Regulators have the power to make or break a drug and dictate who can get it. And regulators in different countries can take different tacks. Consider the case of the Roche cancer drug Avastin. On the same day last year that U.S. regulators revoked their approval of the drug as a treatment for breast cancer, regulators in Europe allowed that use to stand on a limited basis. Those contrasting moves by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in December point up one type of challenge that both new and existing products face — the need to please different regulators.

Regulators and drug makers face added challenges. Regulators must contend with the pressure to fast-track the approval of innovative drugs while at the same time making sure that they are safe and effective. Drug companies risk spending years and hundreds of millions of dollars to develop a drug, only to have regulators turn thumbs down. Different regulatory standards around the world complicate matters further. But whatever standards they happen to use, the FDA and EMA and authorities in other countries play a key role in determining the speed at which new treatments reach patients.

Playing that role requires regulators to walk a fine line between providing access to new, cutting-edge therapies and protecting the public from drugs that might be dangerous. This often creates damned-if-you-do-and-damned-if-you-don’t scenarios that find agencies pilloried for blocking drugs from the market but attacked for approving ones that are later found to be harmful or ineffective. “The first thing you learn at the FDA is that if people aren’t yelling at you from both sides you’re not doing your job right,” says Susan Ellenberg, professor of biostatistics at the University of Pennsylvania School of Medicine and a former director of the office of biostatistics and epidemiology at the FDA’s Center for Biologics Evaluation and Research.

Now, amid growing concern over the dearth of exciting new medicines, the FDA is moving to accelerate the approval of new drugs. Last June, the agency and the U.S. National Institutes of Health (NIH) unveiled plans to join forces to speed drugs tailored to the genetic traits of individuals — an approach known as personalized medicine — into the marketplace. The NIH will create centers to identify personalized drug candidates and form partnerships to move them along, while the FDA will develop standards for approving such drugs. In another initiative, the FDA said in December that companies may start seeking approval for treatments based on two or more drugs, which could lead to much faster rulings than if each drug were reviewed separately.

Demands for faster approval of life-saving treatments have been growing for more than 20 years — ever since advocates for AIDS patients fought for prompt access to promising treatments that were emerging from laboratories. Thanks to a 1992 law that lets drug companies help finance expansion of the FDA’s staff, the section of the agency that reviews human drugs has grown from 1,900 employees in 1989 to nearly 3,000 in 2007. This has helped shorten the median review time from 29 months in 1989 to 13 months in 2006, according to the industry trade group PhRMA. “The FDA has more resources so it is able to approve things faster, no question,” says Frank Rockhold, a senior vice president at GlaxoSmithkline.

But there have been counter-trends as well. The FDA has become more cautious about some products following the highly publicized withdrawals of two painkillers, Merck’s Vioxx in 2004 and Pfizer’s Bextra in 2005, says Dr. Brian L. Strom, a senior fellow at Wharton’s Leonard Davis Institute of Health Economics and chairman of the Department of Biostatistics and Epidemiology at the University of Pennsylvania School of Medicine. Both Vioxx and Bextra were yanked from the market after they were found to increase the risk of strokes and heart attacks.

The FDA now wants more evidence that certain drugs will do no harm. While the agency may have typically required data for 500 to 3,000 patients in clinical trials, it now demands results for 5,000 to 8,000 subjects in some cases, Strom says. “Too often, the FDA has responded to the increased focus on safety by demanding additional studies that gain nothing, but lead to substantial delays and substantial costs,” he adds.

At the same time, the agency has put more emphasis on requiring plans for monitoring risks once a drug reaches the market. “That’s understandable, but it has, in many cases, led to substantial prolongation of review time,” says Jay Siegel, chief biotechology officer and head of global regulatory affairs for Johnson & Johnson Pharmaceuticals. A new branch of the FDA that reviews safety separately from the main drug application further prolongs the approval process, adds Siegel. “Hopefully, with time the agency will figure out how to do this more expeditiously,” he says.

Savvy drug makers can get a head start in winning approvals by including detailed post-market plans with their applications, says John Avellanet, a Williamsburg, Virginia-based consultant and author of the book Get to Market Now! that focuses on meeting FDA requirements.  “I expect that within the next five years, the agency is going to require every new product to come with a plan” for follow-up monitoring, says Avellanet. “The FDA has said, ‘We’re not the experts in your drug. Our job is to see that you’ve got a good plan'” for following it on the market.

Safety vs. Effectiveness

Small differences between agencies can lead to different outcomes, as happened with Roche’s Avastin. The FDA, the world’s largest medical regulatory agency, conducts its own reviews and tends to focus more on the safety of a drug, says Cecil Nick, a vice president of PAREXEL Consulting in Waltham, Massachusetts. By contrast, the smaller EMA, which oversees pharmaceutical regulation on the Continent, farms out the work to universities and consultants and tends to concentrate on drug efficacy. “That doesn’t mean that either agency ignores the other issue,” says Nick, “but perhaps there is a stronger focus on one direction.”

In the case of Avastin, the FDA ruled that the world’s best-selling cancer drug had not been shown to be safe and effective against breast cancer and thus could not be used to treat it. The EMA said Avastin could in fact be effective, but only when used with the Bristol-Myers Squibb chemotherapy drug Paclitaxel, and it left the Roche product on the market as a treatment for breast cancer.

The agencies also took different stands on the GlaxoSmithKline diabetes drug Avandia last year after it was linked to increased risk of heart attacks. The EMA suspended use of Avandia altogether, while the FDA sharply curtailed access to the drug without pulling it from the market. In the United States, Avandia will now be restricted to Type 2 diabetes patients who cannot control their condition with other medications. “There are borderline cases where a patient may benefit but there are also patient safety problems,” Nick says of the rulings on Avastin and Avandia. “The most important thing in medicine is communication, letting the doctors know the risks and the benefits and letting them decide.”

Public reaction to such rulings has been mixed. Some U.S. breast cancer patients objected to the Avastin edict, charging that it took away a helpful therapy. But the National Breast Cancer Coalition supported the decision and hailed the FDA for responding to scientific evidence. Penn medical school professor Ellenberg says a compromise might be achieved by finding “a way to identify the 5% who are likely to benefit” from Avastin and permitting them to use it.

The FDA is now helping other countries develop their own regulatory capabilities. The agency has 67 agreements covering food and drug regulations in place, ranging from guidelines for conducting medical device inspections in Taiwan to a trilateral agreement with Mexico and Canada for the exchange of information on drugs, medical devices, food safety and nutrition.

Also smoothing over differences among regulators are a set of global guidelines that companies use when creating research data. Developed by a Geneva, Switzerland-based group called the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the guidelines aim to standardize data submissions to speed patient access to new medicines. The 21-year-old ICH has issued 65 guidelines on drug quality, safety and efficacy, says Alberto Grignolo, a PAREXEL vice president.

But China and India, the world’s largest emerging economies, are bucking the guidelines by requiring drug makers to submit data from clinical trials held in those countries. Japan had a similar requirement until 2007, when public complaints that the country was gaining access to new drugs up to six years later than other parts of the world caused Tokyo to loosen the restriction. Japanese authorities now require domestic testing only for certain drugs and accept data from trials in other East Asian countries.

Another hurdle to standardization is the fact that many countries, such as the United Kingdom and Germany, require drug makers to show not only that products are safe and effective, but that they are worth the price the companies plan to charge for them. While the FDA is forbidden from taking costs into account, new initiatives in the 2010 health care reform act seek to establish criteria for evaluating the comparative effectiveness of one treatment over another.

Not everyone applauds this development. If a product doesn’t look like a sure winner, companies may be less willing to keep up research for it, says Johnson & Johnson’s Siegel. And while focusing on comparative effectiveness could promote breakthrough cures, “sometimes progress comes in a series of marginal improvements,” Siegel notes. Many good cancer treatments were first used with other drugs and then made better over time. “Now you pretty much have to demonstrate value at the time it reaches the marketplace — that’s the downside.”

Meanwhile, communicating with regulators early and often can speed the review process, according to Siegel. Such talks can help companies identify and address key regulatory issues long before drugs are submitted for approval. “If frequent interaction between the agency and the sponsor can resolve questions expeditiously,” he says, “that intensive interaction is in the best interest of the public.”