" that deals with linking clinical outcomes to risk where you look not only at outcomes but also the consequences of those outcomes and you try to incorporate that in your decision making process.
The second topic, again an awareness topic, was for the committee to be aware of what the initiatives are within FDA right now in the pediatric area. Arzu Selen presented an updated on OCPB's pediatric database where they're trying to capture on an ongoing basis PK/PD information from pediatric studies.
Rosemary Roberts discussed what is currently done in terms of the decision tree that is used to help extrapolate information from adult studies into the pediatric population.
The final topic was in the pharmacogenetics area. Here the intent again was to make the committee aware of what are some of the issues that FDA is facing right now, particularly for drugs that undergo pharmacogenetically determined either metabolism or other differences in response. Larry Lesko presented some of those issues, the labeling that is used that is currently quite inconsistent.
We then specifically discussed TPMT, an enzyme that shows polymorphic expression, and people that don't have that enzyme or that enzyme is reduced in its activity are at a very high risk of potentially fatal side effects. So one of the questions that the committee was starting to address is, is this something that we should incorporate in the label? Should people be asked to genotype, for example? Dr. Weinshilboum was the expert that really presented on that topic.
After the meeting, pretty much within a few days after, we were informed that the committee membership is not allowed to have industry representatives. So we had to renominate two individuals, Dave D'Argenio and Marie Davidian. Both of them are experts in the pharmacometrics and statistics area.
Our next meeting is next month. You can see it's a follow-up meeting, so the topics look very similar to what I just presented to you. The first topic is again to look at risk-benefit information gleaned from exposure- response data. It's basically a follow-up to the dose adjustment approach that Peter Lee presented, and he's presumably going to show us some case examples.
We're going to follow up on the pediatric initiative, trying to develop a template that helps sponsors to collect information in a way that makes it suitable for FDA to capture it and analyze it appropriately.
We're going to follow up on the pharmacogenomics or the pharmacogenetics topic, look perhaps at different pharmacogenomic issues as they relate to labeling.
And there's a new awareness topic that deals with drug-drug interactions as it relates to metabolism and drug transport.
That's all I have.
DR. KIBBE: Questions?
(No response.)
DR. KIBBE: No questions.
DR. VENITZ: Thank you.
DR. KIBBE: Thank you, Jurgen.
Just something I thought of that I'd like Ajaz to do. Since Jurgen was so kind to give us the names of everybody on the committee, maybe we could do that for the ‑‑ okay.
This brings us to committees that are in the "let's get started" phase, the future committees. We should start with Bob Osterberg.
DR. OSTERBERG: Good morning. I'm Bob Osterberg, the acting, as Dr. Kibbe pointed out many times, Associate Director of Pharmacology and Toxicology in the Office of New Drugs. I think our interaction here indicates that both the Office of Pharmaceutical Science and the Office of New Drugs can work together very effectively to resolve scientific problems that perhaps individually we couldn't do.
I'd like to point out to you that the Office of New Drugs pharm-tox group does not have an advisory committee that we can go to and ask specific questions, and we don't have a research laboratory that we can ask to develop data that we can use to make regulatory decisions.
But we do have a Pharm-Tox Coordinating Committee and a Research Subcommittee of that. Interestingly, Dr. Frank Sistare, who runs the Division of Pharm-Tox in OPS at the laboratories, is my co-chair on this Research Subcommittee. Together we have been asked to develop this particular Pharm-Tox Subcommittee of the OPS.
When Mrs. Winkle told me about this particular activity that she had in mind, I saw the merit of it and I immediately said, yes, I think this is a very good idea. My predecessor in this position also said likewise, I'm told. Of course, when we briefed our Office of New Drugs Division Director, he was also very supportive of this activity.
What I'd like to do is to tell you a few things that we're doing within the subcommittee with respect to its development and this morning I'd like to mention some of the things about the committee with respect to background, its objectives, its mission, and its membership, and a few other things.
Now, the Pharm-Tox Subcommittee is an advisory committee. We pay particular attention to the advice given because it's valuable information. The people on the subcommittee will be experts in their field. They'll be well-recognized scientists and we can rely heavily on what they suggest to us. But their advice, like all advisory committee statements, is not binding on the agency. But as you know, we mostly do agree to accept their opinions.
The subcommittee is expected to
provide feedback to the Pharm-Tox Coordinating Committee and to facilitate
activities down at the
Now, the objective of this subcommittee is to provide expert advisory feedback to the Pharm-Tox Coordinating Committee and the nonclinical pharm-tox research disciplines in targeting cross-cutting areas of pharm-tox, the big problems that we see not specific to any division but across the agency, where integration of new scientific knowledge or methodology could be helpful in drug development and in helping to identify laboratory-based research priorities to address what we perceive to be data gaps as identified by the Pharm-Tox Research Subcommittee.
We also anticipate that the
committee will provide input to the
We also expect the committee to advise the Pharm-Tox Coordinating Committee in the evaluation of research data related to pharm-tox activities.
Now, meetings of the Pharm-Tox Subcommittee of OPS will occur on an as-needed basis. There's no point in having a meeting if there's nothing to discuss, but we anticipate at least that two meetings per year will occur, especially in the early phases of getting this activity together and focused on a common concern.
The agendas and topics that will be presented to this Pharm-Tox Subcommittee will come from the Research Subcommittee of the Pharm-Tox Coordinating Committee because that coordinating committee is the major Office of New Drugs pharm-tox group.
Also, activities and recommendations of this subcommittee will be given to this advisory committee and to CDER's Pharm-Tox Coordinating Committee and on an as-needed basis to NCTR's committee.
A member