The Risk Evaluation and Mitigation Strategy for Amgen's platelet producer Nplate mandates enrollment at three levels of a controlled distribution system: institutions, physicians and patients.

Several products have had controlled distribution systems under voluntary risk management programs; Nplate is the first product with an approved REMS containing a high level of user controls and tracking.

Through the REMS, Amgen has signed a formal agreement with FDA that commits the firm to identifying the three levels of users and compiling specific data on the use of the product that will be reported to FDA on a periodic basis. Nplate was approved by FDA on Aug. 22 for chronic use by immune thrombocytopenic purpura patients who are not responding to current therapies.

Monitoring And Education Agreements

Institutions: Hospitals and health care institutions must develop systems and protocols to ensure Nplate (romiplostim) is properly dispensed, to ensure proper inpatient-to-outpatient transition, and to track compliance and cooperate with periodic audits to ensure Nplate is used in accordance with the program requirement.

The product tracking requirements for institutions include collecting the name and unique identification numbers of the prescriber and patient, as well as the date of the Nplate order, the number and size of the Nplate vials, the date of each dose given to each patient, and the overall inventory for the set period of time including the total number of vials ordered.

Physicians: Prescribers must establish a patient monitoring schedule to check weekly complete blood counts (CBCs), including platelet counts and peripheral blood smears, until a stable dose has been achieved. If Nplate is discontinued, CBCs, including platelet counts, must be obtained weekly for at least two weeks.

Doctors must also fill out a program patient enrollment form within 30 days of patient enrollment. They must counsel patients to carry a Patient ID Card and Dosing Tracker, and complete a safety questionnaire every six months during a patient's Nplate treatment.

Patients: Enrolled patients must attest that they understand the MedGuide, are aware of the safety risks, will report any adverse events to the prescriber, and know to carry a Patient ID Card and Dosing Tracker.

The REMS controls are part of a broader education, access and support program for Nplate called NEXUS ("Network of EXperts Understanding and Supporting Nplate and patients").

In addition to the mandatory risk management provisions of the program and distribution controls, Amgen has attached an access assistance program to NEXUS. Eligible patients who are uninsured, underinsured or unable to afford their insurance co-payments may be able to receive reimbursement support and other assistance from Amgen.

Safety risks of Nplate include bone marrow fibrosis, worsened thrombocytopenia after cessation of Nplate, thromboembolic complications, an increased risk of hematological malignancies and progression of malignancy in patients with a pre-existing hematological malignancy or myelodysplastic syndrome, and serious complications due to medication error.

Evaluations Due Every Six Months

Amgen will maintain a call center run by a third-party organization to track enrollment statistics and a database on all three levels of distribution.

The Call Center will monitor to ensure Nplate is only being dispensed to enrolled patients by enrolled hospitals and prescribers, and to make sure those hospitals and prescribers are compliant with the baseline data collection, periodic safety monitoring and reauthorization, discontinuation procedure and post-discontinuation follow-up.

Nplate will be distributed to enrolled certified prescribers via a drop-ship program. Prescribers order Nplate through their usual distributor, who then transmits the order to the NEXUS Program.

Amgen will analyze the data collected by the NEXUS Call Center to track enrollment and discontinuation statistics for the evaluation part of the REMS program: assessments are to be submitted to FDA every six months for the first 24 months following approval and then annually.

Assessments will tally the number of total and newly enrolled patients; enrolled patient person-years; and patients who discontinued use, were lost to follow-up, and who discontinued use and re-enrolled for another course of treatment.

Amgen will also report on the total number of enrolled, newly enrolled, and actively prescribing providers, as well as the number of enrolled institutions that treat, order, or prescribe a patient Nplate.

Amgen Will Report On Patients Not Enrolled

Amgen is also responsible for calculating the numbers of un-enrolled patients, providers and institutions that are taking, prescribing or ordering Nplate.

The company has committed to produce narrative summaries analyzing Nplate discontinuation, inpatient/outpatient transition issues and analysis of the safety issues. The firm will also write summaries of the institution audits performed during the reporting period, of unintended interruptions in treatment, and all NEXUS program changes implemented during the reporting period.

Amgen will also complete assessments of Nplate use data, prescriber/institution compliance with elements of certification and provider and patient understanding of the safe-use of Nplate.

The approved REMS closely resembles that presented to FDA's Oncologic Drugs Advisory Committee in March (¹ Also see "With Promise Of Post-Market Safety Studies, Panel Backs Amgen’s Nplate" - Pink Sheet, 17 March, 2008., p. 3). The sizable risk management package was submitted by Amgen as an amendment to its BLA, delaying its approval date by three months to July 23. The REMS document is 95 pages long and provides a roadmap for products that require very detailed distribution controls.

Interestingly, FDA is coming up on a decision date for another drug for use against ITP: GlaxoSmithKline's Promacta (eltrombopag), with an action date in late September.

Promacta will carry labeling for a different use as second-line, short-term treatment of ITP. The comparison of the REMS control programs should show how far FDA is willing to go to enforce a distinction between the indications for the products through its new REMS authority. FDA has observed that early versions of the Promacta risk management program "appear to anticipate long-term use of the drug" (² Also see "GSK’s Promacta Gets ODAC Nod Despite Concerns Of Off-Label, Long-Term Use" - Pink Sheet, 2 June, 2008., p. 15).

The first version of the Promacta REMS requires all patients and prescribers to enroll in a program that will allow for active pharmacovigilance over two years, during which time prescribers will be asked to fill out a safety questionnaire every six months (similar to Nplate).

Amgen estimates there are currently 140,000 treated patients in the U.S. and Europe, that the condition affects about twice as many adult women as men, and that the median age for the population ranges from 30 to 40 years of age.

Post-marketing Study Requirements

In addition to the REMS, Amgen has agreed to mandatory post-marketing safety studies, an agreement which helped to swing the advisory committee review of the product. (³ Also see "With Promise Of Post-Market Safety Studies, Panel Backs Amgen’s Nplate" - Pink Sheet, 17 March, 2008., p. 3).

Amgen will conduct three observational studies and one clinical trial, all scheduled to begin in the summer of 2009.

The firm will conduct an "Antibody Registry Study" of subjects who have received romiplostim and whose blood samples contain antibodies to either romiplostim or thrombopoietin. Enrollment in the study is dependant on providers - physicians who detect antibody formation to Nplate in patients can request that an antibody test be performed by Amgen.

If a neutralizing antibody is found, Amgen will assess the long-term consequences of the detected antibodies through collection of follow-up platelet count and other clinical data. Patients will be followed until the detected antibodies resolve or stabilize in titer over several months.

For its second post-market study commitment, Amgen will develop and maintain a prospective, observational pregnancy exposure registry study conducted in the U.S. that compares the pregnancy and fetal outcomes of women exposed to romiplostim during pregnancy to an unexposed control population.

The women enrolled in the pregnancy registry that choose to breastfeed their infants will make up the third study - a milk-only lactation study, designed to detect the presence and concentration of romiplostim in breast milk and any effects on milk production and composition.

The first interim report submissions for all three studies are due in May 2010, then annually until FDA determines that sufficient data have been collected.

The fourth study is a clinical trial. FDA states in the Nplate approval letter that "only a clinical trial (rather than a nonclinical or observational study) in which patients with defined underlying risks are carefully evaluated for at least 24 hours following administration of romiplostim will be sufficient to assess the signals of serious risk or identify unexpected serious risks."

The prospective, Phase IV, open-label, multi-center study will evaluate the changes in bone marrow morphology in subjects receiving romiplostim for the treatment of thrombocytopenia associated with ITP.

In the trial, at least 150 patients will receive romiplostim and undergo bone marrow evaluations prior to, during and following romiplostim administration.

A similar evaluation schedule will apply to the detection of antibody formation to romiplostim and thrombopoietin as well as the electrocardiographic detection of cardiac conduction abnormalities.

Interim reports will be submitted in June 2012 and 2013, and the final report will be submitted in December 2014.

- Jamie Hammon (j.hammon@elsevier.com)

Amgen’s Nplate Has First Mandatory Patient Registration Under REMS

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