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FDA walks fine line on drug approvals

Battle over irritable-bowel medication's risks, benefits illustrates pressures facing regulators

By Naomi Aoki, Globe Staff, 6/26/2002

Corey Miller was diagnosed with irritable-bowel syndrome when he was 10 years old, suffering from terrible bouts of abdominal pain and diarrhea. By his late-20s, his pain was so severe he feared he would have to give up his career as an architect.

It was then - February 2000 - that Lotronex was approved. The drug was the first new therapy in decades to treat the disease, and for the 18.5 million Americans who, like Miller, struggled with the illness, it would become a blessing and curse.

Miller began taking Lotronex within weeks of its introduction, and his pain subsided. In the following months, however, many patients began to suffer serious side effects. The drug's maker, GlaxoSmithKline, withdrew Lotronex after complications had hospitalized scores of people and killed several. Patients like Miller who didn't suffer side effects lost access to the drug.

But this month, in an unprecedented move, the FDA agreed to allow Lotronex back on the market - under restrictions that will severely limit its use. Once considered a potential blockbuster for Glaxo, the drug will now be reserved for only the sickest patients - about 180,000 people - who fail to respond to other treatments. The new guidelines also require that the drug's use be closely monitored.

Calling the decision ''unique,'' regulatory officials have said it is not part of an overall strategy to bring back withdrawn drugs. But the FDA decision illustrates the increasingly fine line the agency must walk in its quest to make medicines available to patients while protecting them from potentially fatal side effects. As the FDA has speeded its review of drugs in the past decade, it has been criticized by some for giving too much attention to potential benefits and not enough to potential risks. Meanwhile, the drug industry has begun to complain that a growing number of drugs are now languishing at the FDA over relatively minor safety concerns - a view the agency rebuts.

What is clear, industry watchers say, is the growing pressure to manage the risks associated with drugs at a time when they are becoming increasingly important to the nation's health and drug makers are wading into scientifically uncharted waters to develop therapies for ever-more complex diseases.

''If we withdrew all the drugs that caused harm, we'd hardly have any drugs on the market,'' said Dr. Janet Woodcock, director of the FDA's center for drug evaluation and research. ''Withdrawing a drug is a simple solution that is not going to work across the board.''

The FDA put Lotronex back on the market under a provision that allows the agency to restrict the distribution of drugs to protect patients. It has invoked the rule only four other times, all of them involving drugs that provide a significant benefit for patients with few treatment alternatives but also pose serious risks. The agency has never before used the provision to bring back a drug that was pulled from the market.

''We had closed the books on Lotronex,'' said Ramona DuBose, a GlaxoSmithKline spokeswoman.

But neither the company nor the FDA predicted the patient outcry that would follow after Lotronex was pulled in November 2000. ''Here was a medicine that finally gave me back my life,'' said Miller, 32. ''I was shocked, devastated, and extremely angry. Taking away the medicine was like someone taking my life away from me again.''

Miller, who lives in Georgia, founded the Lotronex Action Group along with another sufferer, Jeffrey Roberts, from Toronto. Hundreds of other former Lotronex users joined the grassroots campaign. Sally Read, of Oregon, wrote letters and e-mails until she thought her ''fingers would fall off.''

Read wrote to Woodcock, DuBose, Glaxo's CEO, anyone she thought could help. She told them about how Lotronex had returned some normalcy to her life only to have it ripped from her a few months later.

The Lotronex bottle in her medicine cabinet, she said, has been replaced by two drugs to treat her symptoms and several others to treat side effects caused by the first two drugs. That's risk, she said. Because of the new restrictions, Read doesn't know if she'll be able to get Lotronex. Read has a digestive disease similar to irritable-bowel syndrome, or IBS, but one that Lotronex is not approved to treat.

''I don't know if I'll be able to get it,'' she said.

Under the new guidelines, Lotronex is supposed to be prescribed only by doctors who are especially familiar with the drug. The label warns that the drug is meant to treat patients who suffer from IBS-related diarrhea, and patients who become constipated should immediately stop taking the drug.

The risks are real, Woodcock said. In the nine months Lotronex was on the market, nearly 140 patients were hospitalized for complications related to constipation or ischemic colitis, a condition in which blood flow is cut off from the colon. Forty-five required surgery and four died, according to the FDA.

The responsibility for managing those side effects needs to be shouldered by everyone involved in marketing, prescribing, and using Lotronex, Woodcock said. Physicians and patients will be asked to sign statements that they are aware of the drug's potential dangers. Pharmacists will be asked to fill only those prescriptions that carry stickers indicating the prescribing physician has signed such an agreement. And the company will be expected to closely monitor the drug's use and safety.

Doctors can still legally write prescriptions for the drug for people outside the narrow group officially approved to receive it. Lotronex was studied primarily in women and was never approved for men, but doctors may prescribe the drug ''off-label.'' Miller is among a group of men who lobbied for the drug's return and remain hopeful they will get the drug.

The Washington, D.C.-based consumer group Public Citizen has been critical of the FDA's decision, saying they believe it ''will come back to haunt'' Woodcock. But Woodcock said restricted marketing programs have proven effective. RU 486, the controversial so-called abortion pill, and thalidomide, the medicine notorious for causing severe birth defects when it was sold in Europe in the 1950s and 1960s, and that was recently approved as a treatment for leprosy, are distributed under such programs.

''There is widespread agreement that medicines need to be used more safely,'' Woodcock said. ''These restricted programs work, but they place burdens on the health-care system - on physicians, pharmacists, on patients in terms of access. We need additional alternatives.''

Once predicted to reach $1 billion a year in sales, Lotronex is no longer expected to contribute much - if at all - to Glaxo's bottom line. The drastically reduced market for the drug simply isn't large enough to cover the costs of production and running the risk-management plan and still bring in any meaningful profit, analysts said. Despite the bleak financial picture, Glaxo's DuBose said, the company decided to continue to manufacture the drug to help the patients who benefit from it.

As prescription drugs become an increasingly important part of health care, however, regulators and industry officials are struggling with how to balance the often-competing elements of risk, benefit, and economic reality. Once approved, drugs are more quickly and widely adopted than in the past, posing the potential for greater harm, Woodcock said. Speedier approvals also mean many drugs reach the US market first, she said. A decade ago, drugs were routinely approved first in other countries, giving US regulators a chance to spot side effects that only emerged in widespread use.

Regulators, physicians, and researchers are also struggling with complex scientific issues as the drug industry takes on new strategies for fighting disease. Biological advances have allowed scientists to explore entirely new areas, vastly increasing the potential for treating human disease. But these research areas remain poorly understood, which also increases the potential risks.

''As we understand more about side effects of these products but also recognize the tremendous benefits, we are going to need new levers to manage the risk-benefit ratio,'' said Dr. Marty Silverstein, senior vice president and head of the health-care practice at Boston Consulting Group.

To that end, the FDA this year established a panel of specialists to advise the agency on issues related to drug safety and risk management. Its first official task was to recommend whether Lotronex should be reintroduced. Many of those recommendations, discussed at a public hearing in April, guided the FDA in its decision to approve Lotronex.

The panel's chairman, Dr. Peter Gross, an infectious-disease specialist at Hackensack University Medical Center in New Jersey, said it is too early to tell what challenges the panel might undertake. But certain themes have begun to emerge: better public education about risks and benefits of prescription drugs, more robust programs for monitoring drugs once they are on the market, and better communication between regulators and the health-care professionals to improve drug monitoring.

''One of the take-home messages is that all of this is an inexact science, and there's some art to it,'' Gross said. ''It's an area where there are a lot of unknowns and where much depends on judgment.''

Naomi Aoki can be reached at [email protected].

This story ran on page C1 of the Boston Globe on 6/26/2002.
© Copyright 2002 Globe Newspaper Company.

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