Cymbalta Fibromyalgia Approval Sets Another REMS Precedent

FDA's approval of Lilly's Cymbalta (duloxetine) for treatment of fibromyalgia sets another precedent in the new era of Risk Evaluation and Mitigation Strategies: the agency will not necessarily seek a formal REMS for products already accompanied by mandatory medication guides.

Cymbalta received approval for the new indication June 13. Like all antidepressants, duloxetine carries a boxed warning in labeling regarding the risk of suicidality in children and young adults (¹ (Also see "Changes To Antidepressant Black Box On Suicide Recommended By FDA Panel" - Pink Sheet, 18 Dec, 2006.) p. 3).

Based on the early precedents of the REMS era, FDA might have considered using its new authority to mandate distribution of consumer medication guides with the product.

Several of the first cases in which FDA used its new post-marketing authorities have focused on distribution of MedGuides. [Editor's Note: An analysis of first batch of REMS appears in the May issue of ² The RPM Report .]

One of those precedent-setting cases involved Biovail's new salt formulation of the antidepressant bupropion, approved in April, soon after FDA formally gained the authority to require post-marketing studies and other risk management strategies. The drug safety provisions of the FDA Amendments Act took effect March 25.

The new Biovail formulation, Aplenzin , was reviewed under FDA's 505(b)(2) process, and deemed equivalent to marketed versions of the ingredient. The decision to require a REMS for Aplenzin suggested that FDA was likely to insist on REMS for other antidepressant ingredients associated with suicidality in the context of new approvals.

Cymbalta, however, was approved without a REMS.

No Need To Invoke FDAAA

An FDA staffmember explained the difference: "Cymbalta was approved for treatment of depression and was required to have a medication guide prior to the enactment of FDAAA. Because the medication guide for Cymbalta did not have to be revised when the new indication, treatment of fibromyalgia, was recently approved, there was no need to invoke FDAAA."

FDA "approved the NDA for Aplenzin (bupropion) after FDAAA went into effect," the agency continued. "For the initial approval of this new drug, FDA invoked FDAAA to require a medication guide as one element of a REMS."

As that explanation indicates, there is in one sense not much difference between the burdens on the sponsor in the day-to-day marketing of the two products.

However, the REMS process involves more than a mandatory medication guide: it also includes formal deadlines for assessment of consumer understanding of the risks. The statute sets up standard review timelines of 18 months, three years and seven years post-approval (³ (Also see "Waking Up To REMS: Sponsors Should Test Risk Management In Phase III" - Pink Sheet, 23 Jun, 2008.), p. 14).

FDA's decision not to add the new requirements to Cymbalta means that Lilly will not have the added burden of preparing for a formal, public reassessment of its communication plan for the drug.

Imposition of a formal REMS may also have affected the competitive dynamics in the emerging fibromyalgia market. Pfizer is the first entrant in the category with Lyrica (pregabalin) (⁴ (Also see "Pfizer Launch Plans For Lyrica Fibromyalgia Approval Include Patient Groups" - Pink Sheet, 2 Jul, 2007.), p. 17).

That product has performed very well, boosted in part by some direct-to-consumer advertising. Cymbalta has also been advertised to consumers for other indications, despite the boxed warning on suicidality.

Now the question becomes whether Lyrica will end up being hampered by new warnings or post-marketing controls. FDA is expected to add warnings about suicidality to the labels for antiepileptic drugs soon, following up on a safety alert first issued in January. (⁵ (Also see "Antiepileptics Show Risk Of Suicidality, May Cause Labeling Convulsions" - Pink Sheet, 4 Feb, 2008.), p. 3).

Pregnancy Registry Required

The fibromyalgia approval did not completely avoid the impact of FDAAA: Lilly will be subject to the new mandatory post-marketing study sections of the drug safety law.

"Since Cymbalta was approved in 2004 for the treatment of depression, we have become aware of adverse pregnancy outcomes in women taking Cymbalta during pregnancy," the agency says in the approval letter for the new indication.

"Now, with the approval of the fibromyalgia indication, the population will be overwhelmingly females of childbearing potential, and a study is necessary to assess this signal of a serious risk," the agency said.

Lilly is directed "to 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 Cymbalta during pregnancy to an unexposed control population."

The registry, FDA said, "will detect and record major and minor congenital anomalies, spontaneous abortions, stillbirths, elective terminations, and any serious adverse pregnancy outcomes. These events will be assessed among the enrolled women throughout the pregnancy. The events will also be assessed among infants through at least the first year of life. Annual interim reports will be submitted until FDA has acknowledged that sufficient data has been collected."

Lilly is to submit the protocol for the study in November and begin enrollment in May 2009.

Old-Fashioned Phase IVs Continue

Lilly also agreed to a post-marketing commitment - not a mandatory trial under FDAAA - that involves assessing lower doses of Cymbalta. Only the highest marketed dose - 60 mg - is approved for fibromyalgia.

At the time FDAAA was enacted, it was an open question whether FDA would still accept Phase IV commitments under existing procedures.

That question was answered in April, when FDA continued to accept post-marketing commitments without invoking FDAAA.

The first example came in April when FDA approved Sucampo's Amitiza (lubiprostone) for a new indication - irritable bowel syndrome with constipation in women (⁶ (Also see "Sucampo/Takeda’s Amitiza First To Fill Zelnorm Void In IBS Market" - Pink Sheet, 5 May, 2008.), p. 9).

Sucampo agreed to a post-marketing commitment - studying a higher dose than the 8 mg approved for IBS - but FDA treated it as a voluntary commitment, rather than a mandatory one under FDAAA.

"The determination of whether a post-marketing study is a commitment vs. requirement under FDAAA is made based on whether the primary goal of the study is to answer a safety question, i.e. has a primary safety endpoint," the agency said.

"Other studies that would be a requirement under FDAAA would be drug interaction or bioavailability studies when scientific data indicate the potential for a serious safety risk or a pharmacokinetic study in a population at risk for potential high drug exposures that could lead to toxicity."

"The post-marketing commitment study in the Amitiza letter did not meet these criteria, and as such was a commitment, not a requirement. FDA can still ask for studies for reasons other than to assess a serious safety risk, but those studies are commitments, not requirements."

Another Precedent For Cymbalta And Requip XL

Cymbalta appears to be one of the first applications approved with both a mandatory, FDAAA post-marketing requirement plus a conventional Phase IV commitment.

It shares that precedent with GlaxoSmithKline's extended-release ropinorole, Requip XL , approved the same day for treatment of Parkinson's.

In that case, FDA invoked its mandatory post-marketing study authority because of "the potential for patients to experience varying serious adverse events depending on the dose of ropinirole administered." Specifically, "we believe that there is a potential for a signal of a serious risk correlated to dose level."

FDA is requiring two multi-dose studies, one in early Parkinson's and one in late.

In addition, the agency asked for a conventional post-marketing commitment: GSK will "evaluate whether ropinirole is a P-gp substrate and/or inducer for major CYP enzymes (e.g., CYP3A4) and, if so, any drug-drug interaction potential through either mechanism. This can be accomplished through a comprehensive literature review or by conducting an in vitro study."

- Michael McCaughan ([email protected])