Every drug comes with some risk. The key issue for regulators, drugmakers, healthcare professionals and patients alike is whether the likely benefit is greater than the risk. This is the question reviewers at the US Food and Drug Administration (FDA) must grapple with in determining whether or not to approve a new product or to leave an already approved product on the market in light of new information about adverse events or other potential negative consequences. In some cases, additional conditions need to be put in place to help manage a drug product's risk.

One way of tilting the benefit:risk balance toward benefit is through a Risk Evaluation and Mitigation Strategy, or REMS. The 2007 passage of the Food and Drug Administration Amendments Act (FDAAA) gave FDA the authority to require a REMS as a condition of approval for any product where agency reviewers determine the drug's benefits would not outweigh the risk without some sort of additional control. "REMS allowed FDA to place very strict requirements on a product that they thought presented great risk of patient harm," says Ed Tabor, vice president of the Strategic Drug Development Unit at Quintiles, and author of Risk Evaluation and Mitigation Strategies for US Drug Development, published by RAPS.

For those products that may benefit certain patients but also carry a high risk of adverse events, making additional controls necessary, prior to FDAAA, FDA had no risk management mechanisms with explicit penalties for companies that fail to implement such controls. "FDAAA allowed FDA to apply fairly strict penalties if the REMS were not followed," says Tabor.

Before REMS, FDA had introduced its predecessor program in 2005, called the Risk Minimization Action Plan (RiskMAP). RiskMAP served as FDA's initial attempt to work with drug sponsors to manage risk as an ongoing, iterative process. REMS, however, provided FDA with explicit enforcement authority to ensure the risk control measures were implemented. Another big difference between REMS and RiskMAP, according to Tabor is that, unlike RiskMAP, every REMS requires continued assessment, usually at 18 months, three years and seven years after approval, to verify that the risk control measures are working.

"There was a lot of anxiety among pharmaceutical companies leading up to the creation of REMS because it seemed like it could be an enormous burden," says Tabor. "There was concern that it could slow down the approval process, and it seemed like FDA could apply it more broadly than RiskMAP." However, the apprehension seems to have been largely unfounded. "There may have been a slight increase, at first, in review time due to REMS, compared with RiskMAPs, but once the system got going, it turned out that REMS actually did not slow things down," says Tabor. In addition, companies that had teams set up to prepare RiskMAPs could fairly easily convert them to work on REMS.

The implementation of REMS not only proved to be much less burdensome to industry than was initially feared, it provided a way for companies to introduce more new products, and for patients to have access to useful treatments that they would not otherwise have. "Where FDA once may have told a company it didn't have enough data for approval, now they can require a REMS that makes approval possible," says Tabor. It's a benefit to both drugmakers and the public.

Some may believe allowing products onto the market that would not be approved without a REMS could increase the potential for patient harm, but Tabor disagrees. "It means there will be fewer patients harmed due to increased controls over risk," he points out. "You have a drug that has a certain risk-say 5% of patients have some adverse event. If it's out on the market without controls, the risk is greater. If you allow that drug on the market with controls, it reduces that risk."

"For example, long-acting opioids; FDA doesn't want long-acting opioids to be so easily available that they can be either stolen or borrowed from patients and used for other purposes. So, you put into place a REMS where you require a new prescription for refills or require the drug to be picked up only at certain pharmacies."

Sponsor companies should begin considering the possibility of a REMS requirement early in the development process. The risk threshold for a REMS is "not necessarily a clear demarcation," says Tabor. "FDA makes this determination, but it is advisable for companies to anticipate if a REMS may be needed."

"If you file an NDA [New Drug Application], and you have not talked about a REMS with FDA, and you have to start preparing a REMS when you're asked for it, it might delay your time to market," Tabor cautions. In the pending reauthorization and update of the Prescription Drug User Fee Act (PDUFA), there is a proposed provision that will require additional review time for a REMS not submitted at the same time as the NDA. A separate REMS submission will be considered a "major amendment," adding another three months to the review time, so failure to factor it in can be costly.

REMS can also be used strategically by sponsors in discussions with FDA. "Say you have a treatment for bone disease and it works, but one of the side effects is it causes severe pain in the spine," says Tabor. "You can say to FDA, instead of having to do another safety study, we'll submit a proposed REMS to restrict it to those patients who really need it, exercising some control over adverse events." As a result, FDA's review might be focused more on approval rather than on a need for additional studies.

"Having a REMS is both a risk and an advantage. There will be certain expenses and resources required but it may allow you to get out on the market sooner. It really behooves regulatory professionals to be able to describe how a REMS might be used, when it may be required and how it may be used strategically."

Since FDAAA was only passed in 2007, there are no products that have gone through a full set of REMS assessments yet, and FDA has not yet made assessment results available to the public. Tabor believes the results, when revealed, will support the program. "It's early to assess the efficacy of the REMS program, but it's my opinion that we'll see a great benefit. I think REMS is here to stay, and it will be interesting to see if other countries follow the example."

Risk Evaluation and Mitigation Strategies for US Drug Development is available for purchase online from the RAPS Store for $34.95 (US) for RAPS members or $44.95 for nonmembers.