United States Patent [19J
`Elsayed et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006045501A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,045,501
`Apr. 4, 2000
`
`[54] METHODS FOR DELIVERING A DRUG TO A
`PATIENT WHILE PREVENTING THE
`EXPOSURE OF A FOETUS OR OTHER
`CONTRAINDICATED INDIVIDUAL TO THE
`DRUG
`
`[75]
`
`Inventors: Marc Elsayed, Bridgewater; Bruce
`Williams, Flemington, both of N.J.
`
`[73] Assignee: Celgene Corporation, Warren, N.J.
`
`[21] Appl. No.: 09/143,569
`[22] Filed:
`Aug. 28, 1998
`Int. Cl? ....................................................... A61N 5/00
`[51]
`[52] U.S. Cl. ........................... 600/300; 600/304; 600/551
`[58] Field of Search ..................................... 434/262, 272,
`434/273; 600/300--301, 304, 313, 338, 376,
`511, 551; 128/920-925, 897-898
`
`[56]
`
`5,299,121
`
`References Cited
`U.S. PATENT DOCUMENTS
`3/1994 Brill et a!.
`.............................. 600/301
`
`5,594,637
`5,619,991
`5,660,176
`
`1!1997 Eisenberg et a!. ... .... ... ... ... ... ... 600/300
`4/1997 Sloane ... .... ... ... ... ... ... .... ... ... ... .. 600/300
`8/1997 Iliff .. ... ... .... ... ... ... ...... .... ... ...... .. 600/300
`
`Primary Examiner-Cary O'Connor
`Assistant Examiner-Michael Astarino
`Attorney, Agent, or Firm-Woodcock Washburn Kurtz
`Mackiewicz & Norris LLP
`
`[57]
`
`ABSTRACT
`
`Novel methods for delivering a drug to a patient while
`preventing the exposure of a foetus or other contraindicated
`individual to the drug. Embodiments are provided in which
`the involved prescribers, pharmacies and patients are regis-
`tered in one or more computer databases. Embodiments are
`also provided in which registered patients receive counsel-
`ing information concerning the risks attendant to foetal
`exposure to the drug. Male patients and female patients who
`are not pregnant may, in certain circumstances, receive the
`drug.
`
`10 Claims, No Drawings
`
`AMN1035
`IPR of U.S. Patent No. 7,765,106
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`

`6,045,501
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`1
`METHODS FOR DELIVERING A DRUG TO A
`PATIENT WHILE PREVENTING THE
`EXPOSURE OF A FOETUS OR OTHER
`CONTRAINDICATED INDIVIDUAL TO THE
`DRUG
`
`5
`
`2
`distribution channels. Also, because drug sharing may fre-
`quently occur, such as among AIDS patients, which may
`result in placing a fetus at risk, a program is needed which
`can be used to educate men and women about the risk of
`teratogenic drugs, such as thalidomide. The present inven-
`tion is directed to these, as well as other important ends.
`
`FIELD OF THE INVENTION
`The present invention relates to novel methods for deliv-
`ering a drug to a patient. More particularly, the present
`invention relates to novel methods for delivering a terata- 10
`genic or other potentially hazardous drug to a patient while
`preventing the exposure of a person, such as a foetus, to the
`drug when such exposure is contraindicated. The novel
`methods permit the distribution to patients of drugs, par-
`ticularly teratogenic drugs, in ways wherein such distribu- 15
`tion can or must be carefully monitored and controlled.
`
`BACKGROUND OF THE INVENTION
`Thalidomide is a drug which was first synthesized in 20
`Germany in 1957. Beginning in 1958, it was marketed in
`many countries for use as a sedative, although it was never
`approved for use in the United States. After reports of
`serious birth defects, thalidomide was withdrawn from all
`markets by 1962. However, during the years it was used, it 25
`was found to be effective in treating erythema nodosum
`leprosum (ENL), a condition of leprosy, and the U.S. Food
`and Drug Administration (FDA) has made the drug available
`for this specific use via a program of the Public Health
`Service. More recently, investigators have found that thali- 30
`domide may be effective in treating AIDS wasting and
`aphthous ulcers occurring in AIDS patients. In addition,
`treatments for other diseases, such as a number of serious
`diseases including cancers, inflammatory bowel diseases,
`Behcet's Disease, rheumatoid arthritis, and macular 35
`degeneration, are also believed to be possible. The FDA has
`recently approved an application by Celgene Corporation,
`which is the assignee of the present patent application, to
`market thalidomide for the treatment of ENL. The medical
`community anticipates that thalidomide will be used for
`treatment of additional conditions and diseases, including
`those set forth above. However, due to the severe teratogenic
`risk of thalidomide, methods are needed to control the
`distribution of this drug so as to preclude administration to
`foetuses. Methods for distribution of other potentially haz- 45
`ardous drugs are also needed to guard against improper
`provision to persons for whom such drug is contraindicated.
`Previous methods for controlling the distribution of drugs
`have been developed in connection with Accutane
`(isotretinoin). Accutane, which is a known teratogen, is a 50
`uniquely effective drug for the treatment of severe,
`recalcitrant, nodular acne. A pregnancy prevention program
`was developed, and the Slone Epidemiology Unit of Boston
`University designed and implemented a survey to evaluate
`these efforts. The survey identified relatively low rates of 55
`pregnancy during Accutane treatment, which suggests that
`such a program can be effective. With more than about
`325,000 women enrolled to date in the Accutane survey, it
`is also clear that such a large-scale study can be conducted.
`However, enrollment in the Accutane survey is voluntary. 60
`Accordingly, assessing the representativeness of the women
`who have been enrolled in the survey has been problematic,
`and it has been difficult to determine whether the survey
`results can be generalized to all female Accutane users.
`Thus, improved methods are needed which are more
`representative of all users of a particular drug, such as
`thalidomide, who obtain the involved drug through lawful
`
`SUMMARY OF THE INVENTION
`The present invention is directed to methods for the
`delivery of potentially hazardous drugs, such as teratogenic
`drugs, to patients. In one embodiment of the invention, there
`are provided methods for delivering a teratogenic drug to
`patients in need of the drug while avoiding the delivery of
`said drug to a foetus comprising:
`a. registering in a computer readable storage medium
`prescribers who are qualified to prescribe said drug;
`b. registering in said medium pharmacies to fill prescrip-
`tions for said drug;
`c. registering said patients in said medium, including
`information concerning the ability of female patients to
`become pregnant and, optionally, the ability of male
`patients to impregnate females;
`d. retrieving from said medium information identifying a
`subpopulation of said female patients who are capable
`of becoming pregnant and, optionally, male patients
`who are capable of impregnating females;
`e. providing to the subpopulation, counseling information
`concerning the risks attendant to fetal exposure to said
`drug;
`f. determining whether patients comprising said subpopu-
`lation are pregnant; and
`g. in response to a determination of non-pregnancy for
`said patients, authorizing said registered pharmacies to
`fill prescriptions from said registered prescribers for
`said non-pregnant registered patients.
`Another embodiment of the invention relates to methods
`for delivering a potentially hazardous drug to patients in
`40 need of the drug while avoiding the delivery of said drug to
`persons for whom said drug is contraindicated comprising:
`a. registering in a computer readable storage medium
`prescribers who are qualified to prescribe said drug;
`b. registering in said medium pharmacies to fill prescrip-
`tions for said drug;
`c. registering said patients in said medium, including
`information concerning the likelihood of said patients
`having a condition which contraindicates exposure to
`the drug;
`d. retrieving from said medium information identifying a
`subpopulation of said patients who have a condition
`which contraindicates exposure to the drug;
`e. providing to the subpopulation, counseling information
`concerning the risks attendant to exposure to said drug;
`f. determining whether patients comprising said subpopu-
`lation have said condition; and
`g. in response to a determination that said patients do not
`have said condition, authorizing said registered phar-
`macies to fill prescriptions from said registered presi-
`crbers for said registered patients for whom said drug
`is not contraindicated.
`The methods described herein provide advantageous and
`effective means for monitoring, controlling and authorizing
`65 the distribution of drugs to patients, particularly teratogenic
`drugs. The methods of the present invention include a
`variety of checks and controls which serve to limit unau-
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`3
`thorized and possibly inappropriate distribution of the drug.
`In the case of teratogenic drugs, the checks and balances
`may be particularly advantageous for preventing distribution
`of the drug to patients whose use of the drug may pose an
`unacceptable risk of foetal exposure. Accordingly, the
`present methods may be advantageously used to avoid
`exposure of foetuses to teratogenic drugs, thereby avoiding
`the terrible birth defects which may result from such expo-
`sure.
`The invention is not limited to the distribution of terata- 10
`genic drugs; other potentially hazardous drugs may also be
`distributed in accordance with embodiments of this inven-
`tion and such drugs may be distributed in such a fashion that
`persons for whom such drugs are contraindicated will not
`receive them. These and other aspects of the invention will
`become more apparent from the present description and
`claims.
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`The present invention is directed generally to methods for
`the delivery of drugs, especially teratogenic drugs, to
`patients. The term "drug," as used herein, refers to any
`substance which is intended for use in the diagnosis, cure,
`mitigation, treatment or prevention of disease, or to affect
`the structure or function of the body. Generally speaking, the
`methods of the present invention may be desirably and
`advantageously used to educate and reinforce the actions
`and behaviors of patients who are taking the drug, as well as
`prescribers who prescribe the drug and pharmacies which
`dispense the drug. As used herein, the term "prescriber"
`refers to any individual who are capable of prescribing
`drugs, including, for example medical doctors. Such educa-
`tion and reinforcement of actions and behavior are often
`necessary to ensure proper prescribing and dispensing of the
`drug, as well as patient compliance with taking the drug. A
`wide variety of educational materials may be employed to
`ensure proper prescribing, dispensing and patient compli-
`ance according to the methods described herein, including,
`for example, a variety of literature and other materials, such
`as, for example, product information, educational brochures,
`continuing education monographs, videotapes and the like
`which may describe the risks and benefits associated with
`taking the particular drug.
`The methods described herein may be advantageously
`employed for the delivery of a drug to a patient for whom the
`drug is contraindicated. As used herein, the term "contrain-
`dicated" refers to any condition in a patient which renders a
`particular line of treatment, including the administration of
`one or more drugs, undesirable or improper. Thus, contrain- 50
`dicated drugs include, for example, teratogenic drugs whose
`administration, for example, to pregnant patients is impor-
`tantly avoided due to the risks to the foetus. The methods of
`the present invention are especially advantageously
`employed for the delivery to a patient of a teratogenic drug.
`The delivery of a teratogenic drug to a patient may be
`advantageously achieved with the present methods while
`substantially (including completely) avoiding the delivery of
`the drug to a foetus (i.e., fetus). The term "substantially," as
`used in reference to avoiding the delivery of a teratogenic
`drug to a foetus, generally means that there is an avoidance
`rate of delivering the drug to a foetus of greater than about
`50%. Preferably, the avoidance rate is greater than about
`55%, with an avoidance rate of greater than about 60% being
`more preferred. Even more preferably, the avoidance rate is
`greater than about 65%, with an avoidance rate of greater
`than about 70% being still more preferred. Yet more
`
`4
`preferably, the avoidance rate is greater than about 75%,
`with an avoidance rate of greater than about 80% being still
`more preferred. In even more preferred embodiments, the
`avoidance rate is greater than about 85%, with an avoidance
`rate of greater than about 90% being yet more preferred. Still
`more preferably, the avoidance rate is greater than about
`95%. In particularly preferred embodiments, a teratogenic
`drug may be delivered to patients with substantially no
`delivery to foetuses (i.e., nearly 100% avoidance rate).
`The drug delivery methods of the present invention pref-
`erably involve, inter alia, registering in a computer readable
`storage medium prescribers who are qualified to prescribe
`the involved drug including, for example, teratogenic drugs.
`Once registered in the computer readable storage medium,
`15 the prescriber may be eligible to prescribe the drug to
`patients in need of the drug. Generally speaking, in order to
`become registered in the computer readable storage
`medium, the prescriber may be required to comply with
`various aspects of the methods described herein including,
`20 for example, providing patient education and counseling,
`and the like, as described in detail below. The registration of
`the prescriber in the computer readable storage medium may
`be achieved by providing the prescriber, for example, by
`mail, facsimile transmission, or on-line transmission, with a
`25 registration card or form, preferably together with appropri-
`ate educational materials concerning, for example, the par-
`ticular drug for which the prescriber is being registered to
`prescribe, as well as suitable methods for delivering the drug
`to the patient, including the drug delivery methods described
`30 herein. The prescriber will preferably complete the registra-
`tion card or form by providing information requested
`therein, and the registration card or form will preferably be
`returned to the manufacturer or distributor of the drug, or
`other authorized recipient of the registration materials, for
`35 example, by mail, facsimile transmission or on-line trans-
`mission. Information which may be requested of the pre-
`scriber in the registration card or form may include, for
`example, the prescriber's name, address, and affiliation, if
`any, with one or more health care institutions. The prescrib-
`40 er's information in the registration card or form is then
`entered into the computer readable storage medium. It is
`contemplated that the registration of the prescriber into the
`computer readable storage medium may also be achieved,
`for example, by telephone. Suitable computer readable stor-
`45 age media which may be employed for registration of the
`prescribers (as well as the pharmacies and patients, as
`discussed below) will be apparent to one of ordinary skill in
`the art, once armed with the teachings of the present
`application.
`In accordance with the methods described herein, phar-
`macies which may fill prescriptions for the particular drug
`being prescribed including, for example, teratogenic drugs,
`are also preferably registered in a computer readable storage
`medium. The computer readable storage medium in which
`55 the pharmacies are registered may be the same as, or
`different from the computer readable storage medium in
`which the prescribers are registered. Once registered in the
`computer readable storage medium, the pharmacies may be
`eligible to dispense the involved drug to patients who are in
`60 need of the drug. Generally speaking, in order to become
`registered in the computer readable storage medium, the
`pharmacy may be required to comply with various aspects of
`the methods described herein including, for example, reg-
`istering the patient (preferably also in a computer readable
`65 storage medium), as well as other aspects of the present
`methods, as described in detail below. As with the registra-
`tion of the prescriber in the computer readable storage
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`6,045,501
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`medium, the registration of the pharmacy may be achieved
`by providing the pharmacy, for example, by mail, facsimile
`transmission, or on-line transmission, with a registration
`card or form, preferably together with appropriate educa-
`tional materials concerning, for example, the particular drug
`for which the pharmacy is being registered to dispense, as
`well as suitable methods for delivering the drug to the
`patient, including the drug delivery methods described
`herein. The pharmacy may then have the registration card or
`form completed by providing the information requested
`therein, which thereafter may be returned to the manufac-
`turer or distributor of the drug, or other authorized recipient
`of the registration card or form, for example, by mail,
`facsimile transmission or on-line transmission. Information
`which may be requested of the pharmacy in the registration
`card or form may include, for example, the pharmacy's
`name, address, and affiliation, if any, with any health care
`institution such as, for example, hospital, health care
`organization, and the like. The pharmacy's information in
`the registration card or form is then preferably entered into
`the computer readable storage medium. It is contemplated
`that the registration of the pharmacy into the computer
`readable storage medium may also be achieved, for
`example, by telephone.
`As noted above, the drug delivery methods described
`herein also preferably involve the registration of the patient
`in a computer readable storage medium. As discussed below,
`the registration of the patient is preferably carried out by the
`registered pharmacy at the time of the patient's initial visit
`to the pharmacy. The computer readable storage medium in
`which the patients are registered may be the same as, or
`different from the computer readable storage medium in
`which the prescriber and/or pharmacy is registered. Once
`registered in the computer readable storage medium, the
`patient in need of a particular drug including, for example,
`a particular teratogenic drug, may be eligible to receive the
`drug. Generally speaking, in order to become registered in
`the computer readable storage medium, the patient may be
`required to comply with various aspects of the methods
`described herein. In preferred form, the pharmacy will
`typically have a registration form filled out for the patient,
`which includes information on the patient, such as the
`patient's name, mailing address, date of birth, and the like.
`Information on the prescribing prescriber and dispensing
`pharmacy, such as the information described above for the
`registration thereof, may also be desirably entered on the
`patient registration form. The completed form may then be
`forwarded to the manufacturer or distributor of the drug, or
`other authorized recipient of the registration form, for
`example, by mail, facsimile transmission or on-line trans-
`mission. It is contemplated that the registration of the patient
`into the computer readable storage medium may also be
`achieved, for example, by telephone.
`In accordance with the methods of the present invention,
`the delivery of the drug to the patient may involve the 55
`following steps. As a prelude to prescribing and dispensing
`the drug to the patient, the prescriber and the pharmacy are
`registered in one or more appropriate computer readable
`storage media, as described above. If the prescriber is not
`registered in the computer readable storage medium, the 60
`prescriber will be ineligible to prescribe the drug. Similarly,
`if the pharmacy is not registered in the computer readable
`storage medium, the pharmacy will be ineligible to dispense
`the drug.
`In the course of an examination of a patient, including 65
`patients suffering from one or more diseases and/or disor-
`ders such as, for example, erythema nodosum leprosum
`
`6
`(ENL), the prescriber may determine that the patient's
`condition would be improved by the administration of a drug
`such as, for example, a teratogenic drug, including thalido-
`mide. Prior to prescribing the drug, the prescriber preferably
`5 counsels the patient, for example, on the various risks and
`benefits associated with the drug. For example, the pre-
`scriber preferably discusses the benefits associated with
`taking the drug, while also advising the patient on the
`various side effects associated therewith. Thus, a patient
`10 who may acquire or impart a condition or disease for which
`the drug is contraindicated is preferably counseled by the
`prescriber on the dangers associated therewith. For example,
`in the case of teratogenic drugs, the prescriber preferably
`counsels the patient on the dangers of exposing a foetus to
`15 the teratogenic drug. Such counsel may be provided
`verbally, as well as in written form. In preferred
`embodiments, the prescriber provides the patient with lit-
`erature materials on the drug for which a prescription is
`contemplated, such as product information, educational
`20 brochures, patient instruction videos, and the like. Thus, in
`the case of methods involving teratogenic drugs, the pre-
`scriber preferably provides patients with literature
`information, for example, in the form of the aforesaid
`product information, educational brochures, patient instruc-
`25 tion videos, and the like, warning the patient of the effects
`of the drug on foetuses.
`With particular reference to counseling provided in con-
`nection with teratogenic drugs, the prescriber preferably
`counsels female patients that such drugs must never be used
`30 by pregnant women. If the patient is a female of child-
`bearing potential (i.e., a woman who is capable of becoming
`pregnant), the prescriber preferably counsels the patient that
`even a single dosage of certain teratogenic drugs, such as
`thalidomide, may cause birth defects. Accordingly, the
`35 patient is preferably counseled to avoid sexual intercourse
`entirely, or if sexually active, to use appropriate forms of
`contraception or birth control. For both male and female
`patients, the prescriber preferably provides counsel on the
`importance of using at least two forms of effective birth
`40 control methods, with one form preferably being a highly
`effective hormonal method, and the other from preferably
`being an effective barrier method. The patients are prefer-
`ably counseled to use the birth control methods for a period
`of time prior to and during treatment with the teratogenic
`45 drug, as well as for a period of time after treatment with the
`drug has been terminated. In preferred embodiments, the
`patient is counseled to use at least two forms of birth control
`for at least about 4 weeks prior to initiation of treatment,
`during treatment, and for at least about 4 weeks after
`50 treatment has been terminated. It may be desirable for the
`prescriber to personally provide female patients who are
`capable of becoming pregnant with a contraceptive device or
`formulation.
`Male patients who are being prescribed a teratogenic drug
`are preferably counseled to use condoms every time they
`engage in sexual relations, since many teratogenic drugs
`may be found in semen. Male patients are also preferably
`counseled to contact their prescriber if they have sexual
`intercourse without a condom, and/or if it is believed that
`they may have caused a pregnancy. As with female patients,
`it may be desirable for the prescriber to provide male
`patients who are capable of impregnating female patients
`with a contraceptive device or formulation. Other advice
`relative to birth control that the prescriber may provide to the
`patient would be apparent to one skilled in the art, once
`armed with the teachings of the present application. If the
`prescriber who is prescribing the teratogenic drug is
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`unaware of certain aspects of the available forms of birth
`control and the advantages and disadvantages associated
`therewith, the patient should be referred to a prescriber who
`is knowledgeable on such matters, prior to be being pre-
`scribed the involved drug. Generally speaking, as discussed
`below, counseling on teratogenecity, birth control, and the
`like is preferably given only to female patients who are
`capable of becoming pregnant, or to male patients who are
`capable of impregnating female patients. In this manner,
`unnecessary counseling, for example, to women who are no
`longer of child-bearing age or men who are incapable of
`impregnating women, may be avoided.
`With further reference to methods involving teratogenic
`drugs, it is also preferred that the prescriber advise the
`patient to not share the drug with anyone else, and particu-
`larly that the drug should be kept out of the reach of children
`as well as women of child-bearing potential. In the case of
`female patients, particularly female patients of child-bearing
`potential, the prescriber should give the patient a pregnancy
`test, preferably a serum pregnancy test, prior to and during
`treatment with the teratogenic drug. To begin receiving the
`teratogenic drug and to continue taking the drug, female
`patients of child-bearing potential should continue to have
`negative pregnancy tests. The patient is also preferably
`counseled by the prescriber to discard or return to the
`prescriber, pharmacy, manufacturer or distributor any
`unused portion of the prescribed drug.
`As would be apparent to one of ordinary skill in the art,
`once armed with the teachings of the present application,
`one or more aspects of the counseling described above may
`be applicable, in certain circumstances, for drugs other than
`teratogenic drugs.
`In addition to receiving counseling on the drug being
`prescribed, including counseling, for example, on birth
`control, and prior to receiving a prescription for the drug, the 35
`methods of the present invention preferably involve requir-
`ing the patient to fill out an informed consent form which is
`signed by the prescriber, as well as the patient. The pre-
`scriber should retain a copy of the informed consent form for
`his/her records. By filling out and signing an informed 40
`consent form, the patient acknowledges that he/she under-
`stands the risks associated with taking the drug. In the
`informed consent form, the patient preferably agrees to
`behave in a manner which is consistent with the prescriber's
`counsel. For example, in cases involving, for example, 45
`teratogenic drugs, the patient may agree to use at least one
`form of birth control, with female patients agreeing to use at
`least two forms of birth control. In preferred embodiments
`involving teratogenic drugs, female patients preferably
`agree also to undergo pregnancy testing, preferably serum 50
`pregnancy testing, before, during and after treatment with
`the teratogenic drug. Female patients preferably will also
`acknowledge that, at the time they are being prescribed the
`drug, especially teratogenic drugs, they are not pregnant,
`they will immediately stop taking the drug if they become 55
`pregnant, and they will not try to become pregnant for at
`least 4 weeks after treatment with the drug is terminated.
`Female patients, especially female patients for whom a
`teratogenic drug will be administered, preferably further
`agree to contact their prescriber if they wish to change one 60
`or more of the birth control methods being used and to have
`an additional pregnancy test if a menstrual period is missed.
`Female patients, especially female patients to be treated with
`teratogenic drugs, will preferably agree also to not breast-
`feed while being treated with the drug.
`Male patients who are being prescribed the drugs accord-
`ing to the methods described herein, especially teratogenic
`
`8
`drugs, will preferably agree to avoid having unprotected
`sexual relations with a woman, particularly a woman of
`child-bearing potential during treatment with the drug. In
`doing so, male patients will preferably further agree to use
`5 a condom during sexual relations with a woman, with latex
`condoms being preferred. Both male and female patients
`will also preferably agree to not share the drug with anyone,
`and to acknowledge that they cannot donate blood while
`taking the drug, with male patients agreeing also to not
`10 donate sperm while taking the drug. In addition, the patients
`will preferably agree to take part in a confidential patient
`survey, for example, before, during and after treatment with
`the drug. The patient survey provides information, for
`example, to the prescriber, manufacturer and/or distributor
`15 of the drug, as well as any group or body which may be
`established to generally provide oversight on the distribution
`of the drug, on information regarding the general lifestyle of
`the patient, including detailed information on the patient's
`sexual behavior. In this manner, the survey may assist in
`20 identifying patients who engage in risky behavior, as well as
`patients who are non-compliant with the methods described
`herein. Such risky behavor and/or non-compliance may lead
`to a suspension or intervention of the patient's treatment
`with the drug, with re-education being provided to the
`25 patient.
`The information obtained from the survey is preferably
`also entered into the computer readable storage medium.
`Once entered into the computer readable storage medium,
`the prescriber, manufacturer and/or distributor of the drug
`30 may be able to glean therefrom information regarding the
`level of risk associated with the administration of the
`involved drug to the various patients. Accordingly, it may be
`possible to identify, from among the entire population of
`registered patients, one or more subpopulations of patients
`for which the involved drug may be more likely to be
`contraindicated. For example, it may be possible to identify
`a subpopulation of female patients who are capable of
`becoming pregnant and/or a subpopulation of male patients
`who are capable of impregnating female patients. Preferably,
`the counseling information discussed above relating to expo-
`sure of a foetus to a teratogenic drug may then be addressed
`primarily to this subpopulation of patients.
`If the risk is considered to be acceptable, the patient may
`continue to receive the drug, using the methods described
`herein. If the risk is considered to be unacceptable, addi-
`tional counseling may be provided to the patient or, if
`necessary, treatment of the patient with the involved drug
`may be terminated, with alternate treatment modalities being
`provided. In preferred embodiments, female patients will
`agree to complete a patient survey at least once every month,
`with male patients agreeing to complete a patient survey at
`least once every three months.
`After the patient has received counseling as described
`above, and has also filled out and signed an informed
`consent form, and it is determined that the drug which is to
`be prescribed is not contraindicated for the patient (such as,
`for example, a negative pregnancy test in the case of female
`patients for whom a prescription is desired for a teratogenic
`drug), the prescriber may prescribe the drug to the patient.
`In preferred embodiments of the present invention, the
`amount of the drug which is prescribed to the patient is for
`a limited amount, preferably no more than about 28 days.
`Refills for the drug will not be permitted without a renewal
`prescription from the prescriber, as discussed in detail
`65 below. In order to have the prescription filled, the patient
`preferably presents the prescription and the informed con-
`sent form to a pharmacy which has been registered, as
`
`AMN1035
`IPR of U.S. Patent No. 7,765,106
`
`

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`6,045,501
`
`9
`discussed above. It is contemplated that the patient may
`bring the prescription to an unregistered pharmacy. If so, the
`pharmacy may take steps to become registered, for example,
`by immediately contacting the manufacturer of the drug.
`Once registration of the pharmacy is completed, the distri-
`bution procedure described herein