EPORTS
`
`Challenges of thalidomide distribution
`in a hospital setting
`
`DANIEL P. Kl-IRAVICH AND CHARLES E. DANIELS
`
`Abstract: The various physi-
`cian, patient, and pharmacy
`requirements for participa-
`tion in the System for Thali-
`domide Education and
`Prescribing Safety (S.T.E.P.S.)
`program and procedures that
`institutions may implement
`in order to comply with these
`requirements are described.
`In 1998, FDA approved the
`marketing of thalidomide
`(Thalomid, Celgene). Because
`of the drug's known terato—
`genic effects, FDA tightly
`controls the distribution of
`thalidomide in the United
`
`States. To comply with FDA
`requirements, Celgene devel-
`oped the S.T.E.P.S. oversight
`program, which includes reg-
`istration of thalidomide pre-
`scribers and pharmacies that
`dispense thalidomide, exten-
`sive patient education about
`the risks associated with tha-
`lidomide, and a registry of all
`patients receiving thalido
`mide. The S.T.E.P.S. program
`is considered part of the
`product label. The pharmacy
`requirements of the program
`were developed with a focus
`on a retail pharmacy practice
`
`model, which does not ade-
`quately reflect current hospi—
`tal practice. The pharmacy
`department of the National
`Institutes of Health Clinical
`
`Center developed a model
`that adapts the S.T.E.P.S. pro-
`gram requirements to inpa—
`tient and outpatient
`institutional pharmacy prac-
`tice.
`Procedures for registering
`patients and prescribers and
`dispensing thalidomide in
`the hospital setting were de—
`veloped: the procedures were
`designed to meet the needs of
`
`both the inpatient and outpa-
`tient pharmacies and to com-
`ply with the requirements of
`the S.T.E.P.S. program.
`
`Index torlns: Administra-
`tion; Anti-infective agents;
`Dispensing; Drug distribution
`systems: Erythema nodosum;
`Patient information: Patients;
`Pharmacists, hospital; Phar-
`macy, institutional, hospital;
`Physicians; Prescribing; Regu-
`lations: Thalidomide
`Am J Health-Syst Pharln.
`1999: 56: l 72 1-5
`
`n July 16, 1998, FDA approved the marketing of
`thalidomide ('I'halomid, Celgene) for the acute
`treatment of cutaneous manifestations of mod-
`
`erate to severe erythema nodosum leprosum, a compli-
`cation of Hansen's disease (commonly known as lepro-
`sy). Thalidornide is currently being evaluated for the
`treatment of life-threatening diseases such as graft-
`versus-host disease, AIDS wasting, and malignancies.‘
`It may also be useful in treating immunologic disorders
`(e.g., systemic and discoid lupus, Behcet’s syndrome,
`Sj<")gren's syndrome, Crohn’s disease, rheumatoid ar-
`thritis), derrnatological conditions, macular degenera-
`tion, tuberculosis, and aphthous ulcers.
`Because of thalidomide's known teratogenic effects,
`FDA used authority under 2 1 C.F.R. 314.520, subpart H,
`to tightly control the marketing and distribution of the
`
`drug. To comply with FDA requirements, Celgene de—
`veloped the System for Thalidomide Education and
`Prescribing Safety (S.T.E.P.S.) program, which is consid-
`ered part of the product label, to support the commer-
`cial availability of thalidomide}
`This article (1) summarizes the objectives of the
`S.T.E.P.S. program, (2) describes the physician, patient,
`and pharmacy requirements for participation in the pro-
`gram, (3) reviews the dispensing process for thalidomide,
`and (4) describes our experience in developing systems
`and procedures in the hospital setting to meet the current
`requirements for participation in the program.
`
`S.T.E.P.S. program
`The goal of the S.T.E.P.S. program is to ensure that
`there is no fetal exposure to thalidomide. This is to be
`
`DANIEL P. Ki-JMVICH, M.S., M.B.A., is Projects Coordinator and
`CHARLB E. DANIELS, PH.D., is Chief, Pharmacy Department, War-
`ren C. Magnuson Clinical Center, National Institutes of Health,
`Bethesda, MD.
`Addre$ reprint requests to Dr. Daniels at the National Insti-
`tutes of Health, Warren G. Magnuson Clinical Center, Building
`10, Room IN-257. Bethesda, MD 20892, or to cdanieIs@nih.gov.
`
`The assistance of Ken Rmztak, Pharm.D., Celgene Corpora-
`tion, and Robert DeChrlstoforo, M.S., and Doreen Chey,
`Pharm.D., NIH Warren C. Magnuson Clinical Center. in provid-
`ing technical help and review is acknowledged.
`Presented in part at the ASHP Midyear Clinical Meeting. Las
`Vegas, NV, December 9, 1998.
`
`Page 1 of 5
`
`Case |PR2015-01102
`
`CELGENE EXHIBIT 2062
`
`Vol 56 Sep 1 1999 Am] Health—Syst Pharm 1721
`
`Page 1 of 5
`
`Case IPR2015-01102
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`CELGENE EXHIBIT 2062
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`

`
`Reports Thalidomide
`
`accomplished by controlling access to the drug; educat-
`ing physicians, pharmacists, and patients about the
`drug’s risks and the requirements for adequate contra-
`ceptive measures; and ensuring ongoing independent
`monitoring for compliance with program requirements.
`Specific requirements for prescribers, patients, and phar-
`macies have been developed as a condition of participa-
`tion in the program. Celgene coordinates the registration
`and drug shipping process, and Boston University’s
`Slone Epidemiology Unit (SEU) is responsible for mon-
`itoring patient and physician compliance. Celgene and
`FDA are expected to monitor compliance with the
`S.T.E.P.S. program requirements to help ensure that
`fetal exposure to thalidomide does not occur.
`Prescriber requirements. Any licensed autho-
`rized prescriber may register in the S.T.E.P.S. program.
`Prescribers need to provide their Drug Enforcement
`Administration (DEA) number (or state medical license
`number or Social Security number) for program identi-
`fication purposes. Each prescriber who requests to par-
`ticipate in the program must agree in writing to
`(cid:127) Provide comprehensive patient counseling on the
`benefits and risks of thalidomide as outlined in the
`informed-consent form.
`(cid:127) Provide appropriate contraception counseling and
`pregnancy testing or refer patients to a qualified
`obstetrician–gynecologist for counseling.
`(cid:127) Verify that female patients are not pregnant before
`initiating therapy.
`(cid:127) Submit completed informed-consent forms to SEU.
`(cid:127) Complete the prescriber portion of the patient mon-
`itoring survey and return the document to SEU.
`(cid:127) Prescribe no more than 28 days of therapy and not
`authorize refills.
`(cid:127) Encourage patients to return any unused thalido-
`mide to their pharmacy.
`Celgene’s customer service division maintains a pre-
`scriber registration database and activates the prescriber
`in the database once the signed agreement is returned.
`A packet of materials is mailed to each interested or
`registered prescriber for use with each patient undergo-
`ing thalidomide treatment. The packet contains an
`FDA-approved informed-consent form, an initial confi-
`dential patient survey, several patient surveys for use
`on subsequent visits, a form for referring patients for
`contraception counseling, a brochure on emergency
`contraception, a brochure on contraceptive choice, a
`brochure containing important information for the
`patient, a patient quiz, and a letter from the Thalido-
`mide Victims Association of Canada. In addition, vid-
`eotapes on the risks, precautions, and requirements
`associated with thalidomide for both men and women
`are distributed to each prescriber to help convey infor-
`mation on the risks and benefits.
`Patient requirements. Patients must be active
`participants in the program. All patients receive pre-
`scriber-provided education on the risks and benefits of
`thalidomide and their responsibilities in taking the
`drug. They are then required to complete the informed-
`
`1722 Am J Health-Syst Pharm Vol 56 Sep 1 1999
`
`consent form and, for women of childbearing age,
`required to test negative for pregnancy before begin-
`ning drug therapy. Patients are eligible to continue to
`receive thalidomide if they agree to and meet the
`following requirements:
`(cid:127) For women of childbearing potential, use two reli-
`able forms of contraception or continuous absti-
`nence and have regular pregnancy tests as defined in
`the informed-consent form and labeling.
`(cid:127) For men, use a latex condom every time they have
`sex with a woman.
`(cid:127) Not share thalidomide with anyone.
`(cid:127) Participate in a mandatory and confidential patient
`survey every 30 days (women) or every 90 days
`(men).
`Pharmacy requirements. Pharmacies must regis-
`ter with Celgene and agree in writing to comply with
`the requirements of the program in order to receive
`thalidomide. Any pharmacy may register. As a condi-
`tion of registration, pharmacies must provide specific
`discreet information, such as their National Association
`of Boards of Pharmacy (NABP) number, as part of the
`distribution-control requirements. If the NABP number
`is not used, as is the case for federal facilities, the DEA
`number can be substituted. Pharmacies must agree in
`writing to
`(cid:127) Collect a signed informed-consent form with the
`initial prescription.
`(cid:127) Register the patient with Celgene.
`(cid:127) Dispense a maximum of 28 days’ supply with no
`refills.
`(cid:127) Dispense thalidomide in the manufacturer’s intact
`blister pack.
`(cid:127) For subsequent prescriptions, verify that the patient
`is registered and seek authorization to dispense the
`prescription by online transmission, fax, or tele-
`phone.
`(cid:127) Not dispense thalidomide unless there are seven or
`fewer days of therapy remaining from the previous
`prescription.
`(cid:127) Accept and destroy, or return to Celgene, any un-
`used thalidomide returned by patients.
`(cid:127) Inform all staff pharmacists of the dispensing proce-
`dures for thalidomide.
`Dispensing process. Initial prescriptions. When a
`registered pharmacy receives the initial prescription for
`thalidomide, the patient must present the pharmacy
`copy of the signed informed-consent form. If the signed
`form is on file at another pharmacy, the pharmacist
`should contact that pharmacy to obtain a copy, unless
`other arrangements are made with Celgene. The signed
`form must be kept on file in the pharmacy, because it
`provides assurance that the patient has been educated
`on the risks and benefits of the drug. It also contains
`information that is required in the dispensing process.
`The pharmacy is responsible for registering the pa-
`tient with Celgene by one of three methods: online
`adjudication, submission of a manual patient-registra-
`tion form by fax (1-888-432-9325), or telephone (1-888-
`4CELGENE). This patient registration process is sepa-
`
`Page 2 of 5
`
`

`
`rate from prescription verification or authorization.
`Patient registration is the process by which the patient
`is entered into Celgene’s database. Prescription verifica-
`tion or authorization is the process by which Celgene
`authorizes the release of the medication. A pharmacist
`who registers a patient by telephone can provide the
`information required for prescription authorization at
`the same time. Pharmacists who use the fax process for
`patient registration and prescription authorization are
`required to fax both forms to Celgene. The pharmacist
`must receive approval either orally or by fax before
`dispensing the drug.
`Subsequent prescriptions. Subsequent prescriptions are
`filled in accordance with many of the same require-
`ments used in the initial prescription-filling process.
`The pharmacist must verify that the pharmacy require-
`ments for length of therapy, number of days since the
`prescription was written, and time limits from the end
`of the previous prescription have been met. The phar-
`macist must then verify that the patient has been
`entered into Celgene’s database. Once patient eligibili-
`ty is confirmed, the prescription needs to be authorized
`through online adjudication, fax submission, or tele-
`phone contact with Celgene.
`If all the elements of the dispensing process have not
`been completed, the pharmacy may be removed by
`Celgene from the list of registered dispensers and be
`unable to participate in the program.
`
`Institutional procedures for implementing
`the S.T.E.P.S. program
`Because the pharmacy requirements under the
`S.T.E.P.S. program are based on the retail pharmacy
`practice model, they present challenges for hospital
`pharmacies in the inpatient and outpatient settings.
`The pharmacy department of the NIH Clinical Center
`has developed procedures to meet the requirements of
`the program in the inpatient and outpatient areas.
`Significant modifications to usual institutional proce-
`dures were required in the inpatient area, drug monitor-
`ing systems, and database systems.
`Institutional guidelines. A member of our phar-
`macy management team, who was designated as the
`project coordinator, carefully reviewed the prescriber
`and pharmacy requirements of the program. The
`project coordinator was responsible for developing in-
`stitutional guidelines that would enable all the pre-
`scribing and dispensing requirements of the program to
`be met and for developing the necessary data systems.
`The guidelines were reviewed by the pharmacy admin-
`istrative staff, the hospital information systems depart-
`ment, the nursing quality assurance board, and pre-
`scribers and were subsequently approved by the phar-
`macy and therapeutics committee. Key individuals in
`the inpatient and outpatient pharmacies were designat-
`ed as associate coordinators to assist the project coordi-
`nator with registering prescribers and patients, as well
`
`Thalidomide Reports
`
`as with implementing the program.
`Systems for sharing information. Patients were
`expected to receive thalidomide primarily on an outpa-
`tient basis, although there are occasions on which a
`patient will start receiving therapy in the hospital and
`then require subsequent outpatient treatment. Two
`databases were developed to provide detailed informa-
`tion on eligible prescribers, registered patients, and
`thalidomide prescriptions filled and to facilitate the
`sharing of this information between inpatient and out-
`patient settings.
`The first database displays all registered prescribers
`and the prescriber information needed in the authori-
`zation process. The database lists registered prescribers,
`their Celgene identification number (DEA number or
`state medical license number or Social Security num-
`ber), the date of registration, and their affiliation (insti-
`tute and branch within NIH). The project coordinator
`maintains the prescriber database.
`A second database lists all authorized patients and
`their previous prescription information. Each pharma-
`cist who dispenses thalidomide is required to enter the
`prescription information into the database before dis-
`pensing. The patient database provides critical patient-
`related information that is found on the consent form:
`the patient’s date of birth and, for each prescription,
`the dispensing date, the hospital status of the patient
`(inpatient or outpatient), the number of days’ supply
`dispensed, the prescriber’s name, and the initials of the
`dispensing pharmacist. The patient database is essen-
`tial in the authorization process in that it allows any
`pharmacy staff member to (1) determine whether a
`patient was previously registered and approved to re-
`ceive thalidomide, (2) acknowledge that the pharmacy
`has received the signed consent form, and (3) provide
`prescription information as to the length and duration
`of therapy.
`Prescriber registration. The NIH Clinical Center
`uses a computerized physician medication order entry
`system. Thalidomide is included as an option in the
`electronic medication index, but selecting the drug
`notifies prescribers that they must be registered and are
`required to use the thalidomide restricted-access
`screens to prescribe the drug. To gain access to these
`screens, physicians are instructed to contact the project
`coordinator, who assists them with Celgene’s registra-
`tion process and provides each prescriber with electron-
`ic access.
`Patient registration and authorization. The
`methods for completing the patient-registration proc-
`ess and for authorizing new prescriptions, particularly
`during off hours, were a major point of discussion.
`Online adjudication permits pharmacies to dispense
`thalidomide on a 24-hour basis, but many hospitals
`(including the NIH Clinical Center) do not use this
`system. Celgene provides telephone and fax services for
`patient registration, patient approval, and prescriber
`
`Vol 56 Sep 1 1999 Am J Health-Syst Pharm 1723
`
`Page 3 of 5
`
`

`
`Reports Thalidomide
`
`verification only on Monday through Friday from 0800
`to 1900, Eastern Standard Time. Registered prescribers
`should be notified of this limitation. Prescribers and
`patients who need to initiate or continue therapy must
`wait until manual verification and authorization can be
`completed.
`As a means of gaining experience with the program
`and preventing registration errors, the project coordi-
`nator and associate coordinators were initially respon-
`sible for patient registration when patients started re-
`ceiving thalidomide. Pharmacy staff was instructed to
`initially contact the project coordinator or an associate
`coordinator when a new order for thalidomide was
`received for a patient who was not in the database.
`Once a signed consent form was received, the coordina-
`tor entered the new patient in the pharmacy depart-
`ment’s database of patients receiving thalidomide and
`filled the first prescription. Once a patient was listed in
`the database, any pharmacist could contact Celgene to
`obtain authorization for the next prescription or med-
`ical order.
`Dispensing issues in the inpatient setting.
`Under the S.T.E.P.S. program, the pharmacy cannot
`dispense more than a 28-day supply of medication or
`dispense additional supplies if there is more than a 7-
`day supply remaining from the previous prescription.
`Celgene requires pharmacies to dispense the entire
`blister pack; the S.T.E.P.S. program does not allow for
`traditional unit dose dispensing. Celgene also requires
`prescribers to specify the number of days of therapy as
`part of the patient survey process. However, prescribers
`rarely know exactly how long a patient will be hospital-
`ized. Dispensing a 28-day blister-pack supply at one
`time presents significant risk-management issues to
`hospitals. Our approach was to write standard medica-
`tion orders specifying that the pharmacy will dispense
`sufficient blister packs to provide for a seven-day course
`of therapy and that new orders are required every seven
`days. This minimized concerns about dispensed medi-
`cations being mislabeled if the dosage was changed,
`avoided problems associated with storing up to 28 days’
`supply of thalidomide on patient care units, and per-
`mitted patients to have their thalidomide prescriptions
`filled at any registered pharmacy at the time of dis-
`charge.
`Dispensing issues in the outpatient setting.
`Most of the prescription orders for thalidomide were
`generated from the outpatient or clinic setting. A new
`prescription is required for all discharged patients. The
`database provides the informed-consent information
`and previous prescription information that is needed to
`authorize a prescription.
`Communications. Routine communications are
`necessary to enable all staff members to focus on partic-
`ular issues related to Celgene’s program or internal
`control issues. We employed several means of commu-
`nication with the medical staff, nursing staff, and phar-
`
`1724 Am J Health-Syst Pharm Vol 56 Sep 1 1999
`
`macy staff during the first six months of the program.
`Nursing personnel were made aware of the special
`requirements for thalidomide by pharmacy briefings in
`the nursing quality assurance committee. E-mail mes-
`sages were sent to prescribers reminding them of the
`special dispensing requirements and of due dates for
`patient surveys. Pharmacy staff members were briefed
`on the special handling and registration requirements
`through staff seminars, written guidelines, and depart-
`mental newsletters and by e-mail. We found that one of
`the most effective communication methods is an infor-
`mation binder in each dispensing area that contains the
`department’s thalidomide policies and procedures and
`other important documents. The binders also contain
`blank patient registration forms and prescription verifi-
`cation forms for use when registration and verification
`by telephone are not possible.
`Communication with Celgene representatives also
`played a major role in the program’s success. Celgene
`provided the names of registered prescribers, and com-
`munications on specific programs were directed to pre-
`scribers.
`Ancillary issues. Because thalidomide has a preg-
`nancy category X rating (i.e., is a known human terato-
`gen), the same institutional policies that apply to han-
`dling other agents in this category were applied to
`thalidomide. For example, because gloves are required
`for handling hazardous drugs, gloves are required for
`handling thalidomide.
`Thalidomide is currently available only as a 50-mg
`capsule. This poses problems for pediatric patients tak-
`ing thalidomide for graft-versus-host disease, as well as
`for adults taking large doses (e.g., 600–1000 mg) for off-
`label indications.
`
`Experience
`Our experience with this program has been positive,
`and the program has been considered successful. Dur-
`ing the first six months, we registered nine outpatients
`and two inpatients in the program. Prescribers have
`complied with the program requirements without
`many objections. We have been able to remind pre-
`scribers about the mandatory completion of the patient
`survey and have not had any problems when faced with
`a transition of drug therapy from the inpatient setting
`to the outpatient setting.
`Prescriber feedback has been limited to the require-
`ments concerning patient surveys. The surveys were
`viewed as quite intrusive for patients who are not at risk
`for fetal exposure. Prescribers should be made aware
`that there is a less intrusive survey available for patients
`under 13 years of age.
`Registration may be problematic if a patient who is
`receiving thalidomide is admitted to the hospital and the
`hospital pharmacy is not registered. The pharmacy will
`need 7–10 days to become registered and receive a drug
`supply. If the decision is made to maintain the patient’s
`
`Page 4 of 5
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`

`
`therapy, the patient may be required to use his or her
`own supply until the hospital pharmacy is registered.
`
`Recommendations
`We suggest that, if a hospital pharmacy elects to
`participate in the S.T.E.P.S. program, the following
`recommendations, at a minimum, be put in place:
`1. Review the program’s requirements. Extensive in-
`formation on the program is available directly from
`Celgene and on the FDA Center for Drug Evaluation
`and Research Web site (http://www.fda.gov/cder/
`news/thalinfo/default.htm). The pharmacy registra-
`tion card and the prescriber’s patient brochure or
`folder should be extensively reviewed to enable a
`full appreciation of the patient’s or prescriber’s con-
`ditions for participation.
`2. Designate a key person to facilitate and coordinate
`the program’s requirements and communication is-
`sues.
`3. Maintain a master list of prescribers who are regis-
`tered in the program to facilitate patient registra-
`tion. Computerize the list within a database if
`feasible.
`4. Determine whether the computer system can iden-
`tify all patient-specific thalidomide transactions in
`the inpatient and outpatient settings. If the com-
`puter system cannot track all activities, a profile
`system or database should be developed. A method
`for tracking the distribution of each patient’s medi-
`cation is needed in order to comply with the length
`
`Thalidomide Reports
`
`of therapy requirements.
`5. For patients who are initially treated in an inpatient
`setting, the pharmacy should not dispense more
`than a seven-day supply of medication for inpa-
`tients. Blister packs must be dispensed intact, so the
`number of blister packs dispensed should be as close
`as possible to the seven-day supply. This will allow
`for an easy transition of the patient to the outpa-
`tient setting.
`6. Obtain and store the signed informed-consent
`forms in a central file.
`7. Follow the hospital’s standard policy for handling
`hazardous drugs or pregnancy category X products
`when handling thalidomide.
`8. Formulate communication strategies for the pharma-
`cy, medical, and nursing staff, who will most likely
`be unaware of the requirements of the program.
`
`Conclusion
`We developed procedures for registering patients and
`prescribers and dispensing thalidomide in the hospital
`setting. The procedures were designed to meet the needs
`of both the inpatient and outpatient pharmacies and to
`comply with the S.T.E.P.S. program requirements.
`
`References
`1. Tseng S, Pak G, Washenik K et al. Rediscovering thalidomide: a
`review of its mechanism of action, side effects and potential
`uses. J Am Acad Dermatol. 1996; 35:969-79.
`2. Thalomid package insert. Warren, NJ: Celgene Corporation;
`1998 Aug.
`
`Vol 56 Sep 1 1999 Am J Health-Syst Pharm 1725
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