Practice Tip: FDA's Allowance of Off-Label Information

The United States Food and Drug Administration (FDA) recently issued a draft guidance document to make “recommendations” and to clarify its position regarding the dissemination of scientific information that discusses unapproved (i.e., off-label) uses of approved products. (The draft guidance document, “Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses ' Recommended Practices,” can be accessed at: http://1.usa.gov/1nHQNGu.)

This guidance follows the FDA's guidance, entitled “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.” The FDA issued the most recent guidance, in part, in response to some industry concerns that the earlier guidance was too limiting on companies' ability to distribute off-label information that might benefit the public.

While the FDA may permit dissemination of off-label information in certain cases, life science companies must be aware that such an allowance does not exempt or protect against potential liability exposure. This article summarizes the FDA's two guidance documents and cautions that, despite the agency's acceptance of off-label dissemination practices, companies should consider the potential liability exposure when distributing information about unapproved uses of their products.

Highlights from 2009

On Jan, 12, 2009, the FDA finalized its Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices (“GRP Guidance”). (http://1.usa.gov/Tmtto9). While not legally binding, the GRP Guidance provided the agency's current thinking about the distribution of journal articles and reprints by drug or medical device manufacturers and representatives.

Types of Reprints/Articles/ Reference Publications

Under the GRP Guidance, a scientific or medical journal article must be published by an organization that has an editorial board consisting of experts in the subject area of the article. The organization should adhere to a policy of full disclosure of any conflict of interest or bias of any author, contributor, or editor associated with the article. The article must be peer-reviewed and published in accordance with sound scientific principles. The distribution of special supplements or publications that have been funded by one or more of the manufacturers of a product mentioned in the publication is prohibited. Further, a scientific or medical reference publication that is distributed generally should be available in bookstores or other independent distribution channels where medical textbooks or periodicals are sold. The reference publication should not be written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer; it should also not be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer.

The information contained in such publications must address adequate and well-controlled clinical investigations that are considered scientifically sound by experts with sufficient training to evaluate the safety or effectiveness of the drug or device. The referenced clinical investigations can include historically controlled studies, pharmacokinetic and pharmacodynamic studies, and meta-analyses if they are testing a specific clinical hypothesis. The information cannot be false or misleading, such as an article or reference text that is inconsistent with the weight of credible evidence derived from adequate and well-controlled clinical studies. An article should not have been withdrawn by the author, disclaimed by the journal, or derived from a clinical investigation the FDA found to be inadequate or not well-controlled. The information also must not present a significant risk to the public health.

Examples of publications that would not be considered consistent with the GRP Guidance include: 1) letters to the editor; 2) abstracts of a publication; 3) reports of Phase 1 trials in healthy subjects; or 4) reference publications that contain little or no substantive discussion of the relevant investigation or data.

Scientific and Medical Information

The 2009 GRP Guidance stated that drug and medical device manufacturers may disseminate scientific and medical information, so long as the information distributed is:

• In the form of an unabridged reprint, copy of an article, or reference publication;
• Not marked, highlighted, summarized, or characterized by the manufacturer in any way (except to provide the accompanying disclosures discussed in this section);
• Accompanied by the approved labeling for the drug or medical device;
• Accompanied, when such information exists, by a comprehensive bibliography of publications discussing adequate and well-controlled clinical studies published in a medical journal or medical or scientific text that have been previously published about the use of the drug or medical device covered by the information disseminated (unless the information already includes such a bibliography);
• Disseminated with a representative publication, when such information exists, that reaches contrary or different conclusions regarding the unapproved use; especially those in cases where the conclusions of articles or texts to be disseminated have been specifically called into question by another article(s) or text(s); and
• Distributed separately from information that is promotional in nature.
• Under the GRP Guidance, a journal reprint and reference publication should be accompanied by a prominently displayed and permanently affixed statement disclosing:

1) That the uses described in the information have not been approved or cleared by FDA, as applicable to the described drug or medical device;

2) The manufacturer's interest in the drug or medical device that is the subject of the journal reprint or reference text;

3) Any author known to the manufacturer as having a financial interest in the product or manufacturer or who is receiving compensation from the manufacturer, along with the affiliation of the author, to the extent known by the manufacturer, and the nature and amount of any financial interest of the author or compensation received by the author from the manufacturer;

4) Any person known to the manufacturer who has provided funding for the study, if applicable; and

5) Any significant risks or safety concerns known to the manufacturer concerning the unapproved use that are not discussed in the journal article or reference text.

Highlights from 2014

As noted, the FDA issued its most recent guidance to clarify certain points. Here are highlights of the 2014 draft guidance:

• Scientific and medical publications should come from a peer-reviewed journal;
• The material should be distributed in an unabridged form, such as a reprint;
• The information should be “scientifically sound” and from an “adequate and well-controlled clinical investigation”;
• The company should distribute the product's approved or cleared labeling with the literature, and provide a comprehensive bibliography of information from other publications, including contradictory literature with the scientific information;
• The publication should be delivered separately from any promotional materials. The 2014 draft guidance added the instruction that, if a sales representative delivers the material, the representative should refer any questions to a medical/scientific officer or department that is independent of sales and/or marketing.

Not surprisingly, the FDA used strong language to caution against false or misleading information or information that “makes the product dangerous to health when used in the manner suggested.” This language seems to broaden the previous standard from the 2009 guidance, which prohibited information that “pose[d] a significant risk to the public health, if relied upon.”

The agency recommended that the information disseminated be independent of any company ownership or control. For example, the company should not fund, influence, edit, highlight, or summarize the information distributed. Additionally, the information should not be distributed primarily by the company or individuals having a financial relationship with the company.

Scientific or medical journal reprints should provide a disclosure, “prominently displayed and permanently affixed,” which includes: 1) any company interest in the product(s) discussed in the material; 2) a statement that some or all of the claims have not been FDA-approved or cleared; 3) any financial interests of the authors; 4) the sources of funding of the study, if known to the manufacturer; and 5) all significant risks or safety concerns known about the unapproved use(s); 6) The guidance referenced Clinical Practice Guidelines (CPGs) and noted the same general rules apply as that for scientific and medical journal articles. The FDA reminded the industry to ensure the information is current and is the latest version.

Additionally, the required disclosure statement for these types of publications requires slightly less information (e.g., any additional significant risks or safety concerns are not required to be disclosed). The FDA allowed the distribution of chapters from medical reference texts and sections of CPGs, but they should be unabridged and not changed.

The agency discussed the use of CPGs, which must be “trustworthy” and should meet the following conditions, at a minimum: 1) be based on a systematic review of the existing evidence; 2) be developed by experts and representatives from affected groups; 3) consider important subgroups and patient preferences; 4) be part of a transparent process; 5) provide a logical explanation of care options; and 6) be part of an ongoing revision process based on evidence.

Any distributed CPG should be current, separate from promotional materials, identify the manufacturer and its interests, and be unabridged.

Potential Liability

The industry should not interpret the FDA's guidance as a recommendation by the agency for off-label information dissemination. The FDA is merely stating its current thinking on the subject. In addition, the agency makes clear that it may take enforcement against unlawful conduct, even if a company complies with the guidances. Furthermore, compliance with the guidances does not excuse or immunize against product liability exposure. It is important to remember that, by definition, off-label means the use is not approved or cleared by the FDA.

The FDA, the federal regulatory body entrusted to product the public health, has not said that the product is safe and effective for the unapproved uses or indications mentioned in the disseminated materials. In fact, the FDA guidances encourage prominent disclaimers about potential safety risks of the unapproved product. Therefore, distributing off-label information is, in essence, distributing information about a use that the FDA has not found to be safe, effective, or both.

A life science company must recognize that, with the good of dissemination, comes the bad. With the potential commercial and medical benefits that may come from the off-label materials come the liability risks of distributing information not endorsed by the FDA for safety and effectiveness. An injured party couldn't care less that a company complied with the FDA's “guidances,” which are not legally binding, if it suffers injury due to a doctor or hospital's utilization of a product for an unapproved use. A judge, jury, or both may be sympathetic to an injured individual who is aggrieved by the actions of a life science company, perhaps perceived driven by financial interests. Holding up the 2009 and 2014 FDA guidances in court as a defense will fall short of a complete defense.

Conclusion

The purpose of this article is not to discourage or dissuade off-label information dissemination. As the FDA recognizes, there are legitimate and beneficial reasons that such distribution may be appropriate. Such a decision is fact-specific, and each company must weigh a number of factors. However, potential liability exposure should be one such consideration.

Alan G. Minsk, a member of this newsletter's Board of Editors, is a partner and practice leader of Arnall, Golden, Gregory LLP's Food and Drug Practice.

The United States Food and Drug Administration (FDA) recently issued a draft guidance document to make “recommendations” and to clarify its position regarding the dissemination of scientific information that discusses unapproved (i.e., off-label) uses of approved products. (The draft guidance document, “Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses ' Recommended Practices,” can be accessed at: http://1.usa.gov/1nHQNGu.)

This guidance follows the FDA's guidance, entitled “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.” The FDA issued the most recent guidance, in part, in response to some industry concerns that the earlier guidance was too limiting on companies' ability to distribute off-label information that might benefit the public.

While the FDA may permit dissemination of off-label information in certain cases, life science companies must be aware that such an allowance does not exempt or protect against potential liability exposure. This article summarizes the FDA's two guidance documents and cautions that, despite the agency's acceptance of off-label dissemination practices, companies should consider the potential liability exposure when distributing information about unapproved uses of their products.

Highlights from 2009

On Jan, 12, 2009, the FDA finalized its Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices (“GRP Guidance”). (http://1.usa.gov/Tmtto9). While not legally binding, the GRP Guidance provided the agency's current thinking about the distribution of journal articles and reprints by drug or medical device manufacturers and representatives.

Types of Reprints/Articles/ Reference Publications

Under the GRP Guidance, a scientific or medical journal article must be published by an organization that has an editorial board consisting of experts in the subject area of the article. The organization should adhere to a policy of full disclosure of any conflict of interest or bias of any author, contributor, or editor associated with the article. The article must be peer-reviewed and published in accordance with sound scientific principles. The distribution of special supplements or publications that have been funded by one or more of the manufacturers of a product mentioned in the publication is prohibited. Further, a scientific or medical reference publication that is distributed generally should be available in bookstores or other independent distribution channels where medical textbooks or periodicals are sold. The reference publication should not be written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer; it should also not be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer.

The information contained in such publications must address adequate and well-controlled clinical investigations that are considered scientifically sound by experts with sufficient training to evaluate the safety or effectiveness of the drug or device. The referenced clinical investigations can include historically controlled studies, pharmacokinetic and pharmacodynamic studies, and meta-analyses if they are testing a specific clinical hypothesis. The information cannot be false or misleading, such as an article or reference text that is inconsistent with the weight of credible evidence derived from adequate and well-controlled clinical studies. An article should not have been withdrawn by the author, disclaimed by the journal, or derived from a clinical investigation the FDA found to be inadequate or not well-controlled. The information also must not present a significant risk to the public health.

Examples of publications that would not be considered consistent with the GRP Guidance include: 1) letters to the editor; 2) abstracts of a publication; 3) reports of Phase 1 trials in healthy subjects; or 4) reference publications that contain little or no substantive discussion of the relevant investigation or data.

Scientific and Medical Information

The 2009 GRP Guidance stated that drug and medical device manufacturers may disseminate scientific and medical information, so long as the information distributed is:

• In the form of an unabridged reprint, copy of an article, or reference publication;
• Not marked, highlighted, summarized, or characterized by the manufacturer in any way (except to provide the accompanying disclosures discussed in this section);
• Accompanied by the approved labeling for the drug or medical device;
• Accompanied, when such information exists, by a comprehensive bibliography of publications discussing adequate and well-controlled clinical studies published in a medical journal or medical or scientific text that have been previously published about the use of the drug or medical device covered by the information disseminated (unless the information already includes such a bibliography);
• Disseminated with a representative publication, when such information exists, that reaches contrary or different conclusions regarding the unapproved use; especially those in cases where the conclusions of articles or texts to be disseminated have been specifically called into question by another article(s) or text(s); and
• Distributed separately from information that is promotional in nature.
• Under the GRP Guidance, a journal reprint and reference publication should be accompanied by a prominently displayed and permanently affixed statement disclosing:

1) That the uses described in the information have not been approved or cleared by FDA, as applicable to the described drug or medical device;

2) The manufacturer's interest in the drug or medical device that is the subject of the journal reprint or reference text;

3) Any author known to the manufacturer as having a financial interest in the product or manufacturer or who is receiving compensation from the manufacturer, along with the affiliation of the author, to the extent known by the manufacturer, and the nature and amount of any financial interest of the author or compensation received by the author from the manufacturer;

4) Any person known to the manufacturer who has provided funding for the study, if applicable; and

5) Any significant risks or safety concerns known to the manufacturer concerning the unapproved use that are not discussed in the journal article or reference text.

Highlights from 2014

As noted, the FDA issued its most recent guidance to clarify certain points. Here are highlights of the 2014 draft guidance:

• Scientific and medical publications should come from a peer-reviewed journal;
• The material should be distributed in an unabridged form, such as a reprint;
• The information should be “scientifically sound” and from an “adequate and well-controlled clinical investigation”;
• The company should distribute the product's approved or cleared labeling with the literature, and provide a comprehensive bibliography of information from other publications, including contradictory literature with the scientific information;
• The publication should be delivered separately from any promotional materials. The 2014 draft guidance added the instruction that, if a sales representative delivers the material, the representative should refer any questions to a medical/scientific officer or department that is independent of sales and/or marketing.

Not surprisingly, the FDA used strong language to caution against false or misleading information or information that “makes the product dangerous to health when used in the manner suggested.” This language seems to broaden the previous standard from the 2009 guidance, which prohibited information that “pose[d] a significant risk to the public health, if relied upon.”

The agency recommended that the information disseminated be independent of any company ownership or control. For example, the company should not fund, influence, edit, highlight, or summarize the information distributed. Additionally, the information should not be distributed primarily by the company or individuals having a financial relationship with the company.

Scientific or medical journal reprints should provide a disclosure, “prominently displayed and permanently affixed,” which includes: 1) any company interest in the product(s) discussed in the material; 2) a statement that some or all of the claims have not been FDA-approved or cleared; 3) any financial interests of the authors; 4) the sources of funding of the study, if known to the manufacturer; and 5) all significant risks or safety concerns known about the unapproved use(s); 6) The guidance referenced Clinical Practice Guidelines (CPGs) and noted the same general rules apply as that for scientific and medical journal articles. The FDA reminded the industry to ensure the information is current and is the latest version.

Additionally, the required disclosure statement for these types of publications requires slightly less information (e.g., any additional significant risks or safety concerns are not required to be disclosed). The FDA allowed the distribution of chapters from medical reference texts and sections of CPGs, but they should be unabridged and not changed.

The agency discussed the use of CPGs, which must be “trustworthy” and should meet the following conditions, at a minimum: 1) be based on a systematic review of the existing evidence; 2) be developed by experts and representatives from affected groups; 3) consider important subgroups and patient preferences; 4) be part of a transparent process; 5) provide a logical explanation of care options; and 6) be part of an ongoing revision process based on evidence.

Any distributed CPG should be current, separate from promotional materials, identify the manufacturer and its interests, and be unabridged.

Potential Liability

The industry should not interpret the FDA's guidance as a recommendation by the agency for off-label information dissemination. The FDA is merely stating its current thinking on the subject. In addition, the agency makes clear that it may take enforcement against unlawful conduct, even if a company complies with the guidances. Furthermore, compliance with the guidances does not excuse or immunize against product liability exposure. It is important to remember that, by definition, off-label means the use is not approved or cleared by the FDA.

The FDA, the federal regulatory body entrusted to product the public health, has not said that the product is safe and effective for the unapproved uses or indications mentioned in the disseminated materials. In fact, the FDA guidances encourage prominent disclaimers about potential safety risks of the unapproved product. Therefore, distributing off-label information is, in essence, distributing information about a use that the FDA has not found to be safe, effective, or both.

A life science company must recognize that, with the good of dissemination, comes the bad. With the potential commercial and medical benefits that may come from the off-label materials come the liability risks of distributing information not endorsed by the FDA for safety and effectiveness. An injured party couldn't care less that a company complied with the FDA's “guidances,” which are not legally binding, if it suffers injury due to a doctor or hospital's utilization of a product for an unapproved use. A judge, jury, or both may be sympathetic to an injured individual who is aggrieved by the actions of a life science company, perhaps perceived driven by financial interests. Holding up the 2009 and 2014 FDA guidances in court as a defense will fall short of a complete defense.

Conclusion

The purpose of this article is not to discourage or dissuade off-label information dissemination. As the FDA recognizes, there are legitimate and beneficial reasons that such distribution may be appropriate. Such a decision is fact-specific, and each company must weigh a number of factors. However, potential liability exposure should be one such consideration.

Alan G. Minsk, a member of this newsletter's Board of Editors, is a partner and practice leader of Arnall, Golden, Gregory LLP's Food and Drug Practice.