In the United States, it is impossible to watch television or read a magazine without seeing a pharmaceutical advertisement. Usually, a seemingly healthy person happily plants a garden on a sunny day, with or without a grandchild; meanwhile, a hurried list of expected adverse events and drug contraindications are read in a concerned tone or relegated to the small print on the next page. Since the Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act passed in 1962, these ads have been regulated by the US Food and Drug Administration (FDA) to ensure that their content is true and not misleading to the general patient population.
Because of this amendment, also called the “Drug Efficacy Amendment,” the path of drug development was forever altered. For the first time, before new drugs go on the market, drug manufacturers would be required to prove the effectiveness of drug products based on adequate and well-controlled clinical studies conducted by qualified experts. In addition to the control of prescription drug advertising and the requirement of efficacy trials, this law also addressed FDA drug approval landscape and set Good Manufacturing Practices in place.1 FDA’s emphasis on patient safety laid the groundwork for what has become the modern pharmaceutical industry.
Social Media Arrives
Pharmaceutical companies have enjoyed success in the past with traditional media and print advertising campaigns for prescription drugs, but with the arrival of social media, the industry seems unsure of the role social media can play in the pharmaceutical space. With a combined total of roughly 3.5 billion people worldwide using social media on a monthly basis,2 it is obvious that the best use of social media is reaching potential patients through advertising.
Why is it, then, according to a recent Tufts Center study,3 that only 11% of clinical trials in North America use social media for patient recruitment? Simply put, the regulations for patient recruitment were created before social media existed. As of June 2014, FDA has released a total of 4 guidance documents that address social media; unfortunately, none of them speak to the promotion of investigational drugs. We will unpack 2 of these guidances, and explore how a company without any drug approvals can infer from them the best regulatory path.
Regulations vs. Guidance
The FDA Code of Federal Regulations (CFR) Title 21 are the laws that govern just about everything we do as clinical research professionals. However, many regulatory professionals will tell you that to say “We follow the regulations,” is an oversimplification. The regulations themselves outline what is needed, but do not necessarily outline how to meet these needs. Here is when we look to the FDA and International Conference on Harmonization (ICH) Guidances as well as industry best practices to flesh out the actual running of clinical trials.
FDA makes it clear that regulations are used to:
…implement their statutory authority. The regulations can create binding obligations and have the force of law… Guidance documents represent the FDA’s current thinking on a topic. They do not create or confer any rights for or on any person and do not operate to bind the FDA or the public. Therefore, the industry can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations.4
Despite this distinction, you would be hard-pressed to find a regulatory professional who would be willing to treat an FDA or ICH Guidance as anything but law.
Clinical Trial Advertising
Unlike the commonly seen post-marketing approval advertising for prescription drugs, investigational drug promotion is much more restricted. The regulations for clinical trial advertising indicate via a general statement that any promotion of an investigational drug is not warranted. To paraphrase, 21 CFR 312.7(a), revised as of April 1, 2014, states that sponsors or investigators, or anyone they might delegate responsibility to, are not allowed to include in advertising that a new drug is safe or effective during its investigation. While promotion or commercialization of a new drug under investigation is not allowable, data or other scientific results can be distributed.5
As many biotech companies know, successful patient recruitment is paramount to clinical trial success. Clinical trials with indications such as diabetes or breast cancer usually enroll quickly and require little advertising, especially if attached to a widely recognized big pharma company. Alternatively, many small pharma or virtual biotech companies specialize in orphan indications that affect small populations of patients.
These companies rely on low-cost, results-driven patient recruitment strategies to pull in patients that otherwise would not be funneled into studies by traditional methods. Advertising on social media has little cost other than time or personnel, but when facing the lack of direct regulatory language, the price of miscommunication could be very high.
FDA has provided clarifying guidance on clinical trial advertising, but notably absent is anything having to do with electronic media or virtual communities. According to the guidance, patient safety has been put in the charge of the Institutional Review Board (IRB) by FDA. In addition to assuring patient consent on each trial, the IRB is responsible for approving any direct advertising of investigational drugs in order to attract research subjects for clinical trials. Included in direct advertising are newspapers, radio, TV, bulletin boards, posters, and flyers. It must not be coercive or promise a certainty of a cure beyond what is outlined in the patient consent and the clinical trial protocol.6
Traditionally, this is a fairly easy process. Advertising content is created, submitted to the IRB for approval in the form in which it will be seen by the potential patients, and put into circulation upon approval. Even though it is not explicitly stated in the regulations or guidances, it seems like a logical safeguard to follow the same process for any content that would appear online. However, it quickly becomes a question of control once the material gets into the collective hands of social media. The easily shareable nature of social media content can “go viral,” or spread rapidly to large numbers of people. Additionally, content may be altered or added to by third parties during the distribution. Which leads to an interesting question: If company-produced content follows the regulations and guidances and has the appropriate IRB approval, should they be responsible for what the average person likes, retweets, shares, pins, or comments?
Third-Party Misinformation
Take, for example, Sanofi-Aventis’s FDA-approved prescription drug Ambien CR. It is a “gamma-aminobutyric acid A agonist, indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.”7 A side effect listed on this drug’s regulatory-approved label is “‘sleep-driving’ and other complex behaviors while not fully awake.”7 A quick online search for Ambien stories will reveal numerous message boards, e-comics, Reddit.com threads, YouTube videos, etc, recounting patient experiences of hallucinating, sleep-eating or sleep-cleaning, and other generally odd behaviors.
One of 2 draft guidances released by FDA in June of 20148 directly addresses correcting such independent third-party misinformation on internet and social media platforms, albeit for prescription drugs. As previously stated, FDA guidances generally address marketed, commercially sold drugs. Companies operating solely in the investigational drug arena should infer best practices from these guidances for their non-approved drug programs.
What is clear from this guidance is that any correction of user-generated content, ie, any commentary or opinions not put forth by the company or its affiliates, is completely voluntary. However, intercession by the company holding the marketed product may be a benefit to public health if the user-generated content is dangerous or harmful.8 Of course, any voluntary response by the company is expected to be regulatory compliant and follow guidances as applicable.
The draft guidance goes on to give recommendations for the correction of misinformation including content of the response, the limitations of online platforms for viewing the response, and the uncontrollability of users to acknowledge or use the company correction.8 While none of which needs to be sent directly to FDA, any regulatory strategist would recommend keeping good in-house records.
Adverse Event Reporting on Social Media
Aside from misinformation and the unfortunate tendency some social media users have to “troll” (ie, intentionally post inflammatory, upsetting, harmful, or extraneous information with the sole purpose of provoking an emotional response), a specific complication of the general populace filling the internet with their experiences is that FDA has plans to eventually include social media platforms in their collection of pharmacovigilance data. Epidemico, a health data collection and analytics company, has developed a program with some FDA funding to mine social media for safety signals.9The program, MedWatcher, searches for adverse events and any tie they may have to specific post-marketed drugs. There are, however, enough limitations on this kind of patient-driven adverse event reporting, such as an uncertain causality, to see social media monitoring as an informational tool rather than an exact data set. For the time being, sponsors of marketed and investigational drugs are only held responsible for reporting adverse events in sponsorcontrolled studies and trials.
Character Space Limitations
Assuming that a company decides to proceed with online content, taking into account the limited existing advertising regulations and the risk of negative social media buzz, there are other barriers to get around. Many of the most-used social media platforms have character, space, or content limitations. While FDA has not yet attempted to discuss picturebased social media like Instagram, the second FDA guidance released in June of 201410 details coping with internet/social media platforms with character space limitations. Extremely popular social media platform Twitter sets a limit on content posts to 140 characters, ensuring all content is brief, which has contributed to Twitter’s popularity.
This draft FDA guidance—again only expressed for approved, marketed products—has the usual reminders about content being truthful and non-misleading, guidelines for making claims on how the product is used and the risks, and, most prominently, the need for a balance between the benefits and the risks. Since this is a tall order for 140 characters, FDA warns that firms should first assess the complexity of their product labeling before first venturing into a character-space-limited platform.10 The best takeaway from this guidance is to include a link by which the patient can find complete product information elsewhere.
Industry Use of Social Media
While pharmaceutical companies are reasonably hesitant to employ social media in advertising and recruitment strategies, the rest of this industry is not. Patient advocacy groups, annual meetings such as the Drug Information Association conference, contract research organizations, and other pharmaceutical vendors are actively utilizing virtual communities. Even FDA and the National Cancer Institute have Twitter handles (ie, official accounts). In this increasingly e-driven industry, it is a way to reach current and potential patients and interact with doctors and hospitals; it even allows a company to keep tabs on competitive trials and drugs. Navigating the regulatory hurdles of developing a social media strategy for clinical trials could be a huge asset, especially for smaller biotech companies.
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