Was it something I said? Communicating before FDA approval.

October 04, 2021

Clients often ask if they can talk about a product before FDA approval. It can be done but important rules must be followed or consequences can be severe—the risk being that the government may conclude certain communications constitute pre-approval promotion or commercialization of an unapproved drug or medical device.

What is the statutory framework for unapproved drugs and devices?

The U.S. Federal Food and Drug Administration (FDA or Agency) does not want a manufacturer to promote or commercialize a product until it has had time to adequately evaluate product safety and effectiveness. Manufacturers therefore need to be careful not to "pre-promote" or "commercialize" products prior to approval because the Federal Food, Drug and Cosmetic Act (the Act) prohibits the introduction of new drugs and certain medical devices into interstate commerce without prior FDA approval, clearance, or licensure (collectively, "approval"). Failure to gain approval causes products that are promoted or commercialized and introduced into interstate commerce to be misbranded and/or adulterated under the Act, depending on the circumstances.

Under the law, "No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application…is effective with respect to such drug." See 21 U.S.C. § 355(a). Recently, distributors of chloroquine were subject to FDA enforcement for such failure to gain approval.

Likewise, in order to market a Class I, II, or III medical device intended for human use, for which a Premarket Approval application (PMA) is not required, a 510(k) must be submitted to FDA unless the device is exempt from 510(k) requirements of the Act and does not exceed the limitations of exemptions of the device classification regulation chapters (e.g., 21 C.F.R. 862.9, 864.9). Pre-market approval of certain medical devices, e.g., high-risk Class III devices, is required. See 21 U.S.C. § 360e(a).

Labeling Considerations

The FD&C Act prohibits statements about drugs and medical devices that are "false or misleading in any particular". See 21 U.S.C. § 352(a). FDA may conclude that statements that pre-promote a product are false and/or misleading. A drug or device is also misbranded under the FD&C Act if unaccompanied by labeling containing adequate directions for respective intended use(s). See 21 U.S.C. § 352(f)(1), 331(a).

Under the Act, "[t]he term labeling means all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article." See 21 U.S.C. § 321(m). The FDA and courts have interpreted "accompanying" broadly and not restricted to information that is physically with a product. One court concluded that labeling "supplements or explains" a drug, and includes "advertising or descriptive matter" where "no physical attachment one to the other is necessary." See, Kordel v. United States, 335 U.S. 345, 348-50, 69 S.Ct. 106, 93 L.Ed. 52 (1948).

Thus, FDA may conclude that pre-approval promotion of a product, even if performed on a social media website and not physically connected to the product, is false and/or misleading and therefore in violation of the law.

Do special rules exist for investigational products?

Exceptions exist for shipping into interstate commerce investigational drugs and medical devices that have not yet gained FDA approval. A drug can be shipped under an FDA-approved investigational new drug (IND) application. See 21 U.S.C. § 355(i); 21 C.F.R. 312. The same is true for an investigational device under an FDA-approved investigational device exemption (IDE). See21 U.S.C. § 360j(g); 21 C.F.R. 812.

Despite being able to ship such investigational products into interstate commerce, sponsors (and investigators) researching such products are strictly barred from promoting investigational products as safe or effective, or commercializing them.

For drugs, 21 C.F.R. 312.7 states [bold emphasis added]:

(a) Promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.; and (b) Commercial distribution of an investigational new drug. A sponsor or investigator shall not commercially distribute or test market an investigational new drug.

For medical devices, 21 C.F.R. Part 812.7 states [bold emphasis added]:

A sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator shall not… (a) Promote or test market an investigational device, until after FDA has approved the device for commercial distribution; or (d) Represent that an investigational device is safe or effective for the purposes for which it is being investigated.

Among other requirements, labeling for investigational drugs and devices must bear certain disclaimers. An investigational new drug must bear a label with the statement "Caution: New Drug - Limited by Federal (or United States) law to investigational use." See 21 C.F.R. 312.6. Likewise, an investigational device must bear a label with the statement "CAUTION - Investigational device. Limited by Federal (or United States) law to investigational use." 21 C.F.R. 812.5.

What can be said about a product before approval?

Truthful and non-misleading product communications that do not cross the line into "promotion" or "commercialization" about an un-approved product are generally tolerated by the government. Scientific exchange regarding new products is acceptable. For example, the IND drug regulation referenced above states:

This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution. [Bold emphasis added.]

Examples of non-promotional communications and non-commercial actions include the following below. If executed improperly such activities can result in product misbranding and/or adulteration.

General Rules
- Audience, communication channel, content, and timing are important factors to consider
- Cannot cross line into branded promotion, commercialization
- Mind colors, fonts, and design elements used—cannot match branded product
- Medical Affairs staff participates in scientific exchange, not commercial staff
- Consider disclaimers (investigational status), maintaining balance, disclosing limitations and risks
Scientific Exchange
- Investigator presentations (e.g., phase 3 data presented at a medical conference)
- Medical Affairs function issuing responses to unsolicited requests and disseminating publications
- Medical Affairs section of exhibit booth
- Scientific advisory boards (e.g., discussions about clinical trial strategy)
Non-Promotional Communication
- Press releases (e.g., regarding first-in-human implants)
- Investor communications (cannot promote products are safe or effective)
- Market research (subject to blinding among other requirements)
- Corporate communications (not an end-around on prohibitions described herein)
Awareness
- Health care practitioner disease awareness communications
- Patient disease awareness communications (not an opportunity to disparage competing therapies)
- No product discussion
- As noted, cannot be branded in any way, shape, or form
- No implied claims
Coming Soon Ads
- "Coming soon" ads about a future product offering
- No claims about product in such ads
Notice of Availability
- Prepare a "notice of availability" for a medical device
- Sponsors and investigators can use a notice of availability to "make known through a notice, publication, display, mailing, exhibit, announcement, or oral presentation the availability of an investigational device for the purpose of obtaining clinical investigators to participate in a clinical study"
- See FDA guidance for more information
Pre-approval communications with payors
- Provision of certain types of information to payors, value analysis committees, formulary committees, pharmacy and therapeutic committees, and similar entities
- Examples: product information, indication sought (trial protocol, patient population, endpoints), anticipated timeline for approval, product pricing, related programs and services, factual data from studies
- See FDA guidance for more information

Communications should be scripted and reviewed by qualified medical, legal and regulatory professionals prior to being shared. Such communications must be truthful, not misleading, factual and substantiated. Data relating to efficacy and/or safety should speak for itself.

An author must stop short of drawing conclusions or engaging in exaggeration or puffery. Such hyperbole is a waste of time. Impressive data are what drive enthusiasm. Likewise, polishing poor data is a fool's errand. Less is more. Stick to the facts.

What aspects of clinical data can be discussed?

Acceptable topics to discuss include things like: the condition under study and/or intent of the research, study design, primary and secondary endpoints, factual data on safety and effectiveness, mechanism(s) of action, product design, constituents, inclusion/exclusion criteria, and the like.

As lawyers who have worked in industry for manufacturers, we certainly appreciate the desire to be exuberant. However, public-facing excitement needs to be tempered prior to approval. Therefore, when issuing a press release for example, do not use colorful adjectives like remarkable, best-in-class, impressive, game changer, strong, cure, effective, safe, advantageous, no side effects, impressive, easy to use, and the like. Avoid use of comparative "-er" words like better, faster, cheaper, or "-est" words like fastest, greatest, shortest. Do not use promotional branding or brand names as doing so may be viewed as promotion by the government. Be factual. No need to jeopardize an FDA submission or invite other ugly events. Competitors are likely watching—be vigilant.

When disclosing data include the "n", p-values, and confidence intervals. Share the good and the bad and do not "hide the ball" when it comes to less flattering data. Where appropriate, balance data with safety information. Avoid comparisons—unless an investigation relates to a head-to-head trial, and if it does, follow all of the rules above.

Notably, there is no "investor exception” codified into law, regulation or guidance that allows manufacturers to promote unapproved products—therefore the rules outlined here apply to all investigational product communications prior to approval. Likewise, the rules apply to investigators, company executives and medical affairs staff.

Lastly, those making communications should disclose their relationship with the company, e.g., investigator, employee, etc., to avoid misleading the intended audience.

Are there special allowances for displaying devices pending 510(k) clearance?

Under certain circumstances, the Agency may allow a device maker to "advertise or display" a product that is undergoing 510(k) review. See FDA guidance for more information.

Government Enforcement Tools

Examples of enforcement tools and consequences associated with pre-approval promotion include the following below.

FDA warning letter, untitled letter, notice of violation
Injunction (e.g., consent decree)
Recall
Seizure
Fines
Disgorgement
Imprisonment
Criminal prosecution
Suspension of product review
Clinical hold
False Claims Act liability (e.g., exclusion)
Shareholder lawsuits
Publicity

Facts and circumstances drive the government response to any given situation. The more problematic behavior and acts, the more severe the response. Infamous cases involving promotion and/or commercialization prior to FDA-approval abound. For example, according to the Department of Justice website the Synthes case involved the following conduct:

From May 2002 until fall 2004 Norian conspired with others, including Synthes and the former executives, to conduct unauthorized clinical trials of Synthes’s medical devices, Norian XR and Norian SRS, [Norian SRS and Norian XR were bone cements that were used in treating fractures] commonly called “bone cement”, in surgeries to treat vertebral compression fractures of the spine (“VCFs”), a painful condition commonly suffered by elderly individuals. These surgeries were performed despite a warning on the FDA-cleared label for Norian XR against this use, and in the face of serious medical concerns about the safety of the devices when used in the spine. Before the marketing program began, pilot studies showed the company that the bone cement reacted chemically with human blood in a test tube to cause blood clots. The research also showed, in a pig, that such cement-caused clots became lodged in the lungs. Notwithstanding this knowledge, the company proceeded to market the product for VCFs without putting it through FDA-required testing. The company did not stop marketing the product until after a third patient had died on the operating table. After the death of the third patient in January 2004, Norian and Synthes did not recall Norian XR from the market – which would have required them to disclose details of the three deaths to the FDA – but, instead, compounded their crimes by carrying out a coverup in which they made false statements to the FDA during an official inspection in May and June 2004. In addition to the prison term, U.S. District Court Judge Legrome D. Davis ordered each of the defendants to pay a fine in the amount of $100,000.

The OIG noted the following regarding the Synthes case in its 2012 semi-annual report to Congress:

Four individuals each pleaded guilty, as responsible corporate officers, to one misdemeanor count of shipping an adulterated and misbranded medical device in interstate commerce.

The executives involved received prison sentences and were later excluded from federally funded health care programs.

In another case, the Department of Justice reported that:

W. Scott Harkonen, M.D., the former chief executive office <sic> (CEO) of InterMune Inc., was sentenced Wednesday before U.S. District Court Judge Marilyn Hall Patel for wire fraud relating to the dissemination of false and misleading statements about the results of a clinical trial of InterMune’s drug Actimmune. Judge Patel sentenced Harkonen to three years’ probation, with six months of home confinement. He was ordered to pay a $20,000 fine and to perform 200 hours of community service. In September 2009, after a seven-week trial, a jury convicted Harkonen of wire fraud for the creation and dissemination of false and misleading information about the efficacy of Actimmune (Interferon gamma-1b) as a treatment for idiopathic pulmonary fibrosis (IPF). Evidence at trial showed that Harkonen was the CEO of InterMune from February 1998 through June 30, 2003 and a member of InterMune’s board of directors. Under Harkonen’s direction, InterMune marketed and sold Actimmune to treat the fatal disease IPF despite the fact that Actimmune was not approved by the Food and Drug Administration (FDA) as a safe and effective treatment. The cost of Actimmune for one IPF patient for one year was approximately $50,000 and the vast majority of the sales of Actimmune were for the unapproved, off-label use of treating IPF. Evidence at trial further showed that Harkonen caused InterMune to issue a false and misleading press release publicly announcing the results of a clinical trial of Actimmune for the treatment of IPF on Aug. 28, 2002. Although the clinical trial had failed, InterMune’s press release falsely stated that the results of the clinical trial established that Actimmune helped IPF patients live longer. The headline of the press release read, “InterMune Announces Phase III Data Demonstrating Survival Benefit of Actimmune in IPF,” with the subheading “Reduces Mortality by 70% in Patients With Mild to Moderate Disease.” In October 2006, InterMune agreed to enter into a deferred prosecution agreement and to pay nearly $37 million to resolve criminal charges and civil liability in connection with the illegal promotion and marketing of its drug Actimmune. InterMune also entered into a five-year Corporate Integrity Agreement with the Office of Inspector General for the Department of Health and Human Services.

We could go on and on. The simple concept to take away from this Gardner Law Regulatory Alert is this: do not promote or commercialize a product until it is approved by the FDA. Consider deploying scientific exchange and other communication avenues where appropriate, but be careful and remain attentive.