Entering the World of REMS: Entereg Sets New Standard

Entereg is the most important new drug approved by FDA so far in 2008. Not because of its commercial prospects, which are far more limited than development partners GSK and Adolor once hoped for, but because it is a precedent-setting use of the agency’s new drug safety authorities—and a case study in how those new tools can save a drug that might otherwise never have been marketed at all.

Michael McCaughan

The Food & Drug Administration’s approval of the post-operative ileus therapy alvimopan (Entereg) after a protracted and difficult review delivered less than Adolor Inc. and partner GlaxoSmithKline PLC hoped for. The indication is much narrower than the companies’ sought when the application was first submitted four years ago. The duration of therapy is sharply curtailed. And distribution will be narrower and more tightly controlled.

All of which means the product will be much less than either company once expected. The most bullish forecasts for the drug are for sales peaking at $200 million in five years, with the two partners each getting just half that amount.

For GSK, Entereg was not even worth mentioning during its second quarter earnings call—even though the company was touting both its recent success in obtaining FDA approvals, and its plan to diversify its product line to build around more brands with modest revenues. Indeed, GSK appears to be backing out of the partnership for Adolor on future indications for the brand.

Entereg is nevertheless the most important new drug to clear the agency in the first half of 2008.

That has nothing to do with the commercial potential of the product itself. Entereg is important because of its value as a case study to help the biopharmaceutical sector react to the new rules of drug safety created by the FDA Amendments Act of 2007.

Entereg marks the first time FDA has applied the new law—and in particular the new Risk Evaluation & Mitigation Strategies authorities—to reach into the marketing of a new drug. It is not that Entereg is the first drug to have a mandatory REMS. Nor are the elements of the REMS itself unprecedented, at least compared to tools used previously by other sponsors in risk management programs designed to ensure appropriate use of products with safety concerns.

But it does mark the first time those tools have been used in a mandatory, legally required program.

So Entereg will go down in history as the first real REMS, making it a vital case study for the entire industry as it prepares for the new commercial realities inherent in the regulatory changes at FDA.

Palpably More

Entereg has one thing in common with the other products approved by FDA thus far using the new REMS authorities: it is lucky to reach the market at all. As with the other REMS pioneers, the enactment of FDAAA helped a long-delayed application finally make it through the review process. (Also see "FDAAA Pays Off: Drug Safety Controls Bring Immediate Returns to Sponsors" - Pink Sheet, 1 May, 2008.)

The Entereg application was first submitted in 2004; after two "approvable" letters, a clinical hold, an advisory committee review and a missed user fee deadline, it is at last reaching the market for a much smaller potential indication. The biggest problem: a signal of cardiovascular toxicity seen in a clinical study for use in chronic pain. That is not the initial indication sought by GSK and Adolor, but is a far bigger potential market for the medicine. (Also see "History in the Making" - Pink Sheet, 1 Jul, 2008.)

That is why Entereg is so valuable. The difference between the Entereg REMS and the first batch of products approved with mandatory Risk Evaluation & Mitigation Strategies is palpable and obvious.

The first four cases where FDA used the REMS authority, the same template was used: the REMS focused exclusively on use of a mandatory consumer medication guide, with a simple request for assessments of the effectiveness of the MedGuide distribution in the marketplace. (Also see "The REMS Era Begins: FDA Applies Soft Touch With New Drug Safety Tools" - Pink Sheet, 1 May, 2008.) FDA has since followed that template in at least two more cases involving revised safety labeling for Intron A and Ziagen, and is also seeking a MedGuide for quinolones. (Also see "Cymbalta for Fibromyalgia: The REMS That Wasn't" - Pink Sheet, 1 Jul, 2008.)

In each of those cases, the REMS is spelled out as part in a few paragraphs included in the letter from the agency approving the drug, and the entire section is less than one page in length.

For Entereg, the REMS commitments were released by the agency as a separate 24-page package of documents, suggesting the much higher level of detail involved in the mandatory program.

It is not that Entereg’s risk management program (the Entereg Access Support & Education program, or EASE) is unusual or elaborate. The program focuses on limiting distribution of the drug to registered hospitals, with an educational focus on ensuring use does not exceed 15 days. In principle, it is not any more onerous than programs already used in the marketplace. Indeed, it is not fundamentally more elaborate than the risk management plan adopted by UCB Pharma for Cimzia, one of the first drugs subject to the new REMS authority.

However, Cimizia’s risk management plan (dubbed CIMplicity) is primarily voluntary—FDA only applied the REMS authorities to the Medication Guide, not to other elements like patient registration and reimbursement support.

For Entereg, many more elements of the program are covered by the formal REMS, marking the first time the agency has reviewed and approved elements of marketing and distribution in the same legal sense that it reviews and approves prescription labeling.

The Entereg REMS package includes three discrete elements:

(1) Supplemental educational materials, including a "Dear Pharmacist" letter and enrollment forms for the EASE program;

(2) A detailed algorithm for a drop-shipment program intended to limit access to registered hospitals; and

(3) Scripts for follow-up surveys intended to assess the impact of the educational program.

Each element marks a significant first in the REMS era, and collectively they add up to the first unequivocal example of how the new law expands FDA’s regulatory reach into distribution and marketing of new drugs.

The Never Ending Review

But perhaps the most significant element of the REMS authority seen in the Entereg program is the requirement that the program be assessed on a defined timeline. Though not the formal "conditional approval" authority some in Congress want FDA to have, it is a start towards that model. In essence, sponsors under a REMS will face pre-defined deadlines where they will have to justify continued marketing of their products. (Also see "The New World for New Drug Approvals: Evolution in Strategies for Getting FDA Drug Approvals" - Pink Sheet, 1 Nov, 2007.)

In the first batch of REMS, FDA applied the statutory minimum requirement for assessment: asking the sponsor to track the impact of the MedGuide distribution program at 18 months, three years and seven years post-launch. The agency did not stipulate in any detail what form that assessment will take.

With Entereg, the agency expects extensive reports from the sponsor, including very specific measures of use of the product in different settings as well as a detailed survey program for hospitals and surgeons. (Also see "Living in a Bipolar World: Implications of the EPO Safety Debate (Part 1) " - Pink Sheet, 1 Jul, 2007.)

More generally, while the Entereg REMS is the most restrictive imposed by FDA to date, it is not the most restrictive possible under the statute. FDA stopped short of asking the sponsor to register and track individual surgeons and patients, the type of control exerted by Biogen Idec in its Tysabri risk management program. (Also see "Pyramid Schemes and Pipeline Dreams: Adapting to a Tiered Regulatory System for New Drugs" - Pink Sheet, 1 Nov, 2007.)

Tysabri itself will be subject to a REMS when FDA formally converts the existing program at the end of September, so sponsors may have to wait until then to see an example of how the most restrictive programs will be handled under the new law.

FDA also has not cut off all hope that Entereg may yet make it to the market for the broader, chronic constipation market. The agency recently lifted the clinical hold on the product in OBD, and Adolor’s Jackson at least is harboring hopes that the project could yet bear fruit. "There is a very good database to build a subsequent submission if that is going to go forward."

GSK, though, has told Adolor it is evaluating its options on that aspect of the partnership—signaling a clear interest in opting out rather than try to prove to the agency’s satisfaction that the cardiovascular signal is a false alarm.

The outcome of those discussions will go a long way towards determining Entereg’s commercial significance. But its place in history is already assured.