The ESA APPRISE Oncology Program

History of the REMS Program

On September 27, 2007, President George W. Bush signed into law the Food and Drug Administration Amendments Act of 2007 (FDAAA), which authorized the FDA to require a Risk Evaluation and Mitigation Strategy (REMS) program for drugs and biological agents.¹ REMS programs are intended to support the safe use of products for which the risks and benefits need to be carefully weighed in general or in specific patient populations. The FDA can require a REMS program at the time of a product’s approval. If a safety problem is detected after approval, the REMS can be required at any time during a drug’s life cycle.

The decision about whether to require a REMS program is based on the estimated patient population likely to be exposed to the product, the seriousness of the condition being treated by the drug, the expected benefit and duration of treatment, and the safety risk created by use of the drug.² The results of this analysis determine the need for and the components of the REMS.

The FDAAA legislation authorized several individual requirements, one or more of which may be combined to make up a product-specific REMS program.² The requirements include:

• a medication guide.

• a communication plan to disseminate risk information to health care professionals (e.g., Dear Healthcare Professional letters).

• elements to ensure safe use.

• an implementation system to monitor and evaluate the program’s success.

Several elements to ensure safe use are outlined in the legislation (Table 1). Products can vary greatly in their REMS requirements. As of December 10, 2010, more than 150 drug products had a REMS program.³ Of those drugs, almost all included a medication guide (Table 2). For other products, such as antidepressants as a class, a medication guide may be required outside of a REMS program.⁴

Table 1.

Elements to Ensure Safe Use

A REMS program to ensure safe use incorporates one or more of the following elements:

Health care providers who prescribe the drug have specialized training or experience or are certified in a specific field. Pharmacies, practitioners, or health care settings that dispense the drug are certified in a specific field. The drug is dispensed to patients only in certain health care settings (e.g., hospitals). The drug is dispensed to patients with evidence or other documentation of safe-use conditions (e.g., laboratory results). Patients are subjected to certain monitoring requirements. Patients are enrolled in a registry.

Data from FDA Amendments Act of 2007.²

Table 2.

Drug Products With REMS Programs—Medication Guide Only

Antiepileptic drugs, selected

Carbamazepine (Equetro)

Ethosuximide (Zarontin)

Ethotoin (Peganone)

Gabapentin (Neurontin)

Lacosamide (Vimpat)

Levetiracetam (Keppra)

Lamotrigine (Lamictal)

Pregabalin (Lyrica)

Primidone (Mysoline)

Tiagabine (Gabitril)

Topiramate (Topamax)

Zonisamide (Zonegran)

Antiretrovirals, selected

Abacavir (Ziagen)

Abacavir/lamivudine (Epzicom)

Lopinavir/ritonavir (Kaletra)

Abacavir/lamivudine/zidovudine (Trizivir)

Nevirapine (Viramune)

Didanosine (Videx, Videx EC)

Telbivudine (Tyzeka)

Saquinavir (Invirase)

Fluoroquinolones, all

Interferon alfa and beta, all

Long-acting beta2-agonist combination products, selected

Formoterol/budesonide (Symbicort)

Salmeterol/fluticasone (Advair)

Thiazolidinediones, all

Other agents

Bupropion (Aplenzin, Wellbutrin)

Colchicine (Colcrys)

Dabigatran (Pradaxa)

Diclofenac oral and topical solutions (Cambia, Pennsaid)

Doxepin (Silenor)

Fenofibric acid (Trilipix)

Mefloquine (Lariam)

Methsuximide (Celontin)

Metoclopramide oral solution and disintegrating tablets (Metozolv ODT)

Milnacipran (Savella)

Morphine oral solution

Naltrexone (Vivitrol)

Olanzapine (Zyprexa)

Olanzapine/fluoxetine (Symbyax)

Omalizumab (Xolair)

Oral bowel prep kits

Oxycodone oral solution

Pancrelipase (Creon, Pancreaze, Zenpep)

Pazopanib (Votrient)

Propylthiouracil

Quetiapine (Seroquel)

Ramelteon (Rozerem)

Repository corticotropin (HP Acthar Gel)

Ribavirin (Copegus, Rebetol)

Rufinamide (Banzel)

Sirolimus (Rapamune)

Sitagliptin (Januvia, Janumet)

Sunitinib (Sutent)

Testosterone, topical (AndroGel, Axiron, Testim)

Trazodone extended release (Oleptro)

Varenicline (Chantix)

Zolpidem oral spray (ZolpiMist)

Data from FDA, as of December 2010. Information for REMS is updated routinely on the FDA Web site.³

Many drugs also include a communication plan. A subset of drugs, including the erythropoiesis-stimulating agents (ESAs), requires elements to ensure safe use with or without an implementation system (Table 3, page 425). The FDA seeks input from patients and health care practitioners when developing the program design to ensure that it will not be unduly burdensome to patients or the health care system.²

Table 3.

REMS Program Requirements by Drug Product or Class

	Medication Guide	Communication Plan	Elements of Safe Use	Implementation System
Alvimopan (Entereg)		X	X	X
Alglucosidase alfa (Lumizyme)		X	X	X
Alosetron (Lotronex)	X		X	X
Armodafinil (Nuvigil)	X	X
Botulinum toxin A (Botox, Dysport, Xeomin) and B (Myobloc)	X	X
Buprenorphine transdermal (Butrans)	X		X
Buprenorphine/naloxone sublingual film (Suboxone)	X		X	X
Collagenase Clostridium histolyticum (Xiaflex)	X	X
Dalfampridine (Ampyra)	X	X
Denosumab (Prolia)	X	X
Dronedarone (Multaq)	X	X
Ecallantide (Kalbitor)	X	X
Eculizumab (Soliris)	X		X
Electrolyte containing bowel prep tablets (OsmoPrep, Visicol)	X	X
Eltrombopag (Promacta)	X		X	X
Endothelin receptor antagonists (Letairis, Tracleer)	X		X	X
Erythropoiesis-stimulating agents (Aranesp, Epogen, Procrit)	X	X	X	X
Everolimus (Zortress)	X	X
Fingolimod (Gilenya)	X	X
Formoterol/mometasone (Dulera)	X	X
Fentanyl buccal film (Onsolis)	X	X	X	X
Glucagon-like peptides (Byetta, Victoza)	X	X
Hydromorphone extended release (Exalgo)	X		X
Isotretinoin (Accutane, Amnesteem, Claravis)	X		X	X
Lenalidomide (Revlimid)	X		X	X
Modafinil (Provigil)	X	X
Morphine/naltrexone (Embeda)	X	X
Nilotinib (Tasigna)	X	X
Olanzapine extended release injection (Zyprexa Relprevv)	X	X	X	X
Oxycodone extended release	X		X
Pegloticase (Krystexxa)	X	X
Prasugrel (Effient)	X	X
Quinine (Qualaquin)	X	X
Romiplostim (Nplate)	X	X	X	X
Sacrosidase (Sucraid)		X	X	X
Salmeterol (Serevent)	X	X
Telavancin (Vibativ)	X	X
Teriparatide (Forteo)	X	X
Tetrabenazine (Xenazine)	X	X
Thalidomide (Thalomid)	X		X	X
Tocilizumab (Actemra)	X	X
Tolvaptan (Samsca)	X	X
Tumor necrosis factor antagonists: certolizumab (Cimzia), etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), golimumab (Simponi)	X	X
Ustekinumab (Stelara)	X	X
Vigabatrin (Sabril)	X	X	X	X

Data from FDA, as of December 2010. Information for REMS is updated routinely on the FDA Web site.³

The Use of Erythropoiesis-Stimulating Agents In Oncology

ESAs have been widely used in cancer patients on the basis of data showing that they decreased transfusion requirements. A 2006 meta-analysis of more than 9,000 patients receiving ESAs, with and without concurrent antineoplastic therapy, reported a 36% decreased need for red blood cell transfusions.⁵ Unfortunately, the authors also found a 67% increase in thromboembolic events (transient ischemic attacks, stroke, pulmonary emboli, deep-vein thrombosis, and myocardial infarction) for those receiving ESAs, conflicting with results of a previous publication.⁶ This earlier analysis, published in 2005,⁶ also indicated a trend toward increased survival that was not supported by the subsequent 2006 study.⁵

A meta-analysis, published in 2008 by Bennett et al., reinforced the elevated thromboembolic risk associated with ESA use compared with a placebo (7.5% vs. 4.9%, respectively).⁷ The authors also found an increased mortality risk with ESAs (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.01–1.20).

A 2009 update to the 2006 meta-analysis⁵ revealed increased mortality with the use of ESAs (combined HR, 1.17; 95% CI, 1.06–1.3) and decreased survival (combined HR, 1.06; 95% CI, 1–1.12) during the active study period.⁸ There was no statistically significant increase in mortality (combined HR, 1.10; 95% CI, 0.98–1.24) or decrease in overall survival (combined HR, 1.04; 95% CI, 0.97–1.11) in the subgroup of patients receiving concomitant chemotherapy and ESAs.

In addition to the meta-analyses of studies investigating ESAs, the FDA Oncologic Drugs Advisory Committee (ODAC) met three times to discuss the findings and the future place of ESAs in the management of patients with cancer. At the first meeting in 2004, two trials with adverse findings were reviewed (Table 4, page 426): Evaluation of NeoRecormon on outcome in Head And Neck Cancer in Europe (ENHANCE)⁹ and the Breast Cancer Erythropoietin Survival Trial (BEST).¹⁰ Based on these trials and previous data regarding thromboembolic events, the FDA-approved labeling of ESAs was updated to warn of the increased risks of thrombosis and tumor promotion.

Table 4.

Summary of Trials of Erythropoiesis-Stimulating Agents (ESAs) Reviewed by the Oncologic Drugs Advisory Committee

Trial	Study Design	Selected Results
Reviewed in 2004
ENHANCE9	Patients with head and neck cancer receiving radiotherapy Randomized to receive an ESA or placebo Target Hb ≤ 14 g/dL for women, ≤ 15 g/dL for men	ESA use was associated with: decreased locoregional progression-free survival (adjusted relative risk, 1.62; P = 0.0008) decreased overall survival (relative risk, 1.39; P = 0.02)
BEST10	Women with metastatic breast cancer receiving first-line chemotherapy Randomized to receive an ESA or placebo Target Hb 12–14 g/dL	Study was stopped early; higher mortality rates in the ESA group than in the placebo group: 12-month overall survival rate 70% vs. 76% (P = 0.01) tumor response and time to progression were similar between groups
Reviewed in 2007
EPO CAN-2011	Patients with non–small-cell lung cancer not receiving chemotherapy or receiving non–platinum-based chemotherapy regimens Randomized to receive an ESA or placebo Target Hb 12–14 g/dL	Study was stopped early; higher mortality rates in the ESA group than in controls: Median survival, 63 days vs. 129 days (P = 0.04)
Amgen study 2001-010312	Patients with non-myeloid cancers not receiving chemotherapy Randomized to receive an ESA or placebo Target Hb 12–13 g/dL	ESA use was associated with: increased cardiovascular and thromboembolic events (9.7% vs. 7.7%; P was not reported) decreased survival during treatment and long-term follow-up (HR for overall survival, 1.22; P = 0.022)
Amgen study 2000-016113	Patients with lymphoma or myeloma receiving chemotherapy Randomized to receive an ESA or placebo Target Hb 13–14 g/dL for women, 13–15 g/dL for men	ESA use was associated with: increased quality of life decreased survival (HR for death, 1.37; P = 0.04)
DAHANCA 1014	Patients with squamous cell carcinoma of the head and neck receiving radiotherapy Randomized to receive an ESA or placebo Target Hb ≤ 15.5 g/dL	ESA use was associated with: decreased locoregional control (56% vs. 69%; P = 0.02) decreased disease-free survival (48% vs. 63%; P = 0.004) No statistically significant difference in overall survival
Reviewed in 2008
GOG-19115	Women with cervical cancer receiving chemotherapy and radiation Randomized to receive an ESA or placebo Target Hb 12–14 g/dL	Study was stopped early; concerns about an increased rate of thromboembolic events with ESAs: 19.2% vs. 7.7% fewer than 25% of planned patients enrolled ESA use was associated with a numerical, but not a statistically significant, decrease in: progression-free survival (58% vs. 66%) overall survival (60% vs. 74%)
PREPARE16	Women with breast cancer receiving neoadjuvant chemotherapy Randomized to receive an ESA or a transfusion Target Hb 12.5–13 g/dL	An unplanned interim analysis after a median follow-up period of 3 years showed an association of ESA use with: decreased overall survival (86% vs. 90%; HR, 1.42; 95% CI, 0.93–2.18) decreased progression-free survival (73% vs. 79%; HR, 1.33; 95% CI, 0.99–1.79)

CI = confidence interval; Hb = hemoglobin; HR = hazard ratio.

Trials: BEST = Breast Cancer Erythropoietin Survival Trial; DAHANCA = Danish Head and Neck Cancer Group; ENHANCE = Evaluation of NeoRecormon on outcome in Head And Neck Cancer in Europe; EPO CAN-20 = Epoetin Alfa in Advanced Non–Small Cell Lung Cancer; GOG = Gynecologic Oncology Group; PREPARE = Preoperative Epirubicin Paclitaxel Aranesp.

In 2007, the ODAC discussed four additional trials that showed adverse outcomes: Epoetin Alfa in Advanced Non–Small Cell Lung Cancer (EPO CAN-20),¹¹ Amgen studies 2001-0103¹² and 2000-0161,¹³ and the Danish Head and Neck Cancer Group (DAHANCA 10)¹⁴ (see Table 4). This review resulted in the addition of a boxed warning to the labeling of ESAs regarding an increased risk of death, more rapid tumor progression, and serious cardiovascular and thromboembolic events.

In 2008, the ODAC was convened to review the results of two additional trials: the Gynecologic Oncology Group (GOG-191)¹⁵ and the Preoperative Epirubicin Paclitaxel Aranesp (PREPARE¹⁶) study. Based on these trials and the earlier literature showing adverse outcomes, the ODAC recommended limiting the use of ESAs to patients receiving palliative treatment. The ODAC also recommended that the FDA require informed consent or a patient agreement before ESAs could be administered. The FDA-approved labels were subsequently revised to state that ESAs were not recommended when the intent of chemotherapy was to cure and when a REMS program was initiated.

In response to published data, national guidelines have been updated. The 2010 American Society of Clinical Oncology/American Society of Hematology guideline recommends ESAs as an option when hemoglobin levels are below 10 g/dL during chemotherapy.¹⁷ The guideline does not include a specific hemoglobin target; instead, it recommends maintaining hemoglobin at the lowest level required to avoid a transfusion. Notably, the guideline differs from the FDA-approved labeling by stating that limiting the use of ESAs to palliative chemotherapy regimens is a clinical judgment and not expressly supported by the literature. The Centers for Medicare & Medicaid Services (CMS) defined the appropriate setting for ESAs to apply only to patients receiving chemotherapy in the palliative setting with a hemoglobin level of less than 10 g/dL and further recommend discontinuing ESAs within eight weeks of the last chemotherapy dose.¹⁸

ESA APPRISE and an Approach to Compliance

In February 2010, based on the ODAC’s recommendations and the FDA’s subsequent action, Amgen and Centocor Ortho Biotech announced that the FDA had approved a REMS program called Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs (the ESA APPRISE Oncology Program).¹⁹ This program incorporates a medication guide, a communication plan, elements to ensure safe use, and an implementation system.²⁰

Medication Guide

The original REMS for ESAs included a requirement that a medication guide be distributed to each patient when an ESA was to be dispensed.²⁰ There was no specific direction with regard to the practice setting (i.e., inpatient or outpatient) or the frequency with which guides should be distributed (i.e., upon therapy initiation or with every drug administration).

In February 2011, the FDA issued a draft guidance explaining its approach to discretionary enforcement of the REMS regulations.²¹ Although not yet formally in effect as of this writing, the draft guidance specifies requirements for in-patient and outpatient sites and when medication guides must be distributed. For hospitalized patients, a guide is not mandatory unless the patient or patient’s agent requests it. Instead, providing patient information, including appropriate use, potential side effects, and follow-up by a health care professional in the course of care, is considered sufficient to meet the regulatory intent. In an outpatient setting, in which the ESA is dispensed to a health care professional to administer to the patient, the medication guide must be distributed upon request, at the first time drug is dispensed, and when the guide’s content has been substantively changed.

The FDA guidance does not affect the duty of the hospital to inform a patient of the REMS program. Although distribution of the actual medication guide is not mandated for each patient with each drug administration, a review of the information must still be included for each patient each time.

(Note: Distribution of the guide is required for all uses of ESAs, whereas other elements of ESA APPRISE are unique to patients with cancer.)

Some logistical considerations are associated with this process and must be addressed by each hospital, such as which member of the health care team is responsible for reviewing the information with the patient (nurse, pharmacist, or physician) and whether the medication guide must be used to facilitate discussion. If the guide is used, the process by which it is stored and retrieved must also be addressed.

For instance, the medication guides are five pages long, they are not supplied in a 1:1 ratio with the product, and they are subject to updates. At St. Vincent Indianapolis Hospital, the nurse reviews the guide with the patient. The guide is printed by the pharmacy from the manufacturer’s Web site at the time of dispensing, It is then sent with the ESA to ensure that the most recent version is used, thereby eliminating the need to store paper copies. The medication guide is distributed with each drug administration to each patient so that the content provided and the method of dissemination are consistent.

Communication Plan

The responsibility of the communication plan rests with the manufacturer. The Dear Healthcare Provider letters and other materials can be accessed at www.esa-apprise.com.²⁰

Elements to Ensure Safe Use²⁰

Three of the elements to ensure safe use are incorporated into the ESA APPRISE Oncology Program: (1) health care provider training and certification, (2) hospital certification, and (3) dispensing following the documentation of safe-use conditions. All prescribers who plan to order ESAs for cancer patients must receive training and must enroll in ESA APPRISE. The manufacturer maintains an on-line list of enrolled prescribers through an independent third party. The hospital must appoint a designee to receive training and enroll in APPRISE on behalf of the institution. At our hospital, the designee is the director of pharmacy.

Training, which is available on the manufacturer’s Web site, includes a review of the risks of using ESAs in cancer patients. Enrollment includes an agreement to conform to the mandates of ESA APPRISE. The hospital designee is responsible for establishing and overseeing a process that includes verification of prescriber enrollment in the program as well as patient and prescriber discussions of risks and benefits before ESAs are dispensed.

One of the elements of ESA APPRISE is a formal, documented discussion between a certified prescriber and the patient regarding the risks and benefits of ESA use in cancer. Both parties sign an acknowledgment form. Outside the hospital, these forms are faxed to a central repository and are also maintained in the patient’s medical record. For in-hospital use of ESAs, forms are not submitted to a central repository; they are provided to the hospital designee only to validate that the discussion has occurred before an ESA has been dispensed. Completion of the form does not constitute patient enrollment in any registry or program; it serves only as documentation of the required discussion between prescriber and patient.

We’ve noted many logistical problems involving the acknowledgment form in our institution, which is a community hospital without an integrated electronic health record (EHR) system. In the REMS program, a prescriber is required to complete the form with the patient for each course of therapy, although many times therapy is initiated in the outpatient setting and continued in the hospital. The hospital could choose to require a copy of the acknowledgment form to verify completion. If so, the form must travel from the office to the hospital, or it must be completed again in the hospital. The office might be unable to provide a copy during off-hours, or the physician might be unavailable to complete it again.

According to the ESA APPRISE Oncology Program, it is the duty of the prescriber to complete the acknowledgment form with the patient. This task cannot be delegated to other members of the health care team. Verification also needs to occur with each admission, and completed forms must be stored and retrieved by the pharmacist or must be provided again by the office or physician with each admission.

Our hospital has opted for a different approach and has determined that a specific medication order set for ESAs is the best approach in treating cancer patients (Figure 1). Included in the order set is a physician’s attestation that the medication guide has been reviewed, the risks and benefits have been discussed, and the prescriber and patient have signed the acknowledgment form. Following confirmation that the prescriber is registered with the ESA APPRISE Oncology Program, this order set serves as our hospital’s documentation of compliance. The patient acknowledgment form, in addition to the medication order set, may be submitted to the pharmacy; however, this is not required, because the physician’s attestation serves as a surrogate.

Figure 1.

Sample ESA Oncology Order Set. AML, CML = acute and chronic forms of leukemia; CBC = complete blood count; Hgb = hemoglobin; PO = orally; t.i.d. = three times daily; Tsat = transferrin saturation.

Implementation

The manufacturer is responsible for confirming compliance with ESA APPRISE. This is achieved through a series of random on-site audits of enrolled hospitals. Those hospitals that are not enrolled or that are not in compliance may not have access to ESAs.²⁰

Conclusion

REMS programs represent a new facet of drug safety regulation. With a growing number of programs and a wide variety of requirements within the programs, hospitals may be challenged to meet the criteria for compliance. The ESA APPRISE Oncology Program represents a difficult challenge, in that ESAs may be high-use agents, and the elements to ensure safe use present logistical considerations for hospital pharmacy departments.