Policy and Medicine

FDA Using Accountability to Deter Illegal Marketing Activity

Using accountability as a tool to deter illegal activity like misbranding and promote corporate transparency was a resounding theme during a discussion last year held by the Food and Drug Law Institute (FDLI). The discussion, moderated by Alan R. Bennett, a Partner at Ropes & Gray LLP, was joined by Lauren R. Calia, a Senior Assistant Attorney General in the Office of the Attorney General for the Consumer Protection Division of the State of Maryland and Jill Furman, Assistant Director, Consumer Protection Branch, U.S. Department of Justice.   

The three government officials used recent cases to exemplify changes in 2011 enforcement laws and priorities. 

Calia discussed a 2011 $68.5 million multi-state consumer settlement with AstraZeneca for the improper promotion of the atypical antipsychotic drug, Seroquel. “The allegations included that the company promoted Seroquel for a variety of off-label purposes, including promotion for patient populations for which there was not an approved indication; failure to disclose that Seroquel was not approved for uses that representatives were promoting; misrepresenting the drug’s approved uses, safety and effectiveness; and, failure to disclose negative information contained in scientific studies concerning the safety and efficacy of Seroquel.” 

Highlighting the injunctive relief provisions of the settlement agreement, Calia emphasized the Court’s recognition of the States’ concern over the company’s lack of transparency and misleading behavior.  Calia explained that the order required the company to present information in the most fair and balanced way to the consumer.  Furman noted that “New trends [in enforcement violations] include: 

• Subverting FDA’s function in the drug or device approval process or during regulatory interaction;
• Misrepresenting significance of scientific studies;
• Safety concerns; and
• Increased judicial scrutiny of proposed settlements 

“It is important to look at the court’s reactions to previous settlements; there is a variation now across the country where we see new matters being brought in districts where matters were not brought before,” Furman explained.  The three driving trends and priorities for enforcement are: 

•      Accountability,
•      transparency and
•      consumer protection 

“From listening to this talk it is apparent to anyone that has practiced in this area that there is no longer one set of regulators at the FDA that you have to satisfy,” Bennett added, “…there is a whole separate group of people looking at what you do, what you say, and how you say it.” 

As the Food and Drug Administration moves ahead with aggressive new enforcement efforts, the costs of non-compliance are more significant than ever. FDA is stronger, with hundreds of new inspectors, a sharp increase in the number of Warning Letters issued, increased misdemeanor citations and greater personal liability.  The result is that the pharmaceutical industry is under fire, facing a growing emphasis on the supply chain and on clinical practices. 

“It is significant that Commissioner Hamburg’s first speech as Commissioner, two years ago, focused on enforcement,” noted Associate Commissioner for Regulatory Affairs Dara Corrigan in a presentation to FDLI last April.  As the new head of Office of Regulatory Affairs, Corrigan said she intends to do everything she can to insure that the FDA is strong and gets stronger.”  Corrigan noted that she organized ORA’s enforcement activities around four principles: 

1. strategic coherency,
2. vigilance,
3. responsiveness, and
4. transparency.  

Corrigan noted that ORA is “about to begin a new way to process enforcement cases that will shorten the review time, eliminate the sequential process within FDA, and not sacrifice the quality or objectivity of the review…There should be a significant decrease in lag between inspection and enforcement.” 

She pointed out that “another example of a way that we are trying to be more timely and responsive is our warning letter improvement process…We issued more warning letters in fiscal year 2010 than in the previous six fiscal years…There was a 42% increase in the number of warning letters issued last year than in 2009.” This year is currently outpacing the 2010 rate. 

In a major announcement intensifying FDA enforcement policies in 2009, Commissioner Hamburg noted that, “The FDA must be vigilant…strategic…quick…and visible.”  In the speech, Hamburg also asserted that: “Effective enforcement has many clear benefits to public health. It enables FDA to intercept unsafe or fraudulent products promptly… and prevent additional harm. By holding violators accountable, enforcement deters others who would put the public at risk or prey upon vulnerable consumers.  Visible and clearly explained enforcement actions inform members of the public about potential dangers.” 

Hamburg added that, “enforcement helps industry too – by maintaining a level playing field for safe products. Making sure that offenders are held legally accountable prevents companies from having to choose between doing the right thing and staying competitive.” 

Her message is “well-known [to] multinationals [that] have endured the dreaded “consent decree of permanent injunction”—which typically involves factory shutdowns until problems are fully remediated—as well as years of vigorous FDA oversight, monetary penalties, and significant intangible effects on brand credibility to healthcare providers, patients, and investors.” 

As a result, the FDLI article asserted that, “Companies can no longer afford to take a traditional compliance approach in this heightened regulatory environment.”  Instead, companies must take the front seat for compliance because “best-in-class compliance is an opportunity for market differentiation,” and “applying systems-based thinking and aligning compliant quality systems with key business processes—practicing the art of compliance—[leads to] even greater rewards are possible.”   

Legal Powers Building 

The fact that the Department of Justice (DOJ) acts as the FDA’s attorney gives the agency increased leverage; for example in December 2010 alone, the DOJ collected some $421 million from pharmaceutical manufacturers to settle False Claims Act cases. The agency’s legal powers continue to increase, with expanded authority to inspect foreign plants, empowering it to recall, destroy, or detain unsafe goods. 

For example, the FDA’s Beyond Our Borders program – which includes setting up overseas posts in China, India, the Middle East, Europe, and Latin America – is a multipronged approach to promote and verify compliance of imported food, cosmetics, and medical products with FDA requirements.  This includes: 

• more frequent FDA inspections,
• greater sharing and use of foreign competent authority inspection reports,
• use of third party certification, and
• increased capacity building with countries that have less developed regulatory systems to ensure product safety. 

While the program endorses Good Importer Practices and a Secure Supply Chain Program, the article noted that, “two recent Government Accountability Office (GAO) reports claim that there is an urgent need for still more foreign inspections, noting that in fiscal year 2009, drugs made in more than 100 countries were offered for entry into the United States.” 

GAO noted that while “FDA increased the number of foreign drug inspections done from fiscal year 2007 to 2009, [it] still conducts relatively fewer foreign than domestic drug inspections each year.  In fiscal year 2009, FDA conducted 424 foreign inspections, compared to 333 and 324 inspections conducted in fiscal years 2007 and 2008, respectively. Inspections on mainland China increased from 19 in FY 2007 to 36 in FY 2008 and 52 in FY 2009; the FDA had 920 Chinese establishments in its FY 2009 inventory. 

FDA Vision on Enforcement 

Under the FDA’s Vision on Enforcement to Support Public Health, launched on August 6, 2009, six steps were outlined to “hone the effectiveness and timeliness of the FDA’s regulatory and enforcement system:” 

1. Set post-inspection deadlines, with industry generally given no more than 15 days to respond to significant FDA-483 inspection findings before the agency issues a Warning Letter or takes other enforcement action.
2. Take responsible steps to streamline the Warning Letter process, by limiting review of Warning Letters by the Office of Chief Counsel to those presenting significant legal issues.
3. Work more closely with FDA’s regulatory partners, working to coordinate efforts to achieve rapid action.
4. Prioritize follow-up on Warning Letters and other enforcement actions, working quickly to assess and follow up on corrective action taken by industry after a Warning Letter is issued or major product recall occurs.
5. Be prepared to take immediate action in response to public health risks. Such actions may occur before a formal warning letter is issued.
6. Develop and implement a formal Warning Letter “close-out” process.” If the FDA can determine that a firm has fully corrected violations, the agency will issue an official “close-out” notice and post this information on the FDA Web site. 

The Challenge: Aligning Compliance and Business Performance 

In the past, the biopharma industry’s “reactive” approach to compliance “resulted in sub-optimal quality.”  Moreover, the separation of compliance and business processes into two “separate silos” by companies has been counterproductive, leading to “business and scientific processes that have been costly and laborious – and unsustainable.”    

Many compliance issues result from poor information flow, yielding high rates of complaints – every one of which must be investigated, using inadequate and sometimes archaic methods,”  and these “issues and potential pitfalls are exacerbated when working in emerging regions.” 

Accordingly, the authors noted that the huge volumes of quality data that businesses have and use must be converted “into actionable information.”  They recommended that industry achieve compliance through “consistent execution, using optimized business processes aligned with global regulatory requirements.”  They noted that companies must use “process-driven compliance,” which is composed of: 

• Process optimization– adjustment of core business and scientific processes to improve outcomes, reduce variance, and ensure consistent execution, and which is typically aimed at minimizing cost, maximizing throughput and/or efficiency, and increasing predictability; and
• Regulatory compliance -  involves adherence to regulatory bodies’ rules and requirements, and ensuring that processes, practices and products are developed and maintained in compliance with established guidance and regulations. 

They noted that, “Compliance can be achieved through consistent execution, requiring:” 

• Globally harmonized processes that optimize performance
• Regulatory requirements incorporated into process steps
• A Quality System aligned to operational performance, tightening the symbiotic relationship between Standard Operating Procedures (SOPs) and business activities
• A web-based tool to help ensure there is a sustainable framework for consistent execution and continuous improvement
• Pre-defined performance criteria that are actively managed. 

These approaches use quality to generate value, allowing companies to: 

• Quickly assess and prioritize regulatory risk exposure;
• Identify key vulnerabilities relative to FDA inspection focal points;
• Run effective audits and drills to enhance inspection readiness; and
• Establish sustainable compliance processes while minimizing the impact on their business.  

Using quality data appropriately yields reliably safe and effective products, effectively adding value to the business by avoiding the need to deal with complaints and recalls of defective products.

Ultimately, “as many firms have learned, the best time to take action is long before quality or enforcement actions occur.” Instead, companies must take “timely and proactive efforts to drive sustainable compliance to minimize the risk of quality problems or enforcement action.”

FDA CDRH – MDUFA Agreement and Strategic Priorities for 2012

The FDA and industry recently came to an agreement in principle for the Medical Device User Fee Act (MDUFA), costing the device industry $595 million over the next 5 years.  With hearings scheduled in the house for next Thursday on MDUFA we should be learing more in the days ahead.  

The Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration (FDA) recently released its strategic priorities for the 2012 year, saying it plans to focus on 4 areas.  CDRH said it plans to concentrate on fully implementing a "total product life cycle approach," enhance its internal and external communication and transparency, strengthen its workforce, and "proactively facilitate innovation."

Before listing this year’s Strategic Priorities, CDRH reported on its accomplishments from 2011.  CDRH noted that it had completed work on fifty action items in 2011. Highlights of the significant amount of work our staff accomplished in 2011 include:                 

• Plan of Action for Implementation of 510(k) and Science Recommendations and completed many of actions in the Plan as well as undertook several additional efforts to improve our pre‐market programs.
• Report, “Regulatory Science in FDA's Center for Devices and Radiological Health: A Vital Framework for Protecting and Promoting Public Health," to provide a broad overview of the many scientific activities in which our staff are currently engaged, as well as what we see as important regulatory science targets in the future as science and technology continue to evolve.
• Guidance on regulatory expectations for in vitro diagnostic devices and therapeutic products developed together such that the therapeutic product depends on the diagnostic test to direct the use of the therapeutic product.
• Critical role on the establishment of the International Medical Device Regulators Forum (IMDRF), a voluntary group of medical device regulators from around the world charged with future direction in medical device regulatory harmonization.
• Completion of the pre‐market reviewer competencies and began a Reviewer Certification Program (RCP) pilot.
• Launched an initiative to identify and promote best‐quality device manufacturing practices. This includes a report, "Understanding Barriers to Medical Device Quality," that reviews the challenges that the FDA and industry face in supporting well‐integrated, best‐quality manufacturing practices and strategies that industry and the FDA can take to overcome these barriers.
• Completed database requirements; began the design and development phase of a unique device identification system. We also sent the draft rule to OMB.
• Launched the Innovation Initiative, which proposed actions the Agency could take to help accelerate and reduce the cost of development and regulatory evaluation of innovative medical devices in a way that maintains or improves patient safety and is based on sound science.  

2012 Strategic Priorities  

In 2012 CDRH will have four priority areas: (1) Fully Implement a Total Product Life Cycle Approach, (2) Enhance Communication and Transparency, (3) Strengthen Our Workforce and Workplace, and (4) Proactively Facilitate Innovation to Address Unmet Public Health Needs. It includes timeframes associated with each strategy, and specific actions CDRH will take to meet those goals or make significant progress towards achieving those goals.

FULLY IMPLEMENT A TOTAL PRODUCT LIFE CYCLE APPROACH 

CDRH said it will make well‐supported regulatory decisions that take into consideration all of the relevant information available to the Center, at any stage of a product’s life cycle to assure the safety, effectiveness, and quality of medical devices, and the safety of non‐device radiation‐emitting products.  

Strategy 1.1. Enhance and Integrate Premarket, Postmarket, and Compliance Information and Functions.  CDRH will have in place strong, mutually reinforcing organizational components supported by integrated knowledge management systems, that work with a unity of effort toward our mission, and that are equipped to anticipate and address changes in the scientific and global‐market landscape.  CDRH said it will strengthen premarket review by continuing to implement its action plan. 

• By April 1, 2012, begin the Triage of Pre‐market Submissions Pilot to increase submission review efficiency and better manage the pre‐market review workload.
• By December 31, 2012, publish a proposed rule to clarify the circumstances under which CDRH could rely on clinical studies conducted in and for other countries.
• By December 31, 2012, finalize all guidance documents issued as part of the plan to improve our premarket programs.
• By December 31, 2012 conduct an evaluation of CDRH staffing, infrastructure, policies, and practices pertaining to medical software 

In 2012, CDRH will continue to take steps to address Class III device types currently allowed to enter the market through the 510(k) process.                  

• By December 31, 2012, clear within CDRH proposed rules for all remaining Class III pre‐amendment medical devices.  

Address Challenges Associated with Globalization.  By September 30, 2012, CDRH will have in place mechanisms to further harmonization efforts and exchange medical device information with foreign regulatory authorities.

• By March 31, 2012, hold the first meeting of the International Medical Device Regulators Forum.
• By September 30, 2012, participate in at least two harmonization activities with one or more foreign regulatory authorities. 

Enhance Compliance Capability.  By December 31, 2012, CDRH will begin to implement its business‐case‐for‐quality initiative to address best‐quality manufacturing practices, including mechanisms for FDA‐industry engagement and increased transparency of device quality data.                 

• By June 30, 2012, select and begin to implement 2012 actions in support of the business‐case‐for‐quality initiative.  
• By December 31, 2012, select actions to be implemented in 2013 in support of the business‐case‐for‐quality initiative.  

By October 31, 2012, CDRH will take steps to enhance the efficiency and clarity of the medical device and radiation‐emitting product recall processes.                 

• By September 30, 2012, develop methods and procedures for the systematic analysis and use of medical device recall information.  
• By October 31, 2012, develop and begin to implement criteria for terminating recalls, including online posting of recall terminations.  

Enhance Collaboration Through Reorganization.  In 2012, CDRH will continue to implement its reorganization plan to enhance and integrate premarket, postmarket, and compliance information and functions.                 

• By December 31, 2012, provide at least two updates to staff on the status of the reorganization.  

Implement a Knowledge Management Strategic Plan.  By October 31, 2012, CDRH will develop and begin to implement a Knowledge Management Strategic Plan to make the best use of information collected or developed by CDRH.                

• By March 31, 2012, hire a Knowledge Management Director.
• By October 31, 2012, finalize and begin to implement CDRH’s Knowledge Management Strategic Plan.  

Assess Real World Device Performance.  By October 31, 2012, CDRH will develop a comprehensive strategy to assess real world device performance.                 

• By April 30, 2012, post on the web a proposed strategy to assess real world device performance and seek public input.  
• By October 31, 2012, develop a comprehensive framework for the timely evaluation and management of significant postmarket signals.  

Enhance CDRH’s Quality Assurance Program.  By December 31, 2012, strengthen CDRH quality assurance framework for periodically auditing the Center’s regulatory programs and decisions and providing recommendations for improvement. 

• By June 30, 2012, hire an Assistant Director for Quality Assurance.
• By December 31, 2012, implement a Center‐wide quality assurance program.  

ENHANCE COMMUNICATION AND TRANSPARENCY 

To improve public health and foster trust among our employees and with our constituencies, CDRH will provide meaningful and timely information about the products we regulate and the decisions we make, through strategic outreach and systems that support transparency and two‐way communication. 

Enhance Communication and Transparency with Our Stakeholders  

CDRH will develop and distribute timely information about medical device and radiation‐emitting electronic products that is useful to our external constituencies, using methods that meet their needs, while giving them opportunities to engage in a dialogue with the Center about the issues important to them.

 In 2012, CDRH will continue to take steps to strengthen information exchange and improve gathering feedback from our external constituencies.                 

• By December 31, 2012, take steps towards establishing a national forum for engaging with patients, consumers and health care professionals in a dialogue about issues of interest to them.  

Improve Internal Communications  

CDRH staff will have access to timely information about what the Center is working on, completed projects, organizational information and will have opportunities to engage dialogue, share ideas and make suggestions to enhance CDRH’s ability to successfully achieve our mission.

By December 31, 2012, CDRH will establish an internal communication program to improve communication of information and ideas to and from CDRH Staff.               

• By September 30, 2012, issue standard operating procedures (SOPs) for sharing information with CDRH Staff. 
• By December 31, 2012, with input from staff, develop and begin to implement a plan to improve internal communication. 

PRIORITY 3. STRENGTHEN OUR WORKFORCE AND WORKPLACE 

CDRH will be a thriving organization with the knowledge, skills, and technical expertise we need to fulfill our mission; a collaborative employee culture; efficient administration of CDRH programs; and a workplace environment that supports productivity.

Continue to support the Life Cycle Approach to CDRH Employee Education.  CDRH employees will have access to high quality educational tools and programs, assuring that we accomplish our mission and meet the anticipated demands of the future.  

By December 31, 2012, CDRH will launch the Experiential Learning Program (ELP) to enhance premarket reviewer knowledge of how medical devices are designed, manufactured, and utilized by providing real‐world learning opportunities.               

• By March 31, 2012, begin the ELP pilot.
• By December 31, 2012, fully implement the ELP.  

By December 31, 2012, CDRH will launch the CDRH Leadership Enhancement and Development Program (LEAD) to provide CDRH managers and supervisors information and tools to assure effective leadership.                 

• By March 31, 2012, begin the LEAD pilot.
• By December 31, 2012, fully implement LEAD.  

Enhance Employee Satisfaction  

CDRH will recognize the value of our employees and provide a workplace environment that supports productivity.  By September 30, 2012, CDRH will make recommendations on how to adequately recognize good employee performance and address poor performance.                 

• By February 28, 2012, form an internal, cross‐Center, staff‐led work group to develop recommendations.
• By September 30, 2012, share with Center staff the work group’s recommendations and seek their input.  

By September 30, 2012, CDRH Offices will make recommendations on what resources are necessary to ensure staff are successful in performing their work.                 

• By May 31, 2012, Offices will solicit recommendations from staff on what resources are necessary to ensure staff are successful in performing their work.
• By September 30, 2012, Offices will share their recommendations and an action plan for implementation with staff.  

PRIORITY 4. PROACTIVELY FACILITATE INNOVATION TO ADDRESS UNMET PUBLIC HEALTH 

CDRH will further enhance our efforts to anticipate emerging technological trends and public health challenges and partner with federal and external stakeholders to facilitate the development of innovative, safe and effective medical devices and advance regulatory science. 

Foster the Development of Innovative Medical Devices. CDRH will work with our federal government partners and external constituencies to facilitate the development of innovative, safe and effective medical devices.  By September 30, 2012, CDRH will create processes and tools that will improve the pipeline for innovative medical devices and transform the way CDRH works with medical device innovators.                 

• By March 31, 2012, using the Entrepreneurs in Residence Program, begin to pilot the Innovation Pathway 2.0.
• By September 30, 2012, assess implementation of the Innovation Pathway 2.0.  

Further Develop a Personalized Medicine Program.  CDRH will work collaboratively with our federal government partners and external constituencies to assure the appropriate regulatory oversight of therapeutics and diagnostics when their safety and effectiveness are intimately tied to one another. 

By September 30, 2012, CDRH will continue to develop policies and procedures to assure that safe and effective diagnostic products that are either innovative themselves or provide innovative uses reach the public. 

• By June 30, 2012, clear within CDRH the final guidance on Companion Diagnostics.
• By December 31, 2012, clear within CDRH draft guidance on co‐development of drugs or biologics and devices.  

Strengthen Regulatory Science.  CDRH will work collaboratively with our federal government partners and external constituencies to advance medical device regulatory science. 

By December 31, 2012, CDRH will have in place mechanisms to enable collaborative work between FDA, our federal government partners and external constituencies to advance medical device regulatory science.                 

• By December 31, 2012, establish a public‐private partnership between industry, the FDA, and academia to advance regulatory science.  

By September 30, 2012, CDRH will expand computer modeling and simulation efforts to support regulatory science.                 

• By September 30, 2012, finalize a strategy for validating and incorporating computer models that are part of the Virtual Physiological Patient Project into a publicly accessible library that can be used in device development and regulatory applications.


FDA Quantitative Summary of the Benefits and Risks of Prescription Drugs: A Literature Review

The Food and Drug Administration (FDA) recently announced the availability of a draft report entitled “Quantitative Summary of the Benefits and Risks of Prescription Drugs: A Literature Review” (literature review report). A literature review was conducted to address a requirement of the Patient Protection and Affordable Care Act (Affordable Care Act).  FDA is publishing the literature review report to allow the public to provide comment on the report as it relates to the Affordable Care Act. 

Submit either electronic or written comments on the literature review report by February 13, 2012.  Comments should be identified by Docket No. 2011-N-0813.  For more information contact Helen Sullivan, Office of Prescription  Drug Promotion,(301) 796-1200, email: helen.sullivan@fda.hhs.gov. 

Background 

Section 3507(a) of the Affordable Care Act requires the Secretary of Health and Human Services (HHS), acting through the Commissioner of Food and Drugs, to determine whether the addition of quantitative summaries of the benefits and risks of  prescription drugs in standardized format (e.g., similar to “Drug Facts” on over-the-counter products) to the promotional labeling or print advertising of such drugs would “improve health care decision making by clinicians and patients and consumers” (section 3507(a), Pub. L. 111-148, 124 Stat. 530). 

In making this determination, the law directs FDA to “review all available scientific evidence and research on decision making and social and cognitive psychology'' (section 3507(b), Pub. L. 111-148, 124 Stat. 530), and to consult  manufacturers and consumers, experts in health literacy,  representatives of racial and ethnic minorities, and experts in women's  and pediatric health. 

To fulfill this requirement, FDA has commissioned an objective review of science-based studies related to the communication of  quantitative benefit and risk information. FDA is making available the  literature review report and is providing a comment period for  interested parties to comment on the literature review report as it  relates to section 3507 of the Affordable Care Act. 

Comments 

Interested persons may submit to the Division of Dockets Management either electronic or written comments regarding the literature review report. It is only necessary to send one set of comments. It is no longer necessary to send two copies of mailed  comments. 

FDA Submits to Congress User Fee Act Recommendations

The U.S. Food and Drug Administration (FDA) last week announced that it had completed its recommendations for three user fee programs that will help speed safe and effective drugs and lower-cost generic drug and biosimilar biological products to patients: 

      Prescription Drug User Fee Act (PDUFA)

     Generic Drug User Fee Act of 2012 (GDUFA)

     Biosimilar User Fee Act of 2012 

The recommendations were transmitted to Congress today by Health and Human Services Secretary Kathleen Sebelius. The programs include the fifth authorization of the Prescription Drug User Fee Act (PDUFA), and new user fee programs for human generic drugs and biosimilar biological products. Work on the proposals was concluded before the agency’s mid-January deadline. 

Consequently, House Republicans last week announced a slew of hearings on health industry fees aimed at speeding up federal regulators' review of new medicines before they can go to market.  The Energy and Commerce Health Subcommittee will kick things off on Feb. 1 with a hearing on PDUFA. FDA Commissioner Margaret Hamburg is scheduled to testify at the hearing. 

On Feb. 7 the panel has scheduled a hearing on a new proposed user fee on generic drugs and biosimilars, which aims to bring in more funds to help alleviate the FDA's backlog of generic drug applications. Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, is scheduled to testify at the hearing. 

And on Feb. 15, the subcommittee has scheduled a hearing on the reauthorization of the Medical Device User Fee Act, which also expires Sept. 30. FDA Center for Devices and Radiological Health Director Jeffrey Shuren is due to testify at the hearing.  The medical device fee is shaping up to be a tougher sell. Device makers want a revamp of the expedited approval process for low-risk devices, but patient advocacy groups say the current system is already too lax and allows dangerous products to get to market with little to no oversight. 

FDA User Fee Programs 

Under a user fee program, industry agrees to pay fees to help fund a portion of the FDA’s drug review activities while the FDA agrees to overall performance goals such as reviewing a certain percentage of applications within a particular time frame. 

“These final recommendations offer a great example of what can be achieved when the FDA, industry and other stakeholders work together on the same goal,” Hamburg said. “At a time of greater budgetary constraint, user fees provide a critical way for leveraging appropriated dollars, ensuring that FDA has the resources needed to conduct reviews in a timely fashion.”  

Said Hamburg: “Human drug user fees have revolutionized the drug review process in the United States since they were adopted 20 years ago, allowing the FDA to speed the application review process without compromising the agency’s high standards.” 

The proposed user fee programs for generic drugs and biosimilars are modeled on the successful PDUFA program “which has ensured a predictable, consistent, and streamlined premarket program for prescription drugs,” Hamburg said.  As a result of the continued investment of PDUFA resources, the United States now leads the world in first introduction of novel drugs. 

PDUFA was created by Congress in 1992 and must be reauthorized every five years. The current program, known as PDUFA IV, will expire on Sept. 30, 2012, unless reauthorized by Congress. FDA’s recommendations for PDUFA V were developed in consultation both with drug industry representatives and with patient and consumer advocates, and are expected to raise more than $712.8 million in fees annually over five years. 

Under the recommendations, fees paid by industry would support continued timely review of critical prescription drugs, as well as advance the development of drugs for rare diseases, provide for enhanced communication with small or emerging companies, increase the use of standardized electronic data to improve quality and efficiency, and foster the use of new clinical endpoints that improve drug development times and help address unmet medical needs. 

The proposed new Generic Drug User Fee program would provide the FDA with needed funding at a time when generic drug applications are on the rise. Whereas most new drugs are reviewed in 10 months, the typical review time for a generic drug is 30 months. The FDA has a backlog of more than 2,000 generic drug applications awaiting review, according to the Generic Pharmaceutical Association.  Generic drug user fees would help ensure consumers timely access to safe, high-quality and effective generic drugs, which account for two-thirds of all prescriptions dispensed in the U.S. 

The FDA proposes collecting $299 million in fees annually to hire additional generic drug reviewers starting in fiscal year 2013. That figure would come from an estimated 750 generic drug applications per year as well as other fees, including the inspection of foreign drug manufacturing sites. In return for these fees, the FDA will aim to review 90 percent of generic drug applications within 10 months. 

The FDA receives 800 to 900 new generic-drug-related applications annually. These applications are increasingly complex and frequently involve products manufactured outside of the U.S. In exchange for fees on facilities and product applications, the proposal includes performance metrics such as review timeframes and a commitment to achieve parity between surveillance inspections of foreign and domestic establishments by the 2017 fiscal year. As a result, FDA expects that the proposal would effectively eliminate the review backlog and significantly reduce review times. 

A biosimilar is a biological product that is highly similar to a U.S.-licensed reference biological product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. The proposed Biosimilar and Interchangeable Products User Fee program is intended for products approved under a new abbreviated approval pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological product. The Affordable Care Act of 2010 contains a subtitle called the Biologics Price Competition and Innovation Act (BPCI) of 2009, which established this pathway. 

Prior to it becoming law, competition in the biologic drug market was stifled. Enactment of BPCI will spark the development of a new segment of the industry, where companies will be able to develop alternative products. This will help spur innovation, improve consumer choice and drive down costs. 

The recommended user fee program for biosimilars includes fees for products in development to generate revenue in the near-term and to provide FDA with the resources needed to support development-phase meetings with sponsors of biosimilar biological product candidates

 

FDA: Transmucosal Immediate-release Fentanyl (TIRF) REMS

The Food and Drug Administration (FDA) recently approved a single shared Risk Evaluation and Mitigation Strategy (REMS) for the transmucosal immediate-release fentanyl (TIRF) products.  This new shared system will replace the individual REMS and allow prescribers and pharmacies to enroll into just one system, easing the burden on the health care system. 

TIRF medicines, which include the brand-name drugs Abstral (fentanyl) sublingual tablet, Actiq (fentanyl citrate) oral transmucosal lozenge and its generic equivalents, Fentora (fentanyl citrate) buccal tablet, Lazanda (fentanyl) nasal spray, and Onsolis (fentanyl) buccal soluble film, are narcotic pain medicines called opiods used to manage pain in adults with cancer who routinely take other opioid pain medicines around-the-clock.  TIRF medicines contain fentanyl, a prescription opioid (narcotic) pain reliever. TIRF medicines are used to manage breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. 

Breakthrough pain is pain that comes on suddenly for short periods of time and is not alleviated by a patient’s normal pain management plan. To use the TIRF medicines safely, these patients must be opioid tolerant based on concurrent regular use of another opioid medication. 

The shared system strategy, called the TIRF REMS Access Program, will be used by all sponsors of TIRF products and is expected to ease the burden on the health care system. The program will begin in March, 2012.Until that time, prescribers, patients, and pharmacies should continue to enroll in the individual REMS programs. 

“This TIRF REMS will ensure safe use and access to these drugs for patients who need them,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “We have worked with the sponsors of both the innovator and generic drugs to develop this single, shared system that will streamline the process and decrease the burden of the REMS on the health care system.” 

The goals of the TIRF REMS Access Program are to ensure patient access to important medications and mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: 

• prescribing and dispensing TIRF medicines only to appropriate patients, including use only in opioid-tolerant patients
• preventing inappropriate conversion between fentanyl products
• preventing accidental exposure to children and others for whom TIRF medicines were not prescribed
• educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose. 

Several TIRF products already have an individual REMS in place. Prescribers and pharmacies already enrolled in an individual REMS program for at least one TIRF medicine will automatically be transitioned to the shared TIRF REMS Access program.

Health care professionals who prescribe TIRF medicines that will only be used in an inpatient setting (hospitals, hospices, or long-term care facilities) will not be required to enroll in the TIRF REMS Access program. Similarly, patients who receive TIRF medicines in an inpatient setting are not required to enroll in the program. Long term care and hospice patients who obtain their medications from outpatient pharmacies must still be enrolled. 

Questions and Answers 

Q1. What are transmucosal immediate-release fentanyl (TIRF) medicines?  

A. TIRF medicines contain fentanyl, a prescription opioid (narcotic) pain reliever. TIRF medicines are used to manage breakthrough pain in adults with cancer who are routinely taking other opioid pain medicines around-the-clock for pain. Breakthrough pain is pain that comes on suddenly for short periods of time and is not alleviated by a patient’s normal pain management plan. To use the TIRF medicines safely, these patients must be opioid tolerant based on concurrent regular use of another opioid medication. 

The current list of TIRF medicines include Abstral (fentanyl) sublingual tablet, Actiq (fentanyl citrate) oral transmucosal lozenge and its generic equivalents, Fentora (fentanyl citrate) buccal tablet, Lazanda (fentanyl) nasal spray, and Onsolis (fentanyl) buccal. 

Q2.  What is a Risk Evaluation and Mitigation Strategy (REMS)? 

A.  A REMS is a risk management plan that uses risk minimization strategies beyond approved labeling to manage serious risks associated with a drug. Under the Food and Drug Administration Amendments Act of 2007, FDA has the authority to require a manufacturer to develop a REMS when FDA finds a REMS is necessary to ensure that the benefits of a drug outweigh its risks.  

A REMS can include a Medication Guide or patient package insert, communication plan, one or more elements to assure safe use, an implementation system, and a timetable for submission of the REMS assessments. 

Q3.  Why did FDA approve a shared, single-system Risk Evaluation and Mitigation Strategy (REMS) for the entire class of transmucosal immediate-release fentanyl (TIRF) medicines, when the TIRF medicines already had individual REMS in place?  

A.  FDA approved a shared, single-system REMS for TIRF medicines to reduce the burden on the healthcare system of having separate REMS programs in place for individual TIRF medicines. Under the new class REMS, prescribers, pharmacies, distributors, and outpatients will only need to enroll in one REMS program - the TIRF REMS Access program - to prescribe, dispense, or receive all drugs in the TIRF medicines class. 

Q4.  Does this new Risk Evaluation and Mitigation Strategy (REMS) apply to all opioids?  

A.  No. This REMS is approved specifically for transmucosal immediate-release fentanyl (TIRF) medicines. This REMS will not affect the prescribing and use of other opioids.  We are continuing work on another class REMS for the class of long-acting and extended-release opioids. 

Q5.  Will this action make it harder for patients to receive their transmucosal immediate-release fentanyl (TIRF) medicines?  

A.  No. FDA does not expect that this new class Risk Evaluation and Mitigation Strategy (REMS) will affect patient access to TIRF medicines compared to the individual REMS. Having a single shared REMS for all of the TIRF medicines will make it easier for prescribers and pharmacies to participate in the TIRF REMS Access program, which we expect to improve patient access. Sponsors will also be required to evaluate the impact of the REMS on patient access to their TIRF medicines as part of required periodic assessments of the REMS, and FDA will review these assessments. 

Q6.  What should prescribers know about the new shared TIRF REMS Access program?  

A.  Healthcare providers who prescribe transmucosal immediate-release fentanyl (TIRF) medicines for outpatient use are required to enroll in the TIRF REMS Access program. Healthcare providers who are already enrolled in an individual Risk Evaluation and Mitigation Strategy (REMS) program for at least one TIRF medicine will not need to re-enroll because they will be automatically transitioned to the shared TIRF REMS Access program. Prescribers will be required to re-enroll in the TIRF REMS program every two years from the date of enrollment into the TIRF class REMS or from the date of enrollment into the individual REMS, whichever was earlier.   

To enroll, prescribers must review the Education Program, successfully complete the Knowledge Assessment, and complete an enrollment form. Additional information about the enrollment process can be found on the TIRF REMS Access program website: www.TIRFREMSaccess.com. This website will be available in March 2012 when the TIRF REMS Access program “goes live”.  

In outpatient settings, all healthcare providers must complete and sign a TIRF REMS Access Patient-Prescriber Agreement Form with each new patient before writing the patient’s first TIRF prescription. Healthcare providers must also provide patients with a copy of the Medication Guide during counseling about the proper use of their TIRF medicine.  Healthcare providers who prescribe TIRF medicines for inpatient use only (e.g. hospitals, hospices, or long-term care facilities) are not required to enroll in the TIRF REMS Access program.  

Q7. What should pharmacies/pharmacists know about the new shared TIRF REMS Access program?  

A. Both outpatient and inpatient pharmacies that dispense transmucosal immediate-release fentanyl (TIRF) medicines are required to enroll in the TIRF REMS Access program. Pharmacies that were previously enrolled in an individual TIRF Risk Evaluation and Mitigation Strategy (REMS) will not need to re-enroll because they will be automatically transitioned to the shared TIRF REMS Access program. Pharmacies will be required to re-enroll in the TIRF REMS program every two years from the date of enrollment into the TIRF class REMS or from the date of enrollment into the individual REMS, whichever was earlier. 

For pharmacies to enroll, a designated authorized pharmacist must review the Education Program, successfully complete the Knowledge Assessment, and complete an enrollment form. Only then can the authorized pharmacist complete enrollment on behalf of the pharmacy. The authorized pharmacist will then train other pharmacy staff in the appropriate dispensing of TIRF medicines according to the TIRF REMS Access program. Additional information about the enrollment process can be found on the TIRF REMS Access program website: www.TIRFREMSaccess.com.  

Q8. What should patients know about the new shared TIRF REMS Access program? 

A. Patients who are prescribed TIRF medicines on an outpatient basis must sign a Patient-Prescriber Agreement with their healthcare provider and will be asked to read the Medication Guide provided to them by their prescriber. Patients can then take their prescription to an enrolled pharmacy. Patients can locate a participating pharmacy by consulting their prescriber or calling the TIRF REMS Access program at 1-866-822-1483. This phone number will be available in March 2012 when the TIRF REMS Access program “goes live”. Patients will be enrolled in the TIRF REMS Access program by the pharmacy at the time their first prescription is filled. 

Patients who receive TIRF medicines in an inpatient setting (e.g. hospitals, hospices, or long-term care facilities) are not required to participate in the TIRF REMS Access program. 

Q9. When does the TIRF REMS Access Program “go live” or become fully operational? What do patients on transmucosal immediate-release fentanyl (TIRF) medicines do in the interim? 

A. The TIRF REMS Access Program will “go live” in March 2012. Until this time, patients prescribed TIRF medicines will continue to get them through the individual Risk Evaluation and Mitigation Strategies (REMS) or risk management plan programs.

FDA Medication Guides – Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS)

The Offices of Regulatory Policy, Medical Policy, Surveillance and Epidemiology, New Drugs, Compliance, and Generic Drugs in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA) issued a new Guidance titled, “Medication Guides — Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS).” 

The guidance addresses two topics pertaining to Medication Guides for drug and biological products: 

1. When FDA intends to exercise enforcement discretion regarding when a Medication Guide must be provided with a drug or biological product that is dispensed to a healthcare professional for administration to a patient instead of being dispensed directly to the patient for self-administration or to the patient’s caregiver for administration to the patient.
2. When a Medication Guide will be required as part of a risk evaluation and mitigation strategy (REMS).  

FDA believes that this exercise of enforcement discretion will allow patients to receive important information about the drugs they will be taking without burdening the healthcare system to provide repetitive information when no material changes have been made. 

The guidance does not apply to the distribution of Medication Guides to patients participating in clinical trials conducted under an investigational new drug application (IND) because the specific information necessary for safe use of the drug, which is comparable to that contained in a Medication Guide, is required to be made available to study subjects in the informed consent forms and the investigators’ brochure. 

BACKGROUND  

In 1998, FDA issued final regulations establishing requirements for the distribution of patient labeling for certain prescription drug and biological products used primarily on an outpatient basis without direct supervision by a healthcare professional. These regulations, codified in 21 CFR part 208, apply to certain drug and biological products that FDA determines pose a serious and significant public health concern requiring the distribution of FDA-approved patient medication information that is necessary to patients’ safe and effective use of the drug products (a Medication Guide). 

All Medication Guides are subject to the standard in § 208.1 and the requirements of part 208, which states that Medication Guides apply primarily to human prescription drug products used on an outpatient basis without direct supervision by a healthcare professional and are applicable to both new and refill prescriptions. 

Section 208.1(c) authorizes FDA to require a Medication Guide if FDA determines one or more of the following circumstances exist:

1. The drug product is one for which patient labeling could help prevent serious adverse effects.
2. The drug product is one that has serious risk(s) (relative to benefits) of which patients should be made aware because information concerning the risks could affect patients’ decision to use, or continue to use, the product.
3. The drug product is important to health and patient adherence to directions for use is crucial to the drug’s effectiveness.  

Part 208 specifies the content and format of Medication Guides and manufacturer requirements to provide Medication Guides for distribution. Manufacturers of drug products for which a Medication Guide is required must: 

• obtain FDA approval of the Medication Guide before the Medication Guide is provided, and
• ensure that Medication Guides are provided in sufficient numbers, or provide the means to produce Medication Guides in sufficient numbers, to distributors, packers,  and authorized dispensers to permit the authorized dispenser to provide a Medication Guide to each patient receiving a prescription for the drug product. 

Part 208 also specifies the requirements for distribution of Medication Guides: 

• Distributors and packers who receive the Medication Guides, or the means to produce Medication Guides, must provide the Medication Guides or the means to provide them to authorized dispensers.
• Each authorized dispenser of a prescription drug product for which a Medication Guide is required must provide the Medication Guide directly to each patient or each patient’s agent when the product is dispensed, unless an exemption applies. 

FDAAA Requirements for Medication Guides as Part of REMS  

The Food and Drug Administration Amendments Act of 2007 (FDAAA) created new section 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355-1), which authorizes FDA to require a risk evaluation and mitigation strategy (REMS) when necessary to ensure that the benefits of a drug outweigh the risks. 

Under section 505-1(e), FDA may require that a REMS for a drug include among other things, when the criteria in 21 CFR part 208 are met, the requirement for an applicant to develop a Medication Guide for distribution to each patient when the drug is dispensed. 

Under part 208, Medication Guides may be safety-related, addressing serious risk(s) (relative to benefits) of which patients should be made aware, and/or efficacy-related, when patient adherence to directions for use is crucial to the drug’s effectiveness. Since the enactment of FDAAA, FDA has considered any new Medication Guide (or safety-related changes to an existing Medication Guide) to be part of a REMS.

However, the Agency has the authority to determine, based on the risks of a drug and public health concern, whether a Medication Guide should be required as part of a REMS when the standard in part 208 is met, and may decide the Medication Guide should be required as labeling but not part of a REMS if FDA determines that a REMS is not necessary to ensure the benefits of the drug outweigh its risks. 

Between March 25, 2008, when the REMS provisions of FDAAA took effect and January 1, 2011, FDA has approved over 150 Medication Guides for products approved under new drug applications (NDAs) and biologic license applications (BLAs) as part of a REMS. One hundred and eight of these REMS included only a Medication Guide and a timetable for submission of assessments of the REMS. 

In some cases, Medication Guides have been approved as part of REMS for drugs that are often provided in inpatient settings or in outpatient settings where the drug is dispensed to a healthcare professional who then administers the drug to the patient. Questions have arisen concerning FDA’s policy on whether the Medication Guide must be provided every time the drug is dispensed because part 208 states that the regulations are intended to apply primarily in the outpatient setting. 

FDA can require the development of — or safety-related changes to — a Medication Guide and can require these to be completed quickly, whether or not a Medication Guide is part of a REMS. Medication Guides are part of labeling and are subject to the safety labeling change provisions of section of the FD&C Act, added by FDAAA. 

Under these provisions, FDA can require the development of a Medication Guide (or safety-related changes to an existing Medication Guide) based on new safety information of which FDA becomes aware after approval of the product. Section 505(o)(4) includes tight timeframes for applicant submission of a supplement containing the labeling changes or a statement detailing the reasons why such a change is not warranted, as well as authority for FDA to order the labeling changes if agreement is not reached within the statutorily specified timeframes. 

Distribution of Medication Guides in Certain Settings 

FDA noted that questions have arisen concerning the requirements for providing a Medication Guide when a drug is not dispensed directly to a patient for self-administration or to the patient’s caregiver, but rather is dispensed or distributed to a healthcare professional who then administers the drug to the patient. 

For example, in an inpatient setting such as a hospital or nursing home, drugs are dispensed by the hospital pharmacist and then administered by hospital staff to patients. Similarly, in an outpatient setting such as a clinic or infusion center, drugs are dispensed or distributed to a healthcare professional who then administers the drug to the patient, sometimes without the involvement of a dispensing pharmacy or pharmacist. In some cases, these drugs are administered to a patient several times a day or several times a week.

Distribution Requirements Under Part 208  

Circumstances under which FDA intends to exercise enforcement discretion regarding Medication Guide distribution 

FDA noted that a Medication Guide need not be provided (i.e., FDA intends to exercise enforcement discretion concerning distribution of a Medication Guide to a patient) when a drug is dispensed under the following circumstances: 

• When the drug is dispensed to a healthcare professional for administration to a patient in an inpatient setting, except as provided in b. below.
• When the drug is dispensed to a healthcare professional for administration to a patient in an outpatient setting, such as in a clinic or dialysis or infusion center, with certain exceptions.  

In these settings, the drug will be administered to a patient by a healthcare professional who should provide the patient instructions on appropriate use of the drug, including what potential side effects may occur or follow-up that may be required as appropriate, and answer any questions the patient may have. 

Circumstances under which FDA will not exercise enforcement discretion and a Medication Guide must be provided to a patient in inpatient and outpatient settings. 

A Medication Guide must be provided to the patient or the patient’s agent (i.e., FDA does not intend to exercise enforcement discretion) in the following situations: 

• When the patient or the patient’s agent requests a Medication Guide.
• When a drug is dispensed in an outpatient setting (e.g., retail pharmacy, hospital ambulatory care pharmacy) and the product will then be used by the patient without direct supervision by a healthcare professional.
• The first time a drug is dispensed to a healthcare professional for administration to a patient in an outpatient setting, such as in a clinic or dialysis or infusion center.
• The first time a drug is dispensed in an outpatient setting of any kind, after a Medication Guide is materially changed (e.g., after addition of a new indication, new safety information). FDA plans to specify in the letter approving a revised Medication Guide when a change is considered to be a material change, and applicants will be directed to notify healthcare professionals that a material change was made (i.e., a new indication, new safety information).
• When a drug is subject to a REMS that includes specific requirements for reviewing or providing a Medication Guide as part of an element to assure safe use (possibly in conjunction with distribution), the Medication Guide must be provided in accordance with the terms of the REMS, as when healthcare providers are required to review the Medication Guide with patients before patients are enrolled in a REMS program.  

The Medication Guide must be provided in outpatient settings, even when the drug is dispensed to a healthcare professional for administration to the patient, the first time the drug is dispensed, and if the Medication Guide is materially changed. In these instances, FDA expects the Medication Guide to assist the healthcare professional in communicating important information about the drug to the patient.

FDA intends to exercise enforcement discretion with regard to providing Medication Guides in certain circumstances as described above. The following table reflects those circumstances, in accordance with the above-described policy. 

Medication Guides as Part of REMS  

While all Medication Guides must meet the standard and requirements in part 208, not every newly required Medication Guide will be an element of a REMS. A REMS is a strategy for managing the risks associated with a drug and a Medication Guide can be one part of that strategy. As the risks associated with the use of a drug increase, the tools needed to ensure safe use of a drug also increase. 

Depending on the risks involved, FDA may approve a Medication Guide under part 208 without requiring a REMS when that alone is adequate to address the serious and significant public health concern and meets the standard in § 208.1. In other cases, FDA may determine that a Medication Guide and other elements of a REMS, such as elements to assure safe use, are necessary to ensure that the benefits of a drug outweigh the risks. 

In most cases, FDA expects to include a Medication Guide as part of a REMS only when the REMS includes elements to assure safe use. However, FDA will include a Medication Guide in a REMS that does not include elements to ensure safe use if FDA determines that having the Medication Guide without a REMS will not be sufficient to ensure that the benefits of the drug outweigh the risks. 

Procedure for Requesting Removal of Medication Guides from REMS  

Applicants who currently have a REMS that includes only a Medication Guide and a timetable for submission of assessments may submit a prior approval supplement that proposes a REMS modification to eliminate the REMS if they do not believe that the REMS is necessary to ensure that the benefits of the drug outweigh the risks. 

Applicants with a REMS that includes a Medication Guide, a communication plan, and a timetable for assessment also may submit a prior approval supplement that proposes a REMS modification to remove the Medication Guide from the REMS, if they do not believe that a Medication Guide that is a part of the REMS is necessary to ensure that the benefits of the drug outweigh the risks. 

FDA will review any such supplements and determine whether the Medication Guide is necessary to ensure that the benefits of the drug outweigh the risks of the drug, as a tool of a REMS. The proposed REMS modification must be accompanied by a REMS assessment. 

• If the REMS has been assessed in the past 18 months, the assessment may consist of a statement to that effect.
• If the REMS has not been assessed in the past 18 months, including a REMS for which the first assessment has not been submitted, the assessment may consist of an update on the status of any postapproval study or clinical trial required under section 505(o) or otherwise undertaken by the responsible person to investigate a safety issue, including the information required under section 505-1(g)(3)(B) and (C) of the FD&C Act. If the REMS is not eliminated (e.g., the Medication Guide is removed from the REMS but the approved modified REMS still includes a communication plan and timetable for submission of assessments), this assessment to support the REMS modification will not replace any assessments required by the timetable for submission of assessments in the approved REMS.  

When the requirement for a REMS that includes only a Medication Guide for a reference listed drug has been removed,12 generic drug applicants may submit a changes being effected (CBE) supplement that proposes a REMS modification to eliminate the REMS (21 CFR 314.70(c)(6)). 

Even if the Medication Guide is removed from the REMS or the requirement for the REMS is removed, the Medication Guide will continue to be part of the approved labeling in accordance with part 208, unless the FDA approves a supplement removing the Medication Guide from the approved labeling.

FDA Guidance Responding to Unsolicited Request for Off-Label Information About Prescription Drugs and Medical Devices

Recently, the Food and Drug Administration (FDA) released a Guidance for Industry, entitled “Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices.”  The draft guidance updates and clarifies FDA’s policies on unsolicited requests for off-label information, including those that firms may encounter through emerging electronic media. 

The draft guidance describes FDA’s current thinking and offers recommendations about how manufacturers and distributors (firms) of prescription human and animal drug products (drugs) and medical devices (devices) can respond to unsolicited requests for information about unapproved or uncleared indications or conditions of use (off-label information) related to their FDA-approved or cleared products, including both requests made directly and privately to firms and requests made in public forums, including through emerging electronic media.  

Comments and suggestions regarding the draft are due within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.   

Background 

The Federal Food, Drug, and Cosmetic Act (FD&C Act) and FDA's implementing regulations prohibit manufacturers and distributors (firms) from introducing new drugs, new animal drugs, and most Class III medical devices into interstate commerce for any intended use that FDA has not determined to be safe and effective. The FD&C Act and FDA’s implementing regulations also prohibit device firms subject to premarket notification requirements under section 510(k), which includes most class II and some class I devices, from introducing such devices into interstate commerce for any intended use that is outside FDA’s substantial equivalence determination (clearance) for such devices. 

Statements that promote a drug or medical device for uses other than those approved or cleared by FDA may be used as evidence of a new intended use. Introducing a product into commerce for such a new intended use without FDA approval or clearance would, under these requirements, generally violate the law. However, once a drug or medical device has been approved or cleared by FDA, generally, health care professionals can lawfully use or prescribe that product for uses or treatment indications that are not included in the product's approved labeling (or, in the case of a medical device cleared under the 510(k) process, in the product's statement of intended uses).

FDA recognized that these off-label uses or treatment regimens may be important therapeutic options and may even constitute a medically recognized standard of care. 

Although dissemination of off-label information can be used as evidence of new intended uses for products in distribution, such information may also be of use to individuals seeking information about a medical product for themselves, patients, family members, or friends. These individuals sometimes submit non-public requests for off-label information directly and privately to firms.

Moreover, the rapid growth of the Internet, including social media tools and other emerging technologies, has made it easier for both consumers and health care professionals to quickly seek information about medical conditions and treatments.  This can cause firms to encounter more requests for off-label information about their products through product websites, discussion boards, chat rooms, or other public electronic forums that they maintain and over which they have full control. 

In addition, third-party sites (i.e., websites and other venues that are either entirely independent of a firm’s control and influence or not fully controlled by a firm) also may reveal questions about off-label uses of a firm’s products. These questions about off-label uses are typically directed to users of the site at large, rather than directly and privately to firms. Such posted information is likely to be available to a much broader audience than just the original requester, especially because communication threads (i.e., questions and replies) are often available for an indefinite period of time.

If a firm responds to unsolicited requests for off-label information in the manner described in the draft guidance, FDA does not intend to use such responses as evidence of the firm’s intent that the product be used for an unapproved or uncleared use. Such responses would also not be expected to comply with the disclosure requirements related to promotional labeling and advertising. 

Firms may choose to respond to unsolicited requests for information about off-label uses of their approved or cleared products in a manner other than that recommended in this draft guidance. Such activity would not constitute a per se violation of the law, but could potentially be introduced as evidence of a new intended use. 

Unsolicited Requests  

FDA defined unsolicited requests as “those initiated by persons or entities that are completely independent of the relevant firm. (This may include many health care professionals, health care organizations, members of the academic community, and formulary committees, as well as consumers such as patients and caregivers).” Requests that are prompted in any way by a manufacturer or its representatives are not unsolicited requests. 

FDA addressed two types of unsolicited requests: 1) non-public unsolicited requests and 2) public unsolicited requests.  Responses to unsolicited requests can likewise be non-public (private) or public. 

Non-public unsolicited requests  

FDA defined a non-public unsolicited request as “an unsolicited request that is directed privately to a firm using a one-on-one communication approach.” 

• Example 1: An individual calls or e-mails the medical information staff at a firm seeking information about an off-label use. In this case, neither the request nor the response would be visible to the public. 

Public unsolicited requests 

FDA defined a public unsolicited request as “an unsolicited request made in a public forum, whether directed to a firm specifically or to a forum at large.”

•  Example 2: During a live presentation, an individual asks a question, directed to a firm’s representative but heard by other attendees, regarding off-label use of a specific product. This request is a public request. Similarly, a response by the firm that is conveyed to the same audience as the original question would be considered a public response.
• Example 3: An individual posts a question about off-label use of a specific product on a firm­ controlled website (or a third-party discussion forum) that is visible to a broad audience. The request could be directed to a firm specifically or posed to users of a discussion forum at large.  This request is a public online request. Similarly, a response by the firm that is visible to the same audience as the original question would be considered a public online response. 

Solicited Requests  

FDA considers requests for off-label information that are prompted in any way by a manufacturer or its representatives to be solicited.  Such solicited requests may be considered evidence of a firm’s intent that a drug or medical device be used for a use other than that specifically approved or cleared by FDA.  Although not exhaustive, the following examples illustrate what FDA generally considers to be solicited requests for off-label information: 

• Example 4: If a firm’s sales rep mentions a use of a product that is not reflected in the product’s approved labeling and invites a health care professional to request more information, resulting requests would be considered solicited requests. 
• Example 5: If a rep of a firm, such as a medical science liaison or paid speaker (e.g., key opinion leader), presents off-label use data at a company-sponsored promotional event (e.g., a dinner) and attendees then ask or submit requests for more information, these requests would be considered solicited requests.
• Example 6: If a firm issues to health care professionals business reply cards that are intended for use in requesting off-label information, presents statements or contact information in promotional  pieces in a manner that solicits requests for off-label medical or scientific information (e.g., “Product X continues to be evaluated in more than 50 trials in a broad range of conditions and patients” and “Call 1-800-… for more information”), or displays a commercial exhibit panel suggesting a new indication (e.g., a sign that reads “Coming Soon, a new use for Product X”), requests made in response to these types of prompts would be considered solicited requests.
• Example 7: If a firm provides a phone number, e-mail address, uniform resource locator (URL), or username that is a word, alpha phrase, or alpha representation implying the availability of off-label information for its product, requests using this phone number, e-mail address, URL, or username would be considered solicited requests.
• Example 8: A firm asks or otherwise encourages users to post videos about their own uses of its product on third-party video-sharing 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. 
• Example 9: If a firm sends out packets of information to known bloggers or online consumer reviewers and encourages them to write about an off-label use of its product on third-party sites and this then provokes a discussion about that off-label use, any requests inquiring about the product’s off-label use as a result of these blogs, whether posted as comments to the third-party site or directed to the firm, would be considered solicited requests. 
• Example 10: If a firm announces results of a study via a microblogging service (e.g., Twitter) and suggests that an off-label use of its product is safe and effective, any comments and requests received as a result of the original message about the off-label use would be considered solicited requests. 
• Example 11: If a firm sets up a website that enables viewers to read prepared standard responses for the firm’s products that are generated from prefixed pull-down menus naming various disease states, including any standard responses related to off-label uses for the firm’s product, resulting requests for off-label information would be considered solicited. Moreover, if this website makes it possible to use search terms to generate standard responses that go beyond the scope of the product information being requested, including off-label use information, resulting requests for and responses to such a search would be considered solicited requests. 

RESPONDING TO NON-PUBLIC UNSOLICITED REQUESTS  

FDA has long taken the position since 1982 that firms can respond to unsolicited requests for information about FDA-regulated medical products by providing truthful, balanced, non-misleading, and non-promotional scientific or medical information that is responsive to the specific request, even if responding to the request requires a firm to provide information on unapproved or uncleared indications or conditions of use. (See Position on the Concept of Solicited and Unsolicited Requests (April 22, 1982); 59 Fed. Reg. 59820, 59823 (November 18, 1994). FDA’s current views (expressed in the draft guidance) remain consistent with these past policy statements. 

Consequently, FDA noted that if responses to unsolicited requests fall within these parameters, FDA does not expect those responses to meet regulatory requirements for promotional labeling or advertising and has not considered these responses as evidence of intended use.   

FDA made the following recommendations if a firm chooses to respond to a non-public unsolicited request for off-label information (i.e. an individual might call or correspond directly with a firm concerning the use of its product for an unapproved or uncleared indication or condition of use). 

1. Information distributed in response to an unsolicited request should be provided only to the individual making the request directly to the firm as a private, one-on-one communication.  

2. Information distributed in response to an unsolicited request should be tailored to answer only the specific question(s) asked. 

FDA noted that a firm should ensure that all pertinent background data are obtained to be able to determine what information is being requested before providing a response. If an unsolicited question is broad in nature, FDA noted that the firm should appropriately narrow the question. In other words, the level of specificity of the question posed is important to ensure that the firm’s response is tailored to the request. 

• Example 12: An individual requests information on the use of a drug or device for one particular disease or condition that is considered off-label for that drug or device (e.g., use of Drug X during pregnancy in patients with diabetes). Generally, a firm should provide information pertaining only to that disease or condition (i.e., the firm should provide a response tailored only to the use of Drug X during pregnancy in patients with diabetes). 

However, if there is information about known or suspected risks associated with other diseases or conditions that is also relevant to the disease or condition for which information was requested, the firm should provide such information to ensure a complete and accurate presentation of the risk issues associated with the requested use (e.g., Drug X is known to cause fetal harm when used in pregnant patients with arthritis, and this risk information should be disclosed as part of the response about use of Drug X during pregnancy in patients with diabetes). 

3. Information distributed in response to an unsolicited request should be truthful, non­misleading, accurate, and balanced.  

Evaluating evidence of intended use may also involve considering the context in which manufacturer communication about an off-label use occurs. For this reason, FDA’s recommendations for responding to unsolicited requests for information by third parties are not identical to its recommendations regarding the spontaneous manufacturer-initiated activity of distributing reprints, as addressed in other FDA guidance. 

A response should provide non-biased information or data relating to the particular off-label use that is the subject of the request, including applicable data that are not supportive or that cast doubt on the safety or efficacy of that use. For example, when conclusions of articles or texts that are disseminated have been specifically called into question by other articles or texts, a firm should disseminate representative publications that reach contrary or different conclusions regarding the use at issue. The response should include complete copies of scientific reprints, technical literature, or other scientific and medical information responsive to the request, not just summary documents or abstracts prepared by the firm. 

The response can include unpublished data on file if they are responsive to the specific request (either supporting or casting doubt on the safety or efficacy of the off-label use). However, to the greatest extent possible, a firm should rely on published peer-reviewed journal articles, medical texts, or data derived from independent sources. To the extent the response consists of published reprints from journals, those reprints should be from journals that have a publicly stated policy, to which the organization adheres, of full disclosure of any conflict of interest or biases for all authors, contributors, or editors associated with the journal or organization. 

4. Information distributed in response to an unsolicited request should be scientific in nature.  

When responding to an unsolicited request for information, a firm should respond with material that is scientific in tone and presentation. The material should not be promotional in tone or presentation. Furthermore, the responsive material should not be distributed along with other material or information that is promotional in nature or tone. 

5. Responses to unsolicited requests for information should be generated by medical or scientific personnel independent from sales or marketing departments. 

FDA recommends that questions or requests about off-label uses be referred to the firm’s medical or scientific representative or department and that sales and marketing personnel have no input on the content of responses to unsolicited questions or requests for off-label information.  FDA recommends that medical or scientific personnel have specialized backgrounds in responding to unsolicited requests for information, including important training, such as appropriately narrowing questions, tailoring responses only to the specific questions being asked, providing unbiased responses, and properly documenting responses. 

6. Information distributed in response to an unsolicited request should be accompanied by the following: 

• A copy of the FDA-required labeling, if any, for the product (e.g., FDA-approved package insert and, if the response is for a consumer, FDA-approved patient labeling or, for new animal drugs, FDA-approved client information sheet)
• A prominent statement notifying recipient that FDA has not approved or cleared the product as safe and effective for the use addressed in the materials provided
• A prominent statement disclosing the indication(s) for which FDA has approved or cleared the product
• A prominent statement providing all important safety information including, if applicable, any boxed warning for the product
• A complete list of references for all information disseminated in response (e.g., a bibliography of publications in peer-reviewed medical journals or in medical or scientific texts; citations for data on file, for summary documents, or for abstracts) 

7. A firm should maintain the following records:  

• The nature of the request for information, including the name, address, and affiliation of the requestor
• Records regarding the information provided to the requestor
• Any follow-up inquiries or questions from the requestor 

If a firm responds to non-public unsolicited requests for off-label information in the manner described above, FDA does not intend to use such responses as evidence of the firm’s intent that its product be used for an unapproved or uncleared use. Such responses also would not be expected to comply with the disclosure requirements related to promotional labeling and advertising. 

EMERGING ELECTRONIC MEDIA  

In addressing new forms of social media and online content on the Internet, FDA recognized that firms are capable of responding to requests about their own named products in a truthful, non-misleading, and accurate manner. Moreover, as these firms are regulated by FDA and have robust and current information about their products, FDA recognized that, “it can be in the best interest of public health for a firm to respond to unsolicited requests for information about off­ label uses of the firm’s products that are made in public forums, especially since other responders may not provide or have access to the most accurate and up-to-date medical product information.” 

However, because product information posted on websites and other public electronic forums is likely to be available to a broad audience and for an indefinite period of time, FDA expressed concern that firms may post detailed public online responses to questions about off-label uses of their products in such a way that they are communicating unapproved or uncleared use information about FDA-regulated medical products to individuals who have not requested such information. In this circumstance, communications to persons who have not requested information may promote a product for a use or condition for which FDA has not approved or cleared. 

FDA is also concerned about the enduring nature of detailed public online responses to off-label questions because specific drug or device information may become outdated (e.g., new risk information may become available).  Accordingly, FDA made the following recommendations to a firm that chooses to respond to public unsolicited requests for off-label information about its product(s), including those encountered through emerging electronic media. 

1. If a firm chooses to respond to public unsolicited requests for off-label information, the firm should respond only when the request pertains specifically to its own named product (and is not solely about a competitor’s product). 

The level of specificity of the question posed in a public forum is important in determining the appropriateness of a firm responding to the unsolicited request. 

-       Example 13: An individual poses the specific question “Can Drug/Device X be used for Condition Y” in a public forum (and this question is not prompted by or on behalf of the firm). It may be appropriate for the firm to respond as outlined below because the question is unsolicited and specific to the firm’s named drug or device. 

However, if an individual poses the non-specific question “What drug/device can be used for Condition Y” in a public communication thread and the firm manufactures or distributes Drug/Device X, which is not FDA-approved or cleared for Condition Y, the firm should not respond to the request because the question is not specific to Drug/Device X. 

2. A firm’s public response to public unsolicited requests for off-label information about its named product should be limited to providing the firm’s contact information and should not include any off-label information.  

• The firm’s public response should convey that the question pertains to an unapproved or uncleared use of the product and state that individuals can contact the medical/scientific representative or medical affairs department with the specific unsolicited request to obtain more information.
• The firm’s public response should provide specific contact information for the medical or scientific personnel or department (e.g., e-mail address, telephone number, facsimile) so that individuals can follow up independently with the firm to obtain specific information about the off-label use of the product through a non-public, one-on-one communication. 

After an individual has privately contacted a firm for more information regarding an off-label use of the firm’s product, the firm should provide a detailed response and maintain records. Therefore, any substantive communication about off-label uses for the product, in response to the original unsolicited off­-label question, should occur solely between the firm and the individual who made the request. Regardless of the fact that the original, unsolicited off-label question may have been available to a very broad audience, the firm should not make its detailed response with off-label information publicly available within the same forum. 

For example, after the requestor has contacted the firm and provided a personal e-mail address to obtain an answer to the off-label question, the firm’s detailed off-label response should be e-mailed to the requestor since this resulting communication will occur solely between the firm and the specific individual making the unsolicited request for the off-label information. 

3. Representatives who provide public responses to unsolicited requests for off-label information should clearly disclose their involvement with a particular firm. 

FDA recommended that a representative who responds to a public request clearly disclose in his/her public response that he/she is a particular firm’s representative and inform the requestor of the name of the firm representative or department to contact should the individual choose to follow up directly with the firm in a non-public forum for detailed information about the unsolicited request for off-label information. 

4. Public responses to public unsolicited requests for off-label information described in numbers 2 and 3 should not be promotional in nature or tone. 

In addition to a firm’s contact and disclosure information, a public response should include a mechanism for providing readily accessible current FDA-required labeling, if any, for the product  (e.g., FDA-approved package insert and, if the response is for a consumer, FDA-approved patient labeling or, for new animal drugs, FDA-approved client information sheet). The public response should not provide any promotional information. 

For example, a public online response should include a direct link to the current FDA-required labeling, if any, but should not include links to any other information (e.g., product websites, product promotional materials, firm websites, third-party websites). Furthermore, the uniform resource locator (URL) or web address where viewers are directed to obtain the FDA-required labeling, if any, should not itself be promotional in tone or content (e.g., should not be www.bestcancercure.com). 

If a firm responds to public unsolicited requests for off-label information, including those encountered through emerging electronic media, in the manner described above, FDA does not intend to use such responses as evidence of the firm’s intent that its product be used for an unapproved or uncleared use. Such responses also would not be expected to comply with the disclosure requirements related to promotional labeling and advertising.

FDA the Headache of Developing a Biosimilar Pathway

A recent article from MedPage Today explored a provision in the healthcare reform bill that called on the Food and Drug Administration (FDA) to create an expedited pathway for approving biosimilars -- the nonidentical "generic" versions of advanced prescription drugs to treat multiple illnesses from cancer to rheumatoid arthritis.  

As we noted back in September, FDA is expected to issue guidance on the subject shortly.  (Well, maybe not) 

The primary concern for the FDA is how to ensure that a biosimilar is the same as its original biologic.  Writing for MedPage Today, Bruce S. Rubin, MD, explained the “crucial differences that separate "generics" from biosimilars.”

He noted that, “Most traditional drugs, like Tylenol, are chemically synthesized, which means they have structures that are consistent and known.  Biologics, on the other hand, are fashioned out of living cells, meaning they have much more complex structures, which are not as easily understood as the makeups of chemically created drugs.”

Dr. Rubin explained that, “Because a chemically created drug can be reproduced easily, the generic versions are no different than their name-brand counterparts and can be verified through testing and analysis.”

However, he noted that, “With biosimilars this is not always the case. That's because biologics are more complex structures that are much more difficult to replicate. An error in reproduction could cause unanticipated or harmful side effects.  This fact illustrates why the FDA needs to exercise added caution when setting out the process and priorities for approving biosimilar products.”

Dr. Rubin explained that, “Right now, no biosimilar exists on the U.S. market; because of their complexity, they weren't included in the Hatch-Waxman legislation that set the regulatory framework for other generic drugs.”  The Affordable Care Act however changed that, which led to FDA beginning to hold meetings last November to develop a biosimilar approval process.

In order to ensure the safety of biosimilar drugs for patients, Dr. Rubin recommended that the FDA:

• Require clinical trials or other appropriate clinical testing before the approval of biosimilars
• Ensure robust pharmacovigilance, the surveillance of a drug's performance, including adverse reactions, after it's been released for marketing. Of primary importance is the creation of a traceability system that includes distinctive labeling, product tracking codes, and a way to report adverse reactions
• Require different names for all biologic medicines in order to prevent confusion for physicians and patients
• Require transparent and clear product labels that educate patients about the trials conducted on that specific product, not just the reference product
• Guarantee that patients and their doctors have the ability to decide treatment by ensuring a treatment plan is not altered by a pharmacist without the consent of the physician and patient

Dr. Rubin asserted that, “Including these requirements would assure patients and their families that the FDA is set on striking the right balance between cost effectiveness and patient safety.”

He emphasized that, “biologics and biosimilars could revolutionize the way the U.S. treats some of the most painful, most deadly diseases. But like the advances that came before them, these new treatments must undergo a thorough evaluation process before their approval.  Patient safety must be considered first if we are to uphold America's system for pharmaceutical review and approval.”

CMS-FDA Breast Cancer and Avastin: FDA Pulls Approval While CMS Pays

Food and Drug Administration (FDA) Commissioner Dr. Margaret Hamburg announced in a 69-page decision that the agency would withdraw the biologic medicine Avastin as a treatment option for women with metastatic breast cancer.  

Avastin (bevacizumab) is an injectable cancer medication manufactured and marketed by Genentech.  Avastin blocks a protein that is important for the formation of blood vessels and is thought to work by preventing the formation of new blood vessels that feed cancer tumors. 

Commissioner Hamburg’s decision will not affect Avastin’s approved indications for se in colon, lung, kidney, and brain cancers, and Avastin will remain on the market. As a result, physicians will be free to prescribe Avastin off-label for metastatic breast cancer. 

The controversy surrounding Avastin for use in metastatic breast cancer came to a climax this past summer when FDA’s advisory committee held an “appeal” hearing concerning its recommendation  that Avastin no longer be indicated for the treatment of breast cancer. 

Despite the committee’s announcement and the June 2011 public hearing, the Center for Medicare and Medicaid Services (CMS) announced that Medicare will continue to pay for Avastin when used to treat breast cancer.  According to a CMS spokesperson: “[t]he drug will still be on the market, doctors will still be prescribing it, and [CMS] will continue to pay for it,” adding that CMS often pays for off-label uses of drugs. 

According to a recent article from the Food and Drug Law Institute (FDLI), CMS’ announcement confirms what drug manufacturers have long argued in the context of civil False Claims Act (FCA) litigation involving claims for “off-label promotion”: Medicare coverage is not driven by FDA approval, but rather is—and should be—based upon physicians’ professional determinations that a given drug is reasonable and necessary” for use by a particular patient for a specific indication. 

The article asserted that, “CMS’decision to continue to provide reimbursement for breast cancer patients using Avastin also stands in contrast to legal and policy positions adopted by the Department of Justice (DOJ) in FCA cases involving promotional practices.” 

CMS’ Position Inherently Conflicts With DOJ’s Position In Recent FCA Investigations and Litigation 

CMS’ assertion that Medicare will continue to cover Avastin regardless of FDA’s decision—and regardless of an FDA finding that there is insufficient scientific evidence to support Avastin’s use in breast cancer—confirms that neither of these factors is dispositive of whether the use is medically “reasonable and necessary,” i.e., eligible for Medicare coverage by statute. 

The article recognized that, “CMS’ position is consistent with the argument that pharmaceutical and medical device companies have long made (with limited success) in FCA investigations and litigation: that neither the off-label status of a particular use nor the quantum of scientific support for that use determines whether the use is properly reimbursable under Medicare’s “reasonable and necessary” standard.” 

Accordingly, the authors asserted that, “the absence of FDA approval or specific scientific evidence supporting a particular use does not establish that those claims are “false” for purposes of FCA liability.”  As the authors explained, “This argument goes to the very heart of the Government’s and qui tam relators’ ability to state—and prove—a claim under the FCA.” 

That statute prohibits, in relevant part, “knowingly present[ing], or caus[ing] to be presented, a false or fraudulent claim for payment or approval.”  If a particular claim for Medicare reimbursement is neither false nor fraudulent, it cannot provide the predicate for an FCA violation. DOJ, however, has opposed this argument when raised by FCA defendants. 

For example, the article discussed the case United States ex rel. Strom v. Scios, Inc., in which DOJ alleged that Scios, Inc. violated the FCA by promoting the drug Natrecor for use in serial, scheduled outpatient infusions when Natrecor was only approved by FDA for intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.  DOJ alleged that during the period at issue, “serial, scheduled outpatient infusions of Natrecor were not eligible for payment by Medicare because this off-label use was neither ‘reasonable and necessary,’ nor ‘medically accepted.’” 

As the authors noted, “According to DOJ, the use failed to meet Medicare’s statutory standard because “the use was not supported by any credible study showing that the serial outpatient infusions were effective.”  DOJ alleged the claims were “false because the off-label use is not covered” by Medicare.” 

Almost by definition, a use is off-label precisely because there is insufficient evidence to support its approval by the FDA.  If the mere lack of conclusive evidence were sufficient to establish falsity, the article explained that “there would be no such thing as a legitimate off-label claim – much less a regulatory framework in which offlabel uses are an ‘accepted aspect of a physician’s prescribing regimen.’” 

Scios further argued that the scenario described in the Complaint is typical in the off-label context: “lacking data from a Phase III, double-blinded, placebo-controlled clinical trial, 4,000 physicians nonetheless determined— more than 170,000 times, based on their own first-hand observations of patients’ actual responses to the drug— that serial infusions of Natrecor were reasonable and necessary for the treatment of chronic heart failure.”   

As the article noted, “This argument espoused the principle that CMS appears to have embraced in its recent announcement regarding Avastin coverage: individual physician judgments determine whether particular uses are “reasonable and necessary.” 

Nevertheless, the court rejected Scios’s argument finding that “[b]ecause the [Medicare] statute permits reimbursement only for ‘reasonable and necessary’ treatments . . . a prescription of Natrecor in a context where it is not ‘reasonable’ or ‘necessary’ would be statutorily ineligible for reimbursement.  This satisfies the FCA’s requirement of a ‘false’ statement.” 

In reaching this conclusion, the authors noted that “the court appears to have relied, at least in part, on the Government’s allegations that Scios overstated the nature of the available scientific evidence to the physicians who prescribed Natrecor for outpatient infusions.  DOJ’s briefs in Strom, however, do not rely on any alleged misrepresentations on the part of Scios. Rather, DOJ argues that the alleged lack of scientific evidence, in and of itself, means that claims for Natrecor for outpatient infusion could not have been “reasonable and necessary” and therefore were not eligible for reimbursement by Medicare.” 

But as the authors explained, “CMS’ announcement regarding Avastin, however, highlights the flaw in DOJ’s theory: neither FDA approval nor the quantum of available scientific evidence, in isolation, determines Medicare coverage.” 

DOJ’s Position Overlooks the Key Role of Physicians 

The FDLI article asserted that, “DOJ’s briefs in Strom improperly ignore the central role that physicians and other health care providers play in determining whether the specific use of a given drug or medical device is “reasonable and necessary” for an individual patient, based upon each patient’s unique circumstances.  Under Medicare’s reimbursement scheme, however (and as CMS’ announcement regarding Avastin confirms), that determination does, and should, control.” 

To further this argument, the authors pointed to the U.S. District Court for the Southern District of Texas, which recently recognized this principle in two FCA cases involving allegations of off-label promotion by two medical device manufacturers.  In U.S. ex. rel Bennett v. Boston Scientific Corporation and U.S. ex rel. Bennett v. Medtronic, Inc., a qui tam relator alleged that medical device manufacturers unlawfully promoted the use of surgical ablation devices to treat atrial fibrillation. 

The authors noted that, “The relator further asserted that the defendants’ alleged off-label promotion “caused physicians and hospitals to submit claims to the government falsely stating that the use of the [devices at issue] was ‘reasonable and necessary’ or ‘medically necessary,’” but that the use of the surgical ablation devices to treat atrial fibrillation could not be medically necessary because the device was not FDA approved for such use. 

In separate opinions, the court granted the defendants’ motions to dismiss, finding among other things that “[t]he decision on medical necessity is made by individual physicians exercising independent professional judgment based on the knowledge of their particular patients. The cases recognize that off-label use of a drug or medical device is distinct from a medically unnecessary use of that drug or device.” 

The authors explained that, “While scientific evidence (or the lack thereof) may be determinative in certain instances, in others, a physician may decide that a particular off-label use of a medical device or drug is reasonable and necessary based upon his or her own observations or based on conversations with other physicians. In either case, the physician’s determination controls whether the use is reimbursable under Medicare.” 

DOJ’s Wrongful Theory Has Significant Impact for FCA Defendants 

The article noted that, DOJ has failed to respect and follow CMS’ policy as to how coverage determinations are made and “because DOJ is responsible for litigating FCA cases and prosecuting criminal off-label promotion cases, DOJ’s flawed theory has a real and substantial impact for pharmaceutical and medical device manufacturers.” 

For example, the authors noted how “DOJ possesses enormous leverage to demand settlements reaching into the millions, and sometimes billions, of dollars in cases involving alleged off-label promotion,” because “the FCA provides for both treble damages and statutory penalties for each false claim allegedly presented.”  Consequently, “DOJ’s financial threats are coupled with the potential for exclusion from participation in federal health care programs as well as FDA debarment.” 

The article noted that, “These pressures frequently force pharmaceutical and medical device manufacturer defendants to settle FCA cases in order to resolve claims that they have committed “fraud” against the federal government by allegedly promoting their products for uses that are not approved by FDA.” 

Ultimately, the authors noted that, “DOJ, both in legal briefs and in public statements, frequently equates alleged off-label promotion with fraud, without identifying allegedly false or misleading actions on the part of manufacturer defendants.  CMS’ recent announcement regarding Avastin, however, underscores that Medicare coverage turns on a particular physician’s determination, in his or her independent medical judgment, that a specific use is “reasonable and necessary” for a given patient.” 

Viewed in this light, the authors asserted that, “it is clear that claims for Medicare reimbursement are not “false or fraudulent” simply because FDA has not found sufficient scientific evidence to approve the underlying use.”  Instead, the authors maintained that “it is inherently unjust for DOJ—in its role as the FCA enforcement agency—to continue to claim that manufacturers are committing “fraud” when its sister agency, CMS, knowingly pays for the off-label use underlying an FCA enforcement action.”

Policy Updates and Enforcement Developments from FDA’s Medical Products Centers: Tips on Social Media

A recent conference hosted by the Food and Drug Law Institute looked at the evolving role of technology, particularly in the realm of advertising and promotion in the life sciences industry.   Speakers identified advertising and promotion of medical products online and especially through social media as a hot topic. 

During the session on “Policy Updates and Enforcement Developments from FDA’s Medical Product Centers,” Wayne Pines, President, Regulatory Services and Healthcare, APCO Worldwide, introduced panelists using FDLI’s the LINK.  FDLI’s online Food and Drug Regulatory Directory features profiles of FDA leadership, including, as Pines demonstrated, the designation of the recently elevated Office of Prescription Drug Promotion (OPDP) in the Center for Drug Evaluation and Research (CDER), formerly the Division of Drug Marketing, Advertising, and Communications (DDMAC).  

Panelists included Thomas W. Abrams, Director, Office of Prescription Drug Promotion (CDER); Lisa L. Stockbridge, Branch Chief, Advertising and Promotional Labeling Branch (APLB), Division of Case Management, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research (CBER); Toni M. Stifano, Consumer Safety Officer, Office of Compliance, Center for Devices and Radiological Health (CDRH); and Dorothy R. McAdams, Team Leader, Post-Approval Review Team, Division of Surveillance, Office of Surveillance and Compliance, Center for Veterinary Medicine (CVM). 

The panelists discussed how the “increasing number of promotional materials and advertising platforms has increased the difficulty of the agency’s job in reviewing promotional material.” Abrams recognized that “because of constantly evolving technology and changing platforms, FDA guidance on social media will focus on issues and principles, not platforms, in an effort to remain as useful and relevant as possible.” 

FDA has now delayed issuing guidance on the use of social media for over a year, despite numerous announcements that guidance would come out in early 2011.  Nevertheless, Abrams “acknowledged the agency’s efforts to involve industry and others through public meetings and submissions of comments to the open docket in developing guidance for social media advertising and promotion issues.” 

Stifano highlighted how CDRH is working with evolving technology and cited how her group has worked directly with eBay to prevent the sale of certain unapproved and recalled devices, as well as prescription devices without a prescription, through that website.  She emphasized however, that unlike CDER and CBER, CDRH does not receive copies of advertisements or final labeling for products reviewed under the 510(k) clearance process. 

She also stated that medical device mobile applications are “a growing area of concern.” As reflected in a guidance document released for comment in July 2011, FDA may limit its oversight on this issue to a subset of applications that are defined as medical devices and either used as an accessory to a regulated device or that transform a mobile platform into a regulated device. 

All of the speakers emphasized the importance of triage in the review process and a risk-based enforcement approach, as well as the critical role companies play in voluntary compliance efforts.  Abrams stated that “The overall trend is improving in the quality of promotional materials,” although he noted that given the vast amount of promotional materials, it is hard to quantify improvement, especially because areas remain “concerning.” 

Stockbridge explained that many of the products at CBER are for rare conditions and limited populations. She also identified the unique public health aspect at stake in vaccine promotion.  McAdams noted that even in CVM, the primary concern in regulating promotional materials for veterinary medicines is always human health. She also explained that her post-approval review team duties include more than promotional review and extend to anything in the post-approval life of a product, such as post approval research and clinical reports. 

Stockbridge highlighted a hot compliance issue that resulted in several untitled letters: the importance of separating committee or professional organization recommendations regarding general public health practice from specific product information based on adequate and well-controlled studies. She asserted that the failure to separate recommendations from product information in this way may be determined to be misleading. 

“Despite the unique challenges faced by each of the Centers’ advertising and promotion oversight staff, the similarity of common violations in each of the product areas demonstrate that ultimately the importance of high quality promotion that is not misleading is critical regardless of what product is being marketed.” 

Although Abrams noted the Agency’s “active and vigorous enforcement program” and “extensive monitoring” of promotional materials, he encouraged dialogue between FDA and industry and the importance of understanding the rationale of the law in complying with regulations. 

RECOMMENDATIONS FOR SOCIAL MEDIA 

In light of the continued uncertainty surrounding the use of social media by pharmaceutical (pharma), biotechnology (biotech) and medical device (device) companies respond, another recent FDLI article offered a handful of web and social media suggestions and practices that can ease the review work we do. 

The article first noted that staff and employees need to be trained to become familiar with social media, mobile sites and apps, to get a better understanding of how the digital environments work to know what is possible, what is not and what questions to ask. 

Promotion Norms and Expectations 

Universal norms for promotional activity in the United States require consideration of the categories of help seeking and disease awareness, promotional labeling and advertising, and within that, reminder advertising. If working on content in the social media and mobile environments: 

1. As with all promotional activity, keep it on label or consistent with labeling if branded.
2. Have an adverse events reporting strategy developed and implemented for social media and mobile implementations. Involve the right parties from pharmacovigilance in the development of the strategy.
3. Ensure all employees and agents of the company are aware of and fully trained on all social media-related company policies (review processes, requirements and standards for branded and unbranded social media activity, interaction with company sponsored or company created sites, identify who are the authorized users if any, how sites are to be monitored and maintained).
4. Provide access to the current full prescribing information with branded content if not a reminder ad, or if the product labeling carries a boxed warning. 

Basic Elements 

In a reviewer’s preparation and work on branded content, one basic element includes balancing claims with appropriate risk information, including an indication statement with efficacy claims, and it should also be presented with any safety disclosure or signal.  Any material facts and limitations of use should be used with the indication presentation. 

Following the hierarchy of safety is recommended, particularly if the product includes a boxed warning. If there is not a boxed warning associated with the product, along with the claims it is wise to use the warnings, precautions and most common adverse events or choose risk information most relevant to the efficacy information presented. 

Navigation, Links and Where Things Go 

Thinking about the particular environments of site content, the team needs to know and understand the navigation and links - how things it together, how to move around, the viewing order, the content and how it is displayed.  A diagram called a wireframe is the perfect tool and is recommended to be part of the reviewer’s package for any website, mobile site or app review. 

It shows a visual structure, function and content description of the pages, and how the navigation and links low.  There can be an assortment of sharing widgets displayed or a “share” button included on a page. his can send the content of the page some place else for posting.  This option illustrates why each view should contain a balanced representation to ensure the proper messages are communicated together, when working with branded content.

When reviewing mobile content it is well advised and practical to have the home page display certain buttons (such as “Indications,” “Prescribing Information” and “Important Safety Information”) that remain consistent and available throughout the mobile presentation as a user navigates through the different branded content options. 

When a user finds a page useful and decides to share it, the same appearance and use of consistent buttons as part of each page allows access to the “Important Safety Information” and “Prescribing Information” if it is branded content that is shared.   

An option or button to the home page is also a good idea, by use of a “Home” button or use of a back link, depending where navigating from.  Other buttons that are commonly utilized are “Log In,” “Favorites” or “Bookmark,” and other options, which allow customization. he capability to search should be a standard function. 

Important Additional  Information 

It is important to note that a link to safety information is likely not going to suffice given lessons from enforcement letters, advisory information provided to companies, and the 2009 draft Guidance for Industry Presenting Risk Information in Prescription Drug and Medical Device Promotion.  The guidance specifies that “to be comparably prominent to benefit information, risk information should generally appear in the same parts of the piece as the benefits.” 

If following this thinking, and keeping in mind the likely display dimensions, an approach that is more consistent with the guidance is presentation of the safety information on the vertical display, which may utilize scrolling in order to view the complete information. 

It is recommended that risk information be visible when the content opens.  The treatment of safety information should be comparable to the treatment of benefit information, including how it is conveyed.  Evaluate the presentation by thinking about the net impression given by all of the elements of the presentation.  

The use of headers and signaling is also part of the Risk Communication Draft Guidance and given the smaller footprint and displays likely in the social and mobile realms, the continuation of safety information from page to page may be a common occurrence that should be managed with signals such as “continued,” “more” and “select.” 

Often there are clinical study pages presented, and there too, safety is a necessary part of the presentation to ensure balance. Mobile sites are useable by many different devices and are not designed as a mobile app for use on a speciic device. 

The opening display should include a verification of who your viewer is by offering categories from which they self-identify—a U.S. Healthcare Professional or a U.S. Patient or Caregiver are two of the common options when the mobile site is not for a general audience.

Site content should always be appropriate for the target audience. Once in the site content area, use caution to keep the selectable options or subject titles as short labels. It is very important that they don’t contain claims that aren’t balanced—read and edit those descriptions to be more generalized. Use terms such as BRAND (generic) Data, or labeling sections such as “Clinical Trials.” And yes, include the established name following the proprietary name. he established name is required if naming the drug, but the proprietary name is not. 

When Users Become Advocates 

Social bookmarking and sharing widgets are the small symbols we see virtually anyplace we venture online.  Some of the most popular sharing sites include Facebook, Twitter, MySpace, StumbleUpon, Google, Favorites, Digg, Delicious and Messenger. 

“Stay Connected,” “Share,” “Email his” and “Embed his Video” are some options, along with many others, to place content from one place someplace else. 

When the “share” button is selected, a display of the widgets for bookmarking or sharing is provided for the user to select from and there is also an option for email.  This can send the content of the page someplace else for posting—could be via those just mentioned or any of the 300+ social networks and bookmarking websites. 

Content is passed from the original site and posted on a social sharing site. If a user posts branded promotional content as is, the content reflects what was reviewed and approved on the original site. Be aware that a user can edit contents and post it on a social sharing site.  The current thinking is that if the company does not create, control, maintain or participate in this content on the social sharing site or someone’s social media page, there is a separation between what is company sponsored and what is not. 

The key is what is within control of the drug company. Be careful with what company employees and agents do. It is may be best to draw the line at where content has been reviewed and approved, and either cannot be edited or is screened before posting live. 

A major concern is always the content of comments added to company sponsored or supported sites.  There are many differences from site to site, but here are some quick bits of information:

YouTube allows disabling the commenting feature, so a company can post a video without allowing comments.

• There is a “Safe Watch” feature that allows channel owners with 10 or more videos to control what videos show up on the watch pages of YouTube.  This was done by Google in response to pharma company concerns about adjacent content.
• It is possible to disable video embedding to limit the use of company videos outside of the company’s more controlled YouTube environments.
• Facebook previously allowed pharma clients to disable viewer commenting on wall posts, photos and videos. On May 17, 2011, Facebook sales representatives sent emails to clients announcing a policy change where Facebook will no longer grant the ability to disable comments, unless the company’s Facebook page is a branded page “solely dedicated to a prescription drug.” Original content can be controlled—there is a distinction. 

Tweeting in Twitter 

Twitter provides a good way to communicate in short messages of 140 characters or less.  A tweet is sent to all of the people who follow the sender, and is also available on the sender’s profile page. If a person re-tweets the message, it then becomes available on their profile page. Twitter is a good way to inform many people quickly about timely events such as a drug approval or the release of new data at a scientific meeting.  Things to think about for a tweet: 

1. Unbranded tweets provide flexibility and allow linking to other branded sites
2. Use of a BRAND (generic) name works for products that do not carry a boxed warning, and can be treated as a reminder ad.
3. For communication about a drug which carries a boxed warning, the tweet should include a URL that navigates directly to display the full prescribing information, and this page can contain other ixed links to the brand website or other related information. Format of the URL to the PI is important. Example: Approval granted by FDA for BRAND (generic)—See Full Prescribing Information and boxed WARNING at www.brand.com
4. Tweets regarding drugs that do not carry a boxed warning may include other URL links directly to the brand site or other information mentioned in the tweet.
5. Use of claims in a tweet is problematic, because the safety information cannot display completely with the 140 character limitation, and linking to safety is not considered a suicient solution.
6. Tweets describing new data for either a marketed product’s investigational use (as of yet unapproved) or for an investigational product should not state any specific investigational uses or potential indications or include any claims of safety or efficacy. Approach it similarly to a reminder ad—BRAND (generic) or generic name only. Beware the name of the medical meeting to ensure the disease or indication is not revealed unintentionally. When not using the product name the tweet may include information such as the company name, data presented at..., study phase. 

Thoughts for ePOCRATeS 

DocAlerts are the messages sent by ePOCRATeS to healthcare professional (HCP) subscribers of the service. Some of these are commercially sponsored by pharma, biotech or device companies.  The DocAlert message is a brief piece of practice relevant information, clinical study results or drug information delivered most often to mobile devices, and contains just enough information for the HCP to determine if they are interested in receiving more in-depth subject content. 

If the HCP selects the option from the DocAlert for more information, a detailed email is sent in response containing what the company sponsor provides as the content and message. 

1. The DocAlert title has a 100 character limitation that is best treated as a reminder ad for products that do not carry a boxed warning. he title is the only information displayed when a subscriber syncs their device and finds new information is available. Multiple titles are sometimes delivered together.
2. For the DocAlert title page, it is best to use an unbranded approach for those drugs with a boxed warning.
3. There is a single tab at the top of the DocAlert. It is a good idea to use this on the DocAlert body as the direct link to the full prescribing information. Because there is a 15 character tab limitation, be eicient in the use of this tab with something like “Prescribinginfo.”
4. The DocAlert body identifies the company sponsor, and typically contains the title, indications, limitations of use and safety information to balance this information in a display area with a maximum 650 characters. When reviewing a branded DocAlert, safety information included ater the company sponsor information will require that the reader scroll down below the viewable 650-character display to view the safety information in its entirety.
5. Remember the use of signals and headings, and in this case, consider signaling the safety information with a header where the complete safety information is presented in the DocAlert body.
6. When a subscriber receives the DocAlert body content, they may choose to “Read More Info,” in which case the full detail is sent by ePOCRATeS on behalf of the company sponsor. 

Email 

1. The email title has a 100 character limitation that again is best treated as a reminder ad for products that do not carry a boxed warning. he title is the only information displayed when a subscriber syncs their device.
2. For the email title page, it is best to use an unbranded approach for those drugs with a boxed warning.
3. The email body is where the bulk of the content is provided. If the content is branded use the standard approaches with prominent links to the safety information and full prescribing information. Included in the body of this branded email should be the indication(s), limitations of use and integrated safety, along with other content and messaging. It is always a good idea to utilize the 2009 draft Guidance Presenting Risk Information in Prescription Drug and Medical Device Promotion to refresh on what to think about. 

Conclusion

Ultimately, the author recommended that companies need to provide their sales, marketing and advertising staff with basic instructions to follow promotional norms and expectations, and how to apply the information of navigation, links and where things go. She also told companies to look for the basic elements, important additional information, and what happens when users become advocates. She asserted that companies should use the details provided for tweeting in Twitter and thoughts for ePOCRATeS to give everyone a stronger understanding of potential approaches, considerations and things to think about.