Articles

Off-Label Discussion Before and During Clinical Trials

Published on February 3, 2016
Authored by Mark DuVal
Categorized as FDA News

Off-Label Communications: A Guide to Sales & Marketing Compliance

3. Off-Label Discussion Before and During Clinical Trials

By Mark E. DuVal  and Bradley Merrill Thompson

I. Introduction

By this point, the book has provided excellent background on the legal underpinnings for off-label promotion and dissemination. The task now is to discuss off-label uses of products in the context of clinical trials. This helps the reader understand how clinical trials intersect with off-label promotion and other forms of communication. Thus the chapter begins with a conceptual layout of how one might view this world. What does a manufacturer confront when it markets a product that has utility well beyond its approved label? Remember, to discuss “off-label” uses implies that the product is already approved, has a label and there is potential for off-label uses of that product. Also, remember that off-label does not mean that the off-label use is inappropriate, nor is it necessarily dangerous. Rather, it means the product is deemed safe enough to be on the market, but it has not been studied for that particular unapproved use.


II. FDA’s Concern: Control Over  the Approval Process

This chapter is essentially about how a company communicates lawfully about all of the uses for which its product is or may be useful. The regulatory regime established by Congress requires products to obtain approval from the Food and Drug Administration (FDA) before a company markets and sells a drug or medical device. To get approval, the company must conduct clinical trials that establish that the benefits of the product outweigh its risks and it deserves to be marketed in the United States. The label that is negotiated with FDA serves as the basis for the claims that can be made about the product.

Anything not in the label may, indeed, be “off-label” because that use has not been clinically studied and approved by FDA. Hence, the tension with off-label uses is that the medical community wants to obtain information about potential new uses and industry wants to provide that information, but FDA is reticent to allow discussion of off-label use because it fears that it undermines the product approval process. FDA wants to maintain the integrity of its approval process by requiring that all new uses receive FDA approval before being promoted for that use.

III. Industry’s Pressures

The discussion about the government and regulatory approvals must give way to some practical assumptions with which corporate America is faced. This will help the reader understand the context in which off-label uses merge with clinical trials in company life. Every company faces these assumptions as it markets products for which there are potential off-label uses.

• Financial pressures. The first assumption is financial pressure to grow sales and profits. A company first obtains approval of its product with an initial indication, but there are new indications for the product that represent a larger market for it and greater sales. There is corporate pressure to maximize this “asset,” whether it is a drug or device, and achieve more sales, and faster. This is true whether the company is large or small, public or private, although there is typically more patience in a privately held company for ramping up sales. Sales and marketing staff have forecasts tied to these corporate expectations; bonuses and advancement within the company are tied to these forecasts. Sales representatives believe they are only as good as their last quarter’s results, and must continually find ways to grow the sales volume in their territory and achieve growth milestones for their own sales awards and bonuses. The chief executive officer (CEO) needs to report to the shareholders growth in sales, acceleration of research and development, cost cutting and an ever-higher return on investment. Everyone is under financial pressure.

• Resource constraints. The second assumption is resource constraints. Even if the company is successful in growing the asset, the financial pressure is relentless and, in turn, puts pressure on the Research and Development (R&D) and Clinical Affairs organizations to produce more indications for existing products to maximize these assets to the fullest. The problem is that when a company is in the mode of making profits for the organization, it struggles with continuing the high rate of investment that it took to get the product on the market for the initial indication for use. That means R&D and Clinical Affairs will be resource constrained. The corporation will put forth the expectation to conduct more clinical research in less time, but the resources may not be there.

• An expectation of compliance. The third assumption is a compliance expectation. Everyone in the organization knows that before an indication is approved, it is illegal to promote it for that use. Yet everyone also knows that physicians frequently invent new uses for a product, uses that are not yet in the labeling. The new uses are usually logical extrapolations of the science behind one approved use of the product as applied to another off-label use. These new uses translate into new sales and the financial pressures are temporarily alleviated—until next year when those off-label sales become a new expectation for the corporation in the forecasting process. This breeds additional pressure to embrace the off-label sales and creates a temptation to grow them. It is in this milieu that corporate compliance steps in, whether that is Legal Affairs, Regulatory or an actual compliance function. Compliance reminds the organization that it can enjoy off-label sales as long as it is not engaging in direct or indirect promotion to create them. This creates a tension within the organization. How does it keep off-label sales going and growing when it cannot engage in off-label promotion

This is the backdrop against which all companies operate. With these three assumptions—financial pressure, resource constraints and compliance expectations—the spotlight falls on a company’s R&D, Clinical and Marketing organizations. When a clinical organization examines how it can help the company achieve its goals of growth by developing new indications from existing products, it looks at its budget, which is not unlimited. It must set priorities for its selection of clinical targets and, within available resources, time, people and money determine which ones to pursue and how.

IV. Pursuing Company-Sponsored  or Investigator-Initiated  Clinical Trials

There are two fundamental ways in which the clinical organization can proceed to conduct clinical trials: by funding company-sponsored trials or investigator-initiated trials (IITs). One yields FDA approval for uses that are currently off-label and the other (i.e., IITs), yields publications and discussion in public scientific forums about the use of an approved product in unapproved uses. Many trials must go through a rigorous investigational new drug (IND) or investigational device exemption (IDE) process before they are commenced. In a company-sponsored trial, the idea originates with the company and the study is designed and conducted by the company through chosen investigators. With an IIT, the idea is initiated by the investigator who requests a grant from the company to conduct a study in which it has a scientific interest. The company usually funds IITs that match its research interests.

There are only so many company-sponsored trials that a company can fund and conduct, given the resource constraints discussed above. IITs allow the company, in effect, to do pilot studies with noncompany resources (other than the grant money to fund them) to see if the company’s drug or device may work in another indication. This is good for society because new uses for products can be explored. It is good for academia because they can deploy and fully utilize their resources to explore areas of product use that industry might not pursue. It is good for industry because all of these potential uses would either not be funded by companies facing financial pressures and resource constraints or they would be funded years down the road. This would delay knowledge of new useful therapies. IITs allow these uses to come to fruition faster.

V. Three “Buckets” for Off-Label Information— Promotion, Dissemination and Communication

When clinical information is generated from company-sponsored trials or IITs, a company must decide how and when that information might be made available to the medical community or the public at large. Of course, when a company sponsors a clinical trial and submits it to FDA for a change in labeling and the labeling change is approved, the product can be lawfully promoted for that use. But what if the information is not yet submitted to FDA, or FDA does not approve the labeling change or if the new information arises out of an IIT? This forces the organization to think about ways it may lawfully address providing information about off-label uses in the context of pursuing clinical trials. There are three “buckets” into which providing information about off-label uses may fall.

The first bucket is promotion. A company cannot promote uses for products that do not yet have FDA approval. Many ways exist to engage in promotion—direct and indirect, express or implied—but promotion of uses not approved by FDA is illegal. Promotion is reserved for approved uses only. But figuring out what constitutes promotion can be complicated. We know that under the Federal Food, Drug, and Cosmetic Act (FDCA) and accompanying regulations, FDA looks at the “intended use” of the product which means the objective and subjective circumstances surround the distribution, marketing and sale of the product to determine the true intended use for the product. This means, for example, that selling a drug or device approved for epilepsy to a physician who specializes in the treatment of pain might be deemed off-label promotion by FDA if those physicians do not normally see epileptic patients.

The second bucket into which discussion of off-label uses falls is dissemination. As has been discussed earlier in this book, the free speech clause of the First Amendment to the U.S. Constitution allows for and protects the free exchange of medical and scientific information. Dissemination was addressed in the Washington Legal Foundation (WLF) case and the former section 401 of the Food and Drug Administration Modernization Act (FDAMA), which expired in September 2006 under a “sunset” provision. Both the WLF case and section 401 allowed the dissemination of medical and scientific information among industry and medical professionals.

In 2008, FDA proposed a new Guidance document that allowed for the exchange of medical and scientific information. It was written to fill the gap left when section 401 of FDAMA sunset. The Guidance document, 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,” was finalized by FDA in January 2009 over the objection of Congressman Henry A. Waxman who in 2009 chaired the House Committee on Energy and Commerce. The Guidance outlines the types of information that may be disseminated, who may disseminate it and how. This scientific exchange permits physicians to request and receive information from companies about the latest studies conducted on their products, whether they are for existing or new uses. Companies are allowed to disseminate information about studies. The key question is how this dissemination may occur.

That leaves the third bucket of communication. Much of what is discussed about off-label uses in a clinical trial occurs in this bucket. Companies conducting company-sponsored trials and IITs can and must communicate about these trials in ways that lawfully and legitimately discuss potential off-label uses of approved products. There are many ways in which the company must communicate about off-label uses of products. For example, studies directed to new, off-label uses often must be disclosed under U.S. securities laws to existing and potential investors. If the results of a trial are potentially “material” to a decision to buy or sell stock, they must be disclosed. This is done through formal securities filings or press releases. Another example is when a company advertises for potential clinical investigators and patients to be enrolled in a trial. This exercise invariably communicates to the world about potential off-label uses of a product.

As the company devises its clinical plan it will reach out to many practicing clinicians around the country to determine what indications to pursue first and what endpoints might be relevant in a clinical trial design. These consultations mean that the company again is communicating pre-approval regarding its product. If a company conducts market research about potential off-label uses of its product that is a lawful communication about an off-label use pre-approval. When a company provides a grant for an IIT and the investigator publishes the results in a peer-reviewed journal article, the investigator may speak about the research results in continuing medical education (CME) programs.

The remainder of this chapter elaborates on the ideas above and provides many more ideas of what types of promotion, dissemination and communication may be lawful in the context of clinical trials.

VI. Avoiding Off-Label Promotion During Clinical Trials

Of the three buckets listed, the advice in this bucket mostly focuses on how to ensure that the company does not commit inappropriate promotion of an off-label use during clinical trials on a new use. This section will examine the contours of the prohibitions against off-label promotion in the context of direct sales activity, trade shows, company-controlled meetings (non-CME) and contracts for the future sale of unapproved capital equipment. It concludes with a discussion about promotion of a product under development that has not yet reached the market at all.

Before delving into those topics, without repeating the history of the development of FDA’s approach to regulating off-label use or the judicial pronouncements on the First Amendment discussed elsewhere in this book, it is helpful to summarize the current law.

• The FDCA section on misbranding and FDA’s regulations on intended use are still in effect. For example, under 21 C.F.R. § 801.4, the words “intended uses” “… refer to the objective intent of the persons legally responsible for the labeling of devices. The intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised. … .” So, FDA can use just about any evidence to show that a manufacturer intended that its product be used in a manner that FDA has not approved. If the agency succeeds in proving that, the company would be guilty of selling an adulterated product in the sense that the product was not approved for the intended use. Alternatively, FDA can argue that a product is misbranded if it does not contain adequate instructions for an intended use, even though the use has not been approved. Either way the product is adulterated or misbranded, and if the company is placing that product in interstate commerce, it may be found guilty of a prohibited act.

• FDAMA section 401 provisions on dissemination of off-label materials and the associated regulations had a sunset provision. While that provision was only a safe harbor, this means that right now in mid-2012 there is no specific statutory authorization for disseminating peerreviewed medical journal reprints or textbooks.

• FDA’s Guidance on CME from 1997 is still in effect. That Guidance document outlines the factors that the agency is likely to take into account when evaluating whether a company has tried to exert undue influence over a CME program.

• Constitutionally speaking, FDA cannot infringe on promotion of products if it has other options. While the courts in Western States and WLF offered much more specific and elegant holdings, it all boils down to at least some notion that FDA has to fit its policies and regulations into the context of the First Amendment.

• FDA finalized its widely publicized proposed Guidance document on the dissemination of peer-reviewed journal articles and medical textbooks. FDA published the Final Guidance document in the Federal Register in January 2009.

• FDA has also issued a Draft Guidance entitled “Responding to Unsolicited Requests for Off-label Information About Prescription Drugs and Medical Devices,” issued in December 2011. It essentially memorializes FDA’s longstanding unofficial position allowing companies to respond to unsolicited requests for off-label information.

Those are the basic rules currently in force from FDA regarding off-label promotion and dissemination. They are certain to change, and may change soon, but the discussion below is all built on those principles.

A. Types of Promotion

As stated at the outset, the discussion of promotion in the context of this chapter on clinical trials for the most part simply focuses on defining what constitutes off-label promotion and, therefore, what is prohibited. While an attempt will be made to explain types of conduct that are allowed, the emphasis will be on what is prohibited simply because it is easier to define.

1. Sales Activity

Off-label promotion in the context of sales activity is prohibited. It is that simple. Sales representatives may not use a sales pitch or other such tactics to encourage physicians or other healthcare practitioners to use a drug or device outside the approved labeling. Another more sophisticated and indirect method of off-label promotion is to suggest “stretching” certain reimbursement codes that a physician might use to obtain government reimbursement where none is available for that off-label use. In fact, drug and device companies have an affirmative obligation to train and manage their sales representatives in a way that is designed to ensure that sales presentations remain on label. Prudent companies also have an obligation to ensure that their sales representatives use only materials that the company has approved, as opposed to letting them create their own. The last section in this chapter discusses how these various rules should be embedded in good promotional practices the company develops, trains against, audits against and enforces.

The only wrinkle is that companies may choose to utilize their sales representatives in supporting nonpromotional dissemination of scientific and medical information (e.g., contained in peer-reviewed medical journal articles). That topic will be discussed in the section on dissemination.

2. Trade Shows

The general prohibition against selling a drug or medical device off-label certainly applies to activities at a trade show. These are selling opportunities and all of the materials handed out and the discussion occurring at the trade show need to be on label. Indeed, because they are gathering places for many of the companies in a given industry, FDA finds it very efficient to send investigators to these meetings, in plain clothes so to speak, in order to monitor what goes on. So, it is very important that the company review the promotional materials carefully and thoroughly train personnel who will staff their booths in the limits applicable to marketing their products.

That said, there are a few limitations to the general rule. Those limitations include:

• Some of these trade shows can legitimately be declared an international event. As such, the company may be permitted to staff an international booth that includes marketing materials and sales representatives trained in uses approved in other regions of the world. In these instances, the booth (or a portion of the booth) must be set up distinctly as international, separate from any U.S. booth.

• Further, it is possible to staff a special section of the booth with representatives of the medical affairs department of the company who would be available to answer unsolicited questions asked by doctors. In these instances, it is important that the company respect all of the parameters of FDA’s unsolicited request Guidance. That Guidance will be discussed under the section regarding dissemination of information.

• It is also possible for a company to recruit clinical trial investigators at a medical convention. A portion of the booth, usually found with medical or clinical affairs, hosts this function. In that section, proposed studies addressing unapproved uses may be displayed. The company cannot state the product is safe or effective for the unapproved use, but it can describe the protocol—its endpoints, inclusion and exclusion criteria, and hypothesis—all of which points to the unapproved use, in an attempt to recruit potential investigators.

• Finally, very informally FDA has offered an accommodation to manufacturers of medical devices who may have only one major trade show a year. FDA generally allows manufacturers to display unapproved medical devices if a 510(k) is pending at the agency. The theory is that devices subject to a substantial equivalence determination are generally not radically different from other products on the market and thus usually have a lower risk profile. Because certain trade shows are only held annually, the agency has acknowledged the hardship a company would endure if it had submitted a premarket notification and was awaiting FDA action when the trade show occurred. There are significant limits to what FDA will permit. While the agency will generally allow a company to show a demonstration model, there must be a conspicuous statement that the device is not yet cleared, and a 510(k) is pending. The company can make no performance claims, but it can explain in general terms the intended use and the basic features. Further, some food and drug attorneys believe that the company can collect business leads, but the company must stop short of anything that looks like it is taking orders or, worse yet, entering into a contract for the sale of the as-yet-unapproved device, unless limited to research or investigational use. Generally companies should shy away from a specific discussion of the commercial price. Some major capital equipment companies, however, give their customers a ballpark understanding of the cost so that they can start to budget if they wish.

3. Contracts for Future Enhancements

As mentioned above in the context of medical devices, FDA has said that companies should not take orders, or be prepared to take orders, that might result in contracts of sale for an unapproved device unless limited to research or investigational use. Frankly, no one is really sure what that means. The phrase “be prepared to take orders” has confounded lawyers for years. And it is particularly difficult to interpret in the context of capital medical equipment.

Here is the problem. Many people in business are accustomed to purchasing or renting copy machines. It used to be true that the technological changes in the photocopying industry occurred so quickly that the machines became obsolete frequently. In order to get companies to buy or rent them, the manufacturers had to offer some sort of assurances that would allow for easy upgrades. More than that, the companies wanted to lock in customers for the long term. For example, a manufacturer might prefer to rent a copier to a customer and promise that the customer would receive the next generation when it came out for no increase in rent so long as the company signed a long-term lease.

With other technologies, some machines are part of systems that need to work together. If a company bought a piece of equipment that was part of a system, the customer would in essence be committing to a specific technological platform. Often it would be attractive for the manufacturer to offer lower prices or other commercial advantages to companies that would commit to use of the platform long term.

The same commercial issues arise in the sale of capital medical equipment. In many areas of medical equipment, technological obsolescence occurs rapidly, and the customers want some assurance that they will be able to use the latest technology throughout the term of the contract. Further, given the financial pressures on the healthcare system, they want the cost savings that come with a longterm commitment. But given FDA’s prohibition against taking orders or being prepared to take orders for unapproved devices, what options are available?

Sales representatives and commercial lawyers get quite creative in trying to figure out how to lock a customer into a technology platform and a long-term agreement. Invariably these folks try to think through whether they can offer their customers an option to purchase the next generation at an unspecified price, or better yet from their perspective, a specified price. Alternatively, some want to make a contractual commitment to make the next generation available by a certain date, or make promises regarding features or performance of the next generation. More modest objectives include simply making a commitment to notify the customer when an upgrade is available. Taking a page from the photocopier industry, others want to structure the agreement as a lease that automatically includes any future generations during the term of the lease. Some feel that they can make these provisions acceptable by conditioning them on the manufacturer’s obtaining regulatory approval or clearance.

Because the FDA language expressing the prohibition is so murky, about the best a lawyer can do for his or her client is to examine the purposes behind the prohibition and to use those purposes as guidance when interpreting the language. Unfortunately, FDA has not been very public even in its discussion regarding the purposes of this language, so some of it is left to conjecture. It seems as though the primary evil the prohibition is designed to avoid is the risk that companies will feel contractual pressure to meet deadlines for shipping a new product.

FDA, we would guess, would be concerned that a contract that includes a date certain for delivery of an unapproved product would cause the company to rush through the development and manufacture of the product, and perhaps to ship the product before FDA has had a chance to approve it. Further, FDA would presumably be concerned about specific promises regarding the use of the product in advance of the use being approved. It is hard to “unring” a bell, and it is hard to correct initial statements about the use of a product that FDA may not completely approve.

Based on that analysis, we can offer some prediction about what the law requires. In truth, these are simply some rules of thumb designed to avoid undue regulatory risk. First, the medical device manufacturer probably should not sign, or perhaps even negotiate, a contract where successful performance (e.g., delivery) would require FDA approval or clearance. Further, some believe that limitation should apply even if the contract conditions performance on FDA clearance or approval (penalty free). Exempt devices or changes that do not require a new 510(k), however, are not included.

Beyond those limitations regarding contracting, it is important that the medical device manufacturer not pre-promote except in compliance with the permitted forms of pre-approval communication described below.

The bottom line is that the sales representatives and commercial lawyers probably should not use most of the contractual approaches outlined above. The least risky approaches include such things as commitments to notify the customer when a new generation is available and certain lease agreements that make no promises regarding any specific future upgrades.

4. Meetings

In perhaps overly simplistic terms, there are two flavors of meetings that involve drug and device manufacturers. The first type of meeting might be referred to in a shorthand way as continuing medical education. These meetings are not organized by the manufacturer, but rather merely are supported by grants that the manufacturer gives to an accredited CME provider. CME meetings are not promotional but instead educational. How companies can get involved in supporting such meetings is discussed below in the bucket on communication.

The other flavor of meeting is one that the drug or device manufacturer controls. Sometimes that control is obvious, and sometimes it is not. But regardless of how visible the control is, if the manufacturer in fact is calling the shots and the meeting is not an accredited CME meeting, it will be treated as a promotional meeting and the company will be held responsible for ensuring that the content is on label.

Examples of these company-controlled meetings abound, and include company-sponsored speakers’ bureaus and various in-service seminars performed for physician customers. Obviously programs like training sessions for the use of medical devices and company-sponsored webcasts are included even if the topics are more general than merely the company’s products.

FDA will view all of the handouts and other materials provided as regulated labeling, and all of it must abide by FDA-approved or cleared labeling. Even if these sessions seem to cover broader medical subjects with educational objectives, because the company is controlling the meeting, FDA will insist that the materials not depart from the label. Furthermore, not just FDA is interested in these meetings. Because they represent interactions between the manufacturer and its physician customers, all of the rules regarding fraud and abuse and anti-kickback apply.

It is possible that in these settings a physician customer might ask an unsolicited request for information about an off-label use. Those requests need to be handled in accordance with the rules laid out below in the section on dissemination of information. They can be more awkward here because of the group setting, but that setting does not alter the fundamental principles of how to respond to unsolicited requests. Prepared remarks by speakers need to focus on the cleared or approved uses or disease state. Further, a speaker should not come prepared with backup slides so that he or she can talk about an unsolicited request, even if one arises. Having prepared slides makes it difficult to argue that the request was unsolicited, and that the response was narrowly tailored to the request.

5. Early Development Phases

So far this chapter has addressed the rules regarding the sale of an approved product and its potential off-label uses. After all, you cannot have an off-label use until you have a label. But there is even an earlier issue to tackle: what can be said about a product in development that has not even reached the market?

As a matter of basic food and drug law, FDA does not regulate research before a product has been developed and is available in some form to either man or animal. Some of the earliest regulatory requirements that apply during the development process are the good laboratory practices triggered by preclinical laboratory work that will lay the groundwork for later clinical investigation and will help form the basis of a submission to FDA. The agency does not regulate what a company says about a product it is developing until the product becomes investigational; that is, available for investigation in humans or animals.

There are two major caveats, however, that a company needs to think about during this unregulated period.

a. Thou Shall Not Promote Beyond the Anticipated Approved Label

While it is technically true that during the early development of a new drug or device FDA does not have regulatory authority to limit what the manufacturer can say, the manufacturer needs to avoid being shortsighted. Whatever the company says during that period about its upcoming product will create an impression in the minds of the customers who may ultimately be asked to purchase the product. If the company describes uses that do not ultimately get approved, the company will be creating an off-label promotion situation once the product is introduced into commercial distribution. Remember that the fundamental statutory and regulatory basis for prohibiting off-label promotion does not speak merely in terms of the contemporaneous label. Rather, it suggests that the agency can use any evidence it can find to establish the company’s intended use for the article. So FDA would have legal basis to use old press releases and other such communications to establish a broader intended use for an article than the FDA approved use. That is the legal theory. In more practical terms, FDA would be concerned if a company communicated broad intended uses during the development phase that customers would remember later when the product is actually introduced into commerce. As stated earlier, it is hard to “unring” the bell.

b. Thou Shall Tell the Truth  in Promotional Materials

Likewise, although FDA would have difficulty proceeding against a company for statements made in advance of any product being placed in commercial distribution (but other laws may still be relevant), once the opportunity to acquire the product exists, any prior statements made would be evaluated for their truthfulness. In other words, there is no free-lunch period prior to the launch of the product in which the company can make any claims it likes. If an early claim is made to a customer that a drug or device can perform up to a certain expectation, and later the product is sold into the marketplace, those early statements enjoy no immunity. Being truthful means, among other things, the statements made are adequately supported by valid scientific evidence (devices) or substantial evidence (drugs) at the time they are made. So at the time the claims are made, the data must exist to support them.

Nevertheless, the regulatory requirements do vary somewhat depending on where a product is in the development process. The table  on 121 illustrates this point in a simplified manner; i.e., it is simplified because there are additional issues that could be added. For example, specific rules for in vitro diagnostic devices or for products approved overseas have not been addressed in the table, nor have products that reach the marketplace through the premarket approval process. Nonetheless, the table  on page outlines the basic developmental steps for the most common medical devices, and summarizes the relevant law.

B. Dissemination of Scientific Information

As stated at the outset, this discussion regarding new uses for existing technology is divided into three buckets. The common thread in all of the promotional settings discussed above is that FDA would assume that the information being communicated is for the essentially singular purpose of promoting sales of the drug and device.

FDA is willing to acknowledge, sometimes rather begrudgingly, that drug and device manufacturers play more than just a commercial role; they are sources of important information about medical breakthroughs. Because of important public policy considerations, the agency has shown flexibility in allowing medical device and drug companies to disseminate important scientific information about the products that they sell even when such information suggests an off-label use. FDA adopts these positions because of an overriding desire to ensure that physicians receive timely and high-quality information that is as much as possible free from bias inherent in commercial interests.

The area of the dissemination of scientific information has bred much public activity and debate. For example, when section 401 of FDAMA sunset on September 30, 2006, FDA was left with a gap in its regulatory framework. The findings of the trial court in the WLFcase technically still stood, including the injunctions set forth by the trial court which prohibited enforcement of two of the three Guidance documents that had been promulgated by the Center for Drug Evaluation and Research. (These Guidance documents addressed 1) the dissemination of reprints and 2) medical reference books that mention off-label uses of a manufacturer’s products, as well as 3) a company’s ability to influence the content of and speakers for CME; the injunction against the CME Guidance was vacated by the appellate court.) FDA had taken the position at the United States Court of Appeals, District of Columbia, that section 401 was a “safe harbor” allowing dissemination of off-label information and the appellate court accepted that interpretation in finding it constitutional.

In other words, if a manufacturer followed the requirements of section 401, it could disseminate medical and scientific information without fear of being prosecuted for off-label promotion by FDA. If a manufacturer chose not to comply with section 401, FDA would not necessarily prosecute the manufacturer for dissemination alone, because that would surely precipitate another WLF First Amendment challenge. FDA said, however, that if FDAMA section 401 were not followed, the dissemination could be used as evidence of the manufacturer’s true “intended use” for the product; i.e., that it was being promoted for an off-label use. So if there was other evidence of off-label promotion, the off-label dissemination activities would be considered part of the totality of the evidence FDA would look at in pursuing enforcement.

As noted above, when section 401 sunset, FDA was unsure of what to do with off-label dissemination in this apparent legislative and regulatory void. It became clear that industry had an expectation— indeed, a constitutional right—that it would continue to enjoy the ability to disseminate materials in accordance with the constitutional law decided in the WLF case and the former section 401 of FDAMA. The question before FDA was whether it should promulgate binding regulations having the force and effect of law or publish a Guidance document sharing with industry its nonbinding Guidance about FDA’s views on how off-label dissemination could be lawfully conducted. FDA chose the latter: to issue a Guidance document on off-label dissemination. But it has not been without its own controversy.

In 2006 FDA established an internal working group to begin work on this document since FDAMA was to sunset on September 30, 2006. By fall of 2007, FDA was close to publishing the Guidance document in draft when the Draft Guidance was leaked to Congressman Waxman’s staff. Congressman Waxman wrote a long letter that in strong terms derided FDA for creating a document that would essentially allow industry to avoid seeking approvals for new use(s) of products, since it could more cheaply and easily just disseminate information about the new off-label use(s). Representative Waxman asserted that permitting even limited dissemination of off-label information would “short-circuit FDA review and approval … [which] undercuts the prohibition on marketing of unapproved uses of drugs and devices and puts the public at risk for ineffective and dangerous uses of drugs.”

While acknowledging a manufacturer’s First Amendment right to disseminate off-label information under certain parameters and conditions, Congressman Waxman requested that then-Commissioner Andrew von Eschenbach refrain from finalizing the proposed Guidance document until the Congressman could hold congressional hearings on the matter. Despite this request, the Commissioner promulgated the Final Guidance in January 2009, just before the Obama administration took office.

FDA has permitted off-label dissemination to occur in two forms: 1) responses to unsolicited requests, and 2) the proactive dissemination of peer-reviewed medical journal reprints and medical textbooks addressing off-label uses of approved products. Unfortunately, in the case of responses to unsolicited requests, there was very little guidance from FDA regarding the contours of acceptable practice. It has, however, been a longstanding practice and unofficial position of FDA to allow off-label dissemination in response to unsolicited requests from healthcare professionals. As discussed briefly above, industry now has Guidance on off-label dissemination from FDA’s Reprint Guidance document and a Guidance document on responding to unsolicited requests for off-label information. We do our best to outline what we understand FDA’s future expectations to be.

1. Unsolicited Requests

Imagine you are FDA and a doctor calls you and says that he has a critically ill patient whose only hope is to take a drug approved for another use. This doctor tells you that he has read something about the use of this drug in patients with the disease afflicting his patient, but he does not know anything about appropriate dosing. He wants to call the manufacturer of the drug and ask if it has ever done a study that would shed some light on the appropriate dosing for patients like his. What do you, as FDA, say?

As you might imagine, it would be very hard for the FDA personnel to say no. Securing that information may well save the patient’s life, and the doctor is trying to act responsibly by getting as much information as he can before taking that route. The company that makes the drug has done nothing to promote the use, but rather the new use was identified by independent researchers. That is essentially how the unsolicited request doctrine started, and it was many years ago.

Only recently has FDA begun to truly define the scope of the unsolicited request doctrine. In December 2011, FDA published a draft “Guidance for Industry: Responding to Unsolicited Requests for Off-label Information About Prescription Drugs and Medical Devices.” In that draft, FDA seeks to finally define with some precision how a company may respond to an unsolicited request, but also takes the opportunity to discuss this topic in the context of social media. Thus the scope of the document goes well beyond replying to traditional requests by doctors, and addresses such topics as the discussion of off-label use in an Internet chat room.

To FDA’s credit, the Guidance document starts by acknowledging the public health benefit of drug and medical device companies sharing information on important scientific issues. Throughout the document, FDA also expresses its significant countervailing concerns that manufacturers not promote unapproved products, and concern for the quality of the information shared. FDA tries to balance those competing concerns in its current draft, but we will have to wait to see what the final draft produces.

In the draft, FDA first tackles the issue of what is a truly unsolicited request. This is a difficult concept for companies to master, because it requires them to be completely reactive rather than proactive. That’s an unnatural trait in the business world. FDA certainly seems to have a narrow view of what qualifies as an unsolicited request, offering numerous examples to make its point. Taking just one of the agency’s examples, in example 8, FDA states:

A firm asks or otherwise encourages users to post videos about their own uses of its product on third-party videosharing sites (e.g., YouTube), which may result in video postings about an off-label use of its product. If the firm’s initial request for posting of videos results in any questions about off-label uses, or if any off-label video posting made in response to the firm’s encouragement of video postings results in questions about the product’s off-label use, these questions would be considered solicited requests.

That’s extremely limiting. Notice that the example does not say that the company encouraged the posting of off-label information; apparently it just encouraged the posting of experiences generally, and that caused any subsequent questions to be considered solicited.

Once a company figures out whether a request is truly unsolicited, then it needs to figure out whether the request is public or private. That’s not too complicated. Basically if the request is made in the physical or virtual presence of others, it’s public. But the consequences of that are significant. FDA does not want companies responding to public unsolicited requests other than to direct the requester to privately contact the company’s Office of Scientific or Medical Affairs.

So if a request is truly unsolicited and if it is made privately, FDA will permit the company to respond in the following manner:

(1) The information supplied may only be given to the individual making the request.
(2) The information supplied must be tailored to answer only the specific question asked. This may mean that the company needs to get the requester to refine his or her question to make it more specific. This is in no way a suggestion, though, that the company in responding should omit information that is necessary for fair balance.(3) The information provided should be truthful, nonmisleading, accurate and balanced. Among other things, this means including data that is not supportive or casts doubt on other data that is provided. For example, the company might need to provide copies of articles reaching contrary conclusions. Further, FDA takes an approach that is very similar to its good reprint practices, in that it wants the articles provided in complete form. Unpublished data can be provided, but FDA makes its preference for published articles plain.
(4) The information should be scientific in nature. This goes to the tone and the presentation format, making sure that marketing-type claims are not included.
(5) The information should be provided by medical or scientific personnel independent of sales and marketing. So not only do these personnel need to be qualified by experience and training, but also they must have the latitude to answer these questions without pressure to encourage sales. FDA clearly doesn’t believe that sales and marketing personnel are qualified to play this role.

(6) The information must include a variety of other affirmative statements such as the FDA required labeling, a statement that the uses are off-label, a “prominent” statement regarding the approved uses, important safety information and a list of references.
(7) As always, FDA also expects the company to maintain records showing the nature of the request, the information provided and any follow-up.

As already mentioned, FDA takes a very different view if the request comes in publicly. This is true whether it’s in an auditorium full of people, or in a chat room or other virtual gathering. The restrictions FDA places on this sort of discourse seem extremely severe. Indeed, one of the restrictions is that a company may not respond publicly with off-label information, but instead should only give contact information at the company for the requester to follow up. Frankly, if no off-label information is provided, the rest of the FDA restrictions seem to make little sense.

Specifically, even though FDA does not allow providing off-label information, FDA goes on to say that in providing a response to a public off-label question, the following restrictions apply:

(1) The company may only respond when the question pertains specifically to its own named product, and is not relating to a competitor’s product.
(2) People who answer these questions should disclose their involvement with a particular firm.
(3) The response should not be promotional in nature or tone.
It seems a bit odd to impose these restrictions when FDA also says that it will not permit the sharing of off-label information in that context.

Hopefully some of these issues will be resolved before the draft becomes final. But in the meantime, this Draft Guidance is the most concrete explanation of FDA’s current thinking with regard to unsolicited requests and memorializes longstanding unwritten policy folklore.

2. Proactively Disseminating Peer-Reviewed  Articles About Marketed Devices

As the reader knows well, Congress passed FDAMA in 1997. That legislation included a safe harbor that defined how drug and device companies could disseminate peer-reviewed journal articles and textbooks to physicians without being accused of off-label promotion. That process has now expired through a sunset provision in the original legislation. Few companies employed that process because it was burdensome, and included a commitment to certify that the company would, within a specified time frame, pursue approval or clearance of the new use.

The reader also recalls that in the late 1990s there were a series of judicial decisions involving WLF and its challenge to FDA Guidance documents and the legislation on the basis of the First Amendment. While part of the original trial court decision was set aside on other grounds, it included some interesting discussion of how a company could ensure that the information it was providing found protection under the First Amendment. The trial court’s advice suggested that a prudent manufacturer would do the following:

• use only articles from bona fide peer-reviewed journals or textbooks published by a bona fide independent publisher,
• only provide the information about approved or cleared products,
• ensure that the materials are not false and misleading,
• disclose the off-label nature of a use, and
• disclose any relationship between the company and the authors.

While the trial court’s decision was reversed in part, the discussion around those factors is still one of the most thoughtful and useful discussions available.

As explained at the opening of this chapter, in spring of 2008, FDA published a proposed Guidance document addressing these issues. In the comments filed, many concerns were raised. Indeed, the proposal was the subject of quite a bit of congressional controversy; nonetheless FDA published the Final Guidance in January 2009.

3. FDA Reprint Guidance

Although it does not carry the legal weight of FDAMA and does not completely mirror FDAMA or its implementing regulations, the Reprint Guidance includes several of the same themes. The Reprint Guidance addresses four specific areas: 1) the type of publishing organization that can produce information to be disseminated; 2) the types of influence a manufacturer should not have over the information to be disseminated; 3) appropriate and inappropriate content of the information to be disseminated; and 4) the manner in which the information can be disseminated lawfully. Notably, the Reprint Guidance does not require manufacturers to submit to FDA certain reprints intended for distribution or supplemental applications concerning the unapproved uses described in a reprint.

Specifically, the Reprint Guidance establishes the following criteria:

• The type of publishing organization. The organization publishing a journal article must: 1) utilize an independent editorial review board composed of members with demonstrated expertise in the subject matter of the article under review who are free to objectively select, reject, or comment on proposed articles as it deems appropriate; and 2) have a publicly stated policy regarding full disclosure of any conflicts of interest or biases of the authors, contributors or editors. The editorial board also must follow the organization’s established peer-review procedures and publish journal articles in accordance with those procedures.3 Any such article must not be in the form of a special supplement or publication funded in whole or in part by one or more manufacturers whose product is the subject of that article.

• Influence of the manufacturer. To ensure objectivity, reference publications written, edited, excerpted or published for, or at the request of, a product manufacturer may not be disseminated. In addition, a disseminated reference publication must not have been edited or significantly influenced by the product manufacturer, or any party in a financial relationship with the manufacturer. Similarly, manufacturers may not disseminate special supplements or publications that a manufacturer funded in whole or in part.4 Finally, a reference publication may not be primarily distributed by the manufacturer, and must be generally available, for example, in bookstores or other locations where medical textbooks are sold.5
• Content of disseminated information. The information must meet the following standard to qualify for dissemination. The information must address “adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate the safety or effectiveness of the drug or device.”6 This can include historically controlled studies, pharmacokinetic (PK) and pharmacodynamic (PD) studies, and meta-analyses.

FDA provides additional clarification to this standard using the following guidelines to describe articles or reference texts that might be untruthful or misleading:

• the article to be disseminated should not be characterized as definitive or representative of the weight of credible evidence derived from adequate and well-controlled clinical studies if:
— it is inconsistent with that weight of evidence; or —  a significant number of studies contradict the article or reference text’s conclusions.

• the information to be disseminated was withdrawn by the journal or disclaimed by the author; and/or

• the article or reference text discusses a clinical investigation where FDA deemed the studies to be inadequate or not well-controlled.

In addition, the information disseminated in a journal article or reference publication must not pose a significant risk to the public health.

Examples of publications inappropriate for distribution include the following: letters to the editor, abstracts, reports of Phase I trials in healthy subjects, and reference publications with little or no substantive analysis of the clinical investigation and resulting data.

Manner of Dissemination. Particular considerations apply to how and when a journal article or reference publication may be disseminated.

• The information provided must be in its original state. The information must be disseminated in its original state (i.e., an unabridged reprint or a copy of an article or reference publication). The reprint or copy may not be edited by the manufacturer in any way, including marking, highlighting, summarizing or characterizing.
• It must include prescribing information and a bibliography. The information must be accompanied by a copy of the approved product labeling and, unless already contained in the body of the distributed material, a comprehensive bibliography of articles or texts discussing adequate and well-controlled studies of the relevant unapproved use. In addition, the information must be accompanied by a publication representative of any articles or texts reaching contrary or different conclusions.
• Requires a disclaimer. The disseminated information must bear a permanently affixed and prominently displayed disclaimer, stating that the subject use of the product has not been approved or cleared by FDA. The disclaimer must also disclose the following:

— the manufacturer’s interest in the product;

— any author known to the manufacturer with a financial interest in the product or manufacturer;

— any author known to the manufacturer as having received any compensation from the manufacturer;

— any person known to the manufacturer as having provided funding for the study; and

— any significant safety risks regarding the unapproved use of the product that are known to the manufacturer and not discussed in the disseminated publication.

• Dissemination cannot be part of promotion. Finally, dissemination of reprints for educational purposes must take place separate and apart from promotional activities. Guidelines for establishing this separation include the following:
— a reprint may not be physically attached to any promotional materials distributed to a healthcare provider by a sales representative;

— sales representatives may not discuss the content of a reprint with a healthcare provider;

— a reprint may be distributed at medical or scientific conferences occurring in an academic setting, but not at promotional exhibitions or speaker programs.

The Reprint Guidance represents recommendations for industry based upon FDA’s current thinking regarding the distribution of scientific and medical information regarding unapproved uses. However, there is no statutory assurance for FDA’s position on reprint dissemination as there was under the FDAMA safe harbor, and FDA states on its website that “guidance documents … do not create or confer any rights for or on any person and do not operate to bind FDA or the public.”9 Accordingly, a manufacturer’s failure to comply with the recommendations set forth in the Reprint Guidance does not constitute a per se violation of law, and a manufacturer’s compliance with the Reprint Guidance does not confer an absolute assurance that the dissemination will not result in an enforcement action. Rather, in the Reprint Guidance, FDA asserts its continuing regulatory authority to determine “whether distribution of medical or scientific information constitutes promotion of an unapproved ‘new use,’ or whether such activities cause a product to violate the FD&C Act has not changed.”10 FDA expresses its intent to exercise its enforcement discretion, such that, “if a manufacturer follows the recommendations described in Section IV of this guidance, FDA does not intend to consider the distribution of such medical and scientific information in accordance with the recommendations in this guidance as establishing intent that the product be used for an unapproved new use.”

It is important to note that the Advanced Medical Technology Association (AdvaMed), in its comments to the draft Reprint Guidance, complained that the bar for information qualifying for dissemination was far too high for the medical device industry. Indeed, not many medical devices, other than premarket approval (PMA) devices, come to market with an adequate and well-controlled clinical trial. AdvaMed argued that the “adequate and well controlled” standard is higher than that set by FDAMA and Part 99 and what may be required for the approval or clearance of devices. In the case of a PMA device, approval is based upon “valid scientific evidence,” which under FDA regulations (21 C.F.R. 860.7(c)(2)), includes:

…evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device … The evidence may vary according to the characteristics of the device, its conditions of use, the existence and adequacy of warnings and other restrictions, and the extent of experience with its use. (Emphasis added.)

Reading this definition, “valid scientific evidence” is much more than simply adequate and well-controlled investigations; it can include information that one would argue has an indicia of credibility, but may be of lesser quality than information derived from an adequate and well-controlled investigation. AdvaMed suggested deleting the “adequate and well-controlled” language and simply using the “scientific soundness” standard applied in FDAMA and Part 99. Instead, FDA in the final Reprint Guidance kept the “adequate and well-controlled” language along with the “scientific soundness” standard so the language incorporates both concepts and reads: “adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate the safety or effectiveness of the drug or device.” Time will tell how FDA will interpret this language.

In the case of a 510(k) device, the impact of FDA’s Reprint Guidance standard is even more severe. The quantum of medical and scientific evidence necessary to clear a 510(k) rarely, if ever, meets this standard and is not required to do so. In fact, very often medical device manufacturers will submit information to FDA seeking clearance of a device, or the addition of a new indication for use, based upon information that would support such clearance but would not qualify for dissemination under the definition used in the Reprint Guidance. Stated alternatively, it is ironic that information that would not qualify for dissemination under the new Reprint Guidance could be used to obtain clearance for a medical device.

Before AdvaMed made its comments to the Draft Reprint Guidance, the standard was very limited and a very high bar for any company, especially a medical device company, to achieve. It read as follows:

The information contained in the scientific or medical journal article or reference publication should address adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate the safety or effectiveness of the drug or device.

When the Reprint Guidance was finalized, it appeared to make some concessions to the points made by both the Pharmaceutical Research and Manufacturers of America (PhRMA) and AdvaMed that the standard excluded a lot of potentially good and important scientific information. The additions are important accommodations on FDA’s part and are found in the italicized sentence below:

The information contained in the scientific or medical journal article or reference publication should address adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate the safety or effectiveness of the drug or device. These can include historically controlled studies, pharmacokinetic (PK) and pharmacodynamic (PD) studies, and meta-analyses if they are testing a specific clinical hypothesis.

It remains to be seen how FDA will interpret this language as well. Will FDA treat this as the sum total of all exceptions to the “adequate and well-controlled” standard or examples of additional types of information that may qualify for dissemination?

Most importantly, it remains to be seen if the new Reprint Guidance will be challenged constitutionally and will pass muster under the First Amendment. One could argue that information of a lesser quality than that stated in the Reprint Guidance, i.e., not from peer-reviewed journal articles extracted from adequate and well-controlled clinical trials, but still having some indicia of scientific credibility, should qualify for dissemination. This is especially true if the material to be disseminated is properly qualified with disclosures and disclaimers about the off-label nature of the information to be disseminated and if the limitations of the information to be disseminated are conspicuously pointed out to the reader. What if the reader is told that he or she should be aware of the limited nature of the information contained in a nonpeer-reviewed article, or an abstract or poster? For example, the disclosure and disclaimer could include any or all of the following: that the information is not taken from a peer-reviewed publication; the number of patients in the study is small; there is no statistical power or significance to the findings; or the inclusion criteria or endpoints are deficient in some way or fashion. These are among the many disclosures and disclaimers and others that could be made.

Clearly there is information short of the standard articulated in the Reprint Guidance that would qualify for lawful dissemination. Suppose the information to be disseminated had the following attributes: 1) information having a sufficient indicia of credibility (albeit short of an adequate and well-controlled trial in a peerreviewed publication), 2) accompanied by appropriate disclosures and disclaimers, 3) accompanied by a bibliography of other articles that might reach the same or different conclusions, and 4) a letter accompanying the information, or a sticker permanently affixed to the information to be disseminated, which discloses the manufacturer’s involvement in the study and/or relationship with the investigator. Would it be appropriate, under the First Amendment, to disseminate the information despite the fact it would not qualify for dissemination under FDA’s new Reprint Guidance (i.e., the information was not taken from a peer-reviewed journal)? These authors suggest that information disseminated with this type of content and in the manner suggested might qualify as being truthful and not misleading under the First Amendment so that it could be disseminated, despite the limitations in FDA’s Reprint Guidance. Surely the First Amendment protects more than just pristine information taken from peer-reviewed journal articles or the other list of “qualified” exceptions. What about a poster selected for presentation at a major medical convention that reviews a medical device that is from an investigator-initiated trial involving 15 patients? Suffice it to say, the constitutional questions do not end with the publication of this Reprint Guidance; they continue.

So what is a drug or device manufacturer to do with the new Reprint Guidance? Most companies, especially large companies, will simply follow the Reprint Guidance verbatim. Other, usually smaller, companies will look at all of these historical discussions, and legal precedent, and develop their own conceptual approach that can be defended on the basis of good public policy. That means developing an approach that the company feels it could defend to FDA, to the courts and to its customers. Below we propose one such approach. We think this approach weaves First Amendment factors with good public policy to justify the use of journal articles that on balance would do more good than create risk.

a. Questions to Ask During the Review of an Off‑Label Peer‑Reviewed Journal Article
(1) Regulatory Status. What is the regulatory category in which the article is marketed (e.g., 510(k) vs. PMA, or NDA vs. GRAS), and what does that say about risk associated with the article?

(2) Type of Off-label Content. To what extent are any statements in the article inconsistent with, or go beyond, the approved or cleared labeling, including the package insert?

(a) Any new indications for use, or intended use?

(b) Any difference in directions for use?

(c) Any difference in performance claims made?

(d) Any other difference? You need to address the outcome of this issue—e.g., what is the difference—before you reach question 3. If there are no differences, stop here. The article may be used subject to copyright law and subject to a review for other compliance issues unrelated to off-label use.

(3) Public Health Value. From a scientific and public health standpoint, why do customers need to see this article? Using a societal perspective, how valuable is the scientific information to the doctor and the patients he or she treats? If the company has to justify some slight off-label content, the use of the article needs to benefit the doctor enough to justify its use.

(4) Ability to Avoid Merely Incidental Off-label Information. Can you avoid giving out the off-label content? Can you get the useful on-label information to doctors another way that is just as effective, or nearly so?

(5) Regulatory History. What is the regulatory history of the off-label use? Has it been presented or submitted to the agency? Has it been rejected? Is there a plan to submit the off-label use for clearance?

(6) Health Risk. Does the off-label use present a health risk? If you are wrong, and the drug or device is not as effective for that use as the article suggests, what is the risk to the patient? How much do you know about the safety profile of the drug or device when used for the off-label purpose?

(7) Evidence Quality. How valid is the science or the study that underlies the article? Is the methodology sound? Do the conclusions appear valid? Does the study design appear to comply with Good Clinical Practices? If FDA reviewed the study, would it find fault? How close do the study data come to meeting the FDA standard to justify their use on-label? If the article compares drugs, does the evidence supporting that comparison meet the FDA evidentiary requirements for such statements (two adequate and well-controlled studies)? Do other articles or studies contradict the conclusions?

(8) Author Ties. What are the ties between the company and the author? To what extent could the outside world conclude that the company has influence over the author?

(9) Peer-Review Process Robustness. How robust is the journal’s peer-reviewing process? How rigorous was the review? How respected is the journal? How rigorous are the journal policies that separate content from advertising? Are there any ties between the journal and organizations that might receive money from the company?

(10) Fair Balance. How is the information presented in the article? Does the author achieve fair balance in the discussion? Are there any apparent biases in the material? Are any of the statements misleading?

(11) Disclosures and Disclaimers. Is there a way to minimize the risk of an incorrect reading of the article by stating its limitations or weaknesses through disclosures or disclaimers? Is it practical to clarify what is on- and off-label? Does disclosing any relationship with the author cure potential for bias? Should you specifically warn against the off-label use?

(12) Overall Pattern of Promotion. Does the company do anything else to communicate the off-label use to the public, such that FDA would conclude there is a pattern or practice of off-label promotion?

Obviously these criteria do not yield a quantitative decision. They are merely factors to consider. How does a company evaluate these factors and make a decision? There is no magic formula; rather, it simply calls for good judgment and balancing of the various factors. Below we suggest some review criteria that the company could apply.

b. Review Criteria
(1) To use an article containing off-label information, the article must produce a value to the doctor. After all, due care has been taken to minimize any risk. The scientific value of getting the information to the doctor must be weighed against the risk that information will turn out to be wrong and the use will turn out to be unsafe or ineffective.

(2) Be careful when you know the agency is sensitive to a given use being promoted. For example, where the agency has explicitly reviewed and rejected a given use, you should consider not disseminating articles about it. There are times, however, where the dialogue with the agency is either not definitive or where the agency is fairly open about what is on- and off-label and disagreements do occur and discussions ensue. In cases where the agency disagrees with the off-label use and the company still would like to disseminate the information, there is a corresponding need to ensure the quality of the data being disseminated is very high (e.g., from robust clinical trial results published in a peer-reviewed journal).

(3) Take all practical steps to reduce the impact of the off-label portions (e.g., by using disclosure statements), or if such content is dominant, to disseminate the information appropriately.

(4) Ensure transparency for any article where there is a material implication that the author could be deemed to be speaking for the company, or biased in favor of the company.

(5) Consider whether the peer-review mechanism is not strong and independent, and balance that against the other factors.

(6) Avoid articles where the content in the article is not fairly balanced.

(7) Provide articles that may balance the article to be disseminated and consider how disclosures or disclaimers might draw the reader’s attention to deficiencies in the test methodology or conclusions of the authors or other limitations of the study design or conclusions (i.e., the study was not a randomized, controlled clinical trial).

To make sure that this is even more complicated, the review does not produce a simple decision either to use or not use the article. While that is certainly a threshold question, if there seems to be some value in using the article, the question quickly becomes how the company should use the article. There is not enough space here to discuss each and every possible use for an article, but we have broken it down simplistically into four possibilities that reflect a range from high-risk articles to low-risk articles. Based on a review of the dozen factors listed earlier, if an article is proper for use under some circumstance, into which of the following categories should the article be placed? We have suggested some rules of thumb for how a company might place articles in each of these four categories. We should underscore as we said before that this is not based on any written law, but our assessment of the ultimate purposes of dissemination.

(1) Distributed only by medical affairs in response to a documented request for the specific information

(a) For articles where the primary thrust is off-label

(b) For articles that discuss any new indications for use, or intended use

(2) Distributed by the sales force only in response to a documented off-label request with restrictions, such as disclaimers, disclosures or other limitations

(a) For articles that contain some off-label content, are well-done studies, and have high public health value

(b) For articles that discuss any difference in directions for use

(3) Distributed by the sales force with restrictions, such as disclaimers, disclosures or other limitations on the type of physicians who might receive them

(a) For articles where the content includes minor off-label information, and the value of the article to doctors is high scientifically

(b) For comparative articles that discuss a difference in performance claims made

(4) Distributed by the sales force freely

(a) Articles that are entirely on-label While we believe the above represents a possible framework for deciding if and how to disseminate literature, every company should probably decide for itself what makes the most sense in its industry with its products.

We truly hope that Congress or the courts (or even FDA) are able to give specific and authoritative guidance to companies trying to make these decisions. Disseminating important literature can be very helpful in advancing the public health, and hopefully governmental authorities will soon reach a decision on the best way to do so.

C. Communications About Off-Label Uses

“Communication” as it is discussed here is often technically “promotion.” Many of the types of communication activities discussed in this section would be considered promotion, except for the context in which they occur. For example, if a marketer discusses off-label uses with a physician it is illegal promotion. But if that discussion takes place in the context of a market research focus panel, the discussion is perfectly permissible and even necessary for the company to conduct to properly position its product for a commercial launch. Of course, in either event the marketer would have to disclose the off-label nature of the discussion. In the first example, the disclosure does not remedy the illegal nature of the off-label discussion. Yet in the second example, a disclosure provides a proper foundation for discussing the off-label use prior to extracting the market research and it is perfectly permissible. There are a number of ways in which legitimate pre-approval dialogue can take place without putting the company in jeopardy with the law, and companies need to explore them. The “communication” bucket is where many of these opportunities or tactics reside.

1. Getting Marketing Utility Out of a Clinical Exercise

It is almost heresy in clinical trials to think, let alone suggest, that the clinical trial might present an opportunity to begin marketing your product. After all, the very purpose of a clinical trial is to determine the safety and effectiveness of a product and to serve as the foundation for the claims to be found in the label, labeling and advertising. The point is more about product awareness so that the market is aware of a product as it progresses through the pipeline. Certainly, a company cannot promote a product prior to its approval, nor can it promote an approved product for off-label uses. In the context of a clinical trial, a company cannot talk about the safety and effectiveness of an unapproved product or indication. But a company can talk about a clinical trial in scientific and straightforward terms and discuss things like the trial endpoints, inclusion and exclusion criteria, and what the trial is designed to show and how. If a company walks this line ethically and intelligently, the company can legitimately and lawfully make the market aware of the new product and its use in many ways. In this manner the marketplace can be prepared for the approval and launch of a product.

This section discusses the myriad ways that companies may lawfully discourse about off-label uses without having it considered a violation of the FDCA. While many of these types of activities are, in isolation, perfectly lawful activities, prosecutors will always look to the totality of the evidence they have against a company to establish the company’s true intended use for that product. If that true intended use is an off-label use, it can cause perfectly legal activities to be tainted by the illegal off-label promotion. In this way, the otherwise legal activities look as if they are in support of an overall plan of illegal off-label promotion, as discussed in more detail in Chapter 7. It is therefore imperative that, when considering the activities in this section, the company is otherwise in compliance with the law and is engaging in the compliance program activities discussed at the very end of this chapter.

2. CME

Returning to the brief CME discussion commenced earlier, the company can legitimately support CME programs that discuss off-label uses of products. FDA, the Department of Health and Human Services Office of Inspector General (DHHS OIG) and Department of Justice (DOJ) are concerned that CME programs can have too much bias and can become promotional. They all recognize the need for CME and that industry underwrites much-needed CME programs. Their collective concern is how to keep it free from commercial bias and distorted truths about products that inform and persuade healthcare providers to uses that are not yet substantiated by adequate and well-controlled clinical studies.

While these concerns are legitimate, they are also somewhat paternalistic and misplaced on several fronts. FDA often puts itself in the position of being a filter for scientific and medical information that would otherwise flow freely to the marketplace. The First Amendment prevents the government from filtering information from society under the often well-intentioned belief that it is protecting people from information that might harm them. FDA should not stand in the way of a free flow of information getting into the hands of those who have a right to receive it, read it, digest it and make decisions regarding it. The First Amendment protects the exchange of medical and scientific information. Many important unapproved uses of drugs and devices are discovered by the medical community, and society benefits greatly from these discoveries. These are uses that FDA has not yet approved. Second, it must be recognized that not all uses will be correct or safe. Off-label use sometimes leads to scientific or medical failures, some small and some large. This does not mean that society should abandon the kind of scientific or medical discovery and discussion that takes place every day. To do that would be to substantially retard progress. Such risk averseness should not impede the kind of true progress that occurs from any of these medical advances, small or large. Third, while government prosecutors chronicle the failures in the off-label arena, they rarely acknowledge when a product, which has been subject to prosecution for alleged off-label promotion activities, is later approved for that very use. This is, in essence, a vindication of that formerly off-label use.

That leads to the need for sponsoring CME. The government is concerned that some medical education providers are so close to a company as to be an extension of the marketing department. In some cases that may be a legitimate concern. CME conducted by an academic institution may at least appear to be free of industry influence. But many third-party medical education providers make their livelihood entirely off the industry. Indeed, some make their living off one or two companies. The question the government legitimately poses is can they truly be independent? For now, FDA, OIG and DOJ seem to accept that “accreditation” by an independent accrediting body will suffice to serve as the independence that society needs to ensure that programs are free from commercial influence. The leading accreditation organization in the United States is the Accreditation Council for Continuing Medical Education (ACCME).

ACCME has adopted the following standards for the sponsorship of accredited CME:

(1) Independence.
(2) Resolution of Personal Conflict of Interest.
(3) Appropriate Use of Commercial Support.
(4) Appropriate Management of Associated Commercial Promotion.
(5) Content and Format Without Commercial Bias.
(6) Disclosures Relevant to Potential Commercial Bias.

While the ACCME is very influential and its standards are sound, industry should be careful to avoid anointing one nongovernmental body as the sole accrediting authority because government (i.e., FDA), has in the past tried to make ACCME’s requirements de facto regulatory requirements without going through rulemaking. This would, in effect, make ACCME a quasi-governmental body without all the checks and balances we have in government. Many organizations from medical societies to major clinical institutions like the Mayo Clinic, Johns Hopkins or Stanford University, certify CME programs. This plurality of CME certifications need not give way to one monolithic organization like ACCME. ACCME, however, and its certification requirements are becoming more universally accepted as those requirements needed to ensure independence, objectivity, balance and scientific rigor for CME programming.

When conducting CME, to meet ACCME or other standards, the provider will be concerned with the role the company wants to play in the conduct of the program. A CME program is an educational venue, not a promotional venue. Therefore, sales and marketing activity should not take place in the room in which the presentations are given. There should be no sales and marketing people in attendance whose job it is to ask leading questions directing the discussion. The company can be listed as a sponsor and marketing or sales activity can take place before or after the educational session in the hallway or exhibit area outside of the presentation room. The company can assist the speakers, if requested, with slide materials, but cannot create the presentation for the speaker. Sponsoring meals and refreshments is allowed. Suffice it to say, there are many rules to follow in the conduct of a CME program.

3. CME as an Informal Safe Harbor

The bottom line is that CME has become sort of an informal safe harbor. Under the CME rules of any organization, manufacturers cannot choose the content of and speakers for CME and then fund and call them “independent” educational activities. The ACCME rules truly require independence from manufacturers. Still, a manufacturer can fund CME programs that are aligned with their commercial interests and, if given the opportunity to comment by a CME provider, the ACCME rules do allow for a manufacturer to suggest content and speakers. Many medical education providers today do “needs assessments” of the medical community to determine what it is they want to hear about and learn. This is different from the past where manufacturers dictated the content. The rules also provide that manufacturers cannot control the invitations to a program, although some invitations may be provided for the manufacturer to give to physicians. Among other things, typical CME rules require program organizers to disclose funding by a manufacturer and for speakers to disclose financial or other involvement with a manufacturer. The rules also prohibit manufacturers from engaging in marketing and sales activities during the program. These and many other safeguards allow manufacturers lawfully to support CME programs that may address off-label uses of their products.

4. “Hybrid” Programs

The tougher call occurs when a reputable institution asks a company to sponsor a grand rounds speaker to make a presentation that may include discussing an off-label use of the manufacturer’s product. Or maybe the program is simply sponsored by a hospital for its staff and covers an off-label use. Alternatively, a program could be sponsored by a county medical association. Those are called “hybrid” programs because they are not necessarily CME accredited programs, nor are they intended to be promotional; they are somewhere between. These programs typically do not carry the stature or independence designed into ACCME accredited programs, yet they are truly not designed to permit a promotional presentation by the company about its product. In these cases, the manufacturer’s legal or regulatory staff has a more difficult decision to make about whether the program should be treated as promotional. Among the factors to consider are: who initiated the idea for the program, who put it together, was the company guaranteed a speaker of its choice, will promotional literature be available, will the program be scientifically balanced, will disclosure be made?

Supporting accredited CME survives as a viable way for manufacturers lawfully to support communication regarding off-label uses of their products. Supporting unaccredited CME or “hybrid” programs poses more risk and requires careful analysis. Before the company simply gives away grants for CME programs, it should have a process and a procedure for doing so. The company should also create a committee to receive and consider requests for funding CME. This committee should not be dominated by sales and marketing staffers. Instead, they should have minority votes on the committee. Some companies give sales and marketing a nonvoting role or do not allow them to participate at all. The company should also have standard operating procedures outlining the criteria for CME grants.

If the CME process within a company is dominated or corrupted by the sales and marketing departments, the government will be very cynical about grants emanating from it. That is not to say that sales and marketing cannot be involved in the process. Many companies take that position, but these authors do not. Marketing and sales personnel have every right to be interested and involved in the grant-making process, but they should not be allowed to be the predominant voice and majority vote. They are intimately involved in the commercialization process and close to the voice of the customer. They often can articulate what the customer is most interested in hearing about in CME programs. Their contributions are valuable, but must be balanced against their self-interest in selling products—no matter whether on- or off-label.

Government prosecutors have a built-in cynicism that bias will be introduced whenever sales and marketing staff are overly involved in creating and implementing CME programs. If grants for CME simply become an extension of the marketing department’s activities, the sales department starts to project a “return on investment” for these programs, and off-label sales projections become part of the company’s internal plans, hazards are created. Such actions can be evidence of a company’s true intended use of CME as a ruse for its off-label promotional activities. But CME properly documented and conducted is defensible medically, morally and constitutionally.

Companies always ask, if they assist in creating the slides at the request of the physician and the main presentation is completely on-label, can there be backup slides that anticipate and address off-label use? The answer is no. If the company creates slides about off-label uses in anticipation of those questions being asked, then it is off-label promotion. The creation of backup slides suggests an intent to cover off-label uses in advance of that actually happening during the question and answer period of the program. The preparation of the backup slides on off-label use suggests that the true intended purpose is to employ the main presentation to set up a desired discussion of off-label uses during the question and answer session. It is acceptable for any paid speaker to answer unsolicited questions about off-label uses as long as they are truly unsolicited. The speaker should not appear to be overly prepared for off-label questions (i.e., providing the audience with slides and commentary when off-label questions arise).

5. Non-CME Programs

The company can also sponsor non-CME programs in which physicians are hired to speak about a company’s products. The benefit is that the company can plan for and drive the agenda for these meetings, where and when it wants, and invite the attendees. The downside, of course, is the programs must be limited to on-label content, except in the question and answer period of the program. They also lack the independence that makes CME programs more attractive to attendees. These speakers are considered promotional speakers— even if their content is highly scientific—because the company has paid them to be on the podium. These programs are promotional and they must be on-label. This could be for individual ad hoc programs or part of an organized speakers’ bureau that is planned and executed at dinner meetings or other venues throughout the year. As with the discussion above, there should be no backup slides anticipating and addressing off-label uses.

6. Company-Sponsored Trials—Clinical Trial Recruitment

When companies conduct clinical trials, a natural pathway is created that allows the company to communicate about the product to be studied. There is a need in conducting the trial to recruit qualified clinical investigators and referring physicians who can refer patients into the trial. A company can engage in advertising and promotion both for clinical trial investigators and referring physicians, and even patients. Clinical trial recruitment is becoming increasingly important to companies that compete for a shortage of patients. As noted above, the clinical trial recruitment process allows one to make the marketplace aware of a new therapy coming to market.

On the medical device side, FDA has created a Guidance document called a Notice of Availability (NOA) for this purpose. The Guidance document is entitled “Preparing Notices of Availability of Investigational Medical Devices and for Recruiting Study Subjects” (March 19, 1999). The NOA allows the company to recruit clinical investigators into a trial by placing advertisements in trade journals and other appropriate places that would be read by potential investigators. FDA is sensitive to the over-utilization and overbroadcasting of the need for clinical investigators. FDA does not want to see the NOA process abused and amount to illegal pre-approval advertising for the product. By the same token, FDA acknowledges the legitimate need for clinical trial recruitment.

In an NOA advertisement, a company cannot state or imply the safety and effectiveness of the product. There can be no comparisons made with other products that imply superiority over other approved therapies. The company can talk about the particulars of the trial and provide the information necessary to inform and properly entice a potential investigator to find out if he or she wants to become an investigator. The company must clearly state the investigational nature and potential use of the product so physicians or patients are clear about its status. In publishing perfectly compliant advertising the company has the inevitable benefit of talking about its product or use in advance of FDA approval or clearance. This has the salutary benefit of creating awareness in the medical community and the patient community about the product prior to FDA approval and launch.

Many questions can arise when conducting clinical trial recruitment. Is the company reasonably targeting the type and number of physicians who need to be reached or is it overbroad? Is the clinical trial recruitment process a bona fide exercise or a ruse to advertise for the product pre-approval? In truth, recruitment efforts unavoidably do have a marketing component to them. They must, however, stay true to the intent behind them by disclosing the investigational nature of the product, make no suggestions that the product is safe or effective, make no comparisons to competitive products or treatments, and be targeted to an audience of appropriate size and qualifications. For example, the advertisement should not be targeted to general practitioners when the product will be implanted by neurosurgeons. A more interesting question comes up, however, if the general practitioners are needed to identify and refer patients to the neurosurgeons for enrollment and treatment.

For patient recruitment, one thing companies often forget is that any advertisement directed to recruiting patients is part of the informed consent process and advertisements must be approved by the Institutional Review Board (IRB). This is so the advertisements do not overly entice patients to participate based upon advertising that features the potential benefits of the product and minimizes the potential risks.

7. Company-Sponsored Trials—Anti-Kickback Issues

Another issue frequently encountered by companies and clinical trial sites is when the company confronts the anti-kickback statute in the course of conducting a clinical trial. A clinical trial provides the company with a legitimate avenue to pay the healthcare provider for the services performed, but this can also be used as a way to shield or disguise payments to customers who are or become high-volume prescribers of the company’s product. The first issue that must be addressed is whether the trial being conducted is bona fide research calculated to result in meaningful, actionable, usable clinical data or is it merely a “seeding” trial intended to get the product in the hands of as many clinicians as possible by using a clinical trial as a means to reward physicians for their use of the product. Trials of this nature often require nothing more than a simple survey form to be filled out by the investigator for which he or she is paid handsomely and disproportionately to the actual work being provided, or the work being provided is bona fide, but paid far in excess of its fair market value for the work being performed.

Another issue arises when companies provide free equipment and in-kind services that, in effect, underwrite the operating expenses of a clinical trial site. It is acceptable to provide computers and other equipment at a clinical trial site for the conduct of the trial. It is also acceptable to place personnel on site to assist in the conduct of the trial. But if the equipment is general purpose equipment and it is left behind at the site, this too may be a kickback if it is used for long periods of time beyond the completion of the clinical trial. The question is whether the equipment was dedicated to the clinical trial only or if it was used briefly for the trial and then left behind as remuneration to the healthcare provider. The other issue is when the company underwrites the cost of a nurse, for example, who acts as a clinical trial coordinator and his or her job is six months to one year in duration, but his or her salary is paid for two years. The remainder of the nurse’s time spent beyond the termination of the clinical trial working for the investigator may constitute a kickback. Both examples can be considered remuneration and a kickback under the antikickback statute to the extent that the in-kind payments underwrite normal operating expenses of the healthcare provider.

8. Investigator-Initiated Trials

A company cannot always fund all the research it would like to conduct because, as was stated at the beginning of this chapter, it has limited resources and must prioritize them. IITs provide a way in which companies can financially support the research interests of physicians who want to study additional uses of an already approved product. IITs are research proposals initiated by a physician on a use of a manufacturer’s product. Most IITs cover off-label uses, but not all. There are also gradations of “off-label.” Off-label does not necessarily mean a new and unapproved use. An on-label use of the product with a change in the dosing regime or use of the product in combination with another drug or device that is not found in the label is technically off-label too. A manufacturer can provide financial support for an IIT that studies an off-label use of the drug or device and require, as part of the funding, that an article be written and published covering that research use. This becomes part of the company’s publication planning. This is yet another legitimate way to communicate about an off-label use in a lawful way. If the underlying study and article are robust enough and do get published, particularly in a peer-reviewed journal, it may be disseminated by the company under the WLF case discussed above or FDA’s Reprint Guidance allowing for the dissemination of off-label information.

It is key for an IIT, to be properly supported, that the study be initiated by the researcher or physician and not the company. If the idea for the study came from the manufacturer and the study protocol was produced by the manufacturer, then the company may be deemed the “sponsor” under FDA’s IND or IDE regulations. As a sponsor, the manufacturer is responsible for many of the regulatory duties associated with the initiation, conduct, monitoring and reporting of the study. FDA does not like it when companies do an end-run around the IND/IDE regulations by having an independent physician appear to be the sponsor of a study when the company is really the sponsor. If the company is truly short on in-house staff and funding, it cannot take on both company-sponsored studies and IITs. Therefore, it is imperative that the company ensure that it is truly the “financial supporter” of an IIT and not the “sponsor” under FDA’s IND/IDE regulations. FDA regulatory counsel can help a manufacturer sort out where the line between a sponsor and a financial supporter begins and ends.

Another issue that has plagued IITs in the past occurs when the research being proposed is “makeweight” and the funding becomes a kickback under the anti-kickback statute. Sometimes the research being paid for is for a mere “survey” to be filled out that produces no meaningful, actionable, usable clinical data. Envision an instrument that takes about five minutes to fill out and simply surveys the patient’s condition, instead of a trial with a hypothesis and protocol. Here the real intent is to find a seemingly legitimate way to funnel money to a high-volume prescriber as a reward for past, present, or future prescribing behavior. These studies, sometimes called “seeding” trials, are not trials at all. They are merely conduits through which money is paid to a physician and for the product to get used. The funded research must be bona fide and paid for at fair market value by the company.

An IIT can produce information that can be part of a poster presentation, a major presentation at a medical convention, a publication and, potentially, an article that can be disseminated by the manufacturer. This is another lawful way to communicate off-label information. Before money is given for IITs, the company should establish standard operating procedures and a committee like that discussed above for the support of CME. Manufacturers often create formal committees that review grant proposals for IITs submitted by physicians and decide if the proposed research fits within the company’s research and commercial interest. As with grants for CME, the committee should have the same composition and struggle with the same issues as with CME. It should not be dominated by sales and marketing personnel.

Many issues arise with IITs. For example, can the company or financial sponsor have some control over the study? Who has written the study protocol and can the company collaborate with the investigator who proposed the study? Can the clinical trial agreement require milestone payments? Can the company “loan” employees to monitor and audit the study, engage in data management and analysis, and the like? Is IRB approval necessary? These and many other issues must be addressed between the investigator and the company before commencing the trial. Suffice it to say that the more indicia of creation and control that are present, the more it appears the company is the true sponsor of the trial. As a trial sponsor, a company cannot abdicate its responsibility to file an IND or IDE, if needed, and to run the trial as a company-sponsored trial with all the regulatory responsibilities attendant to that role. A company sponsor may also need to seek FDA approval to conduct the study, and must monitor the study, file reports, follow-up and submit reports to, and interface with FDA.

9. Investigator-Initiated Trials  and the False Claims Act

A final issue with off-label use arises in the reimbursement arena. There is reimbursement for off-label uses of products in clinical trials; this chapter will not exhaustively treat this topic, but will give a very brief overview. The Centers for Medicare & Medicaid Services (CMS) has policies in place for the reimbursement of products used off-label as part of a clinical study. Physicians and hospitals sometimes like to avoid this reimbursement path because it is more difficult to pursue than simply using an existing code and representing to CMS that the use is on-label and fits a pre-existing code. In addition, clinical trial sites often want to obtain free product for the trial, and medical devices can be very expensive. Frequently, the clinical trial site will treat the patient using the device and bill the government or the third-party payer for the device. This is, in effect, “double dipping” by seeking payment for a product that the clinical site received for free. On the federal government side CMS and the DHHS OIG police the False Claims Act along with the DOJ. Reimbursement for devices used in clinical trials is acceptable and can be lawful and not a violation of the False Claims Act if the product is declared “investigational” when reimbursement is sought and the government is aware of the off-label use. If a clinical site does not declare the use investigational and attempts to bill for the product using an existing reimbursement code for products that are currently on the market, then that can result in a violation of the False Claims Act. A violation of the False Claims Act can result in enormous fines for the physicians and the manufacturer. The company’s liability is derivative of the healthcare provider’s if it caused or induced the inappropriate reimbursement.

10. Patient Registries

Not infrequently today, FDA asks for postmarket follow-up on products in the form of a patient registry. Patients are followed up by documenting when they received a drug or device and for what clinical purpose it was prescribed. Often the prescribed uses are off-label. FDA then requires reports to be filed detailing this information. Companies often pay healthcare providers for that information. The data collection forms often must capture the off-label uses of a product and, by merely listing a potential off-label use on the data capture form, the company is lawfully communicating about the off-label use of that product. Companies are in a much safer position if FDA has required this registry and off-label usage is documented as part of an FDA request than if a company initiated the patient registry on its own and constructed a data capture form that discusses off-label uses.

11. Publication Planning

Companies, as part of a strategy to sponsor investigator-initiated trials, can also engage in a publication planning effort to support the publication of articles resulting from such research. There are many articles that may not be disseminated under the WLF case because they do not meet the rigorous peer-review requirement. But many articles are sponsored and written which are permissible “background noise” in the sense they discuss off-label uses, but cannot be disseminated. These articles form the background for medical or scientific discussion of a product in such off-label uses. A company should consider how it can support the writing of such articles that legitimately discuss these uses as well as peer-reviewed publications.

12. Consultancies

Companies use consultants for a wide range of purposes from designing products, for marketing input, strategic advisory boards, to advise on clinical trial design, to use as speakers and authors, and as clinical trial investigators. Industry and society require that companies seek out the best advice they can to accomplish these objectives. Therefore, companies hire physicians as company consultants. In doing so, a company often must share with consultants what clinical trial uses it is or may consider pursuing for its product. This allows for a legitimate and lawful discussion of potential off-label uses for a product. This right is not unlimited. The company must have a bona fide need for the consultant’s advice. It must hire only as many consultants as are needed to accomplish the purpose of the consulting, and the company must disclose the off-label nature of any uses of the product. Despite these caveats, the company can legitimately use consultants for a myriad of purposes. In doing so, the company can appropriately and lawfully discuss off-label use to the extent it is relevant to the object of the consultation.

13. Market Research

Market research is an extension of consulting in that the physicians hired in market focus panels and feedback groups and other marketing tactics are hired as temporary consultants. But their discrete function is to provide feedback to companies for marketing purposes. In these situations, companies must impart information to prepare for the marketing information that is to be extracted. The participants must know the topic of the consultation to provide the marketing input. When potential off-label uses are the subject of the market research, the company can lawfully communicate about off-label uses for the purpose of the marketing research effort. This often requires, however, disclosure of the off-label nature of the product before the input can be provided.

14. Physician Training

One of the most intractable problems a medical device company can face is when a product is approved for a very narrow purpose and then is used by physicians for an off-label use that has become common for the product. This is a problem not encountered by pharmaceutical companies, because they do not train physicians on the use of their products as medical device companies are required to do. In these situations, physicians often want training on the off-label use, but the company is precluded from doing so because to do so would constitute off-label promotion. The company must take extreme care not to begin training physicians on off-label uses. The only legitimate training that can take place is if during training, the attending physicians request assistance on a use of the product they believe they will encounter in their practice of medicine and it is an off-label use. Only then might it be permissible to delve into an off-label use. Training on an off-label use cannot be initiated by the company.

VII. Compliance—Process  and Procedure

Almost all pharmaceutical and medical device companies must confront the issue of off-label use of their products. Society certainly benefits from such use. There is legislative, judicial and administrative support for the use of products off-label. Congress, courts and FDA all acknowledge the fact and importance of off-label use of products in the practice of medicine and how it can and does advance medical knowledge and care. Yet, in the media and government prosecutions much criticism of off-label uses of products is seen. The reality is that companies cannot avoid off-label use of their products. It is part of the fabric of life in the healthcare sector. As long as the medical community is dedicated to finding the best solutions for patients, off-label use of products will occur. The point is to avoid pretending that off-label use is not occurring or conclude that it is somehow evil. Rather, the right response is to acknowledge that off-label use does and will occur and figure out how to handle off-label uses and resulting sales ethically, responsibly and lawfully. This allows companies to anticipate and prepare to address off-label uses. This will enable the company to avoid bad behaviors within the organization that might get the company into trouble by those who want to benefit from off-label sales.

The DHHS OIG has repeatedly spoken to the need for companies to have a program of compliance. The OIG eventually published the “OIG Compliance Program Guidance for Pharmaceutical Manufacturers” in 2003. The OIG made it applicable to the medical device industry in 2005. The compliance Guidance requests that companies put into place a compliance plan and appoint a person to be in charge of compliance with a degree of autonomy who reports at a high level within the organization or at least has direct access to the CEO, board of directors, other senior management and legal counsel.

The key to a compliance process, as set forth in more detail in Chapter 9, is not in deciding to create something like a code on interaction with healthcare professionals, although having a document like that is critical. Instead, it is the process the company goes through to create such a document. The discussions that ensue are invaluable and may represent the first time an organization ever conducts meaningful discussions about what it means to comply with the law and how dedicated the company truly is (or is not) to compliance. In debating and adopting specific language by which its corporate behavior will be judged, the company begins to understand and take stock of its level of cultural risk, from very conservative to high risk taking. It is equally important, once the document has been created, to give it life by not simply putting it on a shelf to collect dust, but to introduce it to the organization actively in educational and training sessions. Education is for understanding the laws that serve as the backdrop for compliance. Training is to introduce the company’s position on compliance issues, represented by its policies and procedures. Employees should not be expected to simply read a code and other policies and understand and comply with them. Training sessions designed appropriately will help them to come alive, and to be understood, applied and retained.

In addition, key committees will be formed for things like promotional reviews, grants for CME and IITs, pricing and the like. These committees allow the discussions to continue and for compliance to stay in front and center of the organization because in these committees the policies are tested and debated and resolved. In addition to a broad code, the company should adopt subsidiary standard operating procedures (SOPs) that get into more granular detail on specific issues that may not be covered in an allencompassing and much broader conceptual code. This allows for the continual consideration of the company’s position on a host of compliance issues. For example, the company should have an SOP on the dissemination of off-label information. This will help the organization to know what it can and cannot do. It sets standards and expectations.

Compliance is also a continual process. Top management must continually reinforce its importance to the organization. If senior management is cavalier about compliance it will be known by the organization. In short, a company must take compliance seriously by adopting policies and procedures to implement these SOPs. Management must appoint a person who is in charge of compliance and give that person a meaningful, respected and protected reporting structure. Management must periodically review the state of compliance and individual compliance issues and conduct annual and “for cause” audits of the organization to determine its level of compliance. Finally, management must be willing to deal seriously with those who are offenders and who are not in compliance with company policies.

If the company takes compliance seriously, the organization will know it, not only by its talk but also by its walk.

 

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