Why Adjust the Dosage on a Useless Drug?

Merrill Goozner is among our nation’s best health policy reporters. His concern about this FDA decision is one that makes a great deal of sense.

Professors Lisa Schwartz and Steven Woloshin of the Center for Medicine and the Media at The Dartmouth Institute for Health Policy and Clinical Practice are raising alarms about a recent Food and Drug Administration decision to approve a new dosage for the  best-selling Alzheimer’s drug Aricept (donepezil). The decision “breached the FDA’s own regulatory standard” and has led to “incomplete and distorted messages” about the drug, they warned in the latest British Medical Journal.

Aricept has become a $2 billion-a-year blockbuster in large part because people caring for elderly patients with dementia are desperate for something, anything to slow their loved ones’ inexorable decline. The original dose for the drug, which was approved in 1996, provided a short-term improvement in memory that faded to insignificance within six months. With its patent due to expire, the companies behind the drug — Eisai and Pfizer — went to the FDA with a clinical trial in 1,400 patients claiming a higher dosage showed better results. The FDA agreed, which gave the companies another three years of marketing exclusivity based on a use patent for that new, higher dose.

Here’s the medical problem with that higher dosage, according to Schwartz and Woloshin. While the clinical trial showed that patients did slightly better in cognition (like recognizing numbers), the drug had no impact whatsoever on their actual functioning in day-to-day life, at least none that their caregivers could notice. Yet the major side effects of the drug — nausea and vomiting — increased significantly. The article claimed that the FDA had said specifically to the trial sponsors that the higher dose had to have an impact that caregivers could notice to win approval. Schwartz and Woloshin charged the FDA with violating its own standards.

FDA Panel Urges Studies on Pain Drugs Known to Have Severe Side Effects

Somehow I suspect this will not end well.

Particularly because the conditions listed as potential indications for prescription of these clearly dangerous drugs are so common — chronic low back pain, osteoarthritis, and diabetic peripheral neuropathy — this has all the hallmarks of a trainwreck in slow motion.

Few if any people would want to rule out the use of even dangerous painkillers for people with, say, intractable cancer pain. But to jump from that potentially appropriate use (as the pharmaceutical companies always do) to using them from low back pain or arthritis, is breathtakingly irresponsible.

An FDA advisory committee has voted 21-0 that the investigational anti-nerve growth factor (anti-NGF) drug class should continue to be developed for pain treatment, despite the drug class’s link to joint-related adverse events.

There are no anti-NGF drugs currently approved, but three companies are deep into their development programs, testing the safety and efficacy of the drug class to treat a variety of pain, including pain associated with osteoarthritis, chronic lower back pain, diabetic peripheral neuropathy, post-herpetic neuralgia, chronic pancreatitis, endometriosis, interstitial cystitis, vertebral fracture, thermal injury, and cancer.

For Monday’s meeting of the Arthritis Advisory Committee, FDA researchers reviewed data from the three drug companies and concurred with earlier findings that anti-NGF drugs do appear to cause rapid joint destruction. In patients who already had osteoarthritis, the joint deterioration was more severe than if their disease had progressed naturally, and, in some cases, patients who did not have osteoarthritis developed rapidly progressing joint deterioration during the trial.

Lower doses and less frequent administration of anti-NGF agents as well as placebo were both associated with naturally progressing osteoarthritis, while higher doses of anti-NGF drugs and use of an NSAID was linked to rapidly-progressing osteoarthritis as well as osteonecrosis.

An FDA reviewer and an outside academic reviewer performed separate analyses on 355 cases where patients receiving anti-NGF drugs underwent joint replacement surgery. Of those cases, 21% were determined to be rapidly-progressing osteoarthritis, and 7% were determined to be osteonecrosis.

For those not familiar with the terms, osteonecrosis is death of bone tissue and osteoarthritis is joint degeneration.

The ironic fact that the nonsteroidal anti-inflammatory drugs (ibuprofen, Advil, Motrin, etc.) routinely used for arthritis yield short-term pain relief but also cause long-term joint deterioration due to thinning of cartilage, is little known to the public. The FDA panel’s report on these anti-nerve growth factor drugs indicates that these, too, are known in advance to involve similar (and perhaps far more severe) trade-offs.

Not exactly what the doctor should order.

How Should Tobacco Be Regulated?

A new survey published in the American Journal of Public Health finds the following:

Knowledge of current public opinion is important as the Food and Drug Administration (FDA) applies the best scientific evidence available to tobacco product regulation. Based on a nationally representative survey of the US adult population, we report 43% support for banning of cigarettes, 65% for reducing nicotine, and 77% for reducing nicotine if such an action could cause fewer children to become addicted to cigarettes. The FDA should consider protecting children by removing all but nonaddictive cigarettes from the marketplace.

Only recently has the Food and Drug Administration had the power to regulate tobaccoproducts. How it will use that power remains to be seen. The Family Smoking Prevention and Tobacco Control Act of 2009 does not allow the agency to outlaw cigarettes but confers upon it the power to set standards that can reduce nicotine content and regulate chemicals in cigarette smoke.

Short of a ban, what tobacco control measures are justified based on public health benefits while also being defensible regarding concerns about limiting corporate speech? That appears to be where the rubber is hitting the road at this juncture.

What these Harvard School of Public Health researchers have done in their study is to artfully frame the issue in terms of a few specific choices. With 77% support in this survey for “removing all but nonaddictive cigarettes from the marketplace,” there now appears to be strong majority support for a major new form of regulation, though I hasten to add that the tobacco industry and its allies have not yet waged a major anti-regulation ad campaign. If and when they do, the percentages currently favoring stronger regulation may decline. That said, 77% is a strong starting point.

Crafting effective policy to regulate harmful and addictive substances requires evidence, courage and subtlety. There are no easy answers and the politics are complicated. This was underscored by a recent temporary injunction issued by Judge Richard J. Leon of United States District Court in Washington (a George W. Bush appointee), which blocked new FDA rules requiring that all cigarette packs include graphic warnings about cigarettes, similar to those required in Canada and Australia. While Judge Leon’s ruling (which he based largely on the free speech rights of tobacco companies) runs contrary to other judicial rulings on FDA tobacco policy, and may not survive appeal, it raises significant questions as how much maneuvering room is available to the FDA.

Because cigarettes are legal, the severity and wide ranging effects of cigarette addiction are under-appreciated. Lung cancer and heart disease are only two of the diseases tobacco can cause. Several years ago, when I compiled lists of risk factors for all major chronic degenerative diseases to use in the clinical nutrition course I teach, smoking was a risk factor for every single disease.

Years ago, I heard a talk by Dr. Andrew Weil of the University of Arizona Medical School, in which he asserted that a cigarette habit is harder to kick than an addiction to heroin. The massive damage that cigarettes cause to individuals and society as a whole has been amply documented and widely publicized for over 50 years (the landmark Surgeon General’s report was released in 1964), and the case against cigarettes continues grows ever stronger.

It’s time for the FDA to significantly strengthen its tobacco regulations and for the courts to recognize that public health should outweigh tobacco company profits.