UNITED STATES OF AMERICA

P R O C E E D I N G S

(8:05 a.m.)

CHAIRMAN CANTILENA: Good morning, everyone. We'd like to get started.

I'd like to welcome you to the December 16th, 2003, meeting of the Nonprescription Drugs Advisory Committee and jointly with the Reproductive Health Drugs Advisory Committee.

We're here today to discuss the proposition of switching Plan B from Rx to over-the-counter, and before we get started, Dr. Somers has a statement that she needs to read for all of us.

DR. TEMPLETON-SOMERS: Good morning, and welcome to this joint session of the Nonprescription Drugs Advisory Committee and the Advisory Committee for Reproductive Health Drugs.

All committee members have been provided with copies of background materials from both the sponsor and the FDA and with copies of the letters from the public that were received by the December 5th deadline. The background materials were posted on the FDA Web site yesterday morning.

Copies of all of these materials are available for viewing only at the FDA desk outside this room.

Today we have a very large table, a full house, and an exciting topic. So we'd like to start with a few rules of order.

FDA relies on its advisory committees to provide the best possible scientific advice available to assist us in making complex decisions. We understand that issues raised during the meeting may well lead to conversations over breaks or during lunch.

However, one of the benefits of an Advisory Committee meeting is that the discussions take place in an open and public forum. To that end, we request sincerely that members of the committee not engage in private, off-record conversations or interviews on today's topic during the breaks or during lunch.

Whenever there is an important topic to be discussed, there are a variety of opinions. One of our goals today is for this meeting to be conducted in a fair and open way where every participant is listened to carefully, treated with dignity, courtesy, and respect. Anybody whose behavior is disruptive to the meeting will be asked to leave.

We are confident that everyone here is sensitive to these issues and can appreciate that these comments are intended as a gentle reminder. We look forward to a productive and interesting meeting.

Thank you.

CHAIRMAN CANTILENA: Okay, and as I said earlier, my name is Dr. Lou Cantilena, head of clinical pharmacology at the Uniformed Services University. I'll be chairing this meeting.

And we'd like to go around so that everyone can introduce themselves, and we'll start on this side.

DR. ALFANO: Michael Alfano, Dean of the Dental School at New York University.

DR. HAGER: David Hager, Reproductive Health Drugs, from the University of Kentucky.

DR. LAM: Francis Lam from University of Texas Health Science Center in San Antonio, a member of NDAC.

DR. LIPSHULTZ: Larry Lipshultz, Professor of Urology, Baylor College of Medicine.

DR. JOHNSON: Julie Johnson from University of Florida Colleges of Pharmacy and Medicine, from the Nonprescription Drug Committee.

DR. MACONES: George Macones. I'm Associate Professor of OB-GYN and Epidemiology at the University of Pennsylvania on Reproductive Drugs.

DR. PATTEN: Sonia Patten. I'm a consumer representative. I'm an anthropologist on faculty at Macalester College in St. Paul, Minnesota, and I'm part of the Nonprescription Drug Committee.

DR. CROCKETT; I'm Susan Crockett. I'm a general OB-GYN Director of Maternity Services for the CHRISTUS Santa Rosa Family Practice Residency Program, and I'm a member of the Reproductive Health Drugs Committee.

DR. UDEN: I'm Don Uden, a professor at the University of Minnesota College of Pharmacy and member of NDAC.

DR. STANFORD: Joseph Stanford, University of Utah, Department of Family and Preventive Medicine on the Reproductive Health Drugs Committee.

DR. BENOWITZ: Neal Benowitz. I'm an internist and clinical pharmacologist from U.C., San Francisco, on the Nonprescription Drug Committee.

DR. LOCKWOOD: Charles Lockwood, Chair of OB-GYN at Yale and Reproductive Drugs.

MS. TULMAN: Lorraine Tulman, Associate Professor, University of Pennsylvania School of Nursing, Reproductive Health Advisory Group, and I'm the consumer representative for that group.

DR. TRUSSELL: James Trussell from the Office of Population Research at Princeton University.

DR. GIUDICE: Linda Giudice, reproductive endocrinologist and Professor of OB-GYN at Stanford University, and Chair of the Reproductive Health Drugs Committee.

DR. TINETTI: Mary Tinetti, Department of Medicine, Yale, Nonprescription Drug Committee.

DR. HEWITT: I'm Geri Hewitt, Assistant Professor of the Department of OB-GYN and Department of Pediatrics at Ohio State College of Medicine.

DR. GREENE: I'm Michael Greene, Professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School.

DR. CLAPP: Leslie Clapp, pediatrician, Buffalo, New York, and Clinical Associate Professor of Pediatrics, University of Buffalo.

DR. SNODGRASS: Wayne Snodgrass, Department of Pediatrics, University of Texas in Galveston, and clinical pharmacology on the Nonprescription Drug Committee.

DR. LEWIS: Vivian Lewis, Professor of OB-GYN at University of Rochester, and I'm on the Reproductive Health Drugs Committee.

DR. BLASCHKE: Terry Blaschke, internist/clinical pharmacologist, Stanford.

DR. WOOD: I'm Alastair Wood from Department of Medicine, Department of Pharmacology at Vanderbilt, and I'm on NDAC.

DR. EMERSON: Scott Emerson, Professor of Biostatistics at the University of Washington on Reproductive Drugs.

DR. BERENSON: Abbey Berenson, Professor of OB-GYN and Pediatrics at University of Texas Medical Branch at Galveston.

DR. DAVIDOFF: I am Frank Davidoff. I'm the editor emeritus of the Annals of Internal Medicine; also now the executive editor at the Institute for Health Care Improvement, and I'm on the NDAC.

DR. MONTGOMERY: Valerie Montgomery Rice, Professor and Chair of Obstetrics and Gynecology, Meharry Medical College, and I'm on the Reproductive Health Drugs.

DR. GRIEBEL: Donna Griebel, Deputy, Division of Repro. and Urologic Drug Products, FDA.

DR. ROSEBRAUGH: Curt Rosebraugh, Deputy of Over-the-Counter Drug Products.

DR. BEITZ: Julie Beitz, Deputy Director, Office of Drug Evaluation III, CDER, FDA.

DR. BULL: Good morning. Jonca Bull, the Director of the Office of Drug Evaluation IV in CDER, FDA.

DR. GALSON: Steve Galson. I'm the Acting Director of the Center for Drug Evaluation and Research.

DR. KWEDER: I'm Sandra Kweder. I'm the Deputy Director of the Office of New Drugs in CDER.

DR. TEMPLETON-SOMERS: Thank you. I'm Karen Templeton-Somers, Executive Secretary to the Committee, FDA.

And the following announcement addresses conflict of interest issues with respect to this meeting and is made a part of the record to preclude even the appearance of impropriety at the meeting.

The conflict of interest statutes prohibit special government employees from participating in matters that could affect their own or their employer's financial interests. All participants have been screened for interests related to the product, competing products and companies that could be affected by today's discussions The agency has reviewed the interests reported by the committee participants and has determined that there is no potential for a conflict of interest at this meeting.

We would like to disclose that Dr. Michael Alfano is participating as the acting industry representative, acting on behalf of Regulated Industry.

In the event the discussions involve any other products or firms not already on the agenda for which FDA participants have 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 products they may wish to comment upon.

Thank you.

CHAIRMAN CANTILENA: Thank you, Dr. Somers.

We'll now hear from Dr. Sandy Kweder, who will open the meeting for the FDA.

DR. KWEDER: Well, good morning, everyone, and welcome. I'd first like to start off the meeting by acknowledging the large size of the panel today and thanking all of you on the panel for coming here. Sometimes a large panel makes interchange more difficult, but I think Dr. Cantilena is probably up to the challenge.

Your discussion is extremely important to us, but before you begin that, I'd like to provide some background perspective as to how we got here.

Following my remarks, Dr. Curt Rosebraugh will introduce the subject in more detail and get on with some of the scientific presentations.

First, let me be clear that we're here today to discuss the scientific data available to address Barr Lab's application to remove the prescription requirement for their product Plan B. Plan B is an emergency contraceptive that is indicated for use in the unexpected circumstance when another standard contraceptive method fails or fails to be used.

While previously established safety and efficacy data for this medication will be referenced, you'll be asked to consider these data only as they relate to Plan B's suitability for nonprescription status. You'll hear a lot more about FDA's general approach to making decisions about switches from prescription to nonprescription status. So I'm not going to address that further.

But, secondly, I would like to assure you that we at FDA recognize the broad array of issues related to emergency contraception, in general, that may arise in your discussion. None of these are new.

In June of 2000, FDA, CDER particularly, held a Part 15 hearing. The purpose of that two-day hearing was solely to solicit public testimony on the future of prescription to nonprescription product shifts. We requested that experts and any concerned member of the public come and share their perspectives in several areas.

What products should and should not be considered for nonprescription status?

What are the perceived incentives and perceived barriers to such shifts?

And outstanding issues, what are they that might be addressed to modify incentives and barriers?

I was part of the FDA panel listening to that testimony. In addition to other product groups discussed, like cholesterol lowering agents, non-sedating antihistamines and antihypertensives, we heard several hours of testimony regarding oral contraceptives as potential candidates for being available without a prescription, but in particular, many speakers favored or did not favor making emergency contraception nonprescription.

Those in the favoring group pointed out that the clinical safety of the product and the importance of access to emergency contraception are the keys to maximizing its effectiveness. For example, if the product is to be used as directed, the woman must be able to take it within 72 hours of intercourse. This is often not achievable given our current system of pharmacy practice.

They also cited studies in the literature which showed that women do not appear to substitute emergency contraception for other more traditional forms of contraception.

Those who did not favor nonprescription status raised public health concerns about potential effects of wider availability of the product on adolescent health and behavior. For example, these speakers did not find the published literature convincing with regard to the impact of more readily available emergency contraceptives on adolescent behavior. Of particular concern to them were whether nonprescription access would increase sexually transmitted infections and decrease the use of other more effective contraceptives or even affect choices about sexual behavior in adolescent groups.

We at FDA understand the complexity and the multiple perspectives on these matters. We will consider their full breadth before arriving at any final regulatory decision following this meeting.

Finally, I want to say a few words about seeking answers to difficult questions and decision making. One of the things that we at FDA do when we're faced with one is we often look to others' experiences to see what has happened with those who have gone before us.

For example, we look to the experience of products as they may be marketed in other countries. Some of those experiences may come up today in the presentations and your discussions. You may be reassured by these or frustrated because there are not detailed data to answer questions you might like to have addressed.

Please keep in mind that considering the effects of nonprescription or prescription medicines in countries other than the United States is fraught with challenges of interpretation because of differences in pharmacy models.

For example in some countries having things, what might be called behind the country, only means that a person has to ask for them. For example, in those countries this status is applied to hundreds of medicines. The open shelves in the shop are there only for toiletries and other supplies.

In these countries, including many in Europe, most of the products that we routinely consider over-the-counter and readily available even in a grocery store are distributed in this manner at a pharmacist's counter, as are many products that we are used to only having available by prescription.

In other countries, the term "behind the counter" refers to the need to request the product of a pharmacist and obtain or have the opportunity to be counseled by a pharmacist.

The bottom line is that data from these countries can only be looked at from an arm's length, and they do not necessarily translate into data that give solid answers to bigger picture questions that we or you may have. We just have to do the best we can.

Again, thank you for coming and for your willingness to help us with a challenging decision. Discussions at these meetings are as important, if not more important, than any vote tally on the formal questions that we pose, and we're looking forward to your discussion today.

Thank you.

CHAIRMAN CANTILENA: Okay. Thank you, Dr. Kweder.

Dr. Rosebraugh, would you like to continue with the FDA introduction, please?

DR. ROSEBRAUGH: Good morning. On behalf of the Divisions of Over-the-Counter Drug Products and Reproductive and Urologic Drug Products, I'd like to welcome the members of each respective Advisory Committee to today's meeting regarding the nonprescription status of Plan B.

By way of introduction, I would like to briefly go over the regulatory history of Plan B, go over the regulatory requirements for nonprescription marketing of drug products, and outline today's agenda.

Plan B was approved for prescription use on July 28th, 1999, for the indication as an emergency contraception to be used to prevent pregnancy following unprotected intercourse or a known or suspected contraceptive failure. Prescription directions for use indicate that to obtain optimal efficacy, the first does needs to be taken as soon as possible within 72 hours of intercourse, and the second dose needs to be taken 12 hours later.

Women's Capitol Corporation, the applicant for the original prescription NDA, submitted an application for Plan B switch from prescription to nonprescription status in April of 2003. As the efficacy of Plan B, when used as per directed has already been established and the sponsor is not seeking a new indication or dosage regimen, this will not be a topic at today's meeting.

However, the efficacy based on a use in a nonprescription setting is of interest to us.

The purpose of today's Advisory Committee meeting is to determine whether Plan B meets regulatory requirements for nonprescription marketing.

Regarding nonprescription requirements or requirements for nonprescription marketing, the Durham-Humphrey Amendment to the Federal Food, Drug, and Cosmetic Act, which was enacted in 1951, formally differentiates between prescription and nonprescription drugs. This is articulated in the Code of Federal Regulations 21 CFR 310-200(b) and states, "Any drug limited to prescription use under Section 503(b)(1)(C) of the Act shall be exempt from prescription dispensing requirements when the Commissioner finds such requirements are not necessary for the protection of public health by reason of the drug's toxicity or other potentialities for harmful effects, the method of its use, or the collateral measures necessary to its use, and he finds that the drug is safe and effective for use in self-medication as directed in the proposed labeling."

So the bottom line is this regulation provides that a drug be sold nonprescription if it is safe and if adequate directions for use can be written that are discernable to a lay person.

When approaching a possible prescription to nonprescription switch candidate, there are several questions that the agency takes into consideration to assess whether the product is, indeed, a suitable switch candidate. Regarding the questions that we take into consideration, we wonder if the product has an acceptable safety margin, as demonstrated from prior prescription marketing experience; whether it has low misuse and abuse potential, a reasonable therapeutic index of safety; whether the condition that it is being used for can be adequately self-recognized and self-treated with minimal health care provider intervention; whether the benefits outweigh the risks; and when the product used under nonprescription conditions, is it safe and effective?

If the answer to the above questions are yes, then the proposed product may meet regulatory requirements for nonprescription safety and effectiveness and is a candidate for consideration of nonprescription marketing.

In order to address the questions that face switch candidates, the Plan B switch NDA application components included summaries from previously existing data and newly conducted studies. To address the safety profile and misuse and abuse potential of the product, the sponsor has submitted safety data from their original NDA and a review of post marketing safety, both foreign and domestic, and a review of the published literature.

To evaluate consumers' ability to self-recognize the condition they are treating and whether self-treatment with the product is safe, the sponsor has conducted label comprehension and actual use studies. We will be hearing greater detail about these things during this morning's presentations.

This type of data and the studies that the sponsor has performed are consistent with other submissions that have been evaluated in the past where the switch did not involve a change in dosage or indication.

To review today's agenda, we will begin with a presentation by the sponsor, and that will be followed by a question and answer session.

Then following a break, we will have presentations by the FDA. Dr. Dan Davis will be presenting the FDA's review of safety. Dr. Karen Lechter will be presenting the FDA's review of the label comprehension study, and Dr. Jin Chen will be presenting the FDA's review of actual use studies and the literature review.

That will then be followed by a question and answer session of the FDA.

We will then have an open public hearing, then a much deserved lunch, and finally we will dedicate the afternoon to the panel discussion.

During the presentations the joint committee members should consider the information and use the question and answer session to prepare to answer the questions posed to the committee regarding the possible prescription-to-nonprescription switch of Plan B.

With that as a background, the agency looks forward to today's discussion.

CHAIRMAN CANTILENA: Thank you, Dr. Rosebraugh.

Okay. At this time we will move to the sponsor presentation, which will be led by Dr. Ben-Maimon from Barr.

Dr. Maimon, if you would start and then as you go through you can introduce the other members of your team.

For the committee, we'll hold our questions until the end of sponsor presentation.

Thank you.

DR. BEN-MAIMON: Good morning, everybody. I'd like to start by just thanking the panel, the FDA, for giving us this opportunity to present the data supporting the prescription to over-counter switch. We're all very interested, as the FDA stated, in hearing the panel's discussion and comments, and of course, interested in answering as many of the questions as we possibly can.

I'm Carole Ben-Maimon, President/COO of Barr research.

You may have heard that Barr Laboratories has signed a letter of intent to acquire the assets of Women's Capitol Corporation. That includes Plan B for emergency contraception. That transaction has not yet closed, and so today I'm actually representing Women's Capitol Corporation.

A little bit about what I'm going to cover in the presentation today. First, the background, a little bit of an overview, and a discussion about how Plan B prevents pregnancy. I'll talk a little bit about the rationale for the over-the-counter switch, try and not duplicate what was already said, and then I'm going to turn the podium over to Dr. Vivian Dickerson, who is the President-elect for the American College of Obstetricians and Gynecologists, for her to discuss with you the benefit-risk assessment as ACOG sees it.

I'll return to the podium and give you some background on our clinical trials, the label comprehension and actual use, and then Dr. David Grimes, Vice President of Biomedical Affairs at Family Health International and clinical professor at the Department of Obstetrics and Gynecology at the University of North Carolina School of Medicine, will give a presentation and discuss the health consequences of an OTC switch for Plan B.

Finally, I'll return to the podium and discuss with you our CARE Program, which many of you saw in the briefing document. That program is really designed to increase access and awareness, as well as availability of Plan B, and I'll discuss some of the rationale and the presentation for that.

What is emergency contraception? Emergency contraception is therapy for women who desire prevention of pregnancy, have had unprotected sexual intercourse, including contraceptive failures and sexual assault.

It's really important that we look at this in the context of what's going on in this country today. Fifty-three percent of unintended pregnancies occur in women who are using contraceptives. These are method failures or user failures, condoms that break, slip, women who miss their pills, but clearly, 53 percent of the unintended pregnancies are in women who have been using contraceptives.

Unplanned pregnancies are a major health care problem in this country. There are over three million unintended pregnancies in the United States each year. With typical use, 15 percent of women who are using condoms will be become pregnant each year and eight percent of those using oral contraceptives will become pregnant each year.

Half of the unintended pregnancies in this country will result in abortion. It is estimated that up to 50 percent of these pregnancies could be prevented with greater access and use of emergency contraception.

There are two approved products today in the United States: Preven, which was approved in 1998, and Plan B, which you already heard was approved in 1999.

I hope they're not putting you to sleep.

Preven is a combination product with an ethinyl estradiol, and Plan B is actually just a levonorgestrel product, a progestin only product, and that's really of significance as we get into how these products prevent pregnancy.

But you can see that the regimens are essentially identical. Both have to be taken within 72 hours of the active unprotected sexual intercourse, and the second tablet has to be taken 12 hours later.

The most fertile days of the female cycle, the menstrual cycle, are the five days leading up to ovulation and then 24 hours after, and within 24 hours of ovulation, the egg is no longer viable and fertilization cannot occur.

Plan B works like other progestin only oral contraceptives and prevents ovulation. Plan B is an oral contraceptive, not an abortion pill. The direct evidence is highly in favor of the fact that the primary mechanism of action, if not the sole mechanism of action, is prevention of ovulation.

There are two hypothetical mechanisms that have been proposed: interference with fertilization and interference with implantation, but for levonorgestrel only contraceptives, levonorgestrel only emergency contraceptives, there is no data to suggest that either of these are impacted, either of these events are affected by Plan B.

Again, I would reiterate Plan B works by preventing ovulation. It is an oral contraceptive, not an abortion pill.

What's really critical when we consider the over-the-counter switch of Plan B is this chart, and what this is is the data from the efficacy trial that was included in the original NDA that supported the approval of the prescription drug product, and this was the WHO study that was done in the late '90s.

And what it shows is that if Plan B, if the first tablet is taken within 24 hours of the active unprotected sex, the pregnancy rate is as low as .4 percent. Many of you may know that with a single act of mid-cycle sex the pregnancy rate is about eight percent. So clearly, the reduction is significant within the first 24 hours.

If a woman waits until 48 to 72 hours, the pregnancy rate rises to 2.7 percent. It is imperative that women have access to this product quickly so that they can maximize its effect.

What does the prescription requirement do? Well, it creates delays. The woman needs to identify the need, clearly a need that is easily identified by most women given the fact that they have either had a contraceptive failure, coercive sex or rape, or unprotected sex.

They need to then locate a prescriber who is willing to prescribe emergency contraception for them. Again, we can't forget that most of these events are not occurring between nine to five Monday to Friday. They're occurring at night and on weekends, and so this is not always an easy undertaking.

They have to call the prescriber. They have to talk to the prescriber. The prescriber then has to call them back and decide to prescribe the product.

If a woman does not have a physician that she sees regularly or somebody that follows her regularly, the doctor may want for them to come into the office and be examined because clearly, doctors are reticent sometimes to calling in prescriptions to patients who they don't know and probably for good reason.

And so once she gets her prescription, she now has to go to pharmacy, and at the pharmacy I can tell you and will show you data to support this, not a lot of pharmacies stock this product, and the reason is the volume and the demand are quite low to date because awareness is low. So just finding a pharmacy where she can obtain the product in a timely fashion can also be a challenge.

And finally, she can purchase the product. So the prescription setting actually creates significant barriers and time delays as we go through the process.

With that, I'm going to turn the podium over to Dr. Dickerson. Dr. Dickerson is President-elect of the American College of Obstetricians and Gynecologists. She is the Director of Obstetrics and

Gynecology at the University of California Irvine Medical Center, and with that, Dr. Dickerson.

DR. DICKERSON: Good morning. My name is Vivian Dickerson, and I am an Associate Professor at the University of California-Irvine and Director of the General OB-GYN Division at UCI Medical Center.

I have no financial interests or potential conflicts of interest to disclose in this case.

As President-elect of the American College of Obstetricians and Gynecologists, I am representing ACOG in support of over-the-counter status for Plan B. The college rarely presents product specific testimony. However, we are delighted to have the opportunity to present today because we strongly believe that Plan B meets the FDA criteria for over-the-counter status, and because there is a public health imperative to increase access to emergency contraception.

ACOG's mission is to improve health care of women. We pursue that mission through education and advocacy. On behalf of ACOG, a national organization representing over 45,000 members who provide health care for women, I am speaking today to encourage the FDA to act favorably and quickly on the Women's Capitol Corporation/Barr Laboratories application to make Plan B available to women over the counter.

Plan B is safe, and it is effective. It is not teratogenic. It has no potential for overdose or addiction. It does not require special medical screening. It is easy to use, and the labeling instructions are clear and understandable.

We know that Plan B works. It prevents pregnancy. By preventing unintended pregnancy, it also prevents abortion.

We know that women use it correctly and are very unlikely to substitute it for an ongoing method of birth control. For these reasons, ACOG supports the removal of the prescription requirement for Plan B for all women of reproductive age.

As an OB-GYN who has seen thousands of patients over the past 20 years and as a spokesperson for an organization to which 95 percent of all Board certified OB-GYN's in the United States belong, I would like to take the opportunity to clarify why a clinician does not need to oversee a woman's use of Plan B and why women of reproductive age should have access to it.

I think it's important that everyone understand why timely access to Plan B is imperative. Now, this may be a review for most of us, but let me begin by talking about how pregnancy occurs.

First, there must be normal maturation of sperm and egg. Following release into the vagina, the sperm are transported through the cervix, uterus, and fallopian tube. Capacitation of the sperm occurs in the tube in preparation for fertilization of the egg. After ovulation the egg is transported from the ovary to the fallopian tube.

Fusion of the sperm and egg occurs in that tube, and the fertilized egg is transported to the uterus. During transport, the fertilized egg begins to divide until it reaches the blastocyst stage, at which time it implants into the lining of the uterus. This is the point at which pregnancy begins.

It can take five to nine days from the time of fertilization for implantation to actually occur.

Clinical research data demonstrate that Plan B primarily prevents pregnancy by inhibiting or preventing ovulation and secondarily perhaps by impairing the migration and function of sperm. In other words, it prevents pregnancy prior to fertilization.

Plan B is, therefore, most effective when used within 24 hours of unprotected intercourse, although it has been shown to prevent pregnancy for up to three days, and recent data show that it may even work for up to five days after unprotected intercourse.

Each Plan B tablet contains three-quarters of a milligram of levonorgestrel, which is a synthetic progestin contained in many current oral contraceptives. The safety and efficacy of levonorgestrel as a daily contraceptive or a postcoital backup are well established. Indeed, the only absolute contraindication to Plan B is a known or suspected hypersensitivity to the product.

If a woman takes Plan B while pregnant, it will not cause an abortion, nor is there evidence that it increases teratogenicity.

Unintended pregnancy is a substantial problem in the United States. Nearly 50 percent of the 6.3 million annual pregnancies in the U.S. are unintended due to either method failure or failure to use a method.

It is important to recognize that unintended pregnancy does not discriminate. It affects women of all ages, from teenagers to women in their 40s. It is equally as important to recognize that not all women, and adolescents, in particular, have control over the occurrence of intercourse or the use of contraception. Examples of such cases are rape, date rape, partner pressure, or other socio-cultural pressures to engage in sex without contraception.

Overall it is estimated that widespread use of emergency contraceptive pills has the potential to decrease by at least 50 percent the current incidence of unintended pregnancies and subsequent abortions.

Nonetheless, Plan B is no substitute for ongoing methods of contraception, such as the IUD, the birth control pill, or injectable contraceptives, all of which have a higher proven efficacy.

One of the major barriers to the use of emergency contraception is timely access. By removing the prescription requirement, women will be more likely to obtain emergency contraception when it is most effective. Data show that women who had emergency contraception on hand were more likely to use it than women who were simply told about the product or even given a prescription.

However, these data indicate that women do not substitute emergency contraception for an ongoing form of birth control, and this applied to teens as well.

Requiring a prescription for emergency contraception is, in fact, an unnecessary barrier to obtaining and using the product in a timely fashion. Women know when they may be at risk for pregnancy, and the actual use and label comprehension studies indicate that women understand how to use emergency contraception, and that they use it correctly.

A switch to over-the-counter availability of emergency contraception will have a tremendous impact on access to this vital and easy to use therapy.

The label comprehension data also demonstrate that women clearly understand that emergency contraception does not protect against sexually transmitted infections or HIV. There are no data suggesting that women who use emergency contraception are less likely to obtain necessary health services.

In conclusion, on behalf of our 45,000 members who care for women every day, ACOG strongly supports making Plan B available over the counter to all women of reproductive age. If we are truly dedicated to lowering the number of unintended pregnancies and abortions in this country, let's prove it by making Plan B an emergency contraceptive available over the country.

Thank you very much.

DR. BEN-MAIMON: Thank you, Dr. Dickerson.

I'm going to go through very quickly what you've already heard. There are the requirements for the approval of a product to make a prescription to over-the-counter switch.

The produce has to have an acceptable safety profile based on the prescription use and the prescription experience. It has to have a low potential for abuse and misuse. It has to have an appropriate safety index, therapeutic index, as well as a positive benefit-risk assessment.

And finally, it has to be for a condition that is self-recognizable, self-limiting, and requires minimal health care practitioner intervention.

With that, Plan B clearly meets the requirements for OTC use. The post marketing and clinical safety trial data demonstrate an acceptable safety profile in a large number of women who have been exposed to the product. There is a low potential for abuse or misuse. There is no question that the benefits of over-the-counter availability strongly outweigh the risks, and finally, based on the label comprehension studies and the actual use studies, the product has been demonstrated to be or women have demonstrated that they can properly self-select, determine when they need it, how to use it, and they can use it correctly.

There is really no medical reason why Plan B should not be sold over the counter. Over 7,000 women have been exposed to Plan B in clinical trials, and you can see that the vast majority of these trials have used the .75 times two. There were two additional doses in some of the trials, but the vast majority of those 7,000 women have been exposed to the identical regimen that we're talking about here today.

Plan B in these trials has been shown to be 89 percent effective in preventing pregnancy if taken within the first 72 hours of unprotected sex. It reduces the pregnancy rate from eight percent to just over one percent.

The safety profile is also demonstrated. It is well described. The most common side effects are nausea, abdominal pain, fatigue, and all of these are self-limited. Most of them are mild to moderate, and very few, if any, require intervention from a health care practitioner.

There have been no deaths associated with Plan B.

And finally, there is no increase in the incidence of ectopic pregnancy. Professional screening cannot impact the adverse events or the efficacy of the product. As you heard from Dr. Dickerson, the intervention of a health care practitioner before or immediately after does not in any way change the outcome. Most of the events, as I said before, the adverse events are self-limited. They resolve on their own, and the efficacy cannot be impacted by anything except taking it more quickly.

And the critical issue here is that to maximize the effect, women need to have access to it.

With regard to ectopic pregnancy, there has been some discussion as to whether or not there's an increased rate of ectopic pregnancy with Plan B, and this comes from the fact that Plan B is a progestin only emergency contraceptive, and oral contraceptives that when taken continuously, progestin only oral contraceptives, have been questionably associated with an increased incidence of ectopic pregnancy.

There are six trials in over 7,000 women where they systematically followed women and followed the pregnancies and their outcomes. There were 133 pregnancies with only two ectopics. That gives us a rate of about one and a half percent. The background rate in the general population is about two percent. So in a large number of women there is clearly no increased incidence of ectopic pregnancy that has been demonstrated.

In post marketing studies, as well, there are over six million women worldwide who have been exposed to Plan B, and if you look at the exposures and calculate the number of pregnancies anticipated, there is no increased incidence of ectopic pregnancy.

Again, there is no medical reason why Plan B should not be sold over the counter.

Our two trials that you've heard us allude to are a label comprehension study and an actual use study, and I'm going to go through that data now and show you that women can self-select and take the product correctly.

The first study is a label comprehension study that was done in order to determine whether women could read and understand the label in an over-the-counter setting. Women 12 to 50 years of age were included in those trials, and it was performed primarily at malls. There was a sampling of minority women, as well as young women and women with lower educational levels, as well as lower literacy levels, and it was a questionnaire type study.

You can see from this slide the demographics. Here you see the age distribution. We had a large sample of young women 12 to 16. Over half of the population was 17 to 25, the most likely age group to use Plan B. There was a large sample of diverse ethnic groups represented in the United States, and we applied the rapid estimate of adult literacy in medicine test to women. Women took that test who were over 18 but had not completed college. So there was a subset of 395 women who were evaluated for literacy. About 35 percent of those scored in the less than eighth grade literacy category, and this is a way of looking at whether or not women with low literacy can understand the product label.

There were 11 objectives in this trial. There were communication objectives that we were trying to determine whether women understood, and I'm not going to go through them. You actually have in front of you a handout that has all of the 11 objectives, and I'll be referencing that handout as I go through the presentation.

But you can see that the first couple dealt with what the product is intended to do and to be used for. There was a question about sexually transmitted infections and AIDS, how the product is used, and then the side effect profile.

Here this chart shows you the 11 objectives along the bottom. This is the percent of women that were able to answer correctly, and clearly the vast majority, the overwhelming majority of women were able to answer all of the objectives correctly.

The one that had a slightly lower rate of understanding percent of women was objective number two, and I'll talk about that objective in a couple of minutes.

This chart looks at the same 11 objectives along the bottom, and the yellow represents the 12 to 16 year olds, the pink the 17 to 25 year olds, and the blue the 25 to 50 year olds, and then the dot is the actual average, which you saw in the previous slide.

If you look across the overwhelming majority of women were able to understand all of these objectives, and really the only one that showed a trend with a lower understanding, a lower comprehension level in the younger group was objective number two.

This looks at the distribution by literacy level, and the yellow represents the lower literacy women, with the pink representing the women with literacy levels greater than eighth grade, and you can see, again, objective number two has a difference between the two groups, and you might suggest that objective number four also, and I'll be talking about those.

I'm sorry. I also forgot to mention objective number eight, which was also slightly lower on the overall than the others and also shows a distribution.

This, if you refer to your sheet, this objective was the objective that discussed unexplained vaginal bleeding, and at this point in the prescription label unexplained vaginal bleeding is a contraindication. Through discussions with the FDA with regard to this contraindication, it has been decided that this will no longer be a contraindication. It will be a warning. Women should follow up with their health care practitioners if they continue to have unexplained vaginal bleeding, but it will not be and it is not a contraindication to the use of Plan B. So this really goes away, which is why I've sort of ignored it.

Objectives, and I know this is a busy slide. So let me just walk you through it a little bit. Plan B is intended as a backup method and not for regular contraception. That was the objective that was meant here.

Women had to get at least three of these questions correct in order to be counted as having understood the objective. You can see the distribution by age here, and then question number nine, 21, 22, and 25 were the questions that were relevant.

Question number nine and number 22 are direct questions. According to the label, should Plan B be used as a regular form of birth control? And you can see that most women were able to answer both these questions correctly.

The two situational questions here, where we were talking about situations where the partner doesn't want to use condoms and is it for routine birth control or not; these questions women scored lower.

And we have a couple of hypotheses why that may have been. Clearly, the situational questions were more difficult for women to answer. Was it a result of the fact that we used the terminology "husband," where husband implies a monogamous, long-term relationship and pregnancy may not be such a big deterrent?

There could be any number of reasons why women didn't answer these two questions correctly, but clearly, those were the two questions that made it difficult, whereas the direct question suggests that they do understand that it is not a routine form of birth control.

With regard to the lower literacy group, you see the same trend. Question nine and question 22 they do quite well on, but, again, in the lower literacy group there is a trend towards less understanding of the two situational questions.

What we tried to do to deal with that was bold the label, and I know it's hard to see here because of the quality of the PDF, but it's on the board, and I'll be handing out a package to you in a little bit and you'll be able to look at it in your hands.

But we have bolded Plan B should not be used in place of regular contraception. In addition, this is a message that we will be trying to drive home with our ancillary materials through our CARE Program to insure that women do understand that they need to use routine forms of birth control.

This was objective number four, and if you remember, there was some difference between the lower literacy group and the higher literacy group. This question they had to get this number ten correct in order to be able to be counted as correct, and you can see that all of the other answers were correct.

The objective here is that the first pill should be taken within 72 hours, and you can see that the correct answer to ten was as soon as possible and within three days, if they answer that, or within three days. But as soon as possible was not counted as a correct answer because we wanted to see the 72-hour time point.

And clearly that weighs in, and some women -- this was an open-ended question. They had to fill it in. It was not multiple choice -- and so some women put as soon as possible and didn't put within 72 hours, and that clearly is what happened here, and the results of the as soon as possible are down below. So really women do understand that they need to take it within 72 hours, and that is clearly demonstrated in the actual use study, and I'll show that to you in a minute.

So with regard to the results of this study, the intent to treat analysis shows that we had satisfactory responses to all objectives, 80 percent or greater correct responses to nine of the 11 objectives, and the two objectives that were not answered correctly, one of them was the unexplained vaginal bleeding, which is no longer a contraindication and, therefore, no longer relevant.

Finally, in conclusion, the study demonstrates adequate label comprehension, and based on the results and in an effort to insure we had the best label we possibly could, we did make some minor changes before the actual use study and, therefore, enhanced we hoped the understanding and the ability to use the product correctly.

And these just included bolding emergency contraception to make sure that women understood it was for an emergency; bolding a serious medical problem. This section relates to severe abdominal pain, and we wanted to make sure that women understood that if they were experiencing severe abdominal pain, they needed to follow up with a physician because it might be the sign of an ectopic pregnancy.

We bolded the 12 hours to make sure they understood they had to take the second tablet within 12 hours, and we changed the term "birth contraception" to "birth control."

That was the label then that was employed in the actual use study and was used in the actual use study. The actual use study was intended to demonstrate whether or not, to find out whether women could self-select. Could they determine that they had a need and then identify that they needed the product, go get it, and then use it correctly?

We did this study at five Planned Parenthood affiliates and five pharmacies. The pharmacies were all in Washington State. That's because Washington State has a pharmacy access program. So it was feasible to do it there. Other states were not feasible.

The way it worked was women came in, and they said, "I need emergency contraception," and they were then told that there was a study going on and did they want to participate. If they said they did, they were handed the package closed and sealed with the drug facts panel on the back. They were then asked to review that and decide whether or not Plan B was right for them.

If they decided that it was, they then signed an informed consent, and they received the product and a data card and were followed up in one and four weeks.

You can see here the demographics. This is the actual use study. This is the label comprehension study. This is all U.S. women 14 to 44, and what you see here is that we have a large sampling of women 17 to 25, which is the population we would expect being most likely to use Plan B, and clearly a nice number of young women, and then a distribution throughout. And obviously all of the ethnic groups in the United States are presented, well, not all, but most.

The way it worked, there were 665 patients screened; 585 were enrolled and 80 were not. They decided not to participate. Forty-two were completely lost to follow-up. We have no data. Five hundred and forty-three provided data. Three of these women did not take the Plan B. So their information is not included because obviously if they didn't take it, we don't have times of pill taking and stuff.

There were 540, therefore, that supplied us data. Of those, 506 supplied us all three times, the time of sex, the time of the first pill, and the time of the second pill. Five hundred and twenty-three gave us the first and the second pill, and 509 gave us the time between the sex act and the first pill.

So we looked at contraindications. The three contraindications for use are: are you already pregnant? Again, as Dr. Dickerson said, there's no data to suggest that Plan B has any teratogenicity or will have any kind of a negative impact on the pregnancy, but clearly once you're pregnant, you're pregnant. We can't prevent the pregnancy, and so there's no reason to take it.

The contraindication clearly of allergy to any of the ingredients, and finally the unusual vaginal bleeding which will no longer be a contraindication.

Ninety-nine percent of the women who took the product took it without any contraindications. There were only seven women out of the 540 who had a contraindication. One woman was pregnant, and there were six who had unexplained vaginal bleeding, again, no longer a contraindication.

So the vast, vast majority, almost all of the women were able to take it without a contraindication and understood the contraindications.

Could they take it correctly? If you look here, the first pill less than 72 hours after the sex act, 98 percent of the women took the first pill within the 72 hours after the act of unprotected sex. The second pill, the criteria for correct was exactly 12 hours. There was really no latitude, and so 74 percent of the women were able to take the second pill at exactly 12 hours.

To take both pills correctly were 72 percent. So almost all of the women were able to take the product correctly, and one of the things I think is important to note is that this is the same dose and the same regimen as the prescription drug product. And so you can presume that if the distribution in timing that the women take the doses of these pills is similar or the same as the WHO study which supported the safety and efficacy of the product, you can anticipate that the efficacy and the safety will be the same or be similar.

And so we looked at the data in the actual use study for each pill and compared it to the WHO study, the distribution, and you can see less than 24 hours, 25 to 48 hours, 49 to 72 hours, and greater than 72 hours. The distribution, percent of women taking it in each of those time frames -- and this is the first pill -- is very, very similar to the WHO study.

The same holds for the time between the first and second pill, less than 12 hours, 12 hours, 12 to 16, and greater than 16. Again, the distribution is very similar between the two trials.

So we can anticipate that the efficacy and the safety profile should be the same as that that was described and ultimately approved in the pivotal trials that supported the NDA.

With regard to pregnancy, there were ten pregnancies in the trial. That gave us a pregnancy rate of about 1.9 percent. If you remember, the WHO study had a pregnancy rate of just over one percent, very similar. Of the ten pregnancies, four ended in abortion and six were lost to follow-up.

So, in conclusion, the study design simulates the OTC environment. Women were able to come in on their own and identify the need. Subjects were representative of the OTC setting. We had a distribution both in age and various ethnic groups. Subjects were able to self-select. They knew they needed the product. They came and they got it. They took it home, and they were able to use it correctly.

The results are similar to the WHO pivotal study, and thus, Plan B should be as safe and as effective in the OTC setting as it is in the prescription setting.

With that I'm going to turn the podium over to Dr. Grimes to discuss with you the health consequences of over-the-counter levonorgestrel. Dr. Grimes is Vice President of Biomedical Affairs at Family Health International. He is clinical professor at the Department of Obstetrics and Gynecology at the University of North Carolina School of Medicine, and he is one of the few OB-GYNs in the country who are double Boarded in preventive medicine and in OB-GYN.

So with that I'll turn the podium over to him.

DR. GRIMES: Thank you, and good morning.

I begin with a most important message first, and that is that easy access to emergency contraception improves the health and lives of women. It does this through preventing unintended pregnancy with its serious consequences.

For many women the news of a pregnancy is a wonderful gift. Such women readily and happily accept the discomforts, inconvenience, expense, and risks involved with childbearing. Not so for women with an unplanned and unwanted pregnancy. What are the medical consequences for them?

The traditional way in which we assess the safety of childbearing around the world is the maternal mortality rate. Despite impressive progress in recent decades, childbearing remains risky business in the United States of America.

These are the most recent data from the Centers for Disease Control and Prevention in Atlanta. As of 1999, the reported maternal mortality rate was 13 maternal deaths per 100,000 live births. If one corrects this for under reporting of such deaths, the true figure is closer to 20 deaths per 100,000 live births.

What this means is that during the past decade over 4,000 American women have died from pregnancy and child bearing.

But the real human suffering is not in deaths but in morbidity, complications of pregnancy, and childbearing today remains a very complex process. Again, the most recent data from the CDC in Atlanta are on the screen. Forty-three percent of all U.S. women have one or more complications during the hospitalization at which they deliver, such as hemorrhage, infection, obstetrical tears. Indeed, one in four American women are hospitalized at least once during the pregnancy but before delivery for complications of the pregnancy, such as threatened labor, preeclampsia, urinary tract infection.

Now, if you multiply these percents times the millions of pregnancies every year in the U.S., you can see how huge is this burden of suffering, and many of these complications are severe and long lasting.

Now, in medicine we oftentimes have to make difficult decisions between competing risks and benefits. Not so here, not so. Seldom in medicine do we see the scale so forcibly tipped and permanently tipped in favor of benefit, but let's consider yet another dimension of the problem of unintended pregnancy in America, and that is induced abortion.

Induced abortion is prima facie evidence of unwontedness, and despite impressive gains in recent years, we still have far too many abortions in America. As you know, our abortion rates are much higher than in other industrialized nations. Nearly a million abortions reported to the CDC each year. Two measures commonly indicate how frequent is abortion in a population, the abortion ratio and the abortion rate.

The ratio is the number of abortions per 1,000 live births. The rate is number of abortions per 1,000 women of reproductive age, and again, the most recent data from the CDC indicate that for every four live births in America there is one induced abortion, and indeed, two percent, one in 50 American women of reproductive age have an abortion every year.

And here emergency contraception over the counter has an extraordinary role to play by reducing the need for induced abortion, and that's a goal around which there should be broad consensus in America, and this is already happening.

According to the most recent data from the Alan Guttmacher Institute, in the year 2000, despite limited use of emergency contraception, it has averted over 50,000 abortions that would have taken place without its use.

Think what we can do together with easier, wider access to this safe product.

An old concern about emergency contraception and easy access to it was that this would in some way sabotage or undermine ongoing traditional contraception. I heard this discussed just an hour ago on CNN.

There are studies around the world refuting this. It doesn't happen. Moreover, a study done by the World Health Organization looking at frequent repeat use of the product indicated that it would disrupt normal menstrual cycling, which itself would deter women from using it in this fashion.

As you've heard from the prior two speakers, over-the-counter levonorgestrel easily fulfills the three criteria outlined in the Durham-Humphrey Drug Amendment Act of 1951. There are no outstanding medical issues.

Speaking as a gynecologist, my patients have told me that one of the most important benefits to them, difficult to measure, is peace of mind. Unprotected intercourse can cause terrible anguish that may list for weeks to months occasioned by unplanned sex, forced sex or a contraceptive mishap, such as forgotten pills or a torn condom.

I would remind all of us here today that this discussion is ultimately not about a steroid molecule. It is about women, women at a time of acute and often terrible crisis in their lives. Emergency contraception can help by reducing unintended pregnancies, induced abortions, and medical suffering.

In conclusion, today the FDA has an extraordinary opportunity to advance women's health in America by removing needless gratuitous obstacles that stand between women and safe medicine. I would ask you to consider the alternative.

If we allow these obstacles to stand, if access remains limited, we will be indirectly causing unintended pregnancies, induced abortions, and needless human suffering. The public health and the medical evidence is clear and incontrovertible. The choice before us today should be equally clear. Over-the-counter emergency contraception is good medicine. It is scientific medicine. It is compassionate medicine, and it is medicine that women deserve.

Thank you.

DR. BEN-MAIMON: Thank you, Dr. Grimes.

I'm going to try and put some background or some sort of meat on the bones and talk a little bit about what we're seeing happening in the United States with regard to pregnancy rates, teenage pregnancy, and abortion, and then go into some of the issues surrounding emergency contraception.

You can see here the white line is the U.S., women 15 to 44, and the pregnancy rate since 1990, and you can see that the line is decreasing, but somewhat stable.

What's really interesting is the pink line, which are women 15 to 19, which is decreasing disproportionately to the rest of the population. The same thing occurs when you look at abortion rates since 1990. You see the line here where abortions that were decreasing now seem to be somewhat stable, but look at the pink line in women 15 to 19, which is going down. This obviously we would all agree is a very good thing and a trend we'd like to see continue.

Here are the percentages of women using various contraceptives in contracepting women. These are 15 to 19 year olds. These are 20 to 24 year olds, and what you see here is that since 1982 the trend in OC use has been going down, but there has been a corresponding trend increasing in condom use.

Here in 20 to 24 year olds it tends to be more flat, but again, the increased use of condoms is demonstrated in these women, and clearly, this is probably a result of the better understanding and the greater awareness of sexually transmitted infections and the need to use a barrier method in order to prevent the transmission of those infections.

What's interesting here when you look at contracepting women 15 to 19, 20 to 24, 25 to 34, and then 35 to 44 is that young women tend to prefer reversible forms of birth control, such as oral contraceptives and condoms, whereas older women tend to prefer sterilization and more permanent forms of birth control, not something that's terribly unexpected, but clearly an interesting piece of information.

Again, unplanned pregnancies are a major health problem in this country as you've heard from both speakers and the FDA. Education and awareness programs seem to be working, but clearly, we need to do more in order to decrease the incidence of unintended pregnancies and abortion even further.

Despite these programs, there are over three million unintended pregnancies a year, half of them ending in abortion. Again, 50 percent of these unintended pregnancies could be prevented by greater use of emergency contraception.

It's very important to remember that of women who present for abortion, only 1.3 percent of those women have used emergency contraception, and as Dr. Grimes said, this is really the ultimate in unwanted pregnancy. They choose to abort the baby, and so clearly, if only 1.3 percent of them are using emergency contraception, we have a long way to go in increasing access and availability and awareness, and we believe awareness of and access to emergency contraception needs to be enhanced in order to impact this major health care problem that we're facing.

We believe that Plan B is safe and effective for over-the-counter use, and we believe the data supports that. Although pharmacy access programs may increase availability, they create new barriers that need to be dealt with by women who seek them.

And so I'd like to spend a couple of minutes talking about pharmacy access and what is going on with regard to prescriptions in this country for Plan B, and then I'm going to talk a little bit about our CARE Program, which we hope will help to increase awareness and availability, and it's clearly designed to do so.

This is the prescription data from the United States. It's Plan B, and it's retail pharmacies only, and what it shows is at this point there are about 20,000 prescriptions a month for Plan B.

This is California, which is the pharmacy access state. What's important here is that the legislation was actually implemented in January 2002, and you can see that with the implementation of that program, there was an increase in the script writing for Plan B.

This is Washington State, which is flatter, still increasing, but flatter, and their program started in 1997, and so access has been around for quite a bit longer.

There are five pharmacy access states: Washington, California, Alaska, New Mexico, and Hawaii. These are newer so I won't be discussing those, because those states are actually too new to identify what is really happening, but I'm going to talk a little bit about Washington and California.

It's important to note that the legislation in Washington actually provided for pharmacy access, and pharmacy access means access to Plan B without a prescription through a pharmacist. So the pharmacist has to write a protocol, file it with the State Board of Pharmacy, and then they can participate in the pharmacy access programs, and there are certain educational requirements as well.

What you see in Washington State -- and this is the time line -- is that there are about 2,000 scripts a month up from 1,000 over maybe three years ago, but what I think is really important to note is that in a state where there has been pharmacy access for emergency contraception since 1997, there are only 26 percent of pharmacies participate, and only 23 percent of pharmacists. It takes initiative to participate in these trials. The pharmacists have to be trained. They have to apply. They have to want to participate, and so it's not just so straightforward that women can walk in and obtain emergency contraception.

California. One of the things I think that has increased use of Plan B in California is the fact that they had a huge media campaign. They had a huge campaign to try and increase awareness of the product, and they targeted about ten million consumers and health care professionals. Over 900,000 women were with print material; a million women and men through paid advertising; 70,000 health care providers through print material; and approximately eight million people through free media.

What did this result in? Again, the legislation went into effect in 2002, January. So it is essentially two years. Only 14 percent pharmacies and pharmacists participate.

So, again, in a state as large as California, finding emergency contraception without a prescription is still a significant challenge.

What does that mean for the United States? Well, we've got five states. There's 45 left to go. More than 200,000 pharmacists are throughout the United States, 53,000 pharmacies. The pharmacists have to be recruited for pharmacy access, and so this in and of itself is a huge challenge and really limits the ability of pharmacy access to act as the mechanism to increase availability.

Let's look at barriers again. Clearly, here there's the barrier of getting the pharmacists and the states to participate, but let's say we can do that. There's another barrier, and that is that these programs require protocols. Women have to walk into a pharmacy, talk to the pharmacist, answer questions, and qualify for pharmacy access and for emergency contraception.

Many of you can put yourself in the position of a woman, and I don't know if your pharmacies are like my pharmacies, but there really aren't any areas where I could hold a private conversation with my pharmacist and answer these types of questions in a way that would be comfortable for me.

And so clearly, the need to consult with the pharmacist, at least be interviewed by the pharmacist, not and ask questions, but be interviewed and meet certain criteria, could act as a significant barrier for women to seek emergency contraception through pharmacy access.

So again, although Plan B is safe and effective, access and availability are still too limited to have the kind of effect that we believe it can on the incidence and rates of unintended pregnancy.

And with that I'll switch a little bit to the CARE Program. The CARE Program is designed to provide and encourage awareness and increase awareness of women that emergency contraception exist; that they can get it; how they should use it; and in what context it fits in overall reproductive health management.

And it is also intended to increase availability so that when they do need it, they can seek it and they can find it and they can get it. I'm going to take a minute and hand out these packages. You can pass them around.

These packages are the actual packages that we're proposing and are part of the supplemental NDA. You can see that there's an outer package. Feel free to open them. There's an outer package, and in it is a smaller package that opens up and actually has the directions for use. The outer package has the drug facts section on the back, and that's what the women would see when they went into the pharmacy.

Included in the package would be information on routine forms of contraception, as well as sexually transmitted infections. There would also be reference to a hotline which I'm going to talk about in a minute and a Web site, and there's also a data card which I'll talk about in a couple of minutes as well.

But feel free to open them, look at them, and pass them around.

The need for accessible emergency contraception is great, but clearly, awareness is low and availability is limited. The program is designed to increase awareness through education. Programs will be comprehensive in nature, and what we mean by that is we will include information on what we call Plan A: abstinence, family planning, and routine forms of birth control.

The name Plan B was not just a marketing tool. The name Plan B was chosen in order to communicate to women that this is Plan B. Plan A is abstinence, family planning, and routine forms of birth control. Those are the preferred mechanisms to prevent pregnancy.

But when Plan A fails, Plan B is available. The target audience will be consumers, physicians, physicians' assistants, nurse practitioners and pharmacists.

The second part is distribution and availability, and I'm going to talk about that a little later, but the intent of OTC distribution is to minimize delay so that we can maximize the earlier use of the product and lower the barriers in order to maximize appropriate use and, finally, to insure availability.

Again, the communication objectives. Plan A is abstinence, family planning and routine forms of birth control, and I can't reiterate enough how committed we are to helping to support that message.

Plan B is used when a woman has concerns that Plan A hasn't worked for whatever reason. Plan B is not a replacement for routine forms of birth control. Plan B does not treat or prevent sexually transmitted diseases, and follow-up with a health care practitioner is strongly recommended.

What is the problem with regard to awareness and education? Only 43 percent of women know that EC is available in the United States. Only six percent have used it, and one of the most important statistics that we have here today is that only 1.3 percent of women who present for induced abortion have used emergency contraception.

What we're intending to do with our program is try and utilize all of the tools that we have available to us. Barr has a sales force of about 250 representatives that visit approximately 30,000 physicians throughout the country. We intend to distribute informational brochures to those physicians through our sales force so that women while sitting in a waiting room or waiting in an exam room can read about emergency contraception, understand what's going on, and talk to their doctors or their nurse practitioner if they have any questions before this happens.

Again, these materials will also hopefully stimulate discussions with regard to routine forms of birth control and family planning issues.

Educational brochures will also be available at the point of purchase, will be providing display units that can be put out at pharmacies. There will be no trial offers, coupons or samples.

We will have print and radio ads which will include and be mostly designed as public service announcements and informational materials that talk about diagnosis, need, and responsible use. And so the program is really targeted at increasing awareness, making women understand how and where to get emergency contraception and how and when to use it.

This is the label. You have it in front of you so I'm just going to flip through it in an effort to save some time.

There is a card in the package, and women will be able to record the time of the first dose and then calculate the time of the second dose, and of course, it encourages them to take it as soon as possible.

It also refers them to our hotline, as well as to the Web site.

The toll free number will be staffed by a health care professional 24 hours a day seven days a week. So when women need and choose to use emergency contraception, they will be able to call if they need help or if they have questions in order to get additional information.

There will also be a Web site with links for health care practitioners, and we will encourage women if they have any further questions to follow up with their health care practitioner.

From the standpoint of professional education, and I think this is also important because clearly OB-GYNs understand about emergency contraception, but there are many doctors out there who are not as knowledgeable and so we will be advertising in professional journals. We will provide continuing education at medical meetings and in relevant settings. We will work with pharmacists through our national account managers, pharmacy journals, and again provide continuing education through state boards of pharmacies at their annual meetings, as well as major pharmacy meetings.

The problem of distribution. Again, this is really a two-part issue. It's awareness and education, but it's also distribution and availability and access. Only 35 percent of pharmacies in Pennsylvania were able to get Plan B or emergency contraception within 24 hours.

In Albuquerque, New Mexico, which is a pharmacy access state, 89 percent of pharmacies did not have Plan B, and 53 percent of them could not access it within 24 hours. Clearly, the clock is ticking.

Again, although the need is great, availability is still very limited. We are proposing to sell to wholesalers, clinics, or retain chains and stores with valid pharmacy licenses or valid wholesale licenses.

Again, we will be supplying display units for pharmacies to put out with informational materials. We will continue to provide Plan B at a discount to clinics so that all women can have access to it, and again, I'm sure you remember from the briefing package we committed to recommending that Plan B be kept either behind the counter or in view of the pharmacies.

We are very comfortable that Plan B is safe and effective for over-the-counter use. We are very comfortable that it could be sold completely over the counter, but we recognize that there are issues surrounding this product and concerns that need to be addressed, and so we're very anxious to hear what the committee thinks with regard to the placement of these products in pharmacies, and of course, if it's recommended that we recommend keeping it behind the counter, we will take that into consideration and discuss that with the agency.

CARE is intended to encourage appropriate use of Plan B through professional and consumer education. It's intended to insure awareness that Plan B is conveniently available and to teach women when and how to get it. It's intended to reinforce that it is safe and effective with appropriate packaging and labeling, which you see in front of you. And finally, we will have monitoring programs to see whether or not the program is working and what modifications need to be made. As we go through time the needs may change, and clearly, we will be working on that as we go.

Unplanned pregnancies are a major health care problem in the United States. Over three million unintended pregnancies occur each year. With typical use, women using condoms, 15 percent of them will become pregnant each year, and eight percent of women using oral contraceptives will become pregnant.

There are approximately 800,000 unintended pregnancies in teenagers. In 2002, 215,000 women in the United States were the victims of rape or sexual assault. Half of the unintended pregnancies result in abortion, and again, it's estimated that up to 50 percent of these unintended pregnancies could be prevented with the use of emergency contraception.

Plan B will insure that for those who need EC, there will be convenient availability and responsible education. Making this product available over the counter will decrease the barriers and increase access, hopefully resulting in a reduction of the number of unintended pregnancies.

Plan B has a demonstrated safety profile and is suitable for over-the-counter use. Early use is absolutely critical to maximizing effect. The prescription requirement presents barriers that delay the chance for early use of emergency contraception. Plan B meets an unmet medical need, and the Plan B CARE Program insures responsible and appropriate education and distribution.

Plan B for OTC use, along with the CARE Program, will provide important benefits to the consumer. It will enhance availability and minimize delay while maximizing efficacy, and ultimately it will reduce the number of unintended pregnancies, a major health care problem in this country.

With that, thank you very much.

CHAIRMAN CANTILENA: Okay. Thank you.

We now have time for questions from the committee to the sponsor, and I would ask the committee members to signal me so they can be called on. We will not allow cross-talk, and we would ask also that your questions at this point be focused and specific in terms of exactly, you know, the sponsor, you should not be asking any questions of the FDA because you'll have an opportunity to do that later this morning.

So questions from the committee. Dr. Benowitz.

DR. BENOWITZ: I have a couple of pharmacologic questions. The first one is the way this drug is supposed to be given is one dose based at 12 hours. The drug has got a long half-life. There certainly are reasons to think that 12 hours is not important.

One question is whether even having two doses is important, and the second one -- and I know it's not part of this proposal -- but in reading the background material it seemed striking that 1.5 milligrams in a single dose was just as effective and no more toxic and certainly easier to comply with.

And so one question is about the dosing issues, and then I've also got a second question.

DR. BEN-MAIMON: The variations in dose have been studies in other parts of the world, and WHO has actually done some studies looking at single one and a half milligram doses. The issue really is that what's approved today is one dose within 72 hours followed by a second dose 12 hours later.

The safety and efficacy of that product is well documented, and so what we're seeking today is to move the prescription to OTC for that regimen, recognizing that maybe in the future there would be a reason to develop alternate dosing regimens.

DR. BENOWITZ: And what about the first part? What if someone doesn't take a second dose? Will it still work?

DR. BEN-MAIMON: Well, there is not a lot of data on 1.75 milligram dose, but clearly women do take the second dose. I mean, the actual use study demonstrates that, and there's a failure rate for all of these products.

I mean, this is not a foolproof method to prevent pregnancy. It prevents most or a lot of the pregnancies, but it doesn't prevent all pregnancies.

DR. BENOWITZ: Okay, and then a second question. The efficacy data that you showed were quite striking in that taken within 24 hours, the pregnancy rate was .4 percent. On the third day it was 2.7 percent.

The labeling really doesn't make that point very well. It says take as soon as possible, but it clearly doesn't tell a woman that you could have a six or sevenfold difference in efficacy rate if you take it within 24 hours versus 72 hours, and why have you not really emphasized the importance of 24 hours?

DR. BEN-MAIMON: Well, I think we have emphasized the importance of taking it as soon as possible. You can see from what's happening here it's not possible all the time even to get it within 24 hours, and so as soon as possible is, I think, as much as we can say.

In addition, we don't want to discourage women that after the first 24 hours have passed, you know, you might as well give up because it is clearly effective. As you get out even past 72 hours, there's some data to support, as Dr. Dickerson said, there's some data to support that it may be effective out as long as five days.

But clearly, we want women to take it as soon as possible, but we also want them to take it at 24 to 48 and 48 to 72 hours, as well, and not just throw up their hands and give up.

CHAIRMAN CANTILENA: Okay. Thank you.

Over here, Dr. Macones and then Dr. Hewitt.

DR. MACONES: You mentioned about some post marketing information on rates of ectopic pregnancy. I was wondering if you'd just expand on that a little bit more because the numbers are fairly small even from the clinical trials that you've done.

DR. BEN-MAIMON: Okay. Can I have Slide ‑- yeah.

What you see here are the exposure numbers throughout the world. There are over six million women who have been exposed to Plan B throughout the world. Total pregnancies reported are 340, but again, pregnancies are not likely -- remember this is pharamacovigilance data. This is not data from clinical trials. So women are not reporting every normal pregnancy clearly.

There have only been 21 ectopic pregnancies, and when you do the calculation based on the number of uses, the expected number of pregnancies, you would expect to have with a two percent risk 585. So there is significantly fewer reported ectopic pregnancies.

Again, we recognize, again, these are pharmacovigilance data. So they have their limitations, but you get similar numbers when you look at the clinical trials, and although the clinical trials are small, you still have over 7,000 women in 133 pregnancies. So they're not negligible, and those are clearly pregnancies that were followed up.

So I think if you combine this data alongside the data that was presented from the clinical trials, there really is no reason to expect an increase. There is no data to suggest that there's an increased incidence of ectopic pregnancy.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Hewitt. and then Dr. Wood.

DR. HEWITT: Yes, I have a couple questions. The first one is about when patients call in on the hotline or attend the Web site and how their questions will be answered. The first question has to do with multiple acts of intercourse and taking multiple doses of emergency contraception.

I'm thinking specifically if a patient has missed a couple of birth control pills in a pill pack and has not had contraception for an extended period of time. How will she be counseled when she calls in over the phone?

And then secondly, when she calls in with questions about dosing intervals, will they be giving any information on options with dosing of the two emergency contraceptive pills in terms of the 12-hour window? Will they be given options of taking both pills at once?

How will they be counseled with those phone calls? I know when I counsel patients I tell them, you know, you don't need to set an alarm clock for 3:00 a.m. to get up and take your second dose, but how will those kind of questions be answered?

And then my second question has to do with communicating this information to and supporting team use. I know that literacy studies were not done on women less than 18. Do we have any information besides what you gave about how they answered the questions to the 11 points you were trying to convey?

Will any of the materials be sort of teen friendly or be developed specifically to reach younger women?

DR. BEN-MAIMON: Your first question about counseling, and if I don't answer it all, please feel free to come back because I may have missed some of it.

We will have trained professionals, first of all, health care professionals, women, you know, with nursing degrees or pharmacy degrees staffing the phones. Those people will be have a script, and they will counsel women on the different -- we'll have all the different scenarios laid out, and they will counsel women based on a script that will be designed with physicians in order to tell women what to do.

I think if women have missed three or more birth control pills, they would be instructed to take Plan B and to use a routine form of birth control at least for the first week, depending upon where they were in their cycle and what the labeling says for oral contraceptives.

And of course, if there's any concerns, it would be recommended that they follow up with a health care practitioners.

But those scripts would be designed with physicians and would be provided and these people would be trained in order to deal with those types of questions.

With regard to teens, we all want our teenagers to refrain from sexual activity prematurely. I don't think any of us want our teenagers to be sexually active before they are comfortable and should be. And clearly we will be reinforcing the messages of abstinence and all of that, but it is clear that there are 800,000 pregnancies in teenagers every year, and so we really do have to deal with that issue.

The label comprehension study, as you saw, had women in it from 12 to 50, and there were actually a significant number of teenagers 12 to 16 years of age in that study, and I think we presented the objectives, and we can put that graph up again. It is number 24, please.

And you can see here that these are the objectives. The 12 to 16 year olds scored actually quite well for the vast majority of the objectives, and so the materials seem to be pretty appropriate for them, and they do seem to understand and be able to comprehend.

DR. HEWITT: And what about my middle question about the dosing interval? You know, if a patient literally says -- you know, I mean, are they going to be explained any leeway on dosing the second interval, or do you anticipate the scripted response will be 12 hours, period? Are you able to answer that question at this point?

DR. BEN-MAIMON: Yeah, I think it would be 12 hours. I think that's what the labeling says. That's what the data suggests. This is a product that will be taken once. So we're not talking about having to wake up in the middle of the night for, you know, the next week and a half or six weeks.

I think for one time we would recommend that people take it at 12 hours, and that the 12 hours, if it occurs in the middle of the night, they get up and they take their dose.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Wood.

DR. WOOD: Yeah, I have two questions that relate, I guess, to access. The first one relates to the paper that's Tab 8 in our briefing book from Anna Glasier and David Baird that was published in the New England Journal, and they encouraged the patients or, in fact, they provided patients with the equivalent of Plan B to keep in their bathroom cabinet, and that seems to me the obvious way to go. I mean, there's not much point in telling people to buy a fire extinguisher once the fire starts burning. You tell them to get a fire extinguisher and keep it in their kitchen.

And similarly, we've had a lot of medical experience now with defibrillators that the effects of defibrillators are much more effective if they're on site and readily available for use.

So my first question relates to that. Are you going to encourage in the promotion material that people obtain the Plan B and have it available in their bathroom cabinets and for use in the case of an emergency, and if not, why not?

DR. BEN-MAIMON: Well, I think that there is no question that the data suggests that women who have emergency contraception use it more frequently.

There's also no data to suggest that women who have emergency contraception have more unprotected sex. It's just that when they have unprotected sex, they use the product because it's available to them.

And so the materials, I think, will be designed to make sure that women are aware of how to access and how to get emergency contraception. I don't think we've contemplated having specific statements in there that say, you know, "Make sure you have one of these at home."

Again, there's situations of expiration dating and other things that have to be taken into consideration, but of course, we can consider that.

DR. WOOD: My second question related to your comment near the end of your presentation about making it behind the counter. That seemed to me totally counterintuitive, and that seemed to me to raise all of the access issues that you quite eloquently addressed earlier.

So it would seem to me that that would totally obviate the benefits of making Plan B over the counter, and I can't imagine how that would be advantageous.

DR. BEN-MAIMON: We appreciate your comments, and that's one of the reasons we raised it, because we think there are opinions both ways, but we are concerned about putting it behind the counter simply because of the issue of barriers, and that's why we're interested in hearing what the panel thought about that.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Trussell and then Dr. Montgomery Rice.

DR. TRUSSELL: I want to follow up on Dr. Wood's question.

In the pharmacies in my hometown now, condoms, spermacides, KY jelly are all locked in cabinets that can be opened only by the pharmacist, and when I've asked repeatedly why they do this, it's because they were being stolen blind.

(Laughter.)

DR. TRUSSELL: So my question is in your conversation with the pharmacy chains, do you have an indication that this product is going to also be locked in that cabinet? Because my pharmacists are certainly going to lock it in their cabinet.

DR. BEN-MAIMON: Well, what we are proposing, there's a thing called a Planigram, which is the pharmacies lay out where they have all of these products, and you know, they figure out where they're going to place them.

Our recommendation to the pharmacists will be that it be placed in the female health care sections along with pregnancy kits and things like that, which are not locked behind cabinets.

DR. TRUSSELL: In my pharmacies, they are locked behind cabinet.

DR. BEN-MAIMON: Oh, I don't know where you live, Dr. Trussell.

CHAIRMAN CANTILENA: Okay. Thank you, Dr. Trussell.

(Laughter.)

CHAIRMAN CANTILENA: You should consider moving to another neighborhood.

(Laughter.)

CHAIRMAN CANTILENA: Dr. Montgomery Rice.

DR. MONTGOMERY RICE: I thought in the literature that I read that you were removing the vaginal bleeding from contraindication to warning, but when I looked at the package on the back you do not have vaginal bleeding in the warning section. You actually have it under the side effects, which if I was a lay person I would think that that means I was going to have vaginal bleeding after unintended -- unintended vaginal bleeding after taking the medication.

I think that should be clarified because it wasn't clear to me.

DR. BEN-MAIMON: I may be mistaken. I thought it was in both, but it's conceivable that I'm mistaken.

DR. MONTGOMERY RICE: I don't see it on the back.

DR. BEN-MAIMON: Okay. Well, we'll check.

DR. MONTGOMERY RICE: And I think that needs to be clarified.

The other thing that I'm concerned about is that you roll out this wonderful program called the CARE Program and you say you're not going to give out any coupons, samples, or rebates, and so I'm concerned about the lower socioeconomic patient who really requires this medication and the reason the patient may not be taking a reliable contraceptive is because she can't afford oral contraceptive pills.

So I'm wondering what's the reasoning for not having some type of assistance program with obtaining the medication.

DR. BEN-MAIMON: I would like to make a distinction between coupon samples and an assistance program. An assistance program I don't think is something that we've considered. I think we would consider it.

We will be continuing to supply it to clinics at a discount. So it will continue to be available at clinics for women who source it there and who are used to using clinics as access for their medical care.

But I don't want to imply that samples and coupons are related to an assistance program, and that's not something that we've considered, but we would be willing to.

CHAIRMAN CANTILENA: Okay. Thank you. Thank you.

We actually are out of time. So what I'd like to do is ask you to hold your questions until this afternoon. We will have the opportunity to ask questions of the sponsor after lunch as well.

And what we'd like to do now is to pause for 15 minutes. We'll take a 15-minute break, and we'll come back with the FDA.

Thank you.

(Whereupon, the foregoing matter went off the record at 9:50 a.m. and went back on the record at 10:09 a.m.)

CHAIRMAN CANTILENA: It's now time for the FDA presentations, and our first speaker for the FDA will be Dr. Davis.

Dr. Davis.

DR. DAVIS: Thank you.

Good morning. My name is Dan Davis, and I'm a medical officer in the Division of Reproductive and Urologic Drugs.

I did the primary clinical review for efficacy and safety for the original Plan B submission and have followed the sponsor's periodic safety reports and the medical literature on emergency contraception since the approval of Plan B as a prescription drug in July of '99. My responsibility for the current Plan B submission is to evaluate any safety concerns relative to the requested change to a nonprescription status.

The topics to be presented are in the following order: the points to consider for the switch from prescription to nonprescription status; marketing data on U.S. and global use, as well as distribution patterns and availability of levonorgestrel for emergency contraception, which I will often refer to simply as EC throughout my talk; the sponsor's safety data from both the original submission and the subsequent post marketing data; findings from the current FDA safety review; the potential for misuse and abuse; contraindications; and I will close with a summary of the FDA safety conclusions for levonorgestrel.

Occasionally I may mention the term "postcoital contraception," which is a more routine primary method of contraception for women used, taken after intercourse. The topic today is really emergency contraception, which is single use, but a lot of our data for safety comes from original studies dealing with postcoital contraception.

The prescriptions to nonprescription, which has already been carefully discussed by Dr. Rosebraugh and the sponsor, I will concentrate on the first two items here, namely, an acceptable margin of safety and the potential for misuse and abuse.

Dr. Chen will discuss whether the product was safe during the actual use study, and finally, the committee members here will be asked to discuss the benefits relative to risk after all of our morning speakers have presented.

The sponsor's exposure data comes from many different sources, but first of all, I want to just remind people that Plan B is levonorgestrel 0.75 milligrams taken times two doses. The sponsor estimates the U.S. exposure at 2.4 million uses since the approval of Plan B in 1999. Worldwide, emergency contraception pills are available in 101 countries.

The levonorgestrel products in the U.K. and France are identical to Plan B. Exposure is estimated to be at 2.1 million in the U.K. and 1.8 million in France.

Most recent 12-month data that's available from Canada shows 72,000 uses in a one-year period of time.

The above exposure data clearly shows that levonorgestrel for EC has been used by several million women in at least four countries in the recent years.

The distribution patterns show at least four methods of availability. Most common is a routine prescription for EC as needed. Sixty-eight countries, including the U.S. have EC availability by prescription.

Advanced provision of a written prescription or the actual product is becoming more common and is promoted worldwide by many organizations and clinics. Globally EC is available directly from a pharmacist in 33 countries, and as discussed earlier, in five states.

Barr has already covered the availability in the U.S. The largest and longest program is obviously from the State of Washington. The California pilot program started in the year 2000, and by January of 2002, the California legislature passed a law allowing a statewide effort as outlined.

The other three states are Alaska, New Mexico and Hawaii.

The fourth method availability is that EC pills are truly available over the counter in Sweden and Norway. Clinical trial data are considered to be the gold standard for safety data because trials are often use strict protocols, control arms, added visits, more safety monitoring, and good data collection.

The original Plan B submission contains safety data from several clinical sources. The pivotal blinded and comparative World Health Organization Trial included 1,955 women. The primary data sets were submitted with the NDA application and reviewed by our reproductive division, basically by myself, and for both safety and efficacy.

Levonorgestrel alone in that study was compared to the m ore traditional Yuzpe regimen, which is a combination of levonorgestrel and an estrogen.

From three ongoing World Health Organization trials, plus some introductory trials of prescription levonorgestrel in three European countries for use as EC, and the pivotal WHO large trial, no serious events commonly called SAEs had been reported by the approval date for Plan B.

From the literature review, more than 15,000 women from 29 countries in clinical trials using various doses of levonorgestrel for either EC or postcoital contraception had been studied. The data showed that levonorgestrel taken for contraception after intercourse was well tolerated.

This data from the extensive review did not uncover any deaths, cardiovascular problems, thromboembolic events, or serious adverse events. Those adverse events that were reported were consistent across all studies and reflected the AEs that are listed in the current Plan B label.

In summary, the FDA review of the sponsor's clinical trial safety data did not find any safety signals of concern.

We next rely on post marketing data which has been obtained since the approval of Plan B. In contrast to clinical trial data, it is important to note the limitations of post marketing data. They're outlined here.

The use or exposure data is often estimated. The likelihood of reporting adverse events may be greater or lesser, depending on the nature of the event.

Third, we know that there's considerable under reporting of adverse events.

And fourth, many of the post marketing AE reports lack complete clinical information.

There are many different post marketing sources of safety data, but overlapping of the reports often makes it difficult to interpret the data. The sponsor provided different sources of post marketing data.

First were the FDA required periodic safety reports covering from the time of approval up till January of 2003. This contained 345 reports. Reported most often were 123 pregnancies and 64 cases of bleeding. Most of the reported events were mild and short term. All were labeled events, and there were no reports of transfusions, SAEs or deaths.

Many of the reports actually did come from European sources, even though reported to our periodic safety update to the FDA.

The global safety databases included national pharmacovigilance agencies in key European countries and Canada, the World Health Organization Drug Monitoring Program, reports from the manufacturer of Plan B, and several other databases.

From these various global databases there were no reported deaths, no strokes or thromboembolic events. There was one case reported in France in a 22 year old woman who was hospitalized with phlebitis, but did not have any further problems.

In summary, based on all of the safety data from clinical trials involving 15,000 women and from several post marketing data sources worldwide, the sponsor's conclusion is that Plan B is an appropriate candidate for a switch to a nonprescription status.

Our division requested a consultation from the FDA Office of Drug Safety with a focus on serious adverse events and ectopic pregnancies. The consultation reviewed the FDA adverse event reporting system, commonly called AERS, A-E-R-S, and data from the U.K. In the AERS database there were 116 unduplicated cases, and 60 percent of these were for nonserious labeled events, such as vaginal bleeding, pregnancy, abdominal cramps or pain, and nausea and vomiting.

Many of the reports had incomplete information and are, therefore, hard to interpret.

From this data set there were no deaths, serious cardiovascular or thromboembolic events or transfusions reported to AERS from any country. As already noted, we have over four million uses of levonorgestrel from the U.S. and the U.K. since 1999, and this data is primarily U.S. and U.K. data.

There were ten cases of an allergic reaction that were reported. Three were from the United States. Most were minor, although two women did have some difficulty breathing. Nobody was hospitalized.

Under fetal risk, there are eight reports that included five cases of a spontaneous or inevitable abortion, and three cases with congenital anomalies, all reported from Europe. This number of cases is well below what we would anticipate, given the spontaneous abortion rate of ten to 15 percent of all pregnancies and the congenital anomaly rate of 0.85 percent.

The other finding on the AERS database was ectopic pregnancy. There were 28 reported cases. None were from the United States, and there were no deaths. Because the incidence of ectopics is dependent entirely on the total number of reported pregnancies relative to the number of ectopics, we like to use a database where the number of ectopics and total pregnancies is as reliable as possible. For this type of information we look at randomized clinical trials as mentioned earlier.

From the six large randomized clinical trials involving the 7,889 women, we see that there were the two ectopics and a total of 135 pregnancies or an incidence of 1.5 percent. As already pointed out by Barr Pharmaceutical, this is the same incidence as we would expect in the general population. So it does not raise an issue that ectopics should be of concern.

This slide is a little bit busy, but of all of the potential misuse and abuse problems, we considered overdose, higher doses, repeat use, and use in pregnancy, and incorrect dosing.

For overdose, there were no reports in the literature or safety databases of an overdose. Overdose is also unlikely with the expected cost of Plan B.

The second bullet really should be for higher doses, and the best safety data for exposure to higher or repeated doses comes from European trials in the 1970s and '80s, in which levonorgestrel was used for regular postcoital contraception. In these trials levonorgestrel .75 milligrams was used up to eight times per month or total doses of 2.25 milligrams within 24 hours were used and repeated as needed, and a single dose of .4 milligrams taken on average eight to nine times per month for an average of nine consecutive months were also used.

From this database, again, we do not see any safety signals with problems with serious adverse events, deaths, or hospitalizations.

Repeat use, there are many, many different studies that could be quoted. I elected to talk about the Rowlands study from the United Kingdom. The database was over 15,000 medical records of women who did use EC once. The age range was 14 to 29, and these women were followed for four years.

Rowlands found that repeat EC use was uncommon per year or over a four-year period of time. For example, only three percent of the women, 15,000 women used EC twice in the four-year period of time. One percent used EC three times in the four-year period, and .8 percent used EC greater than three times over a four-year period of time.

We also are aware of this one-year study by Glasier and Baird of 1,000 women in Scotland, where EC use was used more often with advanced provision, but for the women using the product more than once in the entire year, 11 percent of the women with advanced provision used EC more than once, and 13 percent of those without advanced provision used EC more than once.

Use during pregnancy shows no clear evidence that inadvertent use of levonorgestrel during a pregnancy will result in abortion or cause fetal problems.

For incorrect dosing, in other words, not using the product strictly according to the label, there are recently published randomized clinical trials that report on a single dose of 1.5 milligrams levonorgestrel being safe and effective. The second dose can be taken later than the labeled 12-hour dose, and we do have information on the first dose being started between 72 and 120 hours.

I'm not going to discuss these further because that's really not the point of our meeting today.

Contraindications from the prescription Plan B label has already been addressed somewhat. The current label for prescription lists three contraindications based solely on the class label for progestin only oral contraceptive pills, which are taken daily for routine contraception. The prescription label clearly states that it is unknown whether these same conditions apply to the Plan B regimen.

Hypersensitivity to any component of Plan B is certainly a contraindication and should be listed. It is a rare event, and there have been no reports of death or hospitalization due to allergy.

Known or suspected pregnancy is not a contraindication. It is listed primarily because the product will not work if the user is already pregnant, and this is really not a safety issue.

The sponsor has talked about removing the undiagnosed abnormal genital bleeding from the label. Our division is in general agreement with that principle, but we still do not have the final label and the final approval of the product.

So our evidence of safety comes from many different sources: the original NDA trial data, which we have discussed; and since that time, there have been four additional published randomized clinical trials enrolling 6,503 women in levonorgestrel only arms and using the same total dose as Plan B.

This gold standard for drug safety and efficacy had the following findings: no reported deaths; no vascular events; no thromboembolic events; and as mentioned earlier, there were two ectopics in 135 pregnancies, which is the same incidence that would be normally expected.

Post marketing data since July of '99 shows the following. There has been obvious extensive EC exposure in the U.S., U.K., and France, and over six million estimated uses. There have been no deaths, heart attacks, strokes, or thromboembolic events reported with EC use in the medical literature or post marketing surveillance.

There's only one report of phlebitis in the 22 year old woman from France. No reports of overdose, and I found no evidence for abuse or misuse.

Of the eight fetal AEs reported in the FDA AERS database, there were the three congenital anomalies and five miscarriages. This is very low compared to the background rate as mentioned earlier.

We have reviewed the data submitted by the sponsor in the current NDA application. We have done our own review of randomized clinical trials, the voluminous medical literature on EC, the FDA's AERS database, and other databases.

Levonorgestrel has been used extensively worldwide for over 35 years, in combination oral contraceptives, levonorgestrel oral contraceptives and for postcoital contraception, and EC.

Plan B, with a total dose of 1.5 milligrams levonorgestrel, has a safety profile that includes no deaths, strokes or thromboembolic events. Single doses up to 1.5 milligrams, repeated doses of .4 milligrams up to 25 months, and repeated doses up to 2.25 milligrams in a 24-hour period of time have been studied.

There is a low potential for misuse and abuse. The safety risks are very limited. We believe that allergy is the only contraindication which is rarely seen, and there are no reported deaths or hospitalizations.

Finally, there are no clear risks to a pregnancy or the fetus that have been demonstrated.

This concludes my presentation. Thanks for your attention, and Dr. Karen Lechter will be our next speaker.

DR. LECHTER: I will first talk in general about label comprehension studies, what they are, and how they're used. Then I'll discuss the Plan B label comprehension study. I'll finish with the agency's primary conclusions from that study.

The purpose of label comprehension studies is to test the proposed labeling with potential consumers. Questionnaires should be based on communication objectives that are the messages in the label that should be communicated, and that should be tested in the study.

The results of the studies are used to refine the labeling, which is sometimes then retested. The improved label is usually used in an actual use trial, which tests the overall use of the product. However, label comprehension studies can test issues that can't be tested in the actual use trial, such as whether people understand what the most common side effects are.

Label comprehension studies test potential consumers and also sometimes those who should not use the product. These studies are usually conducted in shopping malls. Mall participants may be supplemented with participants from other locations.

We ask sponsors to include a substantial number of low literate participants. Some studies deliberately recruit specific populations that have particular medical conditions or who use particular drugs. These participants may be recruited by telephone or by other means.

Label comprehension studies begin with a collection of initial data about participants who then usually take a literacy test. The interviewer shows the labeling to the participants and then asks questions based on the communication objectives.

The types of questions used can be yes/no, true/false, multiple choice, checklists, or open ended styles of questions. We discourage the use of yes/no and true/false questions, but if they are used, we encourage follow-up questions to determine the nature of the participant's understanding about the issue.

We encourage the use of scenario questions in which participants have to apply the labeling information to hypothetical situations, and we usually ask for a question to determine if participants can correctly decide whether the product is appropriate for them to use themselves.

The way the questions are posed can affect the responses. So we watch for biases in the construction of questions. For example, we try to eliminate leading questions and series of questions that all require the same response.

In the Plan B label comprehension study, of the 663 women interviewed, 656 were eligible to participate. They ranged in age from 12 to 50. Those who were age 18 or older who had graduated from college were not tested, nor were those under age 18, not tested for literacy.

We categorized those participants who have an eighth grade reading level or below as low literate.

The first question about the indication was asked with the package removed from site. After that question was answered, the remaining questions were asked with various parts of the label in view. After questions about the label participants were asked about their own sexual activity and contraceptive use.

Before I present the results to you, I'd like to make some comments about scoring and issues affecting the results. In addition to presenting results of individual questions, the sponsor presented results organized by communication objective. For some objectives, all questions relating to that objective needed to be answered correctly for the objective to have been successfully communicated.

However, for other objectives half of three-fourths of the questions needed to be answered correctly. In some cases, partially correct responses were scored as acceptable or correct. For example, responses to the question about the purpose of the product, for that question credit was given to a partial response that it is for contraception even though a full response was that it is for contraception after sex.

Finally, one question about using Plan B for regular contraception was dropped from the analysis because the sponsor said it was confusing. However, another apparently confusing question on the same topic was not dropped.

There are no perfect questionnaires or methodologies. Every study has weaknesses that may affect the results and the interpretation of the results. In this study there were two primary aspects to the questioning that left gaps in our ability to interpret the results.

First, because there were no follow-up questions for some of the questions we don't know if they were answered correctly or incorrectly for the wrong reasons. Also, there were no follow-up questions for incomplete or ambiguous responses.

Another problem with the methodology is that not all participants were categorized by literacy level. Despite these shortcomings, it is likely that these weaknesses did not have a substantial effect on our ability to draw useful conclusions from the study.

The next four slides present the results organized by communication objective. For purposes of shorthand, the tables refer to those with a reading level of eighth grade or below as low lit. and those with a higher than eighth grade reading level as high lit.

Keep in mind, however, that not everyone was tested for literacy. The total column does reflect the total number of participants who were in the study altogether.

In two places, and one of them is on this slide, I have two numbers in a box. The first number represents the fully correct response, and the second number indicates the combination of correct and acceptable responses for that item.

In the low literacy and high literacy column for that question, that represents the acceptable and correct responses for that question. For nine of the 11 communication objectives, the low literate group scored statistically significantly lower than the higher literate group. The objectives for which there were statistically significant differences are indicated with an asterisk, and as you can see, all four of those on this slide had statistically significant differences.

It's not unusual in a label comprehension study for the low literate group to score significantly different than the higher literate group on many of the communication objectives.

This slide shows the communication objectives that score 90 percent or higher overall. These objectives are that the product is not for use by pregnant women. It doesn't prevent STDs, including AIDS and HIV. The purpose is to prevent pregnancy, and it should not be used by women allergic to its ingredients.

I want to point out that the objective about using the product to prevent pregnancy after sex had four different questions associated with it. However, only one of them had the potential to permit participants to indicate that the product is for use after sex rather than before. This was the open ended question about what the purpose of the product was.

Although 90 percent said that the product was for contraception, 45 percent mentioned that it was for use after sex.

This slide shows the communication objectives that scored 85 to 89 percent. Eighty-nine percent understood that the side effects include nausea and vomiting.

Some responses about taking the second pill 12 hours after the first were incomplete, with 69 percent giving a totally correct response of 12 hours after the first pill and 87 percent giving acceptable or correct responses. The acceptable responses usually said 12 hours without specifying 12 hours after the first pill. Eighty-five percent understood to take the first pill within 72 hours.

This slide shows the communication objectives that scored 80 to 84 percent. Eighty-two percent understood to take the pill as soon as possible after sex, and 81 percent understood that if severe abdominal pain develops, the woman should seek immediate medical care.

There were no differences between the literacy groups for this item. As you can see, no asterisks for both of these items.

Two objectives were understood by the full sample at less than 80 percent. The low literate group also scored the lowest on these two messages. We don't know if these two issues were not well understood or whether flaws in the questionnaire prevented us from determining how well they were understood.

Understanding that Plan B should not be used if there's unexplained vaginal bleeding was at 75 percent for the full sample and 69 percent for the low literate. Sixty-seven percent of the full sample clearly understood that the product is for backup, not for regular contraception. Forty-six percent of the low literate understood this message.

For this communication objective, participants had to score correctly on three out of four questions. Scores for these questions ranged from 47 percent to 85 percent. We agree with the sponsor that one question might have been misinterpreted by participants, and we don't give a lot of weight to the results for that question.

Participants who answered these question incorrectly would have had to answer all the other questions in this group correctly to get credit for this communication objective. In the spirit of caution, we should deal with this communication objective as if it needed improvement.

There were no effects of previous sexual experience and no difference due to experience with emergency contraceptives. However, this last finding may be due to the low number of participants with prior EC experience.

So, in summary, some concepts may be less well understood than others. However, some of the lower scores here may have been artifacts of the questionnaire design. There were lower scores for the concepts that Plan B is not for regular use. Do not use it if there's unexplained vaginal bleeding. Get medical help if there's severe abdominal pain, and take the first pill as soon as possible after sex.

Some questions were well understood, including the fact that Plan B is for contraception. It does not protect against STDs. Don't take it while you're pregnant. Don't use it if you're allergic to the ingredients. Nausea and vomiting are side effects, and take the first pill within three days.

Results of the actual use study help assess how well the label communicates in real use situations. However, the actual use study cannot provide information about certain issues that are best tested in label comprehension studies, such as the side effects.

The label comprehension study shapes the label, but it is not the final determination of approvability.

Dr. Jin Chen will now discuss the actual use study.

DR. CHEN: Good morning. My name is Jin Chen. I'm a medical reviewer from the Division of OTC Drug Products.

I will summarize FDA's review of the Plan B actual use study, the pivotal clinical trial that the sponsor submitted with this NDA. This will be followed by a brief literature review of contraceptive behavior studies associated with emergency contraception.

First of all, I would like to briefly go over some basic principles of a typical actual use study. The actual use study intends to simulate OTC setting to assess if potential OTC consumers or users can self-diagnose the medical condition for which an OTC candidate product is indicated. To assess if potential OTC users can self-select the product, that's their understanding of the indication and warnings in a proposed OTC label, and to assess if potential OTC users can self-medicate according to label directions.

The study also evaluates the safety of the product when used under OTC-like setting.

Efficacy is rarely assessed in this kind of clinical study. The study is generally designed as multi-center, open label, single arm, uncontrolled trial.

The study population in the actual use study should represent the anticipated OTC users. Therefore, subjects are generally recruited from geographically diverse OTC-like settings with minimal exclusion criteria. The study may be reached by inclusion of specific subgroup, such as low literacy population and a certain age category.

Subjects may have unlimited access to study product during the study. They should receive minimal intervention from health care professionals during whole study process.

Now, let's look at the sponsor's Plan B actual use study. The primary objectives of this study were to test if anticipated OTC population can correctly self-select the Plan B and it can time both doses of Plan B based on their understanding of the proposed OTC label.

The second objective of this study were assessment of adverse events, frequency of multiple use, and pregnancy rate.

As an additional observation, sponsor compared contraceptive behaviors in the study population before and after study or before and after Plan B use.

This study was conducted in five family planning clinics across five states in U.S., and five pharmacy stores in Washington State. Female subjects of reproductive age who presented requesting emergency contraceptive only were recruited. They made that decision to participate in this study after review of the proposed OTC label. They were allowed to purchase one package of Plan B at the study site during enrollment, and they could re-enroll and purchase additional Plan B during the three-month open study period.

Subjects were followed for four weeks with two contacts, at the first week and the second week, after their enrollment. For those subjects with unknown pregnancy studies or unresolved adverse events as four-week contacts, additional follow-up work was given. Data were collected by phone interview during the follow-up contacts, and a diary card that was provided to each subject with Plan B package.

Of the 665 screened subjects, 585 were enrolled. Eighty subjects were not enrolled. Of the 585 enrolled subjects, 94 percent came from family planning clinics, the remaining six from the pharmacy stores.

The age range of the enrolled subjects was 14 to 44 years. The average age was 22 years. Eighty-seven percent of the enrolled subjects completed at least high school education. Thirty percent had ninth to 11th grade education. Forty percent of the enrolled subjects had previous experience with using emergency contraception, here EC.

Ninety-three percent of the enrolled subjects completed at least one follow-up contact. Most of them, 86 percent, have two follow-up contacts. About seven percent of subjects lost to follow-up.

Based on the follow-up information provided by 543 subjects, 540 used the Plan B during the study, which was 92 percent of the enrolled subjects.

Now, I'm going to briefly summarize each of these five results. First, about self-selection, of the 540 users, 95 percent correctly self-selected Plan B by the following reasons.

Forty percent of users had intercourse without any contraception. The others had a problem with their regular contraception methods, such as condom use failure, missed taking oral contraception pills, and four percent of users had a problem, had accident when using withdraw methods as a contraception.

Five percent of users represented 26 subjects incorrectly self-selecting Plan B during the study. Seven subjects had labeled contraindications, such as unexplained vaginal bleeding, one already pregnancy.

There were two subjects who took Plan B before unprotected intercourse. About three percent provided nonspecific reason for using Plan B.

Timing of doses. According to the dosing instruction, in the proposed OTC label 92 percent of users took the first pill within 72 hours after intercourse. Seventy-two percent of users took the second pill at 12 hours later. Overall 68 percent of users took both pills following the label dosing regimen.

The sponsor realigned second pill timing data using different dosing definition. Ninety-three percent of users took a second pill between six to 18 hours after the first pill. If needing the first pill timing criteria the same, overall 87 percent of users took both pills according to alternate second dosing interval.

Adverse events. There were no serious adverse events and no new safety signal reported in this study. The most common adverse events were transient abdominal pain, nausea, headache, and fatigue.

Contraceptive behaviors. This table shows overall change in contraceptive behaviors of the enrolled population during the one-month study as compared to one month before study. At least one such act without any contraception decreased from 60 percent before study to 20 percent during study. User withdraw method decreased from 28 percent to ten percent. Condom use slightly increased from 79 percent to 90 percent.

Remember those behavior changes were based on one-month observation during this study.

During the one-month observation subjects tended to use more effective contraception methods. One, point, seven percent, which was ten subjects, requested the Plan B more than once during three-month enrollment period through the re-enrollment process.

Pregnancy rate. Ten subjects, which is 1.9 percent, had a confirmed pregnancy. In addition, there were 40 subjects, which was 2.6 percent, that had unknown pregnancy studies, and at the end of the study they were lost to further contacts.

In summary, the Plan B actual use study shows that 95 percent of users correctly self-selected Plan B. Sixty-eight percent of users took the first pill within 72 hours and the second pill at 12 hours later. Eighty-seven percent of users took the first pill within 72 hours and the second pill between six to 18 hours after the first pill.

There were no serious adverse events and no new statistic loss (phonetic). Subjects tended to use more effective contraceptive methods within one month observation. There were no significant differences among demographic subgroups in self-selection, timing of doses, adverse events, and contraceptive behaviors.

However, there were some limitations in this study. The formal period was only four weeks. Subjects were allowed to purchase only one package at the enrollment, although they can come back to the study site to get another package of Plan B, but they had to go through reenrollment process.

There was no literacy testing in this study.

Finally, 94 percent of subjects were recruited from clinics. Due to those limitations, it may be difficult to extrapolate the actual use study results to the OTC setting, particularly to assess non-tour (phonetic) contraceptive behaviors in target OTC population.

To address these concerns, the sponsor submitted eight literature reports regarding contraceptive behaviors related to the advanced provision of emergency contraception. The literature enclosed five published studies, two unpublished manuscripts, and one abstract. Five studies were conducted in the United States. The remaining three studies were conducted in outside the U.S., one study each from U.K., India and Ghana. There were no raw data submitted with these studies.

The study populations were recruited from either family planning clinics or hospital based clinics. Subjects were 15 to 45 years old who come to the clinic not for emergency contraception purpose. Sample size ranged anywhere from 160 to around 1,000 subjects.

Most of those studies were of randomized controlled design, and I have two groups, treatment and control. Treatment groups received in advance one of three courses of emergency contraception pills. Many subjects had emergency contraception pills on hand before unprotected intercourse.

In the control group, subjects were told to obtain emergency contraception pill through prescription in clinics. In one study, subjects had pharmacy access to emergency contraception as an additional control group.

All subjects in both treatment and the control group received EC education, emergency contraception education, and supervision from health care providers.

The formal period among those studies ranged from two to 12 months.

Here's a summary of the results from those behavior studies. The 08 studies, such as with advanced emergency contraception provision, were more likely to use emergency contraception pills. In most of those studies, such as with the advanced EC provision, didn't have more frequent unprotected sex, didn't decrease condom use, didn't switch to mass effective contraception.

The behavior studies are complementary to the Plan B actual use study in some degree. For example, those studies had a longer follow-up period. The sample size in some of the studies were relatively large, and finally, the advanced EC provision is the better part in those studies.

However, there is some limitations in those behavior studies, such as all studies were conducted in clinical setting instead of simulated OTC setting. All of he subjects in those studies received EC education. Three studies were conducted in foreign countries, which may not represent U.S. population.

Six studies provided only one course of emergency contraception pills in advance.

This completes the FDA summary of behavior study. Thank you very much.

CHAIRMAN CANTILENA: Okay. Thank you, Drs. Chen, Lechter, and Davis.

We now have time for questions for FDA presenters, and I would actually like to start with a question for Dr. Lechter.

In the review in the document, you actually talk about concepts which were not clearly understood or for which the data were inconclusive, and really a couple that jump out at me are things that really drive the primary efficacy in terms of the ability to take the first tablet as soon as possible after intercourse and the second in terms of the timing of the second dose.

And I guess overall if you do sort of the score card, I guess I have according, you know, to your information that really four of the 11 objectives in the comprehension study, you know, were not met.

And my question is: was your office involved or was the over-the-counter office involved in sort of going forward with the actual use after a study which I think if you look at other studies that, you know, we've heard about in the past for statins and the heartburn drugs, the overall success of the comprehension study was really not that good?

So my question was, you know: were you involved with shaping the label for the actual, you know, use, and if you were, I would ask, you know, why you didn't ask for a second comprehension study that was done in advance of the actual use study.

DR. LECHTER: Actually I had no involvement. There may be someone else on our team who's more appropriate to answer that question.

DR. ROSEBRAUGH: I'll take a swing at it anyway. We were not involved with the label that went into the actual use study, and it's usually the sponsor's call on when they feel like they're ready. Typically what you will see is somebody will do a label comprehension study, make changes that they think are necessary, and then they'll go into an actual use study.

CHAIRMAN CANTILENA: Okay. Over here. Dr. Hager.

DR. HAGER: I have a couple of quick questions. One, since only 29 of 585 of the subjects in the actual use study were 14 to 16 years of age, and since those 18 years of age and younger were not tested for literacy, indicating not tested for understanding, are there any considerations about age restriction on the availability?

Number two, the comment was made that there was failure to understand the need for getting medical help for abdominal pain. The Washington State data, if you look at the pharmacy data, indicates that the pharmacist said that 85 percent of the subjects needed medical follow-up, needed medical information. Is there concern about failure to diagnose ectopic pregnancy among this population?

And finally, I have a question about effectiveness. Since you accepted an extension from 12 hours for the second dose to 12 to 18 hours, can you tell us about effectiveness with that six-hour delay?

CHAIRMAN CANTILENA: Does someone from FDA want to handle those in order?

DR. ROSEBRAUGH: Well, in order, I think Questions 1 and 2 are things that we are awaiting panel discussion on. So I think it would be premature for us to comment.

Section 3 or Question 3 is also something that I think we are awaiting the panel to comment. I don't know.

CHAIRMAN CANTILENA: Okay. So the short answer is that you have no comment at this point.

DR. ROSEBRAUGH: Correct.

CHAIRMAN CANTILENA: Okay. Dr. Trussell and then Dr. Tinetti.

DR. TRUSSELL: I wanted to follow up on two questions that were asked before, including now a third by Dr. Hager, and it's a question, I think, to Dr. Davis.

On page 8 in Tab 5, Table 3, you have the results of two randomized clinical trials, both of which showed that a single 1.5 milligram dose, both pills taken at once, was just as effective with no greater incidence of side effects.

We saw both from the label comprehension and from the actual use study that one of the sources of problems is people taking the pill exactly 12 hours later, which was declared to be the correct answer, and now the sponsor has even volunteered to put in a card showing the time of the first dose and the time the second dose is supposed to be taken.

We now have these data from two randomized clinical trials that show that they can be taken at once. We can eliminate all of these problems by just simply changing the instructions to take both at one time. You have ample data to support it. This change has already been made based upon the same two studies in France and in the United Kingdom.

CHAIRMAN CANTILENA: Okay. That question, I guess, was for Dr. Daniel (sic), but I guess anyone from the FDA. Would you like to comment on that?

DR. GRIEBEL: Yes. We're aware of those data as well. The regulatory process for changing the label, however, requires us reviewing those data, the primary data, and that would be our process for doing that.

We do not have those data at this time to go through the formal review that is required to do that. So we have the prescription product before us, which had the primary data reviewed, and that's what we're working with.

DR. TRUSSELL: But the consequence is going to be unfortunately that most other medical authorities in the United States, including Planned Parenthood Federation of America, all have switched to taking both pills at once.

So there's going to be a great source of conflicting data out there to the consumer with both of these sets of instructions.

CHAIRMAN CANTILENA: Okay. Thank you.

Dr. Tinetti.

DR. TINETTI: My question relates to the actual use study and which I suppose we're supposed to extrapolate from the results on the knowledge and effectiveness and appropriate use. My question is 94 percent of those people were recruited from clinics, and do we have data on how many of them were actually instructed in the purpose, the timing, the dosing, and so is it really an accurate reflection of what's going to happen in real actual use when people aren't necessarily getting it from clinics?

DR. ROSEBRAUGH: The whole purpose of an actual use study is to try to mimic OTC environment as much as possible, and so that they were not supposed to be instructed in any use of it other than what they could get out of the labeling.

CHAIRMAN CANTILENA: Okay. Dr. Davidoff.

DR. DAVIDOFF: Yes. I had two questions. The first has to do with limitation of most of the studies, at least the published studies, and that is that an actual use, that they did not charge for the drug. The drug was supplied to the participants. As I understand it, the drug was charged for in the sponsor's actual use study.

It seemed to me that the lack of information on the effect of charging for the drug is a substantial limitation. It could work in one of two directions and possibly others. One is charging would, of course, potentially decrease the potential for repeated use and substitution of emergency contraception pills for other more conventional methods of contraception.

On the other hand, charging obviously can and probably would decrease access to some degree. I wondered if you would comment on that particular limitation of the data that's available. That's the first question.

The second has to do with the issue of abdominal pain because it seemed to me from the labeling the significance of abdominal pain is very ambiguous. It is directed primarily at the concern about ectopic pregnancy, quite appropriately, but it seemed to me that this lack of information and the ambiguity of the message about abdominal pain could be interpreted by women as potentially a side effect of the drug, even though it's not mentioned under side effects, and I wondered if there isn't an argument to be made for spelling out in a little bit more detail why there is concern about abdominal pain.

CHAIRMAN CANTILENA: Okay. So if I can then try to summarize, your questions for FDA are to address the issue of charging or not charging in the studies, and the other is the interpretation of the finding of abdominal pain or the message.

Curt.

DR. CHEN: Well, I can answer the first question. I guess the second question maybe give somebody else.

Actually he brought out a very, very important point to FDA. This is a big issue, either charge or not charge. For this study particularly, actually such as were reimbursed in the end of -- after second contact from my understanding, but they were told they would get reimbursed after enrollment for this one.

So somehow this confining factor here, definitely, but if you don't pay, if you don't reimburse, then you probably bring up another issue as you just mentioned. So this is very tight (phonetic), and we certainly would like to hear your suggested opinion on that.

For the second question, I guess I have to pass to -- this is related to ectopic pregnancy, I believe, right? So probably --

DR. DAVIS: Since abdominal cramping, pelvic cramping is a normal and common side effect of the medication, there is then a fine distinction between how much cramping and pain would be then synonymous with or a potential warning signal for an ectopic pregnancy.

Our general feeling was that if severe symptoms persist for greater than 48 hours, that certainly that should be in the label for a reason to contact your health care professional, or even potentially we could label for pelvic pain on one side greater than the other. In other words, we're certainly open to a label change that would reflect the potential risk of an ectopic pregnancy.

CHAIRMAN CANTILENA: Okay. We have Dr. Crockett and then the last question from Dr. Benowitz.

DR. CROCKETT: Yes, thank you.

My question is for Dr. Chen, and it's concerning the actual use study. It struck me in reviewing the actual use study that the company did a really good job of following the Weight Watchers model. They applied education and accountability to taking their product and saw behavioral changes that were very favorable.

And my question to you as an FDA member is: how did an actual use data get done? I want to go back to before it was done. How did it go through the FDA? And what kind of input did you as a group have concerning the design of that study that doesn't actually show actual use patterns at all?

DR. LEONARD SEGAL: Excuse me. I think I can take this question if it's all right.

I'm the medical team leader in the Division of Over-the-Counter Drug Products, Andrea Leonard Segal, and I was part of that earlier process.

And we met with the sponsor on more than one occasion, and it was clear that, see, what we try to do in actual use studies is we try to get an all comers population. If somebody wants to go into a drug store and purchase a decongestant, we would like to know that they can differentiate the product that we're interested in studying from the product that they might actually have sought to purchase.

So consequently, we would like to have a mall setting where we would garner people from all different kinds of realms with all different kinds of purposes. However, this product deals with a very intimate issue, and the agency recognized at the time that we were discussing the protocol design that it might be very difficult for anyone to recruit this kind of a population that might be interested in this kind of an issue in a general mall setting.

So we agreed that it would be okay to use a more precise environment. This is not the first time we've done this in actual use studies. We've done this kind of thing to help sponsors target specific populations at risk when we've been concerned about perhaps somebody with heart disease who might be at risk for a particular product or somebody with kidney disease. That kind of a thought runs through our minds. So that's what we did in this particular case.

Does that address your issue?

DR. CROCKETT: Yes, partially it does. I have less issue with the fact that it was done in a clinic setting than I do with the study structure where the patient received education and had some accountability. They knew that they were going to have to fill in a card. There were going to be contacts, and that accountability in and of itself affects behavior.

And when we're talking about taking something over the counter without that education and that behavior it seems like the sponsor's actual use study is more supporting a behind the counter or prescription setting for this drug.

DR. LEONARD SEGAL: The participants in this study were not supposed to be targeted to receive specific education. That was only the label was supposed to educate them. That's how this study differed from the behavioral studies that were used as supportive evidence for longer use where consumers or participants did receive education, both in the control groups and in the advanced provision groups. In this study education was not a specific element.

With regard to follow-up contact, all actual use studies suffer from this weakness. We are always debating how to derive our data without influencing consumer behavior, and we try to do it in the least obtrusive manner.

But we recognize that it's a flaw. I don't think that it is possible; at least we have not figured out yet how it is possible to conduct a perfect actual use study that would not in any way influence a consumer.

What we often try to do is to not establish routine follow-up visits as much as possible. We try to allow the consumer to have as much rein as to determining when he or she will choose to follow up, but we need some means of data collection.

Does that answer the question?

CHAIRMAN CANTILENA: Okay. Thank you.

And the final question from Dr. Benowitz.

DR. BENOWITZ: My question is to Dr. Chen.

In your review of the contraceptive behavioral studies that were not done by the sponsor but published elsewhere, you talked about emergency contraception in general, and it's my recollection, but please correct me if I'm wrong, that these included both combination estrogen/progestin, as well as progestin only products.

And it's also my impression that the side effect profile is different; that there's much more nausea and vomiting and much more aversive to use the combination products rather than progestin alone.

And do you think that that difference has any impact in terms of how people use this repetitively, in terms of contraceptive behavior?

DR. CHEN: Regarding behavior, actually I believe you referred to a literature study, right?

DR. BENOWITZ: Yes.

DR. CHEN: Okay. Yeah, some study definitely use combination products. Probably most of them, they use Yuzpe regimen.

Do you have another question?

DR. BENOWITZ: Well, my question was the toxicity of the combination product is different and more adverse than the progestin only.

DR. CHEN: Yes, in general, yes.

DR. BENOWITZ: Many women I know have taken the combined product, find it very uncomfortable and really don't want to use it again if they can ever avoid it because they get really sick.

The progestin product does not do that, and my question is does that difference in the product influence your interpretation of the contraceptive behavior and repetitive use behavior.

DR. CHEN: Yes, it could be it could impact, you know, in terms of compliance to take a pill, you know. In general, single ingredient has had less side effects from previous clinical safety trial. So that probably somehow increased compliance in terms to take both pills or one pill, whatever.

DR. BENOWITZ: So, again, a follow-up. Is there any evidence that there's a difference in behavior if you're using combined versus progestin only?

DR. CHEN: We don't have this information from those literature.

Dr. Davis, you may have something?

DR. DAVIS: Just to make a quick comment since I did the review of the original data for Plan B and it was comparative to the Yuzpe trial from the large World Health Organization trial. There's no doubt that the safety profile, and you're referring to nausea and vomiting, was really superior for levonorgestrel only, and that, in fact, superiority claim was granted to Women's Capitol Corporation, and it is labeled such in the Plan B product.

We did not grant a superiority claim for efficacy because it wasn't statistically significant, but the data certainly strongly suggests that the levonorgestrel only is a better product for efficacy than the Yuzpe regimen.

But in comparing the behavior studies, we really -- I'm aware of the fact that many of them were Yuzpe only. One of them switched from the Yuzpe regimen to levonorgestrel only about halfway into the study, but we didn't really look at a comparison then of the two.

But it would be to me logical to conclude that the levonorgestrel only would have a better compliance profile because of the less side effects and reuse profile, too.

CHAIRMAN CANTILENA: Okay. Thank you very much.

And we'll now move into the section of the committee meeting, the open public hearing, and Dr. Templeton-Somers will read a statement before we start this section.

DR. TEMPLETON-SOMERS: Hello. We have a very full open public hearing today. In the interest of both fairness and efficiency, we're running it by some strict rules.

To make the transitions between speakers more efficient, all speakers will be using the microphone in front of the audience. That's at the end of the table there.

Each speaker has been given their number in the order of presentations, and when the person ahead of you is speaking, we ask that you move to the nearby next speaker chair, which is in the corner by Dr. Alfano there.

Individual presenters have been allotted two minutes for their presentations. The two group presentations have been allotted three minutes. We will be using a timer, and speakers who run over their time limit will find that the microphone is no longer working.

(Laughter.)

DR. TEMPLETON-SOMERS: We apologize for the need for the strict rules, but we wanted to give as many people as possible an opportunity to participate and to be as fair as possible.

Thank you for your cooperation.

CHAIRMAN CANTILENA: Okay. Both the Food and Drug Administration and the public are trying to have this a transparent process for information gathering and decision making. To insure transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important to understand the context of an individual's presentation.

For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with the sponsor, its product, and if know, its direct competitors. For example, this financial information may include the sponsor's travel lodging or expenses, you know, covering your testimony.

Likewise, the FDA encourages you at the beginning of your statement to advise the committee if you do not have any such financial relationships. If you choose not to address this issue of financial relationships at the beginning of your statement, it will not stop you from speaking.

And I think we're ready to start. I will just go over one more thing. At the end of the table, you'll find a box with some lights. The lights are a code to tell you 90 seconds the light will be green. For the last 30 seconds it will turn yellow, and when your time is up at two minutes, it will change to red, and that's the point where you will no longer find the microphone is working.

Okay. We have a technical holdup here. Stand by.

Okay. I think we're ready to start. Go ahead, our first speaker.

DR. GOLD: Good morning. As an associate professor in adolescent medicine in the Department of Pediatrics in University of Pittsburgh, I'm delighted to be here today to present our research on providing emergency contraception, or EC, in advance to adolescent girls.

The results of this study will be published this February in the Journal of Pediatric and Adolescent Gynecology.

Next slide, please.

I first want to acknowledge our funding sources as well as the collaborating students who held with the project.

Next slide when you get to it.

We conducted a randomized study comparing the sexual and contraceptive behaviors of girls given education, plus one packet of advanced EC versus those who got education only. By advanced EC, I mean we gave the girls the medicine to have on hand in case they had unprotected sex.

We recruited 301 sexually active girls between the ages of 15 and 20 from an urban adolescent clinic in Pittsburgh. At enrollment, we conducted a 15-minute interview to collect demographics and sexual and contraceptive history.

Then the girls were randomized into the advanced EC or education only group. We then conducted monthly ten-minute telephone interviews for six months.

Next slide, please.

The two groups were well matched on relevant demographic, sexual, and contraceptive history variables. We found no difference by groups in rates of unprotected sex or in the use of hormonal contraception at the one and six-month follow-up interviews.

There was also no difference by group in condom use at the one month follow-up.

Next slide, please.

However, at the six-month follow-up, more girls in the advanced EC group used condoms in the past month compared to those in the education only group. The advanced EC group used EC nearly two times more than the education only group at the one-month follow-up.

More importantly, the advanced EC group started their EC course sooner after unprotected sex compared to the education only group. EC is 50 percent more effective when taken within 12 hours of unprotected sex.

Next slide, please.

These findings imply that having EC easily available does not cause adolescents to have more unprotected sex or to stop using hormonal contraception or condoms. It does help adolescents use EC sooner.

Thank you.

CHAIRMAN CANTILENA: Just made it.

(Laughter.)

CHAIRMAN CANTILENA: Okay. Next speaker, please.

(Applause.)

DR. CULLINS: Good morning. I'm Vanessa Cullins, Vice President for Planned Parenthood Federation of America.

I have no financial relationships with the sponsor.

Planned Parenthood Federation of America wholeheartedly supports Plan B emergency contraception becoming over the counter. As you have heard, Plan B emergency contraception is ripe for over-the-counter availability.

Planned Parenthood Federation of America has followed the extensive body of published literature about emergency contraception pills which consistently shows that emergency contraception is safe, effective, and is used responsibly. Based upon this evidence, the federation has striven to make emergency contraception easily accessible through such programs as Dial EC, through which a prescription is phoned into a pharmacy; Emergency Contraception Online; advanced provision of emergency contraception pills or prescription; and emergency contraception to go through which a walk-in visit results in express availability of emergency contraception.

Since 2000, over two million emergency contraception kits have been purchased from Planned Parenthood affiliates. Based upon affiliate experiences, we confirmed that emergency contraception is used as intended, and women do not use emergency contraception as regular contraception.

Within the federation, which consists of over 850 clinical sites, there have been no reports of serious adverse events attributable to emergency contraception.

Over-the-counter availability insures timely access to a safe medication which works best the sooner it is taken. Continued prescription or over-the-counter status encumbers timely access to emergency contraception.

Even in Washington State where collaborative pharmacy agreements create an environment that's similar to behind-the-counter access, consumer need is not satisfied. All Washington State family planning affiliates have had a marked increase in the amount of emergency contraception that has been purchased and used by women.

Over-the-counter status --

CHAIRMAN CANTILENA: I'm sorry, ma'am. Your time is up.

DR. CULLINS: -- important and timely.

(Laughter.)

CHAIRMAN CANTILENA: Thank you, ma'am.

The next speaker, pease.

DR. STUART: Good morning. My name is Dr. Gretchen Stuart. I'm an assistant professor at the University of Texas Southwestern Medical Center in Dallas, and I'm a practicing OB-GYN, and I'm testifying today on behalf of the National Family Planning and Reproductive Health Association, known as HFPRHA.

I have no financial or other conflicts of interest with Plan B or any other drug companies to disclose.

NFPRHA represents a network of 4,600 clinics which provide family planning services to low income women across the country and are supported with federal funds, such as Title X.

Title X clinics have been on the forefront of efforts to provide emergency contraception in a timely fashion. We salute Barr for making a public commitment to continue selling Plan B at a reduced price to Title X providers.

However, based on first-hand experience, this is not enough. For many uninsured women and teens, the barriers to EC access remain insurmountable. Many have little experience with the medical system and may be too intimidated to make a call to a health care provider to ask for a prescription.

Many clinics are closed on nights and weekends, and many pharmacies fail to stock EC as a prescription product.

For these reasons I couldn't be more supportive of removing any barriers to accessing Plan B for teens. Currently 80 percent of all teen pregnancies are unintended. This statistic necessitates action based on the reality of teens' lives rather than our collective wish that teens postpone sexual activity.

Like it or not, nearly half of all teens are sexually active by the time they graduate high school, and like all women, teens are not always effective contraceptive users and can experience failure.

The economic and social consequences of unintended teens specifically are devastating. Less than one third ever finish high school and leaving many unprepared for the job market and likely to raise their children in poverty. Fifty-two percent of all mothers on welfare had their first child as a teenager.

Given the clarity of the science and the enormous potential to advance the important public health goals of reducing unintended pregnancy and abortion, I strongly recommend that FDA allow Plan B to be placed over the counter on pharmacy shelves and not behind the counter restricted.

Thank you.

CHAIRMAN CANTILENA: Thank you, Dr. Stuart.

Next speaker, please.

MR. MARSHALL: My name is Robert Marshall. I'm a state legislator from Virginia.

As I look around the room today, one name that should be on this NDA is Hugh Hefner. Playboys, adolescent adult males are going to be the primary beneficiaries of this. In fact, I will suggest to you they may be the major purchasers of this, who in turn will sell it to high school kids that we're going to have to deal with with appropriations from the State of Virginia.

Cokie Roberts says, "I always love the demographic figure on abortion. The most pro choice group in the country, young men between the ages of 18 and 25, the most responsible group well known for taking, you know, responsibility for their actions."

Why isn't NDA even considered here? The U.S. Defense Department authorized this for one month, then pulled it off its formulary. At the University of Virginia, these pills are passed out up to 120 hours after intercourse. Physicians there at the medical school are refusing to pass this out.

You all said it was safe. You said it's effective. Perhaps this causes abortion and perhaps of them have a conscience about this and don't want to be forced into this like they will be.

This drug was never proven safe in the first place. Industry watchdogs have, in fact, become industry lapdogs. The FDA did not rely upon any independent test conducted for safety or efficacy. You cited 21 studies, 19 of which dealt with efficacy. One maybe dealt with safety dealing with blood clotting. One from Kaiser Permanente showed that almost 50 percent of women had moral questions about what was going on.

Additionally, I found out the incidence of abortion will not be reduced. I looked at your Web site this morning. Interestingly, the definition of pregnancy has been changed even by the Bush administration from fertilization to implantation, and I've got the proof back here. This was from May 13th to yesterday.

The definitions of abortion and pregnancy were defined and acknowledged by Dr. Abraham Stone, who said, "Measures that prevent implantation are measures that cause abortion." He's from Planned Parenthood. I loved quoting my opponents.

You all are doing a disservice, and you will disrespect the rights of women to be informed as patients to call this --

CHAIRMAN CANTILENA: I'm sorry. Your time is up. Thanks, Mr. Marshall.

The next speaker please.

MS. LASER: My name is Rachel Laser, and I'm senior counsel with the National Women's Law Center.

I have no financial or other conflicts of interest with Plan B to disclose.

The mission of the National Women's Law Center is to reduce barriers for all women with special attention to the needs of low income women. Making Plan B an over-the-counter drug removes barriers to access of this critical contraceptive drug for women and, in particular, low income women.

Women do not use EC in great part because they lack access to it. Barriers to access include gaps in knowledge, obstacles to obtaining a prescription, time constraints and costs, factors that are all exaggerated for low income women.

In order to obtain EC as a prescription drug, a woman must first know that it is an option. Low income women are more likely not to have heard about EC. Positioning EC over the country where it is easily accessible helps to educate all women about its availability.

Next, the woman wanting EC must visit a physician to get the prescription. Nearly one in five women, however, and nearly one-half of uninsured women do not have a regular health provider. These women are hard pressed to obtain an appointment with a physician on such short notice.

A woman must also be able to pay for the visit, plus transportation both to the doctor and then the pharmacy. Secondary costs might include missed work and babysitting. Making EC available over the counter would eliminate many of these hurdles.

Finally, we note that the cost of EC over the counter relative to the sometimes lower cost of EC as a covered prescription drug could impede access for some low income women. For women who have insurance coverage though EC might be off formulary and cost at least as much as it would over the country, and many of the low income women do not have prescription coverage for this product. Nearly one in five women lack health insurance, the majority of whom are low income women.

And although all state Medicaid programs must cover family planning services, almost half of the states do not cover emergency contraception and Medicaid programs.

Finally, public funding could help minimize the cost of EC over the counter.

In summary, although some low income women may benefit from prescription coverage of --

CHAIRMAN CANTILENA: I'm sorry. Your time is up. Thank you, Ms. Laser.

The next speaker, please.

DR. STEWART: Good morning. My name is Felicia Stewart. I chair the board of directors for the Association of Reproductive Health Professionals, an organization of 12,000 reproductive health researchers, educators, and clinicians in the United States and internationally.

I also am an adjunct professor in OB-GYN and reproductive sciences at U.C.-San Francisco.

On behalf of ARHP, as well as the 3,000 members of the National Nurse Practitioners in Women's Health and the 10,000 members of the American Medical Women's Association, I'm pleased to have an opportunity today to speak in support of switching Plan B to over-the-counter status.

ARHP manages the first national emergency contraception hotline and Web site established in 1996 to provide women with information about emergency contraception and referrals to providers. To date our Web site has received over two million visits and approximately 500,000 phone calls.

ARHP also received calls and E-mails from women seeking help. The preponderance of these, and I have to deal with my fair share of them, is not because of problems they have using the medication, but because they have problems finding access to the medication.

Better access is needed. Seeing a provider is not necessary and certainly can be a barrier since this option can be used safely and effectively without prescriber intervention.

We also note that there are some ethical issues involved. It would be unethical to withhold from women a safe, effective treatment that affords a second chance and also unethical to reinforce the idea which woman naturally would assume on the basis of FDA restriction, that there would be some scientific evidence that unrestricted use would be unsafe or dangerous for their health.

Finally, there is unprecedented support for this. ARHP, along with 70 organizations --

CHAIRMAN CANTILENA: I'm sorry. Your time is up, Dr. Stewart.

The next speaker, please.

MS. WRIGHT: I'm Wendy Wright with Concerned Women for America, which is the nation's largest public policy women's organization. We have no financial ties to the sponsor, to the product, or to its competitors, and we're very disturbed by Plan B's promoters' emphasis on access, but not on women's safety.

There have been no studies done on the long-term effects of women after taking Plan B. There have been no studies on the effects of multiple use. In fact, Plan B promoters liberally encourage multiple use. On Plan B's Web site in the Q&A section, it asks how often can Plan B be provided. The answer is Plan B can be provided as frequently as needed.

Additionally, there have been tests done in the pediatric population which is now required by federal law. The Pediatric Equity Act of 2003, just signed into law on December 3rd, requires this.

Consumers are more influenced by ads than they would be by labeling, and the ads that have been put out by Women's Capitol Corporation for Plan B have actually been found in violation of federal law. I will quote from the FDA's letter to Women's Capitol Corporation.

The FDA has concluded that Women's Capitol Corporation's ads are false, lacking in fair balance or otherwise misleading, in violation of the Federal Food, Drug, and Cosmetic Act. Specifically, the direct to consumer radio and print ads overstate efficacy, fail to convey important limitations on use, and minimize important information about risks associated with the use of Plan B tablets emergency contraception.

As a result, the ads raise significant public health and safety concerns. We have provided a full testimony that refutes many of the claims made today by Plan B's promoters that I'll not be able to include in this short testimony.

We've also raised concerns not addressed by the promoters. I would encourage you to please read our full testimony.

Thank you.

CHAIRMAN CANTILENA: Thank you.

The next speaker, please.

MS. FREEMAN: Hello. My name is Linda Freeman. I am the co-chair of the NOW New York State Reproductive Rights Task Force. I am speaking to you today not only as an activist, nor as someone who has used the morning after pill, but most importantly I'm speaking to you today as a woman, a woman who has found access to the morning after pill to be a challenge.

I had just moved from Ohio to New York City and was in my first year of graduate school. My boyfriend had come up for the weekend to visit and our Plan A method of birth control failed and I found myself in need of the morning after pill. What I found may or may not surprise you. It was sure a surprise to me.

Many of the health clinics I phoned wanted between 50 to $150 for a doctor's visit and a prescript for EC. As a graduate student, which all of you were at one time or another, you know that a student's budget is extremely limited. I cannot afford such exorbitant costs.

I continued to phone health facilities throughout the New York City area, hoping that I would find some place that was much more reasonable. Unfortunately I did not. what I did find, however, was the student health center at the school that I was enrolled in. They had the pills in stock, and I was urged to come into the center immediately.

I was lucky but many women are not so lucky. Now that I am out of school I have no longer the peace of mind knowing that the morning after pill is available to me when I need it as long as it's Monday through Friday from nine to five, the hours in which the clinic is open. The cost is now a bit more for me than as a student. Unfortunately my health insurance does not cover birth control pills. It does, however, cover Viagra.

In the past, on Friday, I had an appointment with my OB-GYN, who refused to write me a prescription for the morning after pill, stating that I needed to contact him first to make sure that the need for the pills was warranted, as if I wouldn't know when I needed to take them.

Please keep in mind as you are making your recommendations today that we women are aware of when we need to take the morning after pill. Please do not insult our intelligence nor belittle us. We as women are capable of following directions.

Most importantly, we as women should and must be allowed to make reproductive decisions for ourselves without interference from others, without judgment from others, and without the need for someone else' approval.

Thank you for your time.

(Applause.)

CHAIRMAN CANTILENA: Thank you.

Next speaker please.

MS. DENNER: I'm Carole Denner. I'm a registered nurse with 35 years' experience, and I'm a volunteer with Concerned Women for America.

Over-the-counter labeling conveys the impression a drug has been proven safe as user's labels without any hidden health risks. Neither the 21 studies cited by the FDA in the 1997 invitation for new drug applications, the 39 studies cited by the Women's Capitol Corporation in this over-the-counter application, nor the studies referenced by Dr. Daniel Davis this morning address the long-term potential health consequences to America's women and girls.

What is the maximum safe dose of levonorgestrel monthly or yearly? None of the clinical trials cited were designed to determine any long-term risks based on expected variables for adolescents, women over age 35, concomitant medical conditions.

It was mentioned this morning under need that 43 percent of U.S. pregnancies will experience problems. The greatest percentage of these occur in immigrant or in educated populations, women who choose not to avail themselves or who delay the available prenatal care that is available in the United States. None of the studies cited follow the participants beyond the immediate time frame of levonorgestrel usage. Are there long-term risks?

Taking only one and a half times the recommended daily dose of Tylenol for more than ten days can result in hepatotoxicity, but this wasn't even determined until Tylenol had been on the market for years.

What is the risk to America's women and girls?

The American Medical Association and the American College of Obstetricians and Gynecologists both recommend Plan B go over the counter. Yet they continue to recommend that low doses of the same drug given as a normal birth control pill be given only by prescription. That's how logical and inconsistent.

For the safety of American women and girls, I and the over half a million members of the Concerned Women for America of Virginia, the nation's largest public policy women's organization, ask and recommend that high dose hormone therapy after unprotected sex be available only by prescription by those capable of evaluating women for their health risks.

Thank you.

CHAIRMAN CANTILENA: Thank you. Time's up.

Next speaker, please.

MS. MAHONEY: Hi. My name is Erin Mahoney. I am the Co-chair of the National Organization for Women, New York State Reproductive Rights Task Force.

There are many reasons why the morning after pill should be over the counter, but in these two minutes I have with you, I want to talk about my experience with the morning after pill and why I needed over the counter.

When I needed the morning after pill, I was in Detroit, Michigan for the first time. I had just helped my boyfriend move and we didn't know a sole. We used condoms as our birth control method, but this time I needed the morning after pill. I was luckier than other women in this place. I had gone to a feminist gynecologist that year, and she had insisted that I take a prescription for the morning after pill with me in case I ever needed it.

However, that pill was not cheap. That doctor's visit cost me $150 because my insurance didn't cover annual gynecological exams. It does cover Viagra.

I had the prescription for the morning after pill filled that day and kept it in my medicine bag until that night when I needed it. If I had not had the morning after pill with me, I would not have had the first clue where to start looking for a doctor's office in Detroit, let alone one open on a Saturday night when I needed it.

I read the instructions. I followed them exactly, took the first pill with food and then the second 12 hours later. I didn't get sick or throw up. I was just relieved I wasn't going to get pregnant.

But what really bothers me about this whole process is that if I happen to go to a good doctor that is willing to write me a prescription just in case I need it, I'm lucky. If I go to a doctor who refuses to prescribe it in advance, I'm out of luck.

I shouldn't have to rely on luck to control my life. I shouldn't have to rely on a doctor for a drug that is safe and effective within the first 24 hours after sex.

We have a lot of experts in the room today, but I have taken the morning after pill, and I know what could have happened if I hadn't had it on hand, and I know what could happen to me if it isn't over the counter. I think that makes me an expert.

Because many of us who have experienced the morning after pill have so little time to talk here, we're going to speak outside at the lunch break for the press about our experience taking the morning after pill.

Thank you.

CHAIRMAN CANTILENA: Thank you.

Our next speaker, please.

MS. HARRISON: Good morning. My name is Teresa Harrison of Ibis Reproductive Health, a nonprofit organization that aims to improve women's health choices on autonomy. I'm also on the board of directors of Our Bodies Ourselves, a women's health advocacy group.

Neither organization receives funding from pharmaceutical companies.

Both Ibis and Our Bodies Ourselves support the switch of Plan B to the over the counter. In particular, we support the switch because what we have learned about women's efforts to obtain emergency contraception.

Ibis research shows that women cannot get emergency contraception when they need it. America's ERs turn women away in their hour of need. Recently we surveyed over 1,200 hospital emergency rooms across the country. Less than half would provide emergency contraception to women, even those who have been raped.

Just 16 percent would provide it to any woman who needed it, and an additional 18 percent would only provide it to women of sexual assault.

Our research also found that ERs staff are frequently judgmental or even hostile towards callers. Some ER staff do not value women with contraceptive emergencies.

If Plan B were available over the counter, women without health insurance, women without private doctors, and women who need it on weekends could get EC directly, discretely, and with dignity. They could also avoid an unpleasant and expensive, time consuming visit to the ER.

Please allow Plan B to go over the counter.

Thank you.

CHAIRMAN CANTILENA: Okay. Thank you.

Next speaker please.

DR. KLAUS: I'm Hanna Klaus. I'm an obstetrician-gynecologist with extensive experience in natural family planning and teen sexuality education.

I have no financial relationship with Plan B.

I object to changing the status of Plan B for the following reasons, which are documented in detail in my testimony. There's no time for documentation here.

Progestin slows tubal motility. Both U.K. and New Zealand have warned doctors when they had a 5.9 percent rate of unintended pregnancies which were ectopic. To make a drug with that potential for an increase in ectopic pregnancy available without medical supervision is the height of medical irresponsibility.

When Plan B was the sole contraceptive of women with infrequent coitus, their unplanned pregnancy rate was 6.8 percent with a 33 percent dropout rate due to side effects within six months. People take the course of least resistance to interact to take the drug more than once per cycle, irrespective of warnings, and will likely turn away from it when they experience side effects leaving them even more vulnerable to pregnancy and STD.

The chlamydia and gonorrhea rates have risen nearly 20 percent in this country in the last four years, concomitant to the high profile advertising of the morning after pill which, intended or not, promote the notion that taking Plan B will make up for the lack of sexual responsibility.

Women also have a right to know that Plan B, if taken after conception, prevents implantation. If they have ethical objection to aborting an embryo at any stage, they have a right to the right information.

And finally, conception can only occur in six days in the cycle, making the pills unnecessary for at least 24 days out of each cycle, and that may be fraudulent advertising.

I suggest you teach people their fertility cycle so that they'll know when to say yes and when to say no.

Thank you.

CHAIRMAN CANTILENA: Thank you.

Next speaker, please.

MS. MOORE: Hello. My name is Kirsten Moore, and I'm President of the Reproductive Health Technologies Project, a nonprofit advocacy organization based here in Washington, D.C.

We do not have a financial interest in this product. We do not accept any money from pharmaceutical companies of any kind.

We've been working on the issue of emergency contraception for ten years. We have greatly enjoyed our work in this field trying to raise awareness, reduce barriers to access. We've been involved in dozens of initiatives to promote advanced provision, pharmacy access, public education campaigns, et cetera. These have all been fun, but they've cost a lot of money. They've taken a lot of money. They've taken a lot of time. It takes a great deal to get buy-in from the professional medical community, and our take-away message is that medical practice is slow to change, and that it is time to put the decision about emergency contraception, when and where to use it, in the hands of women.

There is no medical or public health rationale which justifies preserving a prescription access or otherwise restricting access to this product.

Though we are not service providers, we do have first-hand knowledge of the need for better access to EC. Our HTP was the original home of the hotline, and all too often has been on the receiving end of panicked phone calls from women who were desperate to find EC, but could not find a provider, did not wish to see their own provider, or were refused EC by a provider.

We know the prospect of an OTC switch prompts questions about the consequences of nonprescription access and the fear of misuse, overuse, or general irresponsibility. We understand these concerns and fully support effort to insure informed responsible use of EC among women of all ages.

However, concerns about consequences of too much access cannot overshadow the real consequences of the current situation: difficult access, limited access, or no access to health care in EC specifically lead to distress, unintended pregnancies, and abortions. It does not have to be this way. Every woman including young women deserve a second chance to prevent an unintended pregnancy.

Thank you.

CHAIRMAN CANTILENA: Thank you.

Next speaker, please.

DR. JORDAN: My name is Dr. Beth Jordan. I'm the Medical Director of the Feminist Majority Foundation, a leading feminist think tank, grassroots organization, and publisher of Ms. Magazine.

We have no financial incentive or relationship with Barr.

With the largest pro choice student activist in the U.S., the Feminist Majority is committed to working with students and providers to maximize access to emergency contraception on the nation's campuses. Other speakers are to discuss EC safety and efficacy in reducing unintended pregnancy and the abortion rate. I can unique inform you of the situation on campuses by discussing the results of a recent social science study conducted by the Feminist Majority Foundation documenting the lack of availability and inaccessibility of emergency contraception.

College age women are at particular risk for engaging in unprotected intercourse, experience contraceptive failure, and being sexually assaulted. To the maximally effective, EC must be taken within 24 hours. Barriers to timely access place unnecessary and unacceptable burdens upon students.

In 2002, the Feminist Majority Foundation conducted a comprehensive nationwide random sample survey of EC access on campus health clinics. The survey found that only 61 percent provide EC or prescriptions for EC, and only 16 percent have weekend hours.

Anti-reproductive rights politics is an obstacle threatening access to EC on campuses. Anti-abortion legislators and activists who wilfully or naively can cite contraception with abortion increasingly infringe upon a woman's right to choose even contraception.

Leading physicians of the 2002 American College Health Association Conference reported to me that through intimidation, protests from anti-reproductive rights legislators, office holders, and activists discourage student health clinics from offering or advertising EC. Our students deserve better.

ED access must not be dependent on right wing politics, restrictive clinic hours or the individual provider or the clinic provider. Empowering young women to be responsible in preventing unintended pregnancy requires over-the-counter access to emergency contraception 24 hours a day seven days a week.

In 2002, the Feminist Majority Foundation launched a petition gathering support for over-the-counter access to EC. I present more than 30,000 petitions to you as your token of support on behalf of legions of Americans supporting this public health measure.

The scientific evidence and public health imperative is strong and undeniable. Access delayed ‑-

CHAIRMAN CANTILENA: Our next speaker please.

DR. CARROLL: My name is Robert Carroll. I'm a retired physician. I'm here as an individual, not representing any group or organization, and I have no financial involvement.

My interest in the question of permitting over-the-counter sales of the morning after pill stems from my concerning regarding the epidemic of sexually transmitted disease, especially among young people.

I practiced medicine as a general internist from 1949 to 1995. The increase in STDs in the last several years of my practice was startling and disturbing. For the past eight years I have been presenting elective classes on STDs to students at the local senior high school.

As everybody knows, our society has undergone a sexual revolution in the last 30 or 40 years. Our young people have been encouraged to engage in sexual activity with the understanding that it was safe and morally acceptable as long as contraceptives were used.

They were not and are not now being adequately informed of the significant danger of acquiring STDs with or without the use of contraceptives. There are more than 15 million new cases of STDs every year in this country. Not all the news is bad. For the past ten years there has been a slow, but steady increase in sexual abstinence. This trend has been accompanied by a similar slow but stead decrease in abortions and teen pregnancies.

It is self-evident that over-the-counter availability of the morning after pill will lead to increased promiscuity and its attendant physical and psychological damage.

Thank you.

CHAIRMAN CANTILENA: Thank you.

The next speaker, please.

DR. ENGLE: Thank you for the opportunity to present the views of the American Pharmacists Association.

I'm Jan Engle, Associate Dean for Academic Affairs and clinical professor of pharmacy practice at the University of Illinois at Chicago and the immediate past president of APHA.

Decisions to classify products as either prescription or nonprescription are best made by the FDA incorporating a review of safety and effectiveness utilizing clinical research information.

Part of the review must include examining the risks and benefits associated with increasing access to the product. Specifically, the FDA should evaluate how this product has been used in the prescription only environment to assess prescribing patterns and patient use patterns that may support expanded access of the product to an OTC basis.

The provision of the product by pharmacists under the purview of collaborative practice agreements, agreements between pharmacists and physicians detailing the conditions under which a pharmacist will initiate or modify a patient's drug therapy may support the expanded availability of a product. EC is a therapy commonly prescribed under these agreements.

Pharmacists in more than 37 states have the authority to initiate or modify therapy under collaborative practice agreements with physicians and other prescribers. In the case of levonorgestrel, five states explicitly allow pharmacists to prescribe and/or dispense emergency contraception directly to patients under collaborative practice agreements.

A number of other states allow pharmacists to provide the therapy under collaborative practice agreements as well. Washington State was the first state to allow pharmacists to provide EC in a two-year pilot. By the end of the pilot nearly 12,000 patients consulted pharmacists for EC, 40 percent of which were during weekends and evenings or holidays.

It's important to note of the 12,000 interactions, many times pharmacists did not dispense the drug because it was not appropriate. Sixty percent of pharmacists referred at least one patient for further care; 75 percent referred patients because of concerns of eligibility; 50 percent referred for contraceptive services; and seven percent for rape counseling.

Clearly, pharmacist provision of EC under collaborative agreements significantly improve --

CHAIRMAN CANTILENA: Thank you.

Next speaker please.

MS. FLOWERS: My name is Hillary Flowers. I am 23 years old, and I recently moved to New York City from Madison, Wisconsin. I am fully employed, and I have no health care benefits.

When I needed the morning after pill, I was a sophomore in college. I called tons of doctors, but they did not want to see strangers who did not have an appointment. I finally found a female doctor who would see me.

She explained to me that the morning after pill was basically a higher dose of the regular birth control pills. She gave me a pack of regular pills and told me how many to take. I had no side effects.

The cost of my doctor's bill was between 150 to $200.

A few years later, I was in a serious relationship and the condom broke. In this circumstance I was contemplating whether or not to go on birth control pill. So I had birth control pills at my house.

I knew from my previous experience from talking to my doctor that the morning after pill was a higher dose of birth control pill. So I took the same amount of birth control pills as I had taken before, and I recently learned that the number of pills changes depending upon the brand of birth control pills you are taking. The brand of pills I had at the time was probably not the same as I had taken, but I couldn't afford to pay $200 for a doctor's visit, nor did I want to call 20 doctors who did not want to see strangers.

I risked my health in order to take the morning after pill which was so hard to get. I'm a very healthy woman. I have no health insurance, and I am paying student loans. What am I supposed to do if a condom breaks? Not pay rent so I can pay a doctor to get the morning after pill? Take a bunch of birth control pills that I have on hand or that a friend has that I can try to borrow and take 12 hours after?

I shouldn't have to risk my health to prevent pregnancy. I must have the right to control my body and my life with directions in order to know that I'm taking the right kind of pill.

CHAIRMAN CANTILENA: I'm sorry, ma'am. Your time is up.

Next speaker, please.

MS. MANGAN: My name is Kelly Mangan. I'm the Vice President of the University of Florida Chapter of the National Organization for Women.

Women should not be told when or under what circumstances we can control our bodies. Yet here I stand ironically before a panel many of whom are men having to ask for the right to control my body and direct my life.

I have used the morning after pill twice after condoms came off inside me while I was having sex. I didn't get pregnant, and I also didn't have any of these overhyped side effects I keep hearing health professionals talk about.

I got the morning after pill from my campus infirmary to have if I ever needed it, but the nurse who prescribed it asked prying questions about my relationship with my partner and how long I had known him. She also discouraged me from taking the morning after pill again because of possible side effects, while at the same time encouraged me to go back on birth control pills which could have far more serious side effects than the morning after pill.

If the morning after pill was available over the counter, I wouldn't have to spend time and money making doctor's appointments when I needed it. I also wouldn't have to justify myself to nurses and doctors because they disapprove of my sexual relationships, which are none of their business anyway.

If I could really control my fertility, meaning 24 hours a day and without having to bed a doctor or a pharmacist for permission, then I would have more time, more money, and more personal freedom. Basically I would have more control over my life.

CHAIRMAN CANTILENA: Thank you.

Next speaker please.

DR. BRUCHALSKI: My name is Dr. John Bruchalski. I'm a practicing OB-GYN in Fairfax, Virginia and here with the Catholic Medical Association.

The points I want to make today refer to teenagers and Plan B. Point number one, not all women have regular cycles, especially teens. Forty-three percent of girls have irregular periods the first year after menarche. For as long as five years one-fifth of adolescent girls have irregular menses.

Point number two, it's these same women with irregular cycles who are sexually active, suffering from pregnancies and sexually transmitted diseases. We all know that two-thirds of twelfth grade women have had sexual intercourse. We also know that three to four million of the new STD cases this year will be teens.

Most teens rely on a single contraceptive to prevent pregnancy and infections when they're using anything at all. The reduced contraceptive efficacy relates to improper use and frequent discontinuation of contraception.

Conversation and counseling can help prevent this. Therefore, without medical advice from a health professional, the use of Plan B by teens will be disastrous.

Current thought also says that a physical exam is unnecessary before treatment. We are educating our patients about their options presently. Why put this potent medication over the counter and bypass an opportunity for counseling, especially in this affected subgroup, teen women?

I know of no study specifically looking at teens and Plan B.

We are sincerely passing up an opportunity to engage our teen patients about the hazards of sexual intercourse. You've heard these stories from these presenters prior to me. It is in this conversation and counseling that they will become more open and honest with their medical providers.

Conversations lead to trust. Trust leads to following advice. Over-the-counter status decreases conversations.