FDA Draws on New Authority to Mandate Elements of ESA Label

[Barb73]

http://www.oncologystat.com/home/news/F ... eling.html

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FDA and the sponsors of erythropoiesis-stimulating agents were mostly able to reach an agreement on safety revisions to labeling of the anemia therapies, but the agency was forced to employ its new regulatory authority to resolve a couple points of continued disagreement.

The agency's emphasis that it invoked its newfound authority, conferred by the FDA Amendments Act, to mandate safety-related changes, is a notable aspect of the labeling developments. At least in the near term, the update may have more impact in potentially winning points with congressional critics and other agency observers than in altering the ESA market.

FDA alerted the sponsors April 22 that additional safety-related changes to labeling for Amgen's Aranesp (darbepoetin) and Epogen (epoetin) and Johnson & Johnson's Procrit (epoetin) would be required. And, although the companies have objected to extrapolation of safety signals seen in unapproved dosing regimens, the two sides successfully negotiated most of the revisions.

"Amgen and FDA have agreed on many of these changes, including to replace the existing Patient Package Insert with a Medication Guide, and to modify certain sections of the Boxed Warnings, Indications and Usage, and Dosage and Administration sections of the package insert," FDA announced July 30.

"The changes clarify the FDA-approved conditions for use of ESAs in patients with cancer and revise directions for dosing to state the hemoglobin level at which treatment with an ESA should be initiated," a July 31 MedWatch Alert states.

Mandate Addresses Unclear/Misleading Proposal

The revisions generally reflect recommendations made by FDA's Oncologic Drugs Advisory Committee, which met to evaluate two additional studies that show evidence of tumor promotion and/or decreased survival with ESA use in cancer patients ("The Pink Sheet," March 17, 2008, p. 5).

The new labeling addresses "the risk of increased mortality and/or poorer tumor outcomes when erythropoiesis-stimulating agents are given to patients receiving treatment for head and neck cancer, breast cancer, non-small cell lung cancer, or cervical cancer and in anemic cancer patients receiving no active cancer therapy," FDA says in a complete response letter to the two companies.

However, there are issues on which the companies and FDA failed to see eye to eye. The two points of contention relate to inclusion of a warning that ESAs are not intended for use in patients with curable cancers and instructions regarding when to initiate and discontinue ESA treatment.

"We cannot grant final approval because your proposed labeling changes do not adequately address the new safety information regarding the risk of increased mortality and/or poorer tumor outcomes when ESAs are given to patients receiving treatment for certain types of cancer," FDA's letter says.

Citing its FDAAA powers, FDA halted the negotiations July 15 and demanded specific labeling language.

Amgen Can Appeal Mandated Changes

Amgen has five days to appeal or 15 days to submit compliant labeling.

FDA is requiring that the statement "When the anticipated outcome of myelosuppressive chemotherapy is cure, [ESAs are] only indicated for treatment of anemia when red blood cell transfusion is not a treatment option" in the Boxed Warnings and Indications and Usage sections be replaced with "[ESAs are] not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure."

"Your proposed wording ... is misleading because it suggests that you have been granted an indication for treatment of anemia in patients receiving myelosuppressive chemotherapy for cancers in which cure is anticipated," FDA's letter states.

"Clinical studies supporting the approval of [ESAs] were conducted in patients with metastatic disease without the potential for cure. You have not submitted data establishing a favorable risk: benefit ratio in patients receiving myelosuppressive chemotherapy for cancers in which cure is anticipated."

"The proposed language is also unclear in the clinical settings where 'red blood cell transfusion is not a treatment option' is not a commonly understood and accepted concept used in the practice of transfusion medicine. In discussions with an external consultant to FDA, neither FDA nor the expert could identify a clinical setting in which RBC transfusion is not a treatment option," the agency added.

FDA is also requiring specific revisions to the Dosage and Administration: Cancer Patients Receiving Chemotherapy subsection of ESA labeling. Specifically, the agency is directing that the qualifying phrases (in italics) be deleted from labeling:

Therapy should not be initiated at hemoglobin levels ≥ 10 g/dL, except where the patient is unable to tolerate this degree of anemia due to co-morbid conditions.

Withhold Dose if: Hemoglobin exceeds a level needed to avoid transfusion or exceeds 12 g/dL.

"Your proposed inclusion of the qualifying language to the instruction in the Dosage and Administration section is unacceptable because it undermines other components of the dosing directions which instruct healthcare providers to maintain the lowest hemoglobin necessary to avoid RBC transfusions," FDA said.

A boxed warning was added to ESA labeling in March 2007 specifically advising physicians to use the lowest effective dose to avoid transfusions ("The Pink Sheet," March 12, 2007, p. 3).

Furthermore, "you have not identified co-morbid conditions in which maintenance of hemoglobin levels of 10-12 g/dL results in improved survival or decreased serious morbidity," FDA asserts.

ESA Markets Stabilizing, But NCD Looms

New ESA labeling is unlikely to make a major commercial impact in the oncology setting. The most recent labeling revision, in fact, is far from a worst case scenario for Amgen and J&J.

The most recent ODAC panel was split over whether ESA approval should exclude specific cancer types for which an increased risk has been shown or be limited to cancer types where sufficient data is available to evaluate safety. Had FDA taken the second approach, ESA approval would probably be limited to small cell lung cancer.

As it stands now, the changes to labeling largely emphasize that ESAs should be used in treating metastatic cancer patients.

J&J reports that about half of its Procrit sales in the U.S. are for treating cancer patients - about half of whom have Stage I-III non-metastatic tumors. Similarly, Amgen asserts that approximately 40 percent of ESA patients have Stage I-III, or potentially curable, tumors.

Label Consistent With Amgen's Expectations

Both Amgen and J&J report that ESA use in the U.S. for treating anemia in cancer patients is down about 25 percent to 30 percent compared to the second quarter of 2007. It has been a rough spell for the blockbuster anemia therapies, with sales tumbling as each new safety signal prompted fresh scrutiny ("The Pink Sheet," Jan. 28, 2008, p. 5).

However, ESA prescribing trends may be shifting. In a same-day press release, Amgen reported that the new labeling is consistent with its expectations. And taking that into account, the company is predicting that Aranesp sales will stabilize by the end of the year ("The Pink Sheet" DAILY, July 29, 2008).

"We have maintained roughly the same sales run rates of the last three quarters. The new risk/benefit information on ESAs appears to have been incorporated into clinical practice patterns, resulting in fairly stable weekly sales," Amgen Exec VP-Global Commercial Operations George Morrow said during the firm's earnings call July 28.

FDA points out that nothing in the required language inhibits the prescribing of ESAs in patients with curable cancers or prevents physicians from following dosing regimens other than what is described in labeling.

Last year the American Society of Hematology and the American Society of Clinical Oncology issued treatment guidelines supporting higher hemoglobin targets than either FDA or CMS ("The Pink Sheet," Oct. 29, 2007, p. 18).

While ESA sponsors are undoubtedly glad to have put this episode behind them, not every element of uncertainty surrounding the products has been resolved.

CMS also announced on July 30 that it is considering initiating a National Coverage Decision for ESA use in end stage renal disease and in chronic kidney disease. The agency issued an NCD on ESA use in the oncology setting in 2007, significantly restricting Medicare coverage ("The Pink Sheet," Aug. 6, 2007, p. 21).

ESA sponsors are also anticipating labeling revisions in Europe by the end of the year.

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(ONCOLOGY Stat, Resource, By B. Marson, August 4, 2008)

Disclaimer:

The information contained in these articles may or may not be in agreement with my own opinions. They are not posted as medical advice of any kind.

[gpawelski]

For over a year now, regulators have been looking into suggestions that the EPO drugs (Aranesp, Epogen and Procrit), might increase the risk of death and fuel the growth of tumors. But much of that evidence comes from studies in which patients were treated more aggressively than the drugs' labels recommend.

The FDA has said there is now "mounting evidence" of documented effects on survival, tumor progression and thrombotic events which require a reassessment of the net benefit of this class of drugs.

At the 12th annual NCCN conference, an executive with United Health Group, pointed out that in reviewing records of patients who were prescribed the drugs, 44% of those patients had blood work-ups that would indicate they were not even anemic.

Federal laws bar drug companies from paying doctors to prescribe medicines that are given in pill form and purchased by patients from pharmacies. But companies can rebate part of the price that doctors pay for drugs, like the anemia medicines, which they dispense in their offices as part of treatment.

Doctors receive the rebates after they buy the drugs from the companies. But they also receive reimbursement from Medicare or private insurers for the drugs, often at a markup over the doctors' purchase price.

Amazing how they can apply differing standards for proof or benefit when profit is involved! The profit motive did influence some doctors' decisions.

"It's clear that these drugs were overused because sales drop so dramatically in the past year without seeing reports of people dying in the streets," said Dr. Charles Bennett, a professor at Northwestern University, who authored the most recent analysis of anemia drug risks.

Until this revelation, the drugs had a combined sales of over $6 billion a year. After this issue had started to be reported, U.S. Oncology took an 8-10 million dollar hit in its first-quarter SEC report last year, including reduced pre-tax income due to lower use of anemia drugs.

The problem is that few drugs work the way oncologists think and few of them take the time to think through what it is they are using them for.