REMS for ESAs: The FDA mandated program is under scrutiny

Requirements of the Risk Evaluation and Mitigation Strategy for ESAs may be overwhelming, some physicians said.

Beginning March 24 of this year, health care providers who prescribe or dispense, and hospitals that dispense erythropoiesis-stimulating agents to patients with cancer will be required to complete a certification process as mandated by an FDA-approved Risk Evaluation and Mitigation Strategy for that class of drugs.

However, there are questions and complaints about the program, which critics have charged does not take physicians’ concerns into account and has not been fully explained by the FDA. Although the experts who spoke to HemOnc Today wholly supported the FDA’s commitment to patient safety, none were convinced that the approved strategy for patients with cancer, known as Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs (APPRISE) — part of the overall REMS — is the best way of achieving that goal, at least in its current form.

“Physicians are not questioning the FDA’s motives, and we’re not questioning the FDA’s authority,” said Michael Kolodziej, MD, a medical oncologist with New York Oncology Hematology–Albany Medical Center and chairman of the P&T Committee for US Oncology. “What we are saying is that we need to make this work, so that patients get the best possible care and the burden on the practitioners is not onerous.”

Samuel Silver, MD, PhD, director, Cancer Center Network, University of Michigan Health System, said hospitals and academic institutions may have difficulty getting the appropriate people certified. Photo by Paul Jaronski, UM Photo Services

In April 2008, the FDA ordered Amgen, manufacturer of epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp), and Centocor Ortho Biotech Products, distributor of Procrit, to establish a risk management program, after study results showed ESAs caused tumors to grow faster and resulted in earlier deaths in some patients with cancer. ESAs have also been associated with increased risk for myocardial infarction, heart failure, stroke or blood clots in patients who use the drugs for other indications such as kidney failure or HIV.

In response, the companies, in conjunction with the FDA, developed the REMS, including APPRISE. The FDA approved the REMS in February.

How APPRISE works

The companies launched the REMS with the stated goals of 1) supporting informed decisions between patients and their health care professionals who are considering treatment with an ESA by educating them on the risks of ESAs and 2) mitigating the risk of decreased survival and/or poorer tumor outcomes in patients with cancer.

“During the development of the program, we worked closely with [the] FDA, individual physicians and third-party patient advocacy groups to develop a comprehensive program,” said Brenda Sarokhan, senior director of REMS at Centocor Ortho Biotech. “We continue to work with physicians to make sure the enrollment process is as simple and straightforward as possible.”

Among the elements of APPRISE are distribution of the Medication Guide to all patients and documentation using the required acknowledgment form of the risk/benefit discussion between the patient and prescriber of ESAs to patients with cancer. Any prescriber of ESAs must also be certified. The certification exam is a 10- to 15-minute process available online at www.esa-apprise.com.

In addition, an ESA call center established by Amgen and Centocor Ortho Biotech will determine compliance rates at private practices by comparing the number of returned acknowledgement forms with the number of patients initiating a new course of ESA therapy based on the amount of ESA purchased. If audited, private practices must show that the number of prescribers writing scripts for ESAs is not more than the number of certified prescribers and provide the total number of patients who received an ESA based on orders written.

Hospitals must designate an administrator to oversee the program. This designee must complete the training module, inform prescribers of certification requirements, sign the enrollment form, oversee compliance and maintain a list of providers who prescribe ESAs to patients with cancer.

Health care providers who prescribe and dispense ESAs in a hospital setting must complete the training program, agree to provide a Medication Guide to patients, discuss risks and benefits, document this discussion prior to a new course of ESA therapy between the patient and prescriber by both signing the acknowledgement form, and provide the acknowledgement form to the hospital designee for maintenance and storage.

Both the hospital designee and prescribers must get recertified every 3 years. Additionally, prescribers in a private practice setting are required to have a risk-benefit discussion with patients, document that discussion prior to a new course of ESA therapy with both the patient and the prescriber signing the acknowledgement form and fax the acknowledgement form to the ESA call center established by Amgen and Centocor Ortho Biotech.

The requirements for hospital providers concern Samuel Silver, MD, PhD, director of the Cancer Center Network at the University of Michigan Health System and chair of the American Society of Hematology reimbursement subcommittee. He said hospitals may be faced with the prospect of having to ensure certification for dozens of personnel.

“It’s a much bigger issue than just the universe of hematologists/oncologists that are part of a hospital community,” said Silver, who is also the Section Editor of the Practice Management section of the HemOnc Today Editorial Board.

Michael Kolodziej

Prescribers of ESAs for patients with cancer and hospitals dispensing ESAs for patients with cancer that fail to enroll will lose access to ESAs. Cutoff for enrollment is 12 months post-approval of the REMS. The REMS was approved Feb. 16.

Sarokhan said, as yet, there is no enforcement mechanism for APPRISE until the cutoff date for enrollment. As the cutoff date gets closer, the two companies will work with distributors to restrict access to those not certified.

A collaborative effort

The FDA tasked Amgen and Centocor Ortho Biotech with soliciting feedback from various stakeholders. ASH was among the groups consulted, but Silver said the organization’s concerns were not fully reflected in the approved REMS (see related story). He added that ASH wants to play a role in any modifications that go into the strategy.

“ASH’s official position is that it wants to see how this goes, help practitioners through the process and see if there are difficulties as this thing gets rolled out,” Silver said. “If there are difficulties, we would like to be intermediaries with both Amgen and the FDA to make this process as easy as possible for practitioners.”

Niesha Griffith, MS, RPh, director of pharmacy and infusion services at the Arthur G. James Cancer Center at The Ohio State University, has explained the details of APPRISE in several presentations. She said physicians and pharmacists said they feel that their interests were not given their due, especially as it pertains to record-keeping.

“The disappointing thing is that the FDA did not listen to the stakeholders,” Griffith said. “I think Amgen and Centocor Ortho Biotech did their due diligence in talking to people in the field and visiting facilities. They requested that the FDA accept documentation that sites are already doing, rather than adding in another piece of paper for those who are moving to an electronic world, but the FDA required them to collect a form signed by the patient.”

Allen S. Lichter, MD, ASCO CEO, said his organization, which represents more than 28,000 oncologists worldwide, was not consulted while APPRISE was being drafted. Nonetheless, Lichter was not critical of the agency or APPRISE, and said ASCO looked forward to working with the FDA to address any problems with the program.

“We were pleased to see the FDA call for comments about forming partnerships with groups of interested individuals to talk more about the REMS process,” Lichter told HemOnc Today. “We hope to make comments to the FDA and form as close a partnership as possible with them in discussing these issues so we can do the right thing for the benefit of our patients, for the benefit of drug safety and to allow oncology patients to be treated as effectively as possible.

“Our concern is that the ESA REMS was created without input from the oncology community. Certainly, there was no input sought or given by ASCO,” he said.

Sarokhan said the companies worked hard to give as much feedback as possible from various stakeholders to the FDA when submitting APPRISE for approval.

“There was information we did provide to the FDA that was incorporated in the program,” Sarokhan said. “Not all of the information or all of the suggestions, but some, were incorporated by the FDA into the final program. We worked closely with the agency to develop a comprehensive program that wouldn’t be a burden to providers.”

Getting certified

New York Oncology Hematology–Albany Medical Center is a member of the United Network of US Oncology, and the consortium has moved aggressively to get its physicians certified. Kolodziej said member practices held 15-minute training sessions for physicians, and his practice met a self-imposed deadline of June 1 for 100% certification.

However, Kolodziej said US Oncology affiliates have the advantage of a nationwide structure to help them develop systems and answer questions. The typical small community practice does not have a director of pharmacy to overcome some of the obstacles to certification and patient notification.

Silver said he fears that hospitals and academic institutions are facing a huge problem when it comes to certification.

Allen S. Lichter

“If we admit our hematology patients who are on an ESA to the hospital, they could be on a surgical service, and their orders could be written by a surgeon or a surgical intern,” Silver said. “Or, if they’re on a general medicine service, those orders could be written by a hospitalist or an internal medical intern or resident. Does that universe of doctors have to be accredited for the use of ESAs under the REMS program? That’s a much, much larger group — essentially, every physician in a huge hospital system.”

Griffith said the James Cancer Center is developing its plans for getting physicians certified and maintaining patient notification, but added that because the cancer center is a separate institution and not part of The Ohio State Medical Center, it does not face all of the issues that an oncology department incorporated into a larger hospital or medical system may face.

Too much paperwork

ESAs are just one of about 120 drugs with an FDA-approved REMS, and the experts interviewed for this story said they expect that the agency will require many more such plans in the coming years; possibly one REMS for every cancer-related drug released to market. Physicians said at some point, the paperwork will become overwhelming.

“I don’t think there is a specialty in medicine that’s more concerned with drug safety than oncology. After all, we use drugs that cause serious side effects. We are foursquare on the side of making sure drugs are utilized in the safest, most effective fashion,” Lichter said.

“But there is a point at which the administrative burden on physicians’ practice becomes so arduous that it runs the risk of interfering with the daily business of treating patients. One could argue that if the REMS process is important for every drug with potentially serious side effects, then in the future, every new oncology drug will have a REMS associated with it,” he said. “We’re just trying to understand how our colleagues are going to cope with this process.”

Part of the problem is that all of this “paperwork” is on actual paper, which seems to contradict the Obama administration’s push for wider use of electronic medical records (EMRs). In August, the administration announced the availability of $1.2 billion in federal grants to encourage providers to move toward EMRs.

The communication plan outlined in APPRISE calls for dozens of letters to professional societies, oncologists, hematologists and medical professionals who may purchase or prescribe ESAs for patients with cancer. Hospitals and private clinics must keep paper records proving patient notification and physician certification. Patients are to receive a Medication Guide outlining the risks associated with ESAs at the initiation of therapy and every month thereafter.

Kolodziej said keeping track of who had received the guide every month was too complicated, so patients instead receive a guide during every office visit, which is twice monthly in most cases.

“A lot of trees are dying,” he said. “Let’s face it: We live in an electronic world. US Oncology spent a lot of money to institute EMRs. A lot of hospital-based systems use EMRs. The documentation in this system is all paper, and that just seems silly.”

The additional fear is that, as the FDA approves more and more REMS, the requirements will become impossible to meet, especially for physicians working in small practices.

“Most physicians’ practices don’t have a pharmacist, so this is a real hardship on them to try to coordinate how this is going to happen,” Griffith said. “In most cases, a lot of the busywork will fall on nurses, although the risk-benefit discussion really needs to occur between the prescriber and the patient. Physicians in private practice are likely to choose not to use ESAs because they don’t want to deal with the extra paperwork that’s involved.” – by Jason Harris

Is a Risk Evaluation and Mitigation Strategy necessary for erythropoiesis-stimulating agents?

For more information:

• Agres T. “Concern revving up over REMS.” Pharmacy Practice News [serial online]. Available at: www.pharmacypracticenews.com/index.asp?show=currissue&section_id=439&article_id=15105. Accessed: May 11, 2010.
• FDA safety announcement on erythropoiesis-stimulating agents [press release]. American Society of Hematology; Feb. 16, 2010.
• US Food & Drug Administration. Information on erythropoiesis-stimulating agents (ESA) epoetin alfa (marketed as Procrit, Epogen) and darbepoetin alfa (marketed as Aranesp). Available at: www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformation forpatientsandproviders/ucm109375.htm. Accessed: May 11, 2010.
• US Food & Drug Administration. FDA Drug Safety Communication: Erythropoiesis-Stimulating Agents (ESAs): Procrit, Epogen and Aranesp. Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm200297.htm. Accessed: May 11, 2010.
• Young D. “As REMS Trend Grows, Drugmakers Seek Clarity.” BioWorld Today [serial online]. Feb. 17, 2010. Taken from: The Free Library. June 3, 2010. Available at: www.thefreelibrary.com/As REMS Trend Grows, Drugmakers Seek Clarity.-a0219432178. Accessed: May 11, 2010.