FDA Unveils Risk-Management Program for ESAs

[April 1, 2010, AJHP News]

Kate Traynor

BETHESDA, MD 12 March 2010—The risk-management program for erythropoiesis-stimulating agents (ESAs) that FDA unveiled in February is receiving a less-than-enthusiastic response from hospital pharmacists.

Stephen T. Smith, director of pharmacy at the Karmanos Cancer Center in Detroit, likened the new risk evaluation and mitigation strategy, or REMS, to "an unfunded mandate" that imposes new data-collection requirements on hospitals.

Under the REMS, each hospital must ensure that all health care professionals at the facility who prescribe darbepoetin alfa or epoetin alfa for patients with cancer participate in the Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs (APPRISE) program.

Administered by Amgen, which manufactures all U.S.-licensed darbepoetin alfa and epoetin alfa products, APPRISE consists of a medication guide for patients and a training and registration program for prescribers and institutions where ESAs are used in patients with cancer. Training and enrollment can be done online, and the training takes about 10–15 minutes per prescriber, according to Amgen.

Starting next March, prescribers who are not enrolled in APPRISE will lose access to ESAs for the treatment of patients with cancer, FDA officials announced.

Richard Pazdur, director of FDA's Office of Oncology Drug Products, told reporters in February that the main intent of the REMS is to ensure that prescribers tell patients about the special risks ESAs pose during cancer treatment.

"ESAs cause cancers to grow faster [and may] result in earlier deaths in patients with cancer," Pazdur said. He noted that for patients whose treatment goal is to be cancer free, the risks of ESA therapy may outweigh the benefits.

Among other things, FDA wants oncology patients to receive the lowest ESA dose necessary to avoid blood transfusions and to end ESA treatment at the cessation of a chemotherapy course.

A boxed warning in the products' labeling describes the risk of tumor progression during ESA treatment. The warning also states that adverse cardiovascular events, including death, have been documented in patients receiving ESAs while being treated for cancer or other conditions. The warning was first added to ESAs' labeling in 2007 and has been revised as new information has become available.

Under the REMS, a medication guide that describes these risks must be given to all patients "at the initiation of treatment and whenever the treatment is dispensed," Pazdur said. This includes settings where ESAs are used to treat anemia in patients with cancer, kidney failure, or HIV infection.

In the cancer-treatment community, additional elements of the REMS must be followed—including "site level" registration of hospitals and documentation that prescribers are in compliance with APPRISE, according to the REMS documentation. Each institution must designate a pharmacy director or other administrator as the person responsible for documenting compliance with the program.

The documentation includes prescriber-attestation statements, a special patient-consent form asserting that counseling took place, and an agreement to allow Amgen to monitor compliance with the REMS.

Patricia Keegan, director of FDA's Division of Biologic Oncology Products, said FDA is focusing for now on ensuring that the intended patient education occurs. She said the agency is not yet concerned about penalties to impose against Amgen if the REMS does not work as planned.

Alphonsus Okpara, administrative director of pharmacy services for the Harris County Hospital District in Houston, said a benefit of the REMS is that it "will force physicians to have to talk to the patients" about the risks associated with ESAs.

But he is concerned that if an audit reveals that a single physician has not abided by the REMS, the entire institution could lose its ability to purchase ESAs.

"It's going to create a lot of hassle," Okpara said of the APPRISE program. He said the main issue for the health system is ensuring that incoming medical residents and interns are properly enrolled in the program before every rotation.

He said he expects the pharmacy department to be "deeply involved" in the process of complying with the program.

Pazdur acknowledged that the REMS creates new record-keeping responsibilities for health care professionals. He said it took "many, many, many months of discussion" to devise the REMS in a way that does not "interfere in a draconian fashion with the practice of medicine" or unduly burden prescribers.

Smith said his hospital will use a collaborative process involving the pharmacy and therapeutics committee as well as pharmacy, oncology, and hospital quality staff to decide how to enroll prescribers in the program.

"Because physicians need to be enrolled in this program, we also may look at including something within our credentialing process," Smith said. "If we can gather the information during credentialing, [we can] have it in place when the doctor is actually trying to prescribe it."

Smith said roughly 40–50 medical oncologists regularly prescribe ESAs for cancer patients at Karmanos, which shares the Wayne State University campus. But he thinks Wayne State physicians in other specialties who treat Karmanos patients will also need to enroll. In all, he said, about 300 physicians may ultimately need to enroll in the APPRISE program.

Smith said ESAs were among the top 12–15 drug expenses at Karmanos before the products received a boxed warning and the Centers for Medicare and Medicaid Services announced changes in the way it pays for ESAs.

Now, Smith said, the drugs have dropped out of the top 25 at Karmanos.

He said physicians are doing more monitoring of patients' hemoglobin levels and modifying their ESA prescribing practices accordingly.

"I think because of that increased scrutiny that we're not using as much as we used to," Smith said. "[Physicians] will use it when they feel it's absolutely necessary in the best interest of the patient. But I think they're a little bit more cognizant of the risks."

Keegan said this is the first time FDA has created a REMS whose safe-use elements focus on a single indication for multiple agents or for a product that is purchased almost exclusively by hospitals and care providers.

"Many REMS are really focused around the retail pharmacy as the point of restricted distribution," Keegan said. "That would not be a practical or feasible approach for the ESA products."