Life Science Compliance Update

July 17, 2012

FDA: Food and Drug Administration Safety and Innovation Act (FDASIA) and Patient Focused Drug Development

Patient centered
Last week, President Obama signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA). Among the numerous provisions contained in this Act are several provisions that will enhance and increase patient participation in medical product regulation.  Specifically, Sec. 1137 of the new law will allow the agency to develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions.  This will include: 

  • Fostering participation of FDA Patient Representatives as Special Government Employees in appropriate agency meetings with medical product sponsors and investigators; and,
  • Exploring means to provide for identification of FDA Patient Representatives who do not have any, or have minimal, financial interest in the medical products industry. 

Consequently, Theresa Mullin, Ph.D. Associate Director for Planning and Informatics FDA Center for Drug Evaluation and Research (CDER) recently gave a presentation on “Patient-Focused Drug Development.” 


Mullin first outlined FDA’s benefit-risk (B-R) framework, which looks at five (5) key considerations: 

  1. Severity of Condition
  2. Unmet Medical Need
  3. Benefit
  4. Risk
  5. Risk Management 

Severity of Condition and Unmet Medical Need provide regulators with the clinical context for weighing benefits and risks and the associated uncertainties. 

Benefit and Risk incorporate expert judgments based on evaluation of the efficacy and safety data. 

Risk Management incorporates expert judgments on the expected impact of efforts to reduce and further characterize risks. 

Assessment of a drug’s benefits and risks involves analysis of severity of condition and current state of the treatment armamentarium.  Patients who live with a disease have a direct stake in drug review process and are in a unique position to contribute to drug development.  As a result, FDA noted that its review process could benefit from systematic approach to obtaining patient perspective on disease severity or unmet medical need. 

Mullins noted how FDASIA – the provisions reauthorizing the Prescription Drug User Fee Act (PDUFA) – provides resources to support additional program staff to expand activities dedicated to providing review divisions with patient input.  FDA will convene meetings with participation from review divisions, the relevant patient advocacy community, and other interested parties. 

FDA will hold four public workshops per year—a total of 20 meetings over 5 years.  Each meeting will focus on a different disease area, reviewing the armamentarium for that indication, and identifying areas of unmet need. 

BenefitRisk Assessment Framework: Analysis of Condition 

Assessing Evidence and Uncertainties– for a given drug for a given indication‐questions FDA considers include: 

  • What is the treated (or prevented) condition?
  • What are its clinical manifestations (i.e., symptoms that are either reported or observed)?
  • What is known about the natural history and progression of the condition, including in specific subpopulations?
  • How severe is the condition for those who have it?
  • How does severity vary across the subpopulations we have defined? (Note specific subpopulations and nature of differences.)
  • What is the basis for our assessment of the condition and its severity? (Note any relevant literature, clinical experience, expert opinion, etc.)
  • What are the major uncertainties in the available information? What are their implications? 

BenefitRisk Assessment Framework: Unmet Medical Need 

Assessing Evidence and Uncertainties –for a given drug for a given indication‐FDA considers: 

  • What other pharmacological therapies are approved for this condition?
  • How effective are these alternative therapies?
  • How does their effectiveness vary by subpopulation?
  • How well tolerated are these alternative therapies?
  • How does tolerance vary by subpopulation?
  • What offlabel pharmacological therapies might be considered?
  • How effective and how well tolerated are they reported or believed to be?
  • What nonpharmacological therapies might be considered?
  • How effective and how well tolerated are they reported or believed to be?
  • What kinds of evidence are available about the use of alternative treatments for this condition?
  • What is the strength of evidence in each case?
  • What are the major uncertainties in the evidence? What are their implications? 

The presentation then discussed Patient‐Reported Outcome (PRO) Measures, which FDA defined as any report of the status of a patient’s health condition coming directly from the patient, without interpretation by physicians or anyone, about how the patient functions or feels in relation to a health condition and its treatment.”  FDA reviews PRO instruments and looks at whether the instrument measures the concept it is supposed to measure.  FDA looks at whether the instrument is: 

  • Well‐specified and reliable
  • Specific for target population
  • Specific for target indication
  • Adequate measurement properties (e.g., content validity) 

The presentation then noted that qualitative research can be used to establish PRO content validity.  This might include: 

  • Focus groups to generate a pool of patient outcome‐related domains and their components (e.g., What symptoms and functions or activities impacted by disease that are most important to patients)
  • Surveys including a larger and more diverse sample patients with a given condition (e.g., examine the importance and relevance of domains identified by literature review, expert opinion or among a smaller set of patients, to validate these items and perhaps explore other measurement characteristics) 

Mullins then used the example of people with chronic pain.  Focus groups conducted with patients who experience chronic pain identified 19 aspects of their lives (outcome domains) that are significantly impacted by the presence of their symptoms and for which improvements were important criteria that they use in evaluating the effectiveness of any treatment. 

Next Steps PatientFocused Drug Development 

Throughout the rest of this summer, FDA will develop preliminary list of 20 disease areas for public comment to inform planning for the set of 20 PDUFA V meetings.  FDA will also develop a basic roadmap that could be used by patient groups interested in pursuing need for and development of PRO measures in a specific disease area.  This roadmap will identify important but currently unaddressed aspects of their disease experience to potentially be considered in evaluating new therapies. 

In September 2012, FDA will publish an FR notice with the preliminary list of 20 disease areas for public comment.  In October 2012, FDA will plan to hold public meeting to: 

  • Discuss the proposed list of disease areas for the PDUFA meetings and get public input;
  • Discuss strategies for getting broader public input and basic roadmap for identification of important patient outcomes and strategies for collaborative development PRO measures 

FDA Patient Representative Program 

The Patient‐Focused Drug Development initiative will also add to the existing FDA programs designed to integrate patients’ perspectives.  FDA’s patient advocacy programs are run by FDA’s Office of Special Health Issues.  One of their main programs is the FDA Patient Representative Program

Patient Representatives provide FDA with the unique perspective of patients and family members directly affected by serious or life‐threatening disease.  Patient Representatives serve in the several ways, including: 

  • On Advisory Committees, where they offer the patient perspective, ask questions, and give comments to assist the committee in making recommendations.
  • As consultants for review divisions –the clinicians and scientists who review data submitted to determine whether the product’s benefits outweigh the potential risks
  • As presenters at FDA meetings and workshops on disease‐specific or regulatory and health policy issues 

The Programs activities include:


  • Recruitment of New Patient Representatives
  • Selection of Patient Representatives for:
    • Advisory Committees
    • Consultation with Review Division
    • Conducts Training For Patient Representatives
      • Individual FDA 101 Training
      • Monthly Webinars
      • Annual Workshop for Newly Recruited Patient Representatives 

In choosing Patient Representatives, FDA looks for someone who brings a personal viewpoint to the process and communicates a collective patient perspective.  A patient perspective is created when a person goes through personal experience with the disease.  A collective patient perspective is created when the person has knowledge of others’ disease experiences and conveys this collective patient perspective.

 Patient Representatives provide Advisory Committee and FDA insight on issues, problems, and/or questions pertinent to the viewpoint of patients and family members living with a specific serious or life‐threatening disease. 

  • Personal experience with/knowledgeable about the specific illness
  • Ability to articulate the perspective of patients
  • Experience as a patient advocate
  • Formal affiliation with a patient advocacy organization
  • The ability to identify issues through communication with patient constituencies 

Patient Representatives serve on an Advisory Committee when a product or therapy related to specific illness is under review, as either voting or non‐voting member 

  • Voting: must be appointed as special government employees (SGEs); requires disclosure of personal financial information to the FDA in order to determine whether their financial interests pose a possible conflict of interest on an advisory committee
  • Non‐voting: may only vote on procedural matters concerning the conduct of the meeting
  • In both cases: expected to provide the patient perspective, ask questions, and offer comments to assist the committee in making recommendations 

Drug Development Patient Consultant Program 

FDA also uses patients in its Drug Development Patient Consultant program.  This program incorporates the perspective of patient advocates into the drug development process; allows opportunity to participate in the FDA drug review regulatory process. 

Patients are selected to participate in meetings by matching a specific illness and proposed indication for the new therapeutic drug being developed.  Patients may participate in meetings (via telephone ) between the FDA and drug companies. 

The newly selected patient consultant receives training and participates in monthly telephone lecture series in preparation for these meetings.  To provide consultation to both FDA and the drug company, it is important that the patient consultant have background information on the drug under review.  About three weeks before each meeting, the patient consultant is mailed the meeting package containing the meeting issues and questions. The patient consultant reviews the meeting package in preparation for the meeting.

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July 21, 2011

US House Energy and Commerce PDUFA Hearing: Transformation of the FDA

FDA Green 
Earlier this month, the House of Representatives Energy and Commerce Subcommittee on Health held a hearing on the reauthorization of the Prescription Drug User Fee Act (PDUFA). The hearing, entitled, “PDUFA V: Medical Innovation, Jobs, and Patients,” was held in room 2123 of the Rayburn House Office Building.


Congress first authorized PDUFA in 1992 and last reauthorized the user fee in the Food and Drug Administration Amendments Act of 2007 (FDAAA).   Under the user fee authority, FDA collects funds from drug sponsors to help expedite the human drug approval process.  In FY 2009, FDA spent a total of $855 million on the review of human drug applications.  $512 million of that total came from user fees.

As part of its agreement with industry on these fees, FDA committed to attain certain performance goals, including reviewing 90 percent of priority new human drug applications within 6 months and standard new human drug applications within 10 months.

The funds collected come from the following three basic types of user fees: application review fees, establishment fees and product fees. Under the application review fee, drug manufacturers pay fees for FDA’s review of new or supplemental drug approval applications and biologic license applications.

For FY 2011, the fees are $1,542,000 for each application requiring clinical data, $771,000 for applications not requiring clinical data and $771,000 for supplements requiring clinical data. Another user fee is the establishment fee under which a manufacturer must pay an annual fee for each manufacturing establishment. This fee is just under $500,000 for each establishment. The third fee is the product fee. Under this fee, the manufacturer must pay an annual fee of approximately $87,000 for certain products.

Following the process prescribed by statute, FDA and industry recently negotiated an agreement regarding the size and scope of the user fee for FY 2013-2017. On September 1, 2011, FDA will publish the details of the agreement recommendations on its website. A public meeting on the recommendations will follow in October 2011.

By January 15, 2012, FDA must send its final recommendations to the Committee and the Senate HELP Committee as required by statute.  PDUFA IV expires on September 30, 2012,

In the past, these user fee reauthorizations have been viewed as opportunities to examine and improve the FDA regulatory process. The hearing presents a chance for Members to hear from FDA and other witnesses on the issues that the Committee should consider in reauthorizing PDUFA.

Health Subcommittee

In his opening statement, Health Subcommittee Chairmen Joseph Pitts (R-PA) asserted that the reauthorization of PDUFA “is too important to leave to the last minute” because the drug industry employs thousands of people in the United States and provides good jobs that America cannot afford to lose.

Energy and Commerce Chairmen Fred Upton (R-MI) also submitted an opening statement, in which he acknowledged the importance of addressing concerns about the lack of predictability and certainty at FDA, which appear to be stifling American innovation, costing American jobs, and hurting American patients.  Mr. Upton also noted that the Committee would review the risk/benefit analysis used by FDA when approving drugs and whether the agency is striking the right balance on this delicate issue. He note that there are concerns that FDA is failing to consider the views of patients who need access to life-saving drugs, including those drugs that carry some risk.

Moreover, Upton note that the Committee would evaluate provisions of FDAAA, including those affecting advisory committees and Risk Evaluation and Mitigation Strategies (REMS), as well as the rigid and unrealistic conflict of interest provision that has prevented FDA and its advisory committees from utilizing some of science’s best minds and left advisory committee slots unfilled. He noted that the committee must also look at implementation of FDAAA’s REMS provision and whether it has caused delays in the approval process.

Conflict of Interest Rules and FDA Advisory Panels

During the hearing, Republicans focused on rolling back new conflict-of-interest rules they say are depriving the FDA of needed expertise from the drug industry.  Democrats, focused largely on the safety of imported drugs.

Congress tightened the FDA's conflict-of-interest rules in 2007, as part of the last FDA reauthorization.  But Republicans on the House Energy and Commerce Committee said they may try to loosen the standards in the next reauthorization, which needs to pass next year.

Committee Chairman Fred Upton (R-Mich.) said the upcoming bill should reverse "rigid, unrealistic conflict-of-interest provisions" that have delayed drug approvals. The rules govern who can participate in FDA advisory panels, which study safety and effectiveness issues.

"No longer can we afford to sideline experts simply because of their ties to the pharmaceutical industry," Rep. Phil Gingrey (R-Ga.) said during the hearing.

Janet Woodcock, the director of FDA's drug center, said the limits have slowed down the advisory committee process. The agency sometimes goes through the long haul of finding experts in a given field only to discover ties to the pharmaceutical industry toward the end of the process, she said.  Below is a summary of her testimony.


There were two panels during the hearing.  The first panel consisted of Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research (CDER) at FDA.  We will have a summary of the second panel next week, which included:

Paul J. Hastings, President and CEO, OncoMed Pharmaceuticals, Inc., on behalf of Biotechnology Industry Organization (BIO)

Jonathan Leff , Managing Director, Warburg Pincus LLC

Marc Boutin, Executive Vice President and COO, National Health Council

Ellen Sigal, Ph.D., Chair and Founder, Friends of Cancer Research

Allan Coukell, Director of Medical Programs, Pew Health Group, The Pew Charitable Trusts

Janet Woodcock, MD

Dr. Woodcock first emphasized how PDUFA has produced significant benefits for public health, providing patients faster access to over 1,500 new drugs and biologics since enactment in 1992, including treatments for cancer, infectious diseases, neurological and psychiatric disorders, and cardiovascular diseases.

She noted research from the Tufts Center for the Study of Drug Development, which showed that the time required for the FDA approval phase of new drug development has been cut by 60 percent since the enactment of PDUFA, from an average of 2.0 years for the approval phase at the start of PDUFA to an average of 1.1 years today.

She asserted that the increased resources provided by user fees have enabled FDA to provide a large body of technical guidance to industry that clarified the drug development pathway for many diseases, and to meet with companies during drug development to provide critical advice on specific development programs. In the past five years alone, she noted that FDA has held over 7,000 meetings within a short time after a sponsor’s request.   In FY 2009, more than half of the meetings FDA held with companies at the early investigational stage and midway through the clinical trial process were with companies that had no approved product on the U.S. market.

Dr. Woodcock explained that improvements in the efficiency of the drug review process and the quality of new drug applications is evident in the trends toward greater first-cycle approvals for novel drugs, known as “priority” new molecular entities (NMEs). She noted that the average first-cycle approval rate for priority NMEs has increased from 46 percent in PDUFA I to 68 percent to date in PDUFA IV. First-cycle approval rates have also increased for standard NMEs from an average of 30 percent in PDUFA I to 38 percent to date in PDUFA IV.

She recognized that PDUFA provides FDA with a source of stable, consistent funding that has made possible FDA’s efforts to focus on promoting innovative therapies and help bring to market critical products for patients.  She also noted how PDUFA funds help support the use of existing mechanisms in place to expedite the approval of certain promising investigational drugs and also to make them available to the very ill as early in the development process as possible, without unduly jeopardizing the patients’ safety.

One such program she noted is accelerated approval, instituted in 1992. She noted that over 60 critical products have been approved under accelerated approval since the program was established.

Consequently, Dr. Woodcock noted however that new authorities granted to FDA under FDAAA put strains on the review process time frames agreed to, as well as on post-market review activities, which compete for the same resources.  In addition, the significant increase in the number of foreign sites included in clinical trials to test drug safety and effectiveness has created additional challenges for completion of FDA’s review within the existing PDUFA review performance goals.

Accordingly, Dr. Woodcock briefly summarized FDA’s top priorities identified by public stakeholders, the top concerns identified by industry, and the most important challenges identified within FDA

A Review Program for New Drug Applications (NDA,) New Molecular Entities (NME), and Original Biologics License Applications (BLA)

To address the desire for increased communication and greater efficiency in the review process, an enhancement being considered in FDA’s review program for NME NDAs and original BLAs in PDUFA V would include pre-submission meetings, mid-cycle communications, and late-cycle meetings between FDA and sponsors for these applications.

To accommodate this increased interaction during regulatory review, FDA’s review clock would begin after the 60-day administrative filing review period. The impact of these modifications on the efficiency of drug review for this subset of applications would be assessed during PDUFA V.

Enhancing Regulatory Science and Expediting Drug Development

Dr. Woodcock explained five enhancements to focus on regulatory science and expediting drug development.

1. Promoting Innovation Through Enhanced Communication Between FDA and Sponsors During Drug Development

This enhancement involves a dedicated drug development communication and training staff, focused on improving communication between FDA and sponsors during development. This staff will be responsible for identifying best practices for communication between the Agency and sponsors, training review staff, and disseminating best practices through published guidance.

2. Methods for Meta-analysis

With the growing availability of clinical trial data, an increasing number of meta-analyses are being conducted based on varying sets of data and assumptions. If such studies conducted outside FDA find a potential safety signal, FDA will work to try to confirm—or correct—the information about a potential harm that will create uncertainty for patients and health professionals. To do this, FDA must work quickly to conduct its own meta-analyses to include publicly available data and the raw clinical trial data submitted by drug sponsors that would typically not be available to outside researchers. PDUFA V enhancements being considered include the development of a dedicated staff to evaluate best practices and limitations in meta-analysis methods. Through a rigorous public comment process, FDA would develop guidance on best practices and the Agency’s approach to meta-analysis in regulatory review and decision-making.

3. Biomarkers and Pharmacogenomics

PDUFA V enhancements being considered include augmenting the Agency’s clinical, clinical pharmacology, and statistical capacity to adequately address submissions that propose to utilize biomarkers or pharmacogenomic markers. The Agency would also hold a public meeting to discuss potential strategies to facilitate scientific exchanges on biomarker issues between FDA and drug manufacturers.

4. Use of Patient-reported Outcomes (PRO)

Assessments of study endpoints known as patient-reported outcomes (PROs) are increasingly an important part of successful drug development. PROs measure treatment benefit or risk in medical product clinical trials from the patients’ point of view. PDUFA V enhancements being considered include an initiative to improve FDA’s clinical and statistical capacity to address submissions involving PROs and other endpoint assessment tools, including providing consultation during the early stages of drug development. In addition, FDA will convene a public meeting to discuss standards for PRO qualification, new theories in endpoint measurement, and the implications for multi-national trials.

5. Development of Drugs for Rare Diseases

FDA’s oversight of rare disease drug development is complex and resource intensive. Another PDUFA V enhancement being considered includes FDA facilitation of rare disease drug development by issuing relevant guidance, increasing the Agency’s outreach efforts to the rare disease patient community, and providing specialized training in rare disease drug development for sponsors and FDA staff.

Enhancing Benefit-Risk Assessment

PDUFA V enhancements include expanded implementation of FDA’s benefit-risk framework in the drug review process, including holding public workshops to discuss the

application of frameworks for considering benefits and risks that are most appropriate for the regulatory setting. FDA would also conduct a series of public meetings between its review divisions and the relevant patient advocacy communities to review the medical products available for specific indications or disease states that will be chosen through a public process.

Enhancement and Modernization of the FDA Drug Safety System

The enhancements being considered for PDUFA V include two post-market, safety focused initiatives.

1. Standardizing REMS


FDAAA gave FDA authority to require REMS when FDA finds that a REMS is necessary to ensure that the benefits of a drug outweigh its risks. Some REMS are more restrictive types of risk management programs that include elements to assure safe use (ETASU). PDUFA V enhancements being considered would initiate a public process to explore strategies and initiate projects to standardize REMS with the goal of reducing burden on practitioners, patients, and others in the health care setting. Additionally, FDA would conduct public workshops and develop guidance on methods for assessing the effectiveness of REMS and the impact on patient access and burden on the health care system.

2. Using the Sentinel Initiative to Evaluate Drug Safety Issues

FDA’s Sentinel Initiative is a long-term program designed to build and implement a national electronic system for monitoring the safety of FDA-approved medical products. PDUFA V enhancements would enable FDA to initiate a series of projects to establish the use of active post-market drug safety surveillance in evaluating post-market safety signals in population-based databases. By leveraging public and private health care data sources to quickly evaluate drug safety issues, this work may reduce the Agency’s reliance on required post-marketing studies and clinical trials.

Required Electronic Submissions and Standardization of Electronic Application Data

The predictability of the FDA review process relies heavily on the quality of sponsor submissions. PDUFA V enhancements would include a phased-in requirement for standardized, fully electronic submissions during PDUFA V for all marketing and investigational applications.  Through partnership with open standards development organizations, the Agency would also conduct a public process to develop standardized terminology for clinical and nonclinical data submitted in marketing and investigational applications.


User Fee Increase for PDUFA V

Implementing the PDUFA enhancements being considered would add $40.4 million to the estimated PDUFA user fee revenue amount in FY 2012. This translates to a modest 6 percent increase, and a total estimated base of $712.8 million in FY 2013.4

PDUFA V Enhancements for a Modified Inflation Adjuster and Additional Evaluations of the Workload Adjuster

In calculating user fees for each new fiscal year, FDA adjusts the base revenue amount by inflation and workload as specified in the statute. PDUFA V enhancements being considered include a modification to the inflation adjuster to accurately account for changes in its costs related to payroll compensation and benefits as well as changes in non-payroll costs. In addition, FDA would continue evaluating the workload adjuster that was developed during the PDUFA IV negotiations to ensure that it continues to adequately capture changes in FDA’s workload.

Additional Initiatives to Encourage Development of New Therapies

In closing, Dr. Woodcock noted how both FDA and the pharmaceutical industry are facing economic and scientific challenges in drug development. She recognized that only a profitable industry can continue to fund the research and development necessary to find new cures.

As a result, she acknowledged that it is critical for FDA to “work with industry and other stakeholders to take steps to reduce uncertainty and increase the success in the other phases of drug development.” She noted that, to promote the development of innovative new therapies, FDA is working on advancing our scientific base.

She also acknowledged how FDA will transform itself over the next decade from a domestic Agency, operating in a globalized world, to a truly global Agency fully prepared for a regulatory environment in which product safety and quality knows no borders. To achieve this transformation, the Agency is developing an international operating model that relies on improved information sharing and gathering, data-driven risk analytics, and the smart allocation of resources through partnerships.

May 27, 2010

FDA: Off Label May Be the Wrong Label

The Food and Drug Administration (FDA) has acknowledged for years that "good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment.”  According to a recent article in Forbes, this knowledge has increasingly begun to consist of off-label prescriptions, which are sometimes necessary for the practice of good medicine.  


As the agency's website recognizes, “if physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects."


In addition, the American Medical Association (AMA) believes that "physicians have the training and experience necessary to determine the best or preferred method of treatment," including off-label prescribing, which is often be considered "reasonable and necessary medical care, irrespective of labeling." In fact, doctors can be subject to malpractice liability if they do not use drugs for off-label indications when doing so constitutes the standard of care.


Before a drug can be sold in the U.S., it must be certified by the FDA as safe and effective for a specific, or "on-label," use.  Once approved, although physicians may legally prescribe it for any other purpose (off-label), the manufacturers of such drugs are only legally able to educate and inform physicians about the “on-label” use.  Companies can re-apply through the FDA to have the original drug approved for additional uses.


But with companies recently dealing with huge settlements involving off-label fraud (Pfizer; Eli Lilly; and AstraZeneca), how exactly do physicians find this “firm scientific rationale” and “sound medical evidence?” It is especially hard for physicians and patients to learn about off-label usages of drugs because the FDA, with support from many in Congress, has sought repeatedly to limit physicians' and patients' discretion about treatment decisions, including restricting physicians from prescribing drugs off-label. Forbes described two examples.


First, the Food and Drug Administration Amendments Act (FDAAA), which took effect on March 25, 2008, gave the FDA sweeping new powers, which included the ability to require a Risk Evaluation and Mitigation Strategy (REMS) for any newly approved drug. According to the FDA, a REMS is "a strategy to manage a known or potential serious risk associated with a drug or biological product," which could be said to encompass virtually any medicine. FDA noted that a REMS can include a Medication Guide, Patient Package Insert, a communication plan, elements to assure safe use, and an implementation system, and must include a timetable for assessment of the REMS."


Essentially, REMS made “off-label prescribing much more cumbersome and difficult” because for safe use of a drug, FDAAA consisted required that:


-   Health care providers who prescribe the drug have particular training or experience, or are specially certified;   

-   Pharmacies, practitioners or health care settings that dispense the drug are specially certified;     

-   The drug is dispensed to patients only in certain health care settings, such as hospitals;  

-   The drug is dispensed [only] to patients with evidence or other documentation of safe use conditions, such as laboratory test results;    

-   Each patient using the drug is subject to certain monitoring; and   

-   Each patient using the drug is enrolled in a registry."


In addition to these requirements that reduce physicians' off-label prescribing, FDA also restricts drug manufacturer promotion of off-label uses, which encompasses any and all contact with health professionals or patients. Manufacturers are only able to send peer-reviewed medical journal articles and excerpts from medical textbooks to physicians and are permitted to answer questions asked directly by physicians only under certain circumstances.


The second problem arose from an October 2009 lawsuit with Allergan drug Botox, which was approved for treating muscle spasms, but has been “widely used off-label” for other medical issues.  The company argued that the FDA is not authorized by the Federal Food, Drug and Cosmetics Act to “ban the distribution of truthful information about safe and effective off-label uses of medicines” because it would be an unconstitutional abridgment of commercial free speech. The federal District Court for the District of Columbia will hear oral arguments from the parties later this year, and a final decision could take years.


The trouble for Allergan and other companies was that FDA ordered the company to send detailed safety updates to physicians who prescribe Botox for both on-label and off-label indications. As a result, “the company felt that regulators had placed it in a Catch-22 situation: Complying fully with the order could violate the FDA ban on promoting drugs for off-label uses,” and result in significant fines that would threaten the company and its employees with criminal penalties.


FDA's off-label policies have raised concerns over the past decade.  In fact, “a federal district court held that the near-blanket ban on disseminating truthful and non-misleading information about off-label uses was an unconstitutional restriction of commercial speech.” The regulations were only maintained because FDA “claimed that the rules merely established a "safe harbor" under which manufacturers would be automatically deemed in compliance with the law, but that the regulations did not really prevent all off-label promotion.”  Then in 2009, the agency issued a guidance document that acknowledged explicitly that drug and device firms may sometimes distribute medical journal articles and text book excerpts to physicians.

It should also be noted that FDA has issued Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.  FDA also has Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.  Both of these documents provide significant resources and guidance for companies regarding off-label promotion of drugs.


With recent opinion polls by the Pew Research Center showing that Americans are dissatisfied with their government, the regulation of off-label prescriptions becomes an important issue because of how many patients it affects.  It is estimated, “on the basis of articles in medical journals and information gleaned from conferences” that doctors use off-label prescriptions almost “100 million times a year.” By some estimates, at least 20% of all prescriptions written are off-label, and those uses often constitute the accepted standard of care. For example, “the practice is well known in cancer and cardiac treatment, where as many as half of all prescriptions are for off-label uses. In the absence of off-label prescribing, physicians would have fewer treatment options and many patients would die or suffer needlessly.”


Moreover, a “series of national surveys commissioned by the Competitive Enterprise Institute has shown that a large majority of physician specialists--including oncologists, cardiologists, emergency room doctors, orthopedic surgeons and neurologists--believe the FDA's policies have made it more difficult for them to learn about new uses for drugs and medical devices, and that the agency should not restrict information about off-label use.” The authors recommend that the FDA should maintain a database of information about off-label uses of drugs to make it easier for physicians and safer for patients.


Doctors should not have to worry about being sued for not using drugs for off-label indications when doing so constitutes the standard of care, and they should not be restricted from learning about them either.  As the authors correctly assert, “these FDA policies compromise physicians' ability to learn about and use new pharmaceuticals,” and should be revised to reflect the important role off-label prescribing plays in the daily practice of numerous physicians. FDA should also consider how 100 million prescriptions are going to get filled without off-label prescriptions, and who is going to pay the legal costs for doctors who are prohibited or prevented from prescribing off-label usage of drugs.


Perhaps the term off label has the wrong label, perhaps it should be referred to as investigational use.


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