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Center for Drug Evaluation and Research

Pharmacy Compounding Advisory Committee

May 6, 1999

Advisory Committee Conference Room, 1066

Food and Drug Administration

5630 Fishers Lane

Rockville, Maryland 20852

Proceedings By:

CASET Associates, Ltd.

10201 Lee Highway, Suite 160

Fairfax, Virginia 22030

(703) 352-0091



Randy P. Juhl, Ph.D., Chair

Igor Cerny, Pharm.D.

Judith Martin Riffee, R.Ph.

William J. Rodriguez, M.D., Ph.D.

Tony Welder, R.Ph.

Loyd V. Allen, Jr.,, Ph.D.

Carmen A. Catizone, M.S., R.Ph.

Elizabeth I. McBurney, M.D.

Sarah L. Sellers, Pharm.D.

Garnet E. Peck, Ph.D.

Christopher T. Rhodes, Ph.D.

William J. Rusho, R.Ph.

Lawrence Trissel, F.A.S.H.P.

Consumer Representative:

Rose-Ellen M. Hope R.Ph.

Industry Representative (non-voting):

David Liebman, R.Ph.

Industry Representative (non-voting):

Joan M. LaFollette, R.Ph.

Consultants to the Committee (Voting):

Kenneth B. Giddes, B.A., M.B.A. (Patient Representative) (Voting on hydrazine only)

Guest Experts of the Committee (Non-voting):

Sid Gilman, M.D.

Janice Dutcher, M.D.

Guest Speakers:

E. William Rosenberg, M.D.

Christopher T. Bever, Jr., M.D.

Donald Sanders, M.D.

Andrew R. Blight, Ph.D.

Ronald Cohen, M.D.

Sharon Hamm, Pharm.D.

Dr. David Jacobus



Call to Order/General Introductory Remarks 1

Dr. Randy Juhl

Conflict of Interest 3

Ms. Jane Peterson

Introductory Remarks 5

Ms. Jane Axelrad

Dermatological Drug Products


FDA Presentation

Dr. James Vidra 21

Dr. Paul Brown 23

Dr. Martin Okun 25

Questions from the Committee 33


FDA Presentation

Dr. Joel S. Hathaway 42

Dr. Paul Brown 44

Questions from the Committee 50

Squaric Acid Dibutyl Ester

FDA Presentation

Dr. Joel S. Hathaway 56

Dr. Paul Brown 58

Dr. Martin Okun 59

Questions from the Committee 62



American Academy of Dermatology Presentation 64

Dr. E. William Rosenberg

Open Public Hearing 87

Discussion and Vote on Dermatological Products 95

Neuropharmacological Drug Products

Dr. John Feeney 133


Dr. Christopher T. Bever, Jr. 141

Dr. Ron Cohen, Dr. Andrew R. Blight 166

Ms. Sharon Hamm 159


Dr. Donald Sanders 209

Dr. David Jacobus 231

Open Public Hearing 247

Discussion and Vote on Neuropharmacological Drug 262


P R O C E E D I N G S [8:30 a.m.]

Agenda Item: Call to Order/General Introductory Remarks

DR. JUHL: Good morning. Welcome to the second meeting of the Pharmacy Compounding Advisory Committee. We have a full couple of days worth of work to do. I think we will -- we have started on time and we will make every effort to end on time as well.

Our first order of business, if we could go around the table and have everyone introduce themselves and their position. We have members of the committee. We have FDA staff as well. And to remind you that you need to be relatively close to the microphone and speak to it and our transcriptionist will wave her hands if we are not doing a good job of speaking into the microphone.

So, let me start -- Dave, if you would begin for us, please.

DR. LIEBMAN: Good morning. I am David Liebman. I am a compounding community pharmacist.

MS. RIFFEE: Good morning. I am Judy Riffee. I am on faculty at the College of Nursing, University of Florida.

MS. LA FOLLETTE: I am Joan LaFollette. I work with Bristol-Myers Squibb in Princeton, New Jersey.

DR. SELLERS: Sarah Sellers, now from North Carolina, currently studying for the boards.

MR. CATIZONE: Carmen Catizone, representing the National Association Boards of Pharmacy.

MS. HOPE: Rose-Ellen Hope, consumer rep, associated with Public Citizen.

DR. JUHL: Rose-Ellen is a new member of the committee. Welcome.

MR. RUSHO: William Rusho, University of Utah.

MR. TRISSEL: Lawrence Trissel, University of Texas, M.D. Anderson Cancer Center.

DR. JUHL: Randy Juhl, University of Pittsburgh, School of Pharmacy.

DR. MC BURNEY: Elizabeth McBurney, dermatologist in private practice and on the clinical faculty at LSU Medical School in New Orleans.

DR. PECK: Garnet Peck, professor of industrial pharmacy, Purdue University.

DR. RODRIGUEZ: Bill Rodriguez, Children's Hospital and George Washington University.

DR. ALLEN: Loyd Allen, International Journal of Pharmaceutical Compounding.

MS. AXELRAD: Jane Axelrad. I am the associate director for Policy in the Center For Drug Evaluation and Research and one of the co-chairs of the Pharmacy Compounding Steering Committee that was created by FDA to address the FDA Modernization Act implementation.

I am going to introduce Lana, who isn't here yet, but my co-chair, Lana Ogram, who is the director of the Division of Prescription Drug, Compliance and Surveillance in the Office of Compliance in the Center for Drugs, will be joining us, I hope, shortly.

DR. DeLAP: Bob DeLap, FDA Office of Drug Evaluation 5. Our office includes the dermatology area.

DR. OKUN: I am Marty Okun. I am a medical reviewer, Division of Dermatologic and Dental Drug Products.

DR. JUHL: Thank you.

Our next order of business is the reading of the conflict of interest waiver by our executive secretary, Igor Cerny, who is taking care of details somewhere.

Jane Peterson, who will actually be our executive secretary for our next meeting.

Agenda Item: Conflict of Interest

MS. PETERSON: The following announcement addresses the issue of conflict of interest with regard to this meeting and it is made a part of the record to preclude even the appearance of such at this meeting. Based on the submitted agenda for the meeting and all financial interests reported by the committee participants, it has been determined that all interests and firms regulated by the Center for Drug Evaluation and research, which have been reported by the participants present pose no potential for an appearance of conflict of interest at this meeting, with the following exceptions.

Since the issues to be addressed by the committee at this meeting will not have an impact on any particular compound, but rather may have widespread implications with respect to this industry, in accordance with 18 USC 208, the participants have been granted a waiver, which permits them to participate in today's discussion. Copies of these waiver statements may be obtained by submitting a written request to the Agency's Freedom of Information Office, Room 12A30 of the Parklawn Building.

In the event that the discussions involve any other compounds or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such 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 compounds they may wish to comment upon.

DR. JUHL: Thank you.

Well, at our first meeting in October to just review a little bit, we began the process of developing the bulk list of drugs that will be available for pharmacists to compound with. There were, I guess, two things that we did there, not only review some individual drugs, but to begin to feel comfortable with the criteria of doing the same.

There were a number of drugs that we had on the list to consider last October that we were uncomfortable with making decisions on for reasons of their complexity or the lack of information. That leads us to our task today. We did the easy ones then. These are more difficult.

So, during our sessions for the next two days we will consider a variety of compounds for a variety of different maladies with a variety of different safety issues.

To kind of start us off, I would like to have Jane Axelrad make her introductory remarks.

Agenda Item: Introductory Remarks

MS. AXELRAD: First, I would also like to welcome everybody here. It was very difficult I understand for several of you to get here today and we really appreciate, you know, the effort that you made to get here. I would also like to introduce before I get into my remarks the other FDA staff who are in the room, some of whom we may be calling upon to answer questions. So, I would ask them to go around and introduce themselves.

DR. JUHL: Except we will need a microphone for them to do that.

DR. BROWN: My name is Paul Brown. I am a pharmacologist from the Division of Dermatologic and Dental Drug Products in CDER.

DR. VIDRA: I am Jim Vidra, the review chemist for DNCB. I am also in the Derm and Dental Division.

DR. HATHAWAY: I am Dr. Steve Hathaway, a chemist with Derm and Dental.

DR. DeCAMP: Dr. Wilson DeCamp(?), chemistry team leader, Derm and Dental.

DR. COSMOS: Mary Jean Cosmos(?), supervisory project manager, Division of Dermatologic and Dental Drug Products.

DR. JACOBS: Abby Jacobs, pharm tox team leader, Derm and Dental Drug Products.

DR. O'CONNELL: Kathryn O'Connell, medical officer, Dermatologic and Dental Drug Products. I am filling in for Dr. Wilkin(?), who is the division director and he is out of town.

DR. TENNELLI: Good morning. Bob Tennelli, CDER, Office of Compliance.

DR. CHAMBERS: Wiley Chambers, deputy director, Division of Anti-Inflammatory Analgesic and Ophthalmic Drug Products.

DR. RICHMOND: Fred Richmond, team leader, Adverse Drug Reaction and Compounding Team within the Office of the Compliance.

DR. MITCHELL: Wayne Mitchell, Regulatory Policy Staff here in CDER.

DR. BROWN: Ron Brown, pharmacist in the Office of Compliance.

DR. SCOTT: George Scott, pharmacist, Office of Compliance.

DR. HEINER: Betty Heiner(?), Federal/State Relations, Office of Regulatory Affairs.

DR. BASAT: Martha Gottem(?) Basat. I am chemist in the Dental Derm Division.

DR. JONES: Mike Jones, pharmacist, Office of the Center Director.

DR. LANDISH: John Landish, Office of Planning and Evaluation.

MS. AXELRAD: Thank you. I really wanted them to introduce themselves. Many of them are members of the Pharmacy Compounding Steering Committee and others are from the division that you will be hearing from this morning, who were involved in the reviews. Over the course of the next two days, you will be hearing from many other Center staff, who have been involved in reviewing these individual compounds because we have had the review divisions involved this time to a fairly extensive amount and they have done a lot of work, but they will introduce themselves as they come.

But I really wanted to recognize the people who have been contributing to our implementation effort. I also want to thank the committee sort of more broadly for being willing to serve on this advisory committee. I know that it is really a lot of work for you all to prepare for the meetings and to come, but it is really very helpful for us to have a panel of distinguished experts to consult with as we work on implementing the law.

I am looking forward to productive discussions over the next two days.

It has been six months -- sorry -- seven months since we last met and we have been very busy during this interim period, working to implement Section 503(a) of the Food, Drug and Cosmetic Act, which was added by Section 127 of the FDA Modernization Act.

I would like to spend a few minutes bringing you up to date on our efforts over the past months and then we will begin our presentations on the drug substances that were nominated for the bulks list.

On January 7th of this year, we published the proposed rules in the Federal Register that would include a list of bulks drug substances that may be used in pharmacy compounding under the exemptions in Section 503(a) of the Act, even though they are neither the subject of a USP or NS monograph nor a component of an FDA-approved drug.

In that Federal Register notice and proposed rule, we proposed 20 drug substances for inclusion on the list, based upon the recommendations we received from the committee at the October meeting. We indicated in the notice that ten additional substances were still under review by the Agency and we solicited comments on these substances. These are the substances that will be discussed with the committee today and tomorrow.

The proposed rule also included and requested comments on the criteria that the agency is proposing to use to determine whether a nominated substance should appear on the bulk drugs list. We discussed these criteria with the committee in October and the criteria proposed for comment reflected the deliberations of the committee.

The comment period for the proposed rule ended on March 23rd, 1999. The proposal generated over 190 comments from individuals or organizations. The vast majority of these comments, about 86 percent, were submitted by multiple sclerosis patients, friends of multiple sclerosis patients, physicians and other individuals in support of the drug substance 4-AP.

These comments were letter or e-mail testimonials about the benefits of 4-AP. Unfortunately, the comments did not include as much scientific or technical data about the use, safety or efficacy of 4-AP as we had hoped. But you will be hearing quite a bit about that this afternoon from our Review Division and a number of outside speakers.

The remaining comments on the proposed rule addressed a wider variety of issues. For example, several expressed support for one or more of the bulk drugs under consideration, especially the dermatological drug products, like chemtheradine(?), DNCB and squaric acid. Several expressed opposition to drugs under consideration, such as mild silver protein or poracetan(?) and several raised larger policy concerns about the Agency's overall efforts in this area.

We are in the process of evaluating these comments and preparing the final rule. The discussions today and tomorrow of the nominations of the substances to be included on the bulk drugs list that may be used in compounding will be considered when we develop the final rule. And, of course, this rule will never be actually final because it may continue to evolve as substances are added or removed from the list.

When the committee last met, we discussed 60 drugs that were being considered for inclusion on a list of drugs that have been withdrawn from the market, because they have been found to be unsafe or ineffective. When we discussed that list, we were concentrating on drugs that have been withdrawn from the market for safety reasons.

As you know, Section 503(a) provides the drug products that appear on a list of drug products published by FDA in the Federal Register, that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective may not be compounded under the exemptions in Section 503(a).

A proposed rule containing this list was published for comment before our last meeting on October 8th, 1998, and a final rule containing a list was published on March 8th, 1999. The committee has been provided copies of the final rule in background packages. And I believe there are copies available elsewhere.

The only comments concerning specific substances that we received on that rule were comments recommending against inclusion of adrenal cortex and neomycin sulfate on the list of drugs that could not be used and comments in favor of including dexphenfluoramine(?) and phenfluoramine(?) on the list.

In the case of adrenal cortex, the Agency decided that the substance should be included on the list that could not be compounded and we included it in the final rule because of our concerns about significant risks associated with the substance, both in terms of bovine spongioform(?) encephalopathy, BSE, and the associated risks of getting Creutz-feldt-Jakob disease and in terms of the risk of under treatment of serious conditions and our rationale is laid out in the final rule.

The Agency decided to postpone final action on parenteral drug products containing neomycin, neomycin sulfate, because of the pendancy of various administrative actions concerning that drug. The preamble to the final rule indicated that neomycin sulfate may be added to the list at a later date.

Therefore,, the final rule contains 59 substances that may not be used for pharmacy compounding under the exemptions in Section 503(a) of the Food, Drug and Cosmetic Act. The list may be updated periodically if other drugs are removed from the market for safety reasons. We hope, of course, they aren't, but we will take that into account.

With regard to drugs that have been withdrawn for efficacy reasons, you may recall that at our last meeting, we mentioned three drugs that were nominated for inclusion on the list of bulks drug substances that may be used in pharmacy compounding under the exemptions in Section 503(a), but that had been withdrawn from the market for efficacy reasons.

Those three were betahistine, hydrochloride, cyclandelate and pentylenetetrazol. We deferred consideration of these because the Agency had not yet determined how we would handle drugs that had been removed from the market for efficacy reasons.

We have now concluded that we do not intend to devote Agency resources to compiling a list of drugs that have been withdrawn from the market only for efficacy reasons. Instead, we have decided that we are going to only focus on drugs that are nominated for inclusion on the list of bulk drug substances that could be used in compounding.

The reason is that if a drug substance is a subject of an approved drug application for at least one indication, it can be used in compounding. If the drug substance is the subject of a USP or NS monograph, it can also be used in compounding. And if it doesn't meet either of these criteria, it can't be used unless it appears on the bulks list.

Therefore, we don't plan to develop a separate list of drugs that may not be compounded because they have been withdrawn only for efficacy reasons. Instead, if something is nominated for inclusion on the bulks list, the fact that it may have been withdrawn for efficacy at some previous date will be considered, along with other information and the other criteria that we have developed to make a decision as to whether it ought to appear on the bulks list.

That is the approach that we are planning to take for those three compounds. In November of last year, we published a guidance concerning our enforcement policy during implementation of Section 503(a). The committee has been provided with copies of that guidance. At our last meeting in October, a number of questions were raised about what was going to happen in terms of the transition period, while we were developing the many documents that we had to develop to implement the statute.

This guidance recognizes that implementation of the new law requires us to develop many different rules and other documents that were not going to be in place when the statute took effect last November 21st. The guidance that FDA will not action to enforce certain provisions of the compounding statute until the related regulation or other document is completed.

For example, it says that FDA will not take action against a pharmacist who compounds a difficult to compound drug product until the agency promulgates the regulations required by the statute identifying what are demonstrably difficult drug products.

In this guidance, the Agency also establishes a specific transition scheme for bulk drug substances that are under consideration for inclusion on the bulks list. In the guidance, FDA gives compounders a one-year period to nominate new substances for the bulks list and that period was from November 21st, 1998, when the statute took effect, until November 21st of 1999.

We indicate that we will exercise enforcement discretion and will not normally take regulatory action against a drug substance that has been nominated during this period while that substance is being evaluated and as long as the substance does not appear to present a significant safety risk.

For those substances that are nominated after November 21st, 1999, FDA will evaluate the substances, but they may not be used in compounding unless and until they are placed on a list if the compounding is going to qualify for the exemptions.

On January 21st, 1999, we announced the availability for comments of a draft standard memorandum of understanding to be entered into by the states that implements the provisions of Section 503(a), that addresses the interstate distribution of compounded drug products.

The comment period on this draft has been extended until June 1st, 1999, and we have received many comments on it, I think, over a thousand comments on this. So, we will be very busy analyzing the comments and doing what we need to do to get that out.

We will finalize the memorandum of understanding in consultation with the National Association of Boards of Pharmacy after evaluating the comments.

We are also working hard on the general pharmacy compounding implementing regulations and on the third list that we were directed to develop, the list of difficult to compound drug products that may not be used in compounding if it is to qualify for the exemptions under Section 503(a). We expect to present the first portion of the list of difficult to compound drug products to you at our next meeting sometime this fall.

Finally, you should know that the day before Section 503(a) took effect, seven compounding pharmacies sued FDA in Federal District Court in Nevada, challenging the constitutionality of certain parts of Section 503(a) on First Amendment grounds. The suit challenged the constitutionality of the provision that states that to qualify for the exemptions under Section 503(a), a pharmacist may not advertise the compounding of particular drugs or classes of drugs, but may advertise the compounding service.

The suit also challenged the provision that for compounding to qualify for the exemptions, it had to be based on an unsolicited prescription. The court issued a temporary restraining order preventing FDA from enforcing these provisions, while the lawsuit is pending and the parties briefing the case said that the court can decide whether to impose a permanent injunction.

Before I turn this over to our first speakers on specific drugs, I would like to briefly mention that three drugs have been nominated for the list that we do not intend to present to you in formal presentations at this meeting.

The first is pentylenetetrazol, one of the bulk drug substances that was deferred after our last meeting because it had been withdrawn for efficacy reasons. Our Review Division searched the literature for articles regarding the use of this compound in humans and was unable to find any information on it. The drug is apparently used in animal testing to induce seizures in animals so that anticonvulsant medications can be tested.

I checked with the International Academy of Compounding Pharmacists, who nominated this substance for inclusion on the list and they were unable to identify any literature on this subject. Therefore, we decided that we really had no basis for including on the list and really nothing to present to the committee on it. So, we won't be presenting anything further on that.

The second compound is chloramine-T. The Agency received a single nomination for this substance. The nominator reported the use of the substance by only one pharmacist at a rate of up to twice a year in a dental office for a root canal procedure. Our review of available data indicated that chloramine-T is an antiseptic agent and possibly an antibacterial. It has some uses in veterinary practices, which is not relevant here because the compounding exemptions only apply to human drugs and not veterinary medicines.

Very little literature could be found on chloramine-T. In reviewing the dental literature, chloramine-T is mentioned in a 1984 edition of Accepted Dental Therapeutics under "Root Canals and Cavity Preparations. However, the current edition of the American Dental Association Guide to Dental Therapeutics, 1998, does not mention chloramine-T. Similarly, chloramine-T is not mentioned in a current endodontic text.

Based on our review of the literature, it appears that this is an outdated therapy for human use in dentistry and that its use is extremely limited. Lacking data on its historical use and with a lack of any evidence of widespread use, we don't believe that the substance should be included on the list of bulk drug substances and we don't intend to present any additional information about this to the committee.

The third compound that we are going to talk about is Peruvian balsam. We received a single nomination for Peruvian balsam. The nominator reported use of this ingredient by only one pharmacist in dermal and dental preparations amounting up to 16 ounces per year. Our review of available data indicated that Peruvian balsam is a gum resin used as a protectant in most cases. It is also an active ingredient in a product licensed as a biologic, used to test for allergic reactions to the balsam.

Because we could not document widespread use of this substance and because of its high potential for producing allergic reactions, CDER believes that this substance should not be consider for inclusion on the list for compounding and do not intend to present a formal presentation on this substance at the meeting.

Of course, if anyone on the committee or any member of the public can supply us with additional evidence that any of these three compounds are widely used in pharmacy compounding or additional information supporting their placement on the list, we will be happy to consider it.

That concludes my prepared remarks. I can take any questions that you might have on what I have said before I turn to the first substances on the agenda.

DR. JUHL: Questions for clarification?

Hearing none, we will move to our first topic of conversation, dinitrochlorobenzene. There will be a series of FDA presentations by Dr. Vidra, Dr. Brown and Dr. Okun.


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