Off-label Speech

• Publication year: 2023

Off-Label Speech

David A. Simon

OFF-LABEL SPEECH David A. Simon^* Abstract

This Article argues that the Food and Drug Administration ("FDA ") should regulate drug manufacturer speech about off-label uses based on the evidentiary support for the relevant use. The more evidence that an off-label use is safe and effective, the less restrictive the regulation should be. The less evidence that an off-label use is safe and effective, the more restrictive the regulation should be. Although intuitive, this is not exactly how current regulation of off-label information works. If the FDA approves a drug, the manufacturer can advertise to doctors and patients for the approved indication. Drug manufacturers cannot, however, promote or provide information about an approved drug for an unapproved use—so-called "off-label" use—unless they fall within two narrow safe harbors. Yet many off-label uses are just as safe and effective as on-label (approved) ones. Other off-label uses are supported by quality clinical trial data even though they are not approved.

While the FDA recognizes that not all off-label uses are equally (unsupported by the same level of evidence, it has faced legal and practical challenges regulating information about them in a nuanced way. Courts have held unconstitutional the FDA's regulations purporting to ban promotional off-label speech by drug manufacturers. And the safe harbors it has constructed are too shallow for much useful speech. To address these challenges, this Article

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proposes a new approach: working collaboratively with the Centers for Medicare and Medicaid Services, the FDA can use drug compendia—which identify, evaluate, and rate off-label uses—to create a graded system for regulating how drug manufacturers disseminate information about off-label uses that links informational restrictions to the level of evidence supporting the disseminated use. Not only does this system enable a flexible and evidence-based regulatory regime, it also can be easily designed to survive constitutional scrutiny.

Table of Contents

Introduction..........................................................................................551

I. The Framework and Challenges of Regulating Information About Off-Label Uses................................................................558

A. Regulating Off-Label Information: Prohibitions and Safe Harbors .......................................................................... 559

1. Prohibited Off-label Information...................................... 560
2. Safe Harbors for Off-label Information ............................ 563

a. Trustworthiness Requirements.................................... 565
b. Content Requirements ................................................ 567
c. Form/Format Requirements........................................ 568
d. Manner of Distribution Requirements......................... 568

B. Legal and Practical Challenges to the FDA Framework ......... 569

1. Legal Challenges .............................................................. 569
2. Practical Challenges......................................................... 574

C. Solving Legal and Practical Challenges: Linking Information to Evidence................................................................................. 577

II. Drug Compendia.........................................................................580

A. Drug Compendia. Generally................................................... 581
B. Direct Regulation of Compendia............................................. 586
C. Indirect Regulation and Evidence for Uses in Drug Compendia ............................................................................. 591
D. Limitations of Compendia: Lnconsistency, Opacity, and Conflicts of Interest................................................................. 595

III. Tying Information to Evidence................................................ 601

A. Using Compendia off the Shelf: No or Indirect Regulation ...... 601

1. No Regulation: Use the CMS Reimbursement Rules .......... 603
2. Indirect Regulation: Use New Evidentiary Ratings ............ 604

B. Regulating Compendia............................................................ 607

1. Regulation by the FDA Alone............................................ 607
2. Regulation by Collaboration between the FDA and the

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CMS ................................................................................. 608

C. Illustrating Indirect Regulation ............................................... 615

1. Using the FDA Guidance Documents ................................ 616
2. Toggling Informational/Promotional Activities.................. 619
3. Off-label Detailing........................................................... 621

Conclusion.............................................................................................622

Appendix.................................................................................................624

Introduction

Doctors need information about drugs. And drug companies are ready to give it to them. When the information concerns a use of a drug the Food and Drug Administration ("FDA") approved, drug companies can promote their approved drugs to physicians.¹ Drug companies that want to provide information to physicians about an unapproved use of an approved drug, on the other hand, cannot do so except in limited circumstances.

There are two reasons why. The first is that unapproved uses of approved drugs—so-called off-label uses—often pose greater risks, both physically and monetarily, to patients than approved, on-label uses.² Because the FDA has not vetted unapproved uses, they may lack the evidentiary support enjoyed by their on-label counterparts. When drug companies promote off-label uses, they increase the probability that a physician will prescribe a drug off-label³ —and, hence, increase the risk that the patient suffers harm from the unapproved use.

The second is that promoting off-label uses undermines the FDA approval process. Currently, a primary function of FDA approval is to incentivize firms

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to generate and disclose clinical trial data about a drug's safety and efficacy.⁴ If companies can promote drugs off-label once a drug is approved, they have little incentive to conduct clinical trials to obtain approval for off-label uses.⁵ Rather than spend large sums of money to conduct clinical trials for an uncertain result (an FDA approval determining a drug is safe and effective), drug companies can spend much smaller amounts for a sure thing (promote the off-label use and obtain additional sales regardless of safety/efficacy).

Yet many off-label uses are necessary and appropriate.⁶ For some patients, they are the only available treatment; for others, they represent the medically accepted "standard of care." Here, dissemination of off-label information can have positive, rather than negative, effects. By providing the physician information about a previously unknown treatment option, dissemination of off-label information increases the chance that a physician will prescribe a drug off-label to a patient who needs it. Limiting promotion of off-label uses, in this case, increases the risk that a physician will not prescribe a needed off-label treatment.⁷

In the FDA's view, the risk of too much off-label information outweighs the risk of too little. Despite the FDA's position that off-label drug promotion is

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illegal, however, courts have not been inclined to agree.⁸ Indeed, recent judicial decisions have called into question whether any prohibition on off-label promotion is constitutional.⁹

Responding to these judicial losses, the FDA has carved out safe harbors for manufacturer off-label speech.¹⁰ Unfortunately, these safe harbors are rather wooden and impractical. Drug manufacturers must provide an excessive amount of information in a format that is not useful to physicians. And there are few gradations on the kind, nature, and content of information drug manufacturers can provide if they fall within the safe harbors. All off-label uses that qualify for a safe harbor can be distributed in only the prescribed manner—a manner a physician is unlikely to find helpful.

Both of these challenges—the practical and the legal—are fundamentally about the quality and kind of evidence that supports an off-label use. When there is weak or no evidence supporting an off-label use, the risks posed by dissemination of off-label information are high. Restrictions on speech in such cases are likely to be constitutional because manufacturer statements about potential off-label uses are unlikely to be supported by evidence.¹¹ When strong evidence supports an off-label use, by contrast, the risks posed by dissemination

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of off-label information are low—and the risk of not disseminating enough information is high. Here, restrictions on off-label information dissemination are unlikely to be constitutional because manufacturer statements about potential off-label uses are likely to be supported by evidence. Put differently, restrictions on unsupported statements will be more likely to satisfy the constitutional test than will restrictions on supported statements.

Since both the legal and practical challenges of off-label promotion relate directly to the evidence supporting off-label uses, this Article argues that the best way to address them is to tie informational restrictions of off-label uses directly to the evidence base for the disseminated use.¹² Uses supported by strong evidence could be disseminated more than those supported by weak or no evidence.

To tie dissemination to evidence, this Article argues that the FDA, working with the Centers for Medicare and Medicaid Services ("CMS"), should regulate and use drug compendia: privately produced, publicly regulated publications that collect, evaluate, organize, and rate information about drugs...