Drug Safety Oversight Board Meeting, May 19, 2011

Public Summary

The Executive Director updated the Drug Safety Oversight Board (DSB or Board) on Drug Safety Communications posted and in development since the March 17, 2011 meeting. The following is a list of the posted risk communications:

Drug Safety Communications Posted since the January 20, 2011 DSB meeting:

• May 18, 2011: Updated Risk Evaluation and Mitigation Strategy (REMS) to Restrict Access to Rosiglitazone-containing Medicines including Avandia, Avandamet, and Avandaryl: FDA issued a DSC informing the public of new restrictions to the prescribing and use of rosiglitazone-containing medicines. These medicines treat type II diabetes and are sold under the names Avandia, Avandamet, and Avandaryl. Healthcare providers and patients must enroll in a special program in order to prescribe and receive these drugs. The new restrictions are part of a Risk Evaluation and Mitigation Strategy (REMS). The restrictions are based on data that suggested an elevated risk of heart attacks in patients treated with rosiglitazone. The decision to restrict access to rosiglitazone medicines was made on September 23, 2010.
• May 6, 2011: Glass syringes pre-filled needleless glass syringes and IV port connection problems: FDA issued a DSC alerting the healthcare community about syringe connection problems when certain needleless glass syringes containing the cardiac drugs adenosine and amiodarone are used with particular types of intravenous (IV) access systems.
• April 22, 2011: Tysabri - Safety update on Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab): FDA continues to evaluate the risk of progressive PML and updated the label to give new information about the size of this risk, as well as to include new safety information about patients who have taken other drugs that suppress the immune system, who may be at a higher risk for PML.
• April 15, 2011: LABA - FDA requires post-market safety trials for Long-Acting Beta-Agonists (LABAs): FDA completed a safety review and is now requiring the manufacturers of LABAs to conduct five randomized, double-blind, controlled clinical trials comparing the addition of LABAs to inhaled corticosteroids versus inhaled corticosteroids alone.
• April 14, 2011: TNF Blockers - Safety Review update on reports of Hepatosplenic T-Cell Lymphoma in adolescents and young adults receiving tumor necrosis factor (TNF) blockers, azathioprine and/or mercaptopurine: FDA issued a DSC informing the public that it continues to receive reports of a rare cancer of white blood cells ( known as Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factor (TNF) blockers, as well as with azathioprine, and/or mercaptopurine.
• April 14, 2011: Olmesartan - Safety Review Update of Benicar (olmesartan) and cardiovascular events: FDA issued a DSC stating the benefits of Benicar continue to outweigh potential risks when used for the treatment of patients with high blood pressure according to the drug label.
• April 08, 2011: Revlimid - Ongoing safety review of Revlimid (lenalidomide) and possible increased risk of developing new malignancies: FDA issued a DSC informing the public that we are aware of results from clinical trials conducted inside and outside the United States that found patients treated with Revlimid (lenalidomide) may be at increased risk of developing new types of cancer compared to patients who did not take the drug.
• April 08, 2011: ADHD Medication: FDA issued an update to its previous Ongoing Safety Review of Stimulant Medications used in children with Attention Deficit/ Hyperactivity Disorder. The update states that FDA has received and is currently reviewing preliminary results of the studies sponsored by FDA and AHRQ to research potential cardiovascular risks associated with medications used to treat ADHD in children and adults.
• April 07, 2011: Benzocaine sprays - FDA continues to receive reports of serious and potentially fatal adverse effects with the use of benzocaine sprays for medical procedures: FDA issued a DSC alerting healthcare professionals that the Agency continues to receive reports of methemoglobinemia, a serious and potentially fatal adverse effect associated with benzocaine sprays. Symptoms may appear within minutes to one to two hours after using benzocaine. In severe cases, methemoglobinemia can result in death.
• April 07, 2011: Benzocaine gels and liquids - Reports of serious and potentially fatal adverse effects with the use of over-the-counter (OTC) benzocaine gels and liquids applied to the gums or mouth: FDA issued a warning to the public that the use of benzocaine is associated with a rare, but serious condition called methemoglobinemia and results in the amount of oxygen carried through the blood stream being greatly reduced. In severe cases methemoglobinemia can result in death.
• March 29, 2011: FDA Drug Safety Communication: Special storage and handling requirements must be followed for Pradaxa (dabigatran etexilate mesylate) capsules: FDA issued a DSC alerting the public to important handling requirements for Pradaxa (dabigatran etexilate mesylate) capsules. Capsules should only be dispensed and stored in the original bottle or blister package.
• March 24, 2011: PPI Update - Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors: FDA has determined that a warning regarding a potential increased risk of fractures on the Drug Facts label for OTC PPIs s not indicated at this time.

The DSB discussed three topics:
1. Bad Ad Program
2. Biosimilars
3. Update on CT Scans, Radiation Exposure, and a Potential Risk of Cancer

The views expressed by non-CDER employees are those of the individual and not necessarily the opinion of their respective government agency or institution.

Bad Ad Program

The board invited two guest experts, Dr. Aaron Kesselheim and Dr. Michael Steinman, both of whom have published on Bad Ads for drug marketing to healthcare professionals, and related topics.

Dr. Kesselheim is an Assistant Professor of Medicine at Harvard Medical School and an internal medicine physician in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital. Dr. Kesselheim discussed off-label prescribing and off-label marketing of pharmaceuticals. He noted a study from 2001 finding that 21% of prescriptions for 160 commonly prescribed drugs were for off-label uses, while 73% of off-label prescriptions had little scientific support for their use. Although some off-label use may be appropriate, he described how inappropriate manufacturer promotion can encourage non-evidence based off-label uses and the rationale behind FDA’s rules limiting such promotion. Dr. Kesselheim has studied health care fraud in depth, so he discussed the experiences of whistleblowers in identifying illegal off-label promotion and the motivations that lead them to bring this behavior to light. Finally, Dr. Kesselheim reviewed a recent study he completed surveying the abuses of drug marketing by pharmaceutical representatives, such as discussing off-label uses without being asked, self-serving presentations of literature, free samples as a marketing tool, disguised financial gifts, influence in physician educational programs, ghostwriting of medical articles, and seeding of clinical trials. He noted that an important feature of the Bad Ad Program is that it engages health care professionals as whistleblowers on behalf of FDA and provides a greater reach in identifying inappropriate promotion than FDA could have acting alone. He concluded that the success of the Bad Ad program will hinge, in part, on a short turnaround for investigations, providing feedback to complainants to reinforce their senses of justice and integrity, and finding a mechanism for coupling the Bad Ad Program with physician education about the potential risks of off-label promotion.

Dr. Steinman is an Associate Professor of Medicine in the Division of Geriatrics at the University of California San Francisco (UCSF) School of Medicine and a staff physician at the San Francisco VA Medical Center. Dr. Steinman reviewed the ideas and goals of the Bad Ad Program and outlined the impact of marketing and promotion on clinician behavior and prescribing. He discussed how a cornerstone of drug marketing is the formation of a positive relationship between the drug sponsor and the clinician. He noted that with the increased scrutiny of clinician relationships with pharmaceutical sponsors, there has been a shift to other forms of promotion that are more subtle and difficult to detect, such as support of professional education and clinical trials.

In further reviewing the Bad Ad Program, Dr. Steinman discussed how it is valuable outreach program created to educate healthcare providers about misleading drug promotion and to provide them (HCPs) with an easy process for reporting misleading promotion that occurs in field setting such as doctor’s offices and dinner programs. He discussed that a key element of the Bad Ad Program should be its educational mission, educating HCPs about how drug marketing really works, including the relationship-based features of marketing and the potential use of continuing medical education and research as a means of increasing drug sales.

The Board also heard four presentations from the CDER Division of Drug Marketing, Advertising, and Communications. The presentations discussed FDA’s regulation of prescription drug promotion, a social science perspective about whether and how physicians are influenced by prescription drug promotion, and the elements of the Bad Ad Program and success to date.

The Board discussed the following:

• Background information regarding the development of the Bad Ad Program
• The published literature addressing the potential influence of drug marketing efforts on clinician prescribing tendencies
• The hidden marketing efforts that can influence physician prescribing such as monetary support of continuing medical education
• The technique of drug sponsors in forming relationships with physicians for the purpose of influencing prescribing habits
• The elements constituting a Bad Ad, such as exaggerating efficacy claims and minimizing drug risks either through written or spoken words or visual means
• The actions to date that FDA has taken to implement the Bad Ad Program
• Potential efforts to increase awareness of the Bad Ad program within the healthcare provider community
• Reasons why healthcare providers may or may not report a Bad Ad and how to improve reporting of a Bad Ad
• How to provide incentives to healthcare providers to report a Bad Ad, such as minimizing red tape, providing periodic reports or updates on a complaint, and demonstrating the Bad Ad Program can work by reducing Bad Ads
• The three phases of the Bad Ad program including the current Phase 2 which involves collaboration with medical societies, presenting at teaching hospitals, and engaging medical schools
• The goal of working with the drug industry, avoiding antagonism, and leading a change to drug ads and interactions between healthcare providers and pharmaceutical representatives that reflect the drug’s approved indications and balance risks and benefits

Biosimilars

The Board heard a presentation about Biosimilars and the Biologics Price Competition and Innovation (BPCI) Act of 2009. The presentation included the following discussion points:

• Background of the BPCI Act and how it created an abbreviated licensure pathway for biologic products shown to be biosimilar or interchangeable with an FDA-licensed reference product
• The regulatory definitions of biosimilar, reference product, biosimilarity, and interchangeability
• The distinction between biosimilar and interchangeable
• General requirements for a 351(k) application, which is the mechanism for requesting approval of a biosimilar biological product
• Selected implementation issues and challenges
• Selected issues regarding exclusivity following approval
• A summary of the Part 15 hearing on this topic in November 2010

Update on CT Scans, Radiation Exposure, and a Potential Risk of Cancer

Medical technology and procedures involving CT scans are regulated by both the Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH). CDER regulates the contrast agents used in the scans, and CDRH regulates the CT scanners and issues regarding radiation exposure from the scans.

The Board invited a guest expert, Dr. Charles Anderson, who is the Chief Consultant for Diagnostic Services and a staff radiologist at the Veterans Health Administration (VHA). He noted that the VHA has a total of about 200 CT scan machines in its facilities across the USA.

Dr. Anderson reported on initiatives within the Veterans Health Administration over the past year regarding CT scans. The VHA has a total of about 200 CT scan machines in its facilities across the USA. These initiatives included a comprehensive study of brain perfusion protocols, and expansion of the VA National Health Physics Program with inspection of CT scan machine sources. Each VHA facility will review procedures to optimize or limit radiation exposure with CT scans, revisit informed consent procedures for scans with higher exposures, and work towards storing the radiation dose administered in the electronic health record and in a dose registry. In addition the VA will procure a decision support system to ensure imaging studies meet appropriateness guidelines. Dr. Anderson noted that the number of CT scans per covered life in the VHA increased slightly from 2008-2010, with about 16% of all active patients undergoing at least one CT scan in 2010.

Four additional CDRH and CDER staff presented on FDA initiatives to assess and reduce radiation exposure from CT scans, nuclear medicine testing, and other radiographic exposures. An area of increasing utilization is in CT-cardiovascular examinations and CT-dental exposures. FDA is promoting, along with other healthcare stakeholders, the Image Gently and Image Wisely campaigns, designed to reduce radiation exposure for children and adults, respectively.

The Board discussed the following:

• Background information regarding the discussion of this topic at the April 2010 DSB meeting
• A stochastic risk of cancer from radiation exposure
• A deterministic risk of burns from acute exposure to excess radiation
• An overview of FDA’s initiative to reduce unnecessary radiation exposure from medical imaging
• The Image Gently and Image Wisely campaigns
• The largest exposure of the public to radiation from medical imaging involves CT scans.
• The increased usage of nuclear medicine techniques
• Collaborations between FDA and external organizations to reduce radiation dose from medical imaging
• Potential improvements in newer generation CT scan machines designed to both limit and accurately record radiation exposure