The recent FDA’s Office of Prescription Drug Promotion (OPDP) draft guidance on Internet/Social Media Platforms with Character Space Limitations – Presenting Risk and Benefit Information for Prescription Drugs and Medical Devices effectively bans Twitter for pharma advertising. It does the same with Google Sitelink ads.
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K-messsage’s take on the FDA’s social media guidance from June 17th:
1. DO NOT use Twitter for promotional messaging about prescription drugs and medical devices
2. DO NOT use Google Sitelinks for promotional messaging about prescription drugs and medical devices
3. DO PERFORM social media monitoring to identify and engage in conversation about your prescription drugs and medical devices with misleading information on prescription drugs or medical devices
4. KEEP your Twitter presence for corporate and employer branding and for correcting misinformation
K-message believes that this is not what the Agency wanted to achieve, but we strongly suggest to all risk-averse pharmaceutical companies to cease any promotional activities for prescribed drugs in both space limited channels.
While the guidance includes imaginary examples of legally approved tweets and ads, in the real world it will not be possible to recreate such compliance for any of the existing products. Or at least it would cause a serious “Headhurtz” for the pharma marketing teams.
FDA requires to include in the tweet both benefit and risk information, and to link from the tweet to full page with Important Safety Information, preferably using word “risk” in an URL. As tweet has only 140 characters, it would be almost impossible to crunch in risks related to the product, even if you decide to skip benefit part.
The same happens with FDA’s proposal on how to use Google Sitelink ad format. The Agency may not know that, but what is displayed in the ad depends on the Google’s own algorithm, that tries to increase CTR. The chance of having very similar, risk focused links displayed under the ad, even if we manage to be always on the top of SERP, is limited. From our perspective the risk of not being able to follow the guidance is too high. Our recommendation is to use other Search Engine Marketing tactics instead.
Above does not mean, that pharma marketing on twitter is no longer possible. From the global perspective, the new regulation (if adopted without changes), affects only the United States market. Globally, there is no promotional activity directed to consumers, so there is no need to send promotional tweets. Instead, pharmaceutical firms focus on their corporate brands and disease awareness education – without promoting or even mentioning prescription drugs in the communication. So, yes, advertising prescription drugs and medical devices on twitter seems to be forbidden. But you should keep your presence there for
Dallas Buyers Club is a powerful movie. Based on true story of Ron Woodroof it shows how patient has to fight the system instead of receiving a treatment for the deadly disease. Everything seems to ally against suffering patient. Health Care Professionals driven by greed offer inefficient therapy under strict clinical trial regime. FDA officers are enforcing cruel regulations confiscating “illegal” but life-saving medications. Even the judge from liberal California, although compassionate is forceless. Dallas Buyers Club is a coalition of suffering people turned into outlaws for trying to save their lives.
Is pharmaceutical industry and its regulators really so cruel? Why Woodroof and his club were persecuted instead of receiving help? Is it possible that such story happens today with some other disease?
Clinical Trials – Why Ron could not get AZT in the proper dose in the hospital.
At the moment depicted in the Dallas Buyers Club, AZT (zidovudine, also known as azidothymidine, trade name Retrovir) in the U.S. was in the clinical research, probably in Phase III of the process.
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Phases of Clinical Research
Phase 0: The first in-human research of new drug is called an exploratory investigational new-drug study or phase 0 study. It is done before traditional phase I trials. Smaller than therapeutic doses of a new drug are given to a small group of patients (typically fewer than 15) for roughly a week to determine pharmacodynamic and pharmacokinetic properties.
Phase I: Researchers test a new drug or treatment in a small group of healthy volunteers for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
Phase II: The drug or treatment is given to a larger group (about 100 -300) of people who have the disease or condition that the product potentially could treat. In this phase researchers see if the medicine is effective and are able to further evaluate its safety.
Phase III: The drug or treatment is given to large groups (1000 to 3000) of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use.
[/box] Phase 2 and Phase 3 clinical trials generally involve a “control” standard. It means that some of the participants do not get tested substance, but inactive placebo or other, existing treatment if available. To avoid any bias, there is a special process to randomly decide who gets a tested substance, called randomization. At this point no one knows if the new therapy is efficient or maybe dangerous, so getting placebo is not necessarily worse option. Additional process to avoid bias in the results of the research is called blinding. Single-blinding means, that patients do not know whether they are treated with tested substance. Even better procedure, double-blinding means that also the research team does not know who receives what. Patient is informed about the substance s/he receives only at the specified time of the study, when it cannot impact the results. Due to this procedures, it is not possible for patient to decide a dosage or even to be sure that the specific drug is given. In the story of Dallas Buyers Club, Ramona starred by Jared Leto could not be sure that her medicine is AZT and not just placebo. Clinical studies are necessary to identify adequate dosage and eliminate risks that could overwhelm benefits of new therapy. There is always limited number of participating patients with specific conditions, so it takes long time to gather representative sample and see the results of the study. The whole process takes years to be completed, but it is needed to approve new drug to be available on the market.
AIDS patients could not wait for clinical trials, this is why Dallas Buyers Club and other similar communities existed. In that time, there was no easy, legal way to provide access to the treatment for patients in need. This experience affected current regulations in the U.S., and now there is a number of ways that allow access to the investigational or non-approved therapies for serious or life-threatening conditions, including but not limited to HIV/AIDS. Additionally, there is a way to expedite process of approval for the treatment in so-called FDA fast track drug development program.
Access to Investigational Drugs Outside of a Clinical Trial (expanded access)
Expanded access, sometimes called “compassionate use,” is the use of an investigational drug outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition who has no comparable or satisfactory alternative treatment options. FDA regulations allow access to investigational drugs for treatment purposes on a case-by-case basis for:
individual patients, including in emergencies
intermediate-size patient populations
larger populations under a treatment protocol or treatment investigational new drug application (IND)
To permit treatment of a patient with an investigational drug under an expanded access program, FDA requests following conditions to be met:
The patient’s disease or condition has no satisfactory approved therapy. An example of this is a rare type of cancer that has no known or approved treatment. Or, it may be the case that the available treatments did not work for the patient.
The potential benefit for the patient justifies the potential risks. An example of this is the potential for longer survival with a disease or condition.
The expanded availability of the untested drug will not interfere with that product’s development. For example, access to an investigational drug should not interfere with enrollment in clinical trials needed to demonstrate the drug’s safety and effectiveness.
Additionally, the drug manufacturer and the patient’s doctor must make special arrangements to obtain the drug for the patient. These arrangements must be authorized by the FDA. These safeguards are in place to avoid exposing patients to unnecessary risks.
Just as in clinical trials, these investigational drugs have not yet been approved by the FDA as safe and effective. They may be effective in the treatment of a condition, or they may not. They also may have unexpected serious side effects. It is important for you to consider the possible risks if you are interested in seeking access to an investigational drug. [box type=”info” ]
How to Get Expanded Access to an Investigational Drug?
The process must begin with your healthcare provider, who should follow these steps:
Your healthcare provider must contact the company that manufactures the drug to make sure it is willing to provide the drug.
Your healthcare provider must submit an Investigational New Drug (IND) [link to section below] application to the appropriate FDA review division.
In an emergency situation, the request to use the drug may be made via telephone or other rapid means of communication, and authorization to ship and use the drug may be given by the FDA official over the telephone. With emergency INDs, shipment of and treatment with the drug may begin prior to FDA’s receipt of the written IND submission that is to follow the initial request.
In a non emergency situation, the IND must be received by FDA before shipment of and treatment with the drug may begin. These non emergency requests are known as individual patient INDs.
The IND Application
The IND application is required to gain access to an investigational drug outside a clinical trial. The application should include the following information:
Statement that this is a request for an individual patient IND for treatment use (specifying whether it is an emergency IND or individual patient IND), which should be included at the top of the correspondence and on the mailing cover.
Brief clinical history of the patient including:
Response to prior therapy
Rationale for requesting the proposed treatment, including a list of available therapeutic options that would ordinarily be tried before the investigational drug, or an explanation of why use of the investigational drug is preferable to the use of available therapeutic options
Reference for a published protocol or journal article, if appropriate
Proposed Treatment Plan including:
Dose (how much and how often)
Route of administration (by mouth, injection, etc.)
Planned duration (how long the product is to be taken)
Modifications (e.g., dose reduction or treatment delay) for toxicity
Chemistry, Manufacturing, and Controls Information and Pharmacology and Toxicology Information, including a description of the manufacturing facility. This can be done by providing a letter of authorization (LOA) that refers to this information if it has been previously submitted to FDA (for example, to an existing IND or new drug application). The treating physician should contact the sponsor of the previously submitted information for the authorization and letter. The LOA should include identifying information, such as the sponsor’s application (e.g., IND) number.
Informed Consent Statement noting that informed consent and approval by an appropriate institutional review board (IRB) will be obtained prior to beginning treatment. In the case of an emergency, treatment may begin without prior IRB approval, provided the IRB is notified of the emergency treatment within 5 working days of treatment.
Investigator Qualification Statement that specifies the training, experience, and licensure of the treating physician. The first two pages of a curriculum vitae typically contain this information and are usually sufficient.
FDA Form 1571 completed with the treating physician listed as the sponsor. Download Form 1571 and view the instructions.
For the drugs that are the first available treatment or have advantages over existing treatments, the Food and Drug Administration has developed four distinct approaches to make such drugs available as rapidly as possible:
Prior to approval, each drug marketed in the United States must go through a detailed FDA review process. Since 1992, under the Prescription Drug User Act (PDUFA) a Priority Review designation is used to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. A Priority Review designation means FDA’s goal is to take action on an application within 6 months (compared to 10 months under standard review). Priority Review does not affect the length of the clinical trial period.
It takes many years to fully assess whether a drug provides a real effect on how a patient survives, feels, or functions, and brings a clinical benefit. To make drugs for serious conditions that filled an unmet medical need approved earlier, FDA can use Accelerated Approval process and base its decision on a surrogate endpoint. A surrogate endpoint is a marker of therapeutic effect, that is thought to predict clinical benefit but does not measure it. Drug still needs to be evaluated after approval in Phase IV studies, and basing on the results of this Phase IV FDA can change its initial decision on approval (ie. withdraw one of labeled indication, or completely withdraw drug from the market if confirmatory tests do not prove enough clinical benefit).
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
A drug that receives Fast Track designation is eligible for some or all of the following:
More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval
More frequent written correspondence from FDA about such things as the design of the proposed clinical trials and use of biomarkers
Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met
Rolling Review, which means that a drug company can submit completed sections of its Biological License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA
Breakthrough therapy is the latest program at FDA that will complement the programs listed above. It facilitates and expedites drug development and review for serious conditions and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
A drug that receives Breakthrough Therapy designation is eligible for the following:
All Fast Track designation features
Intensive guidance on an efficient drug development program, beginning as early as Phase 1
Early access to the innovative drugs is still a topic for regulators not only in the U.S. In the United Kingdom the latest development is an Early Access to Medicines program unveiled by the Government on 7th of March 2014. The program aims to accelerate access to innovative medicines for serious conditions, allowing doctors to prescribe the drugs after an initial scientific assessment by the Medicines and Healthcare Products Regulatory Agency (MHRA). The program, funded by pharmaceutical companies, will be launched on April 2014. Suitable drugs will receive a “promising innovative medicine” (PIM) designation. PIM designation will be based on several years of clinical data assessed by MHRA, but before completion of Phase III trials. This will probably save several years in comparison to the standard process for approval, that will be run in parallel to the new program. Early Access to Medicines is modeled after the FDA’s breakthrough therapy designation. British regulatory agency estimates that one or two therapies could be designated under the scheme each year.
It seems there is no need for Dallas Buyers Club anymore.
Federal Drug Administration (FDA) has announced its draft guidance on Social Media in Pharma. What question does it answer and what remains still unregulated? What are the consequences of this guidance and expected next steps?
When finalized this guidance will regulate all Internet activities of pharmaceutical companies operating in the United States. The guidance was long expected by the pharma industry. According to earlier announcements from FDA more comprehensive guidance shall be released by July 2014.
Main proposals of the new FDA guidance for Social Media in Pharma
Pharma companies responsibility for the content published in social media:
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A firm is responsible for product promotional communications on sites that are owned, controlled, created, influenced, or operated by, or on behalf of, the firm.
Under certain circumstances, a firm is responsible for promotion on third-party sites.
A firm is responsible for the content generated by an employee or agent who is acting on behalf of the firm to promote the firm’s product.
Pharma companies obligation to submit interactive promotional materials to FDA:
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At the time of initial display, a firm should submit in its entirety all sites for which it is responsible on Form FDA 2253 or Form FDA 2301. For example, the firm should submit the comprehensive static product website with the addition of the interactive or real-time components.
For third-party sites on which a firm’s participation is limited to interactive or real-time communications, a firm should submit the home page of the third-party site, along with the interactive page within the third-party site and the firm’s first communication, on Form FDA 2253 or Form FDA 2301 at the time of initial display.
Once every month, a firm should submit an updated listing of all non-restricted sites for which it is responsible or in which it remains an active participant and that include interactive or real-time communications. Firms need not submit screenshots or other visual representations of the actual interactive or real-time communications with the monthly updates.
However, if a site has restricted access and, as such, FDA may not have access to the site, a firm should submit all content related to the discussion (e.g., all UGC about the topic), which may or may not include independent UGC, to adequately provide context to facilitate the review. Screenshots or other visual representations of the actual site, including the interactive or real-time communications, should be submitted monthly on Form FDA 2253 or Form FDA 2301.
When submitting the site, FDA recommends that a firm take formatting factors (e.g., appearance, layout, visual impression) into consideration to enable the Agency to view the communications as a whole.
What the industry expected to be addressed? Is it addressed with the new FDA draft guidance?
In general FDA has addressed two of five main points raised by pharmaceutical companies. Those are responsibility for the content published in the Internet and in Social Media, and 2253 Submissions requirements.
Internet control and 3rd party controlled social media responsibility
FDA has defined scope of responsibility for pharma companies. In general pharmaceutical companies are responsible for any content that they have control or influence on. Let us repeat the phrasing of the document:
[box type=”info” align=”aligncenter” ] Pharma companies responsibility for the content published in social media: 1. A firm is responsible for product promotional communications on sites that are owned, controlled, created, influenced, or operated by, or on behalf of, the firm.
2. Under certain circumstances, a firm is responsible for promotion on third-party sites.
3. A firm is responsible for the content generated by an employee or agent who is acting on behalf of the firm to promote the firm’s product.
FDA requires all prescription drug labeling and advertising to be submitted at the time of initial dissemination through an FDA Form 2253. [21 C.F.R. § 314.81 (b)(3)(i)].
Until this draft guidance however, it was not clear what are companies obligations for submitting social media content. For the sake of security social media activities were limited to the safe topics and avoided mentions of any product. It may change now, as the guidance states clearly what and when should be submitted to the Agency. While industry may not be happy with the request to feed FDA with all User Generated Content that may be considered promotional, at least now everyone knows what to report.
What is left unanswered by the new FDA Guidance on Social Media in Pharma?
Space limitations and one click statement rule
FDA requires that every promotional material includes comprehensive information about the product, including safety information. Due to space limitation and “hypertexted” nature of the digital media, pharmaceutical industry developed theory of so called “one-click rule”. The assumption was that to meet FDA’s expectation it is enough to provide on the interactive promotional material a link to the website that would include required information.
This has been questioned by the Agency which issued enforcement letters to 14 companies who used Google display advertisement where risk information was available under “one-click”. In the following statements FDA declined existence of any one-click rule, but did not offer any alternative. New guidance does not refer to this aspect of the regulation. Therefore any promotional activities mentioning pharmaceutical products on platforms with limited message space ie. on Twitter are still not possible.
Another issue that is not addressed by the guidance is off-label use discussion. Promotional messages may not recommend or suggest the drug for off-label uses. Technically it means that anyone in relation to the company is not allowed to even mention any use of the drug that is not approved by FDA. Any response to such mention in social media by pharmaceutical company may be considered as suggesting and therefore promoting off-label use. As we are discussing here open communication channels available to general public, even scientifically valid and supported by pending trials question about any product use that is not approved has to remain unanswered. This limitation remains in force with the new draft guidelines.
Drug Safety and Adverse Events Reporting
Drug Safety or Pharmacovigilance is probably the most important reason why embracing social media in pharma marketing is so slow. It is extremely important (human life is at stake), and there are too many questions unanswered around it.
The first obligation is to provide possibility to report any adverse event to the public. For websites addressed to US-based audience it is usually solved by adding MedWatch icon/link, or easily available report form. In social media this is much more difficult, as there is no way to include such link in every message.
If the company engages in social media, should not it also proactively monitor this space for any possible adverse events? Companies are obliged to report any AE found within limited timeframe, but there is possibility that report is discovered long after it was posted online. It may be written in exotic language and not recognized immediately.
Another question is if the company is obliged to actively pursue any post that may be adverse event but does not include all necessary information for AER. If that would be the case the workload could be overwhelming. Another complication is when the post mentions generic name of the drug manufactured and distributed by many companies. Shall all of them contact the original poster to find out missing information?
Those questions remain unanswered with the draft guidelines.
What will happen next?
All interested parties can submit their comments to FDA within 90 days from the date of publication in the Federal Register (01/14/2014) to www.regulations.gov electronically or in written form to the addresses provided in the document. We also expect more comprehensive guidance as mandated in FDA Safety and Innovation Act (FDASIA) of 2012. Section 1121 of FDASIA orders FDA to, “issue guidance that describes FDA policy regarding the promotion, using the Internet (including social media), of medical products that are regulated by the FDA.”.
After months of negotiations, FDA finally lost patience and sends a warning letter to Google-backed 23andme, a genome testing company. 23andme was marketing its saliva based genetic test device and the test (Personal Genome Service) itself without an obligatory marketing clearance.
What FDA’s letter means
The letter is very direct and harsh and its tone, reminding Mrs. Anne Wojcicki, the founder of 23andme, that FDA really tried to help:
More than 14 face-to-face and teleconference meetings, hundreds of email exchanges, and dozens of written communications, we provided you with specific feedback on study protocols and clinical and analytical validation requirements, discussed potential classifications and regulatory pathways (including reasonable submission timelines), provided statistical advice, and discussed potential risk mitigation strategies
The letter is the final warning. If 23andme fails to cease its marketing activities and provide a plan to align itself to the regulatory demands, FDA will start a regulatory action without further notice. These actions include, but are not limited to, seizure, injunction, and civil money penalties – FDA warns.
At K-Message, we usually praise innovation, courage and development of new ways of dealing with complicated problems. 23andme could be a hero of our story. But Mrs Anne Wojcicki‘s approach is hard to support.
FDA’s main concern is, as specified in the letter, a potential risk of negative impact of the often alarming test results coming from PGS. False positive or false negative from the PGS may affect actions of the people. Someone who was falsely informed that has high risk of breast cancer (BRCA mutation), can undergo prophylactic surgery, chemoprevention, invasive screenings and last, but not least will suffer tremendous psychological stress.
On the other hand, false negative may lead people from the risk groups to ignore prevention at all. Another dangerous part of 23andme service is informing about personal reaction to the drug. It produces a risk of “self-managing” therapy and lowering adherence to the therapy prescribed by real HCP. Such non-compliance may lead to serious risk of illness, injury and even death, as in the FDAs example of wayfarin, popular anticoagulant or “blood thinner“, which may cause internal bleeding if overdosed.
Problems with 23andme technology
23andme technology is far from being bulletproof. The assumptions it bases on, the links between particular genes and diseases are not really mapped and confirmed in regular clinical trials on big samples. Even Mrs. Wojcicki admits, that her goal is to gather a test sample big enough to falsify the assumptions on which results are presented to the patients.
But it is not only about state-of-knowledge about human genome as today. Even the software that generates PGS results can mislead patients, as described in this personal story “My deadly disease was just a bug”. It also happened, that 23andme simply mixed the samples and 96 of its users recveived data od someone else, who just had a bad luck to have his/hers saliva on the same testing plate.
It does not make Mrs. Wojcicki any more apologetic though.
Right to know, but what?
The problem is, Mrs. Wojcicki often diminishes such concerns. She said once, that the main concern of doctors is that her service generates “non-billable, educated questions“. When the Agency first warned 23andme together with other gene testing companies in 2010, Mrs. Wojcicki’s line of defense was freedom to know information about your own body.
FDA has nothing against testing itself and having this knowledge available. The problem is that the knowledge has to be true and not misleading. As Mrs. Elizabeth A. Mansfield, director of personalized medicine in the F.D.A.’s medical device division, said to NYT, the agency agreed that people had a right to their genetic information.
The concern, she said, was that 23andMe was also providing interpretations of what that data meant medically. Some commentators, that come more from a tech than pharma tend to see the conflict between 23andme and FDA as “new vs old” clash.
We believe it is not the case this time. It is rather good ol’ regulatory action against dangerous false claim in healthcare, or even quackery. 23andme does not offer substantial evidence to support the reports provided to their clients. Their often misleading information can lead to health risk, and therefore FDA has to intervene. It has nothing to do with freedom of the information, as the information is too often false and affects really important matter.
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