Expert Opinion on Drug Safety
`
`ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20
`
`Managing the teratogenic risk of thalidomide and
`lenalidomide: an industry perspective
`
`Robert Bwire, John Freeman & Florence Houn
`
`To cite this article: Robert Bwire, John Freeman & Florence Houn (2011) Managing the
`teratogenic risk of thalidomide and lenalidomide: an industry perspective, Expert Opinion on
`Drug Safety, 10:1, 3-8
`
`To link to this article: http://dx.doi.org/10.1517/14740338.2011.527331
`
`Published online: 02 Dec 2010.
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`CFAD VI 1083 - 0001
`CFAD VI v. CELGENE
`IPR2015-01103
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`1.
`
`2.
`
`Introduction
`
`Core content of the pregnancy
`prevention program
`
`3. Operating the pregnancy
`prevention program: lessons
`learned
`
`4.
`
`5.
`
`Conclusion
`
`Expert opinion
`
`Editorial
`
`Managing the teratogenic risk of
`thalidomide and lenalidomide: an
`industry perspective
`
`†
`, John Freeman & Florence Houn
`Robert Bwire
`Celgene Corp., Global Drug Safety & Risk Management, Summit, NJ, USA
`
`Celgene has developed and operated pregnancy prevention programs since
`1998 with the first approval of thalidomide in the US. With the development
`and marketing of lenalidomide, an analog of thalidomide, the company fur-
`ther advanced its risk management activities, which now cover several territo-
`ries across the globe. To date, the program is a success in as much as it has
`minimized the risk of fetal exposure and subsequent development of fetal
`malformations. Nonetheless, the company understands the need to provide
`a mechanism for intervention and remediation when at-risk behaviors are
`identified, and this forms an integral part of the risk management processes.
`The implementation of the thalidomide and lenalidomide pregnancy preven-
`tion program partners patients, healthcare professionals, regulators and the
`company in a spirit of shared responsibility. This paper also presents the
`authors’ experience and perspective on the challenges of managing a preg-
`nancy prevention program, which at its core aims at ensuring that the
`product’s benefits outweigh the risk of fetal exposure.
`
`Keywords: lenalidomide, pregnancy prevention, risk management, thalidomide
`
`Expert Opin. Drug Saf. (2011) 10(1):3-8
`
`1. Introduction
`
`1.1 Background
`Thalidomide (a-phthalimidoglutaramide) was marketed in the 1950s and early
`1960s as a sedative--hypnotic agent, gaining rapid popularity as a purportedly safe
`alternative to barbiturates [1]. Peripheral neuropathy was an initial concern [2], but
`this was superseded by an epidemic of phocomelia, an extremely rare congenital
`abnormality that was associated with maternal thalidomide usage [3-5]. Between
`the period of thalidomide’s first marketing to its worldwide withdrawal in 1961,
`an estimated 10,000 children were born with a range of defects and disabilities,
`including severe congenital deformities, as a result of the drug’s unrecognized
`teratogenic effects [2,6].
`Thalidomide displays a broad spectrum of pharmacological and immunological
`activity and has been used in clinical practice to treat a wide range of diseases,
`including hematological malignancies. In 1998, Celgene’s brand of thalidomide
`Ò
`, Celgene, Warren, NJ, USA) received the FDA approval to treat mod-
`(Thalomid
`erate to severe erythema leprosum nodosum. It was subsequently approved for use
`in combination with dexamethasome for the treatment of newly diagnosed multiple
`myeloma based on response rates. To prevent the risk of fetal exposure to thalido-
`mide and to ensure benefits outweighed the teratogenic risk, Celgene worked
`closely to meet the FDA requirements on the development of a risk management
`program (RMP), the System for Thalidomide Education and Prescribing Safety
`Ò
`). Under the S.T.E.P.S program, all prescribers, pharmacists and
`(S.T.E.P.S
`patients who prescribe, dispense and receive thalidomide, respectively, are required
`to enroll in this restricted distribution program, regardless of what disease is being
`
`10.1517/14740338.2011.527331 © 2011 Informa UK, Ltd. ISSN 1474-0338
`All rights reserved: reproduction in whole or in part not permitted
`
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`Managing the teratogenic risk of thalidomide and lenalidomide -- an industry perspective
`
`treated. Because of S.T.E.P.S, thalidomide is now available in
`the US to the medical community. Details of the S.T.E.P.S
`program have been described elsewhere [7].
`With the development and marketing of lenalidomide, a
`second-generation immunomodulatory drug structurally related
`to thalidomide and potentially teratogenic in humans, Celgene
`similarly worked with the FDA to develop an RMP,
`Ò
`. Details of
`the RevAssist program have been
`RevAssist
`described elsewhere [8]. Lenalidomide was first approved in
`the US in 2005 for the treatment of patients with transfusion-
`dependent anemia due to low- or intermediate-1-risk myelodys-
`plastic syndromes associated with a deletion 5q abnormality
`with or without additional cytogenetic abnormalities. In 2006,
`it was also approved in the US for the treatment of multiple
`myeloma in combination with dexamethasone in patients who
`have received at least one prior therapy. Lenalidomide is only
`available in the US through RevAssist, which shares many fea-
`tures with the S.T.E.P.S program. However, there are impor-
`tant differences between the two programs, among which are
`the availability of lenalidomide through contracted pharmacies
`(a limited number of US specialty pharmacies).
`The S.T.E.P.S and RevAssist programs in the US have pro-
`vided Celgene with the experience to develop and implement
`thalidomide and lenalidomide risk management programs in
`ex-US territories. Both US programs are resource intensive
`and perceived as putting a heavy workload on the prescribers
`and pharmacies and also require significant electronic and
`telecommunication interaction for patients, prescribers, phar-
`macies and Celgene with the system. As Celgene expanded
`into other territories, these risk management programs were fur-
`ther refined and streamlined, taking into consideration the
`national legal and regulatory framework whilst maintaining
`their effectiveness in achieving their cardinal goal of preventing
`fetal exposure.
`The objective of this paper is to present the range of
`Celgene’s global experience in managing effective risk man-
`agement programs, particularly a pregnancy prevention
`program (PPP) in patients on thalidomide or lenalidomide,
`within the context of existing regulatory guidelines and direc-
`tives, and underscore that RMPs such as ours that require
`additional tools beyond routine pharmacovigilance build on
`core objectives through the participation of stakeholders,
`culminating in the development of country-specific RMPs.
`
`1.2 Objective of the thalidomide and lenalidomide
`pregnancy prevention program
`Thalidomide’s teratogenicity is species-specific, dose-specific
`and influenced by gestational age. The lowest doses and the
`shortest treatment period where characteristic birth defects
`in human fetuses are observed is 25 mg/day for 2 -- 3 days
`and 50 mg/day for only 1 day [9]. There is a significant risk
`of birth defects when thalidomide is administered during
`the period of embryonic organogenesis, principally between
`20 and 36 days post-fertilization or 34 -- 50 days after the
`last menstrual cycle [10].
`
`The primary objective of the thalidomide and lenalidomide
`PPP is the prevention of fetal exposure in women treated with
`the drug(s) as well as female partners of male patients.
`
`2. Core content of the pregnancy prevention
`program
`
`The identification and description of the risk(s) and the series
`of steps necessary for mitigating the risk are key drivers in the
`development of any risk management programs, which must
`be feasible if they are to successfully achieve their goals.
`To achieve the primary PPP goal of preventing fetal expo-
`sure, no single element operating in isolation is deemed suffi-
`cient to mitigate risk. However, this is achieved through a
`series of in-built PPP steps which operate in parallel within
`the pre-planned risk mitigation strategy. Four PPP elements
`can be discerned that are discussed in the following sections.
`
`2.1 Participant education
`Patients and healthcare professionals are provided with infor-
`mation on the risks of thalidomide and lenalidomide espe-
`cially with regard to the potential of fetal exposure and the
`resultant severe life-threatening congenital malformations.
`Additional educational materials for the healthcare profes-
`sional and the patient have been developed, specifically
`re-emphasizing the key messages for minimizing the potential
`for fetal exposure to the drug.
`Healthcare professionals play a key role in providing adequate
`education and counseling to the patient on the teratogenic risks
`associated with thalidomide and lenalidomide. It is a require-
`ment that healthcare professionals prescribing/dispensing tha-
`lidomide or lenalidomide advise patients on the drug’s fetal
`risks and the measures that must be in place to mitigate the
`risk. Patients must agree to adhere to the conditions of the
`PPP in order to be eligible to receive the drug. The educational
`component of the program is designed with the objective of
`improving both the healthcare provider’s and patient’s knowl-
`edge about the teratogenic risk and facilitating modification of
`patient behavior through the promotion of informed uptake of
`use of effective forms of contraception. Promotion of behavioral
`change in terms of choices relating to the selection of contracep-
`tives and their consistent use is influenced by multiple factors.
`However, it is our belief that adequate targeted education pro-
`vided by healthcare professionals, underscoring the scientific
`rationale for the need of contraception, does promote patient
`acceptance and motivation to use contraceptives. In 134 females
`of childbearing potential (FCBPs) surveyed in the US lenalido-
`mide RevAssist program, 97% reported being aware of the
`need to use two forms of birth control methods when engaged
`in heterosexual intercourse, and all the women reported to be
`using birth control methods as per program requirements [8].
`
`2.2 Target risk population and monitoring
`The main target groups for prevention of pregnancy are
`FCBP and male patients with partners who are FCBP. It is,
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`therefore, important to define and identify who is an FCBP
`and who is a female not of childbearing potential in order
`to tailor messaging around the thalidomide and lenalidomide
`teratogenic risk. In addition, information on what constitutes
`adequate contraception must be provided for each category of
`reproductive potential in accordance to what is available in a
`country. As part of the PPP of the thalidomide and lenalido-
`mide risk management, FCBP must undergo monthly preg-
`nancy testing and the drug only dispensed if the pregnancy
`test is negative. A false positive pregnancy test result in the
`program, where the majority of female patients receiving tha-
`lidomide or lenalidomide are older and have hematological
`malignancies, is not uncommon. A study in aging women
`examining factors affecting b hCG testing performance stand-
`ards showed that serum b hCG increases with age in non-
`pregnant women [11]. There has been at least one case report
`of elevated b hCG in a nongravid, premenopausal patient
`with MM, where immunochemical
`investigations demon-
`strated that myeloma
`cells
`expressed immunoreactive
`b hCG, which may explain the positive pregnancy test results
`in a nongravid woman [12]. In a US study of the thalidomide
`S.T.E.P.S program, positive pregnancy tests were registered in
`72 out of the ~ 6000 FCBPs, with 69 (95.8%) of these tests
`found to be false positives [13].
`
`2.3 Controlled distribution
`A component of the PPP involves the description of the pro-
`cess of drug distribution from the point of prescription to
`final dispense of the product to the patient. Thalidomide
`and lenalidomide are available with a prescription from a
`healthcare professional, and in most cases this is an oncolo-
`gist/hematologist with an understanding of the pregnancy
`prevention program.
`The drugs are made available through a restricted distribu-
`tion program, which range from various degrees of restriction
`of drug use (e.g., to hematologists/oncologists with demon-
`strated evidence of having trained on the pregnancy preven-
`tion program) and fulfillment of important in-built steps
`that assure safe use, such as a negative pregnancy test in
`FCBP, before the drug is dispensed. The locally implemented
`country-specific controlled distribution program is arrived at
`after consultations with the relevant stakeholders, for exam-
`ple, regulators, healthcare professionals and thalidomide vic-
`tims’ groups where these exist. In addition, Celgene has over
`the years come to recognize the positive impact of the Named
`Patient Program, operating prior to post-marketing launch
`where this is possible within the national regulations, as a
`means of working with stakeholders to test the practicability
`of implementing the post-marketing RMP.
`
`2.4 Evaluation of the pregnancy prevention program
`effectiveness
`Once risk management plans/programs are in place, it is
`imperative, through a process of continuous evaluation, to
`measure whether the program is achieving its primary
`
`Bwire, Freeman & Houn
`
`objective. Through Celgene’s pharmacovigilance activities
`and a program requirement for healthcare professionals
`and patients to report all suspected and confirmed pregnan-
`cies in female patients or female partners of male patients,
`the company is able to directly assess the effectiveness of
`the pregnancy prevention program. In some of the pro-
`grams, for example, RevAssist and S.T.E.P.S in the US, peri-
`odic surveys of patients and prescribers are performed as an
`integral part of the program. Through these surveys, infor-
`mation on patient and prescriber understanding of the pro-
`gram can be assessed. An analysis of the results of the
`lenalidomide surveys from December 2005 to December
`2006 showed that > 95% of FCBP and males on the drug
`demonstrated understanding of the teratogenic risks poten-
`tially associated with lenalidomide and the behaviors neces-
`sary to minimize the risk [8]. Where the survey results
`suggest poor understanding of the program goals, there is
`active follow-up with the patient and prescriber. Follow-up
`in most of these cases revealed an error in response rather
`than lack of understanding around the teratogenic risk of
`lenalidomide and measures necessary to mitigate that risk.
`Additional surveys to measure program effectiveness and
`compliance are ongoing in multiple countries.
`FCBPs constitute about 3 -- 5% of the population on tha-
`lidomide or lenalidomide. By April 2010, about 300,000
`patients worldwide had been exposed to the Celgene thalido-
`mide, with four confirmed fetal exposures in female patients.
`So far, there has not been a report of in utero exposure result-
`ing in congenital malformation as a result of exposure to Cel-
`gene thalidomide. By June 2010, there were > 140,000
`patients worldwide who had been exposed to lenalidomide.
`During this period, there were two confirmed fetal exposures
`to lenalidomide in pregnant female patients within the post-
`marketing setting. Similarly, there has not been a report of
`in utero exposure resulting in congenital malformation as a
`result of exposure to lenalidomide.
`
`3. Operating the pregnancy prevention
`program: lessons learned
`
`Celgene operates pregnancy prevention programs across mul-
`tiple countries and regions with diverse regulatory environ-
`ments, ranging from well-developed regulation or national
`guidelines (e.g., in North America and the EU [14,15]) to a
`complete absence of national pharmaceutical regulation on
`risk management programs that go beyond routine pharma-
`covigilance as a means of ensuring a product’s benefits out-
`weigh its risks. Celgene mandates all its territories to adopt a
`PPP for lenalidomide and thalidomide even if there is no local
`regulatory expectation, and as a matter of policy discusses the
`proposed PPP with national regulatory agencies. Currently,
`thalidomide and lenalidomide PPPs are under development
`or have been implemented in > 50 countries, and they take
`into account
`the established local medical practices and
`regulations and even cultural considerations.
`
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`Managing the teratogenic risk of thalidomide and lenalidomide -- an industry perspective
`
`3.1 Corporate commitment
`Celgene’s commercial model is built around RMPs, and the
`majority of the company’s sales relate to products under an
`RMP,
`specifically a pregnancy prevention program. An
`RMP implementation requires corporate commitment and
`is labor-intensive on all participants: the patient, prescriber,
`pharmacies and the company. Celgene has had to build a per-
`sonnel network dedicated to supporting PPP activities at a
`corporate and local affiliate level and has defined dedicated
`personnel to take responsibility for running the programs.
`This network of Celgene staff is responsible for the develop-
`ment and maintenance of PPP activities, closely liaising with
`other functions within the safety and regulatory departments.
`Adequate resourcing of risk management activities is a critical
`factor in program success. Irrespective of whether the imple-
`mented system is an intensive, multi-component, integrated
`program such as RevAssist and S.T.E.P.S or one that is less
`onerous and dependent on augmented communication of
`the teratogenic risk and pregnancy minimization measures,
`operating a pregnancy prevention program with a global reach
`does require additional resources that go way beyond those
`that are usually allocated for routine pharmacovigilance.
`
`3.2 Definition of core PPP standards
`Nested levels of decision-making are integral through any risk
`management program, and coordination at all strata within
`the company to ensure understanding, consistency and plan-
`ning of activities should be clearly defined. Celgene has a
`global governance structure that through interactions with
`internal and external stakeholders has facilitated to delineate
`the company’s core thalidomide and lenalidomide PPP
`standards. These core standards are the starting point in any
`country’s PPP development.
`
`3.3 Implementing the program: global standards but
`with a local flavor
`Implementation of core standards differs from region to
`region or country to country. Country-specific programs are
`implemented in accordance with the healthcare system orga-
`nization and in sync with the national legal or regulatory envi-
`ronment and cultural considerations, among others. The
`responsibilities and accountabilities around the execution of
`the PPP take into consideration the individual roles of pre-
`scribers and pharmacists within the framework of their roles
`in providing healthcare. For example, in the UK and Ireland,
`pharmacies must be registered with Celgene in order to dis-
`pense thalidomide. In addition, they must agree to implement
`and audit the use of a Prescription Authorization Form (PAF)
`or ensure that the contents of the PAF are incorporated into
`the institution’s standard prescription. The PAF requires
`both the prescribing physician and the pharmacist to docu-
`ment and confirm that the key elements of the PPP have
`been undertaken. The results of the self-audit are reported
`periodically to the national competent authorities and to the
`European Medicines Agency (EMEA). In some countries,
`
`pharmacists do not play a prominent role in program execu-
`tion as the prescribing physician is accountable for all aspects
`of the PPP.
`Further, local legal or regulatory considerations might be a
`source of conflict with the public health imperative champ-
`ioned by the company; for example, due to local privacy laws
`in some US states, follow-up on outcomes that are a subject
`of an identified risk (pregnancy in the case of the PPP) might
`present particular difficulties. Nonetheless, the company rou-
`tinely undertakes intensive measures to obtain outcome data
`and relevant follow-up information. This is an undertaking
`that requires significant resource mobilization and cooperation
`with healthcare professionals who are the source of informa-
`tion. It is important that regulatory authorities understand
`and appreciate this challenge as companies must balance their
`actions for acquiring data that informs decisions on the effec-
`tiveness of the program against individual rights that are
`protected and enshrined within the national legal framework.
`
`3.4 Balancing practicality with burden
`Steps that assure safe use of a product, which are integral in a
`specific risk management program, should not be burdensome
`on the healthcare system, but at the same time ought to be
`designed in such a way that they realistically and effectively mit-
`igate the risk of interest. In the US RevAssist and S.T.E.P.S, all
`physicians, pharmacists and patients who prescribe, dispense
`and receive the drug, respectively, are required to enroll in the
`pregnancy prevention program, regardless of the disease being
`treated. The system also ensures that results from the required
`pregnancy tests are documented and linked to prescription acti-
`vation and dispensing through an interactive voice response
`system or via telephone customer service contact prior to dis-
`pensing the drug [15]. Besides, patients and prescribers must
`complete required surveys to demonstrate knowledge of pro-
`gram goals and identify changes in risk status. Patient surveys
`are either monthly or six monthly depending on a patient’s
`reproductive risk category. Physicians are required to complete
`a survey for each prescription to be written for each patient to
`minimize risk of fetal exposure. In the US, PPP healthcare pro-
`fessionals must devote time and resources to ensure all require-
`ments of the program are met. Taking into consideration the
`healthcare delivery environment and issues relating to patient
`data protection in ex-US territories, Celgene has worked with
`regulators and other stakeholders to develop less resource-
`intensive programs outside the US. These programs do not
`require monthly surveys and have fewer transactional elements
`between the users and the supporting technology platforms,
`but nonetheless do have mechanisms that allow for the collec-
`tion and assessment of data relevant to evaluate program effec-
`tiveness, with opportunity to intervene when corrective
`measures are required.
`
`3.5 Stakeholder input
`The success of any RMP hinges on the realization and
`appreciation of
`the
`local
`regulatory environment
`and
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`recognizes that proactive pharmacovigilance systems are best
`elaborated through a process of consultation with relevant
`stakeholders. In the EU, for example, stakeholder input to
`the PPP was solicited from the EMEA and the rapporteurs,
`Thalidomide Victims Groups in the UK and Sweden, Euro-
`pean Haematologists and Pharmacists, European Female
`Health Advisory Board and National Competent Authorities,
`among others. Thus, the PPP, as an integral part of the thalid-
`omide and lenalidomide RMP represents a new direction in
`pharmacovigilance, involving a greater and more inclusive
`role of stakeholders in developing visible and transparent
`strategies that promote patient safety.
`
`3.6 Continuous evaluation of the program
`Through the company’s enhanced adverse event reporting of
`pregnancies, Celgene continuously monitors the effectiveness
`of the program. Equally important are ongoing surveys in var-
`ious countries designed to evaluate compliance to the PPP
`either from the perspective of the healthcare professional or
`the patient. Program evaluation could also be expanded to
`assess the overall burden of a specific risk management strat-
`egy which may have impact on patient access to drug or affect
`a healthcare professional’s prescribing patterns. In a 2010 pro-
`spective qualitative market research study enrolling 36 patients
`and aimed at understanding patients’ experience with the
`Canada lenalidomide RMP, most patients stated to have
`had easy access to the drug although five (13.9%) patients
`reported a delay between program enrolment and initiation
`of first treatment [16].
`
`3.7 Updating additional educational materials
`According to the current EU guideline [13], the need for
`additional educational material and the form in which it
`should be provided depend on the safety concern. Celgene
`has developed additional educational materials for the preg-
`nancy prevention program, detailing the teratogenic risk of
`thalidomide and lenalidomide and the steps that must be in
`place to mitigate the risk of fetal exposure. The educational
`material should be used to enhance messaging and under-
`standing of the teratogenic risk of thalidomide and lenalido-
`mide, and such material is in addition to the routine drug
`information leaflet made available to patients and healthcare
`professionals. We are concerned that using these additional
`educational materials as a means to communicate any other
`identified/potential risks besides the teratogenic risk has the
`potential of lessening the impact of the materials as the target
`audience might perceive these materials as a substitute for the
`Summary of Product Characteristics (SmPC)/Product Infor-
`mation and the Patient Information Leaflet (PIL). In the
`US,
`the thalidomide and lenalidomide restricted distri-
`bution program with Elements to Assure Safe Use relates to
`the products’ teratogenic risk, which offers opportunity to
`focus messaging on the serious and significant
`risk of
`congenital malformations. It must be acknowledged that
`both thalidomide and lenalidomide do carry other safety risks,
`
`Bwire, Freeman & Houn
`
`but these are adequately addressed in the SmPC/Product
`Information and the PIL.
`
`4. Conclusion
`
`Celgene has developed and operated PPPs since 1998, with
`the first approval of
`thalidomide in the US. With the
`development and marketing of lenalidomide, an analog of
`thalidomide, the company has further advanced its risk man-
`agement activities, which now cover several territories across
`the globe. To date, the program is a success in as much as it
`has minimized the risk of fetal exposure and subsequent devel-
`opment of fetal malformations. Nonetheless, the company
`understands the need to provide a mechanism for intervention
`and remediation when at-risk behaviors are identified, and
`this forms an integral part of our processes.
`The implementation of the thalidomide and lenalidomide
`PPP partners patients, healthcare professionals, regulators
`and the company in a spirit of shared responsibility. However,
`the implementation strategies differ across regions/countries
`but draw on well-defined core standards.
`
`5. Expert opinion
`
`Over the last few years, the concepts for pharmacovigilance plan-
`ning that were set out in the International Conference on
`harmonization E2E [17] have evolved to FDA’s Risk Evaluation
`and Mitigation Strategies (REMS) and the EMEA’s Volume
`9A requirements. As per current EU requirements as detailed
`in the EU guideline [14], the EU RMP must be submitted in a
`format that conforms to the standard template. The template
`provides an intuitive structure that characterizes the identified
`and potential risks of a product and steps that might mitigate
`the risks. However, this template is repetitious and EMEA and
`stakeholders, including companies, should study ways of stream-
`lining content to result in a concise and robust document. The
`FDA has issued a draft guidance on the content and format of
`REMS [18]. Further, aligning the templates and guidance with
`common critical expectations of regulators would result in a
`harmonized document for use by the industry across regions.
`The periodicity of submission, which ties the EU RMP
`submission to the time of submission of the PSUR places an
`enormous burden on companies as
`resources must be
`deployed to finalize both documents at the same time, and
`yet the finalization of the EU RMP is often dependent on
`the finalization of the PSUR.
`In the US, each manufacturer must create de novo their own
`drug restricted distribution system, if needed, for their product.
`Increase in numbers of restricted distribution REMS may be
`burdensome on each patient, prescriber and pharmacy as the
`programs have unique and varied features. Some standardiza-
`tion of administrative functions such as enrolment identifica-
`tion information, the technology platforms and standardized
`formatting of information may lessen the barrier for prescribing
`and dispensing, and may also help industry so long as
`
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`Managing the teratogenic risk of thalidomide and lenalidomide -- an industry perspective
`
`companies can manage their own programs based on their
`expert knowledge of product risk management.
`Thus, harmonization and efficiencies would not only assist
`industry, but would advance a global focus on public health.
`
`Declaration of interest
`
`authors of
`The
`Celgene Corp.
`
`this paper
`
`are
`
`employees of
`
`the
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`Affiliation
`
`†
`, John Freeman & Florence Houn
`Robert Bwire
`†
`Author for correspondence
`Celgene Corp.,
`Global Drug Safety & Risk Management,
`Summit, 07901 NJ, USA
`E-mail: rbwire@celgene.com
`
`Expert Opin. Drug Saf. (2011) 10(1)
`
`Downloaded by [Jason Palguta] at 10:31 08 January 2016
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`CFAD VI 1083 - 0007