Out of Order: The undiscovered country

—William Shakespeare’s barber

One of the ironies of drug discovery is that unlike a new planet in the heavens or a new element in the periodic table, drugs are rarely discovered only once. For years after the original compound or biomolecule is identified, companies and physicians are constantly trying to discover new applications for the drug, typically based on its current use or what is known about its mechanism of action.

Nowhere is this better exemplified than in oncology, where entire business models are built on developing an individual therapeutic for multiple disease types, using the low-hanging indications as proof-of-concept for the trickier indications.

Suddenly, the pharmacy fills with drugs like Taxotere (docetaxel) and its five cancer indications. Or in the autoimmune sector, anti-inflammatory biologics like Remicade (infliximab) and Humira (adalimumab) with their six and seven indications, respectively. (Please don’t ask me to list the indications for methotrexate.)

To get regulatory approval, however, each of these drugs had to go through a rigorous clinical trial program where efficacy was quantified in statistical terms, as were the risks of adverse events. And both of these parameters were clearly logged in research papers and product monographs.

Drug rediscovery isn’t merely the purview of drug companies, though.

Every day, in clinics large and small, physicians around the globe test drugs new and old on patients with conditions for which the drugs are not indicated. They prescribe these drugs off-label.

The rationale for off-label prescription can vary significantly.

Perhaps it was a case study the physician read in a journal or heard at a conference. Perhaps a colleague down the hall or in a nearby hospital tried it. Or maybe it was just a logic exercise based on similarities between conditions—an oncology anti-emetic should help with severe morning sickness, right?

Regardless, the rationale is always sound (to the physician, at least), and the physician acts with the best intentions for his or her patient.

The FDA says this very thing in its guidance on off-label prescribing:

The problem is that the physician typically acts from anecdotal or indirect evidence with little or no sense of appropriate patient profiling, dosing or adverse event risks. While the physician is no doubt educated, his or her guess about what’s good for the patient may not be.

In July, Health Canada (the snowier version of the FDA) finally bowed to pressure and agreed to establish a database of reported adverse events arising specifically from off-label use of drugs, a practice already instituted in several jurisdictions, including the United States.

The idea is that physicians intending to prescribe drugs off-label should have a resource that gives them a sense of the risks to their patients.

A side effect (pardon the expression) may be, however, that none of this data may inform the physician’s choice in a significant way at all if it is anecdotal. It holds no inherent statistical significance—there are no controls and patient selection criteria may be all over the map.

If 25 cases of birth defects are reported in infants whose mothers received an oncology anti-emetic during pregnancy, should the FDA send out a warning? Perhaps yes. But how clearly can the organization define the risk if it doesn’t have a record of how many pregnant women were prescribed the drug?

Is there a 25-percent chance of a problem or a 0.025-percent chance? Is the risk higher when the drug is given in early pregnancy, late pregnancy or throughout? And how did the physician determine the adverse event was due to the anti-emetic?

Add to this conundrum the question of what responsibility the company that produced the drug holds.

Should they add the adverse events data to their product monographs in the warning section? And if so, can they also have access to the efficacy data to balance the risks with its benefits?

I worry that good drugs will get a bad reputation for problems that arose when they were used incorrectly. (The anti-emetic drug already had clear warnings not to be used in pregnant women due to lack of data on any effects.) These drugs already have enough of an uphill battle when used correctly.

—Julia Child’s rat catcher