Drug-makers are mostly prohibited from disseminating information on unapproved uses of approved products. Sometimes, the rules discourage manufacturers from even investigating these applications. This leads to inefficiencies in the market and, worse, can harm public health by slowing adoption of superior treatments. A veteran expert witness discusses the issues and shows how to thread this needle.

The question—and problem—of drugs being used or promoted off-label has been in the headlines of late, but it has been top-of-mind for many in the industry for many years. The news that a study of the cancer drug Targretin appeared to reduce amyloid plaques in mice—thereby possibly reversing Alzheimer’s Disease—sent patients and family members scurrying to doctors asking for prescriptions. A similar story that Novartis’s MS drug Gilenya was being tested for ALS brought about calls for coverage of the unproved use. Caught in the middle of this are the pharma firms, who have a large stake in these uses but, for the most part, are the only parties forbidden to talk about off-label use in any meaningful way.

NO FREE SPEECH

The FDA bars drug companies from engaging in any commercial or near-commercial communications about unapproved uses of their products. This specific suspension of the First Amendment is unique: I am not aware of any other industry that is prohibited from discussing potential new uses of its products with customers. The Federal Trade Commission (FTC) regulates the content of many commercial messages (not pharmaceuticals), but it concentrates on preventing and correcting fraud—if the “claims” made in an ad are not overt lies, then everything is okay. A few years ago, Volvo ran ads claiming that life expectancy in the U.S. had gone up because their cars were so safe. That message was not only okay with the FTC, it won awards. If a drug company made that claim, it would get a warning letter! Off-label or “unapproved” uses of a prescription drug, even if they are well accepted and proven to be true, cannot be discussed if the FDA has not yet said it is okay by them. Some companies have been forced to pay penalties for “off-label marketing” up to the date the FDA finally got around to approving the use.

The current restrictions on providing information on off-label use have two very different negative consequences. First, for the pharmaceutical industry, it limits manufacturers’ ability to generate, or even control, optimal sales levels—the current restrictions reduce the legitimate profit-making of any medicine, which reduces the commercial viability of every drug and every company. This also reduces the amount of money available for funding R&D. Second, for the public health, it suppresses potentially valuable information about possible new uses for medicines that are already available; this prevents the manufacturer— who should have the most and best information— from offering that information unless asked in very specific ways—and, even then, limits the response to a very narrow range. This drastically lowers the patients’ chances of getting effective treatments fast, delaying proper therapy for months if not years, and increasing the risk that patients will receive ineffective or inappropriate therapies instead.

FDA’S ROLE

The FDA’s stated mission is “to promote and protect the public health by helping safe and effective products reach the market in a timely way and monitoring products for continued safety after they are in use.” But in practice, the agency behaves as though its mission is to protect health only—they leave the “promote” part out. So they prevent unsafe drugs from getting on the market but do not seem to help good and needed new drugs get approved, or to help important new uses get adopted. The history of the agency is filled with examples of hidebound bureaucratic stickling that harmed the public health—refusing, for example, to approve promising new HIV therapies while the AIDS epidemic raged at its height.1 More recently, the agency has refused to approve drugs for weight loss without the companies undertaking dramatically larger and more costly clinical trials (despite the agency buy-in of the designs of the original trials) while we are in the middle of what has been called an “obesity epidemic.”

I’m not the only one who thinks this is so, and critics come from every point of the political compass. I recently heard former Vermont Governor Howard Dean assert that the FDA has become the pharmaceutical industry’s biggest commercial challenge, because they have their risk-benefit ratio so skewed. He also pointed out that FDA won’t change unless Congress makes them change—and the chances of Congress doing anything in the foreseeable future is about as likely as me winning a Nobel Peace Prize. Nobody can count on FDA shifting its position (and don’t go looking for me in Oslo, either).

PHARMA SHARES SOME BLAME

But it’s not just the FDA’s fault. Often, a drugmaker’s own legal department (sometimes referred to as the “sales prevention” department) has become so cautious, fearful, and FDA-shy that they establish internal rules far stricter than even the FDA would impose. I can’t really blame them for this: I’ve testified as an expert witness in several cases where plaintiffs’ attorneys have become multi-millionaires by accusing companies of off-label promotion. When faced with the prospect that an overzealous (or greedy) plaintiff’s attorney will drag your firm before a judge and jury devoid of both sympathy and understanding, most corporate attorneys would argue that caution is prudent. I can’t argue against that.

So, the pharmaceutical industry is in a unique— and uniquely uncomfortable—position. Nobody said that life was fair. The restrictions against off-label “marketing” grow ever stricter, as FDA keeps moving the fairness goalposts out of the end zone and onto the warning track. And the consequences of getting caught (or even accused) grow ever more onerous, because plaintiffs’ attorneys know a good thing when they see it. As the walls move in, the industry must act with ever growing caution. FDA is currently circulating its draft guidance on responding to unsolicited requests for off-label information about drugs2, in which they describe the conditions under which providing information will and will not be acceptable in its view. This offers a very small arena in which to work, but stepping outside of that restricted zone could have very costly consequences—it’s not fair but it is fact.

STAYING OUT OF TROUBLE

In the near term, your options as marketers are limited. But here are some guidelines I’ve garnered from seeing the kind of spin lawyers can put on information:
1. If your marketing plans—or other documentation— mention any potential off-label use, make it clear that you are not advocating or promoting that use. Just acknowledge that off-label use may occur. Do not make it appear that off-label use is part of your business plan.
2. If your forecasts include assumptions of off-label use, be sure to note that these sales are incidental to your marketing activities and not in any way a result of those activities. Make it clear that you are not marketing the off-label uses.
3.Ask—or instruct—your vendors to limit any discussion of off-label use. I have spent hours arguing—not always successfully—that a marketing-research vendor’s advice is not the same as a marketing plan. If your vendor’s advice conflicts with your own legal department’s guidance, then ask the vendor to either limit the discussion or make clear that it is their idea and not your policy.
4.When in doubt, ask. Your legal or regulatory affairs group—even if you think they are a pain—is there to prevent problems. Work with them to stay within the guidelines they have set and to help them to see your perspective on the issues. Things will work better if you see them—and they see themselves—as part of the team, not as blockers standing between you and the goal.

If a solution to the problem of the restrictions on off-label information does exist, it can only be a legislative solution. The law needs to clarify what a company can say, and I would argue that the law needs to give the companies more latitude in this area.

PM360/WorldOne Spot Survey: Off-Label Prescribing

In February, PM360 and WorldOne Interactive (www.worldoneinteractive.com) conducted a lightning MedLIVE poll of U.S. primary care physicians. We asked them about their attitudes and habits regarding off-label prescriptions and about their attitudes towards receiving information on off-label uses from pharmaceutical representatives. We tabulated the first 50 responses, and here’s what they said.

QUESTION 1. IS IT IMPORTANT TO YOU THAT WHEN YOU WRITE A PRESCRIPTION IT IS FOR AN FDA-APPROVED USE? PLEASE INDICATE WHICH OF THE FOLLOWING STATEMENTS BEST DESCRIBES YOUR ATTITUDES TOWARD THIS TOPIC:

12%: I don’t really care whether the use is approved by the FDA or not (e.g. FDA approval of use not important).
64%: I would prefer to write prescriptions for FDA-approved uses but sometimes need to write off-label (e.g. FDA approval of use somewhat important).
24%: If the use is not approved by the FDA I would prefer not to write the prescription at all but sometimes I must (e.g. FDA approval of use is very important).

QUESTION 2. IN YOUR PRACTICE, HOW OFTEN DO YOU PRESCRIBE MEDICATION FOR INDICATIONS OTHER THAN THOSE ON THE LABEL?

6%: Never
20%: Very seldom (2% or less of Rxs)
20%: Occasionally (2% to 10%)
36%: Not uncommon (10% to 30%)
18%: Frequently (30% to 60%)
0%: Mostly (60% or more)
0%: Not really sure when prescriptions are on- or off-label

QUESTION 3. WOULD YOU LIKE TO BE ABLE TO RECEIVE INFORMATION ON OFF-LABEL APPLICATIONS OF APPROVED PHARMACEUTICALS FROM REPRESENTATIVES OF THE MANUFACTURER? WHICH OF THESE STATEMENTS BEST DESCRIBES YOUR POSITION:

NO: 28%

20%: No. The source is biased, and cherry-picked information is worse than nothing at all.
8%: No, for other reasons.

YES: 72%

30%: Yes. I understand the source may be biased but I am confident in my ability to use the information.
42%: Yes, if the information comes only from well-designed, peer-reviewed studies.
0%: Yes, for other reasons.

References
1. See Acceptable Risks, by Jonathan Kwitny (1992, Simon & Schuster) for an eye-opening discussion of how the FDA’s bureaucratic ways and inability to let reason affect their decisions resulted in a lot of unnecessary deaths and the lack of timely approval of new drugs.
2.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM285145.pdf

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