Off base with off-label?

When a new drug leaves a company’s shelves for pharmacies and hospitals, we rest easy in the belief that it has passed through a rigorous—some say too rigorous, others say not enough—clinical trial process

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When a new drug leaves a company's shelves for pharmacies and hospitals, we rest easy in the belief that it has passed through a rigorous—some say too rigorous, others say not enough—clinical trial process that has checked, rechecked, and checked again the therapeutic's safety and efficacy. Sure, there is post-market follow-up for unforeseen effects—the Phase IV process—but for all intents and purposes, the clinical trial process is over. Or is it?
One thing that pharmaceutical companies can't control is how the drug is used once it leaves their doors. They can provide prescribing information and other supporting data, but it is up to the clinicians on the other end to decide who gets the drug…and perhaps more importantly, why they get the drug.
Off-label prescribing—physicians prescribing drugs to treat a condition for which the compounds were not specifically designed or tested—has always worried me. It's not that I doubt the goals of physicians to help patients, nor the fact that their pathophysiological and pharmacological knowledge goes well beyond mine. I think I worry more about the lack of controls over this practice; the seemingly Macgyver nature of the practice.
Off-label prescription, however, does an end-run around the clinical trial process. In effect, the prescribing physician has set up his or her own private clinical trial; a trial that does not have the guidance of a medical review board or governmental agency. Instead, the trial is based purely on the experiences and judgment of the prescribing physician.

Given this lack of regulatory oversight, I was surprised to hear that Dr. Scott Gottlieb, Deputy Commissioner for Medical and Scientific Affairs at the FDA, was in favor of off-label prescribing. He offered his views on its merits at the Windhover FDA/CMS Summit last December.

"Some people believe that patients should be treated only according to the clinical evidence included in a drug's approved indications," he says. "Yet this evidence may be two or maybe three years old, especially in a fast-changing field like cancer, where off label use of medicines provide important opportunities for patients to get access to the latest clinical practice and for doctors to tailor their patients' treatment plans based on medical need and personal preferences."

"In the end, it is very hard for us here in Washington to anticipate and understand everything that goes on in a doctors' office, when patients are confronted with hard and uncertain choices," he adds. "Many decisions are guided by tiny bits of pertinent evidence, not because people prefer it that way, but because peoples' problems don't fit the clean categories that may be studied in a clinical trial."

While this may be true, I question how often the outcomes from off-label prescribing are shared publicly. Pure speculation on my part, but I suspect that the majority of off-label experiments are reported no further than a patient's medical chart. The typical physician doesn't have the time or the connections to follow-up on positive results with a drug company or medical association to launch a full-scale clinical trial. And who wants to talk about null or negative outcomes?

I'm not advocating the cessation of off-label prescribing. What I would like to see, however, is a mechanism whereby physicians can (and must) share the outcomes of this practice—positive, null, and negative—so that we can all benefit from the collective wisdom and make better informed decisions.
For physicians and pharmacologists, this information would expand their therapeutic armamentarium or provide warnings about otherwise hidden dangers. For drug companies, the data would provide clues to new avenues of discovery (e.g., Viagra) and potential pathophysiological pitfalls.
Earlier in the same speech, Gottlieb basically voiced the same opinion: "The best way to influence [prescribing] decisions—to make sure doctors and patients carefully weigh known but rare side effects against benefits—is to make sure that they have access to timely, complete information about these risks and benefits."
Without the shared information, we will all continue to fly blind.
The off-label process is very important to advancement in the medical field. Physicians use personal conversations, e-mail, blogs, letters to the editor, and other informal means to tell fellow practitioners of success or failure with off-label uses of marketed drugs. That avoids the bureaucratic delays and inefficiencies tied to official drug regulation. The FDA acknowledges the benefits of off-label prescribing, as you describe.
Dr. Jack Coupal, nuclear pharmacist,
Unified HealthCare LLC, Louisville, KY

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