Drug Safety Oversight Board Meeting, February 18, 2010
The Executive Director updated the Drug Safety Oversight Board (DSB or Board) on Drug Safety Communications posted and in development since the January 21, 2010 meeting. The following is a list of the posted risk communications:
Drug Safety Communications Posted since the January 21, 2010 DSB meeting:
- January 21, 2010: Sibutramine, marketed as Meridia
- January 29, 2010: Serious liver disorder associated with the use of didanosine (Videx/Videx EC)
- February 5, 2010: Tysabri and progressive multifocal leukoencephalopathy (PML)
- February 16, 2010: Erythropoiesis-Stimulating Agents (ESAs)
- February 17, 2010: Maalox Total Relief and over-the-counter line extension
The DSB heard presentations and discussed two topics:
- Genetic testing for cisplatin-induced ototoxicity
- Issues surrounding the heparin potency change
The views expressed from non-CDER employees are those of the individual and not necessarily the opinion of their respective government agency.
Genetic Testing for cisplatin-induced ototoxicity
Cisplatin, a platinum-based chemotherapy drug, is used to treat various types of adult and pediatric cancers. Chemotherapeutic drugs are generally designed to destroy human cancer cells; however, normal cells can also be destroyed. Common toxicities of cancer chemotherapy are related to the destruction of these normal cells. Cisplatin is associated with various toxicities including ototoxicity (hearing loss). The mechanism for cisplatin-induced ototoxicity is thought to be secondary to damage to the cochlea’s outer hair cells. Children are at higher risk than adults, with hearing loss occurring in up to 60% of children receiving cisplatin. It can progress from high to low frequency hearing loss with successive cisplatin doses. The hearing loss is permanent, usually affects both ears, and may progress even after cisplatin therapy has stopped.
The Board discussed FDA’s role in addressing and communicating about genetic testing in patients who are at specific risk for ototoxicity associated with cisplatin use. The Board invited Dr. Bruce Carleton, from the Child and Family Research Institute of the University of British Columbia, and Co-Leader of the Canadian Pharmacogenomics Network for Drug Safety, as a guest speaker. He provided an overview of the purpose and goals of the Canadian Pharmacogenomics Network for Drug Safety and the research being done to identify genetic markers that can increase the risk of specific adverse drug reactions.
The Board also invited Dr. Carmen Brewer, Chief of Audiology at the National Institute on Deafness and Other Communication Disorders. Dr. Brewer provided the Board with a perspective on the social and developmental impact of hearing loss in children.
The Board discussed the following:
- An overview of cisplatin use in pediatric cancers
- Risk factors for cisplatin-induced ototoxicity
- The Children’s Oncology Group’s current ototoxicity monitoring guidelines for cisplatin therapy
- Various ototoxicity grading criteria (e.g. the American Speech Hearing Association, the National Cancer Institute Common Terminology Criteria for Adverse Events versions 3.0 and 4.0 and Brock’s criteria)
- The efficacy and response rates associated with alternative platinum therapies, such as carboplatin and oxaliplatin, for pediatric cancers
- Current research evaluating the use of otoprotective agents
- Cisplatin, carboplatin, and oxaliplatin drug utilization data
- The Canadian Pharmacogenomics Network for Drug Safety
- A study (Nature Genetics 2009; 41:1345-50) identifying genetic variants in thiopurine methyltransferase (TPMT) and catechol o-methyltransferase (COMT) associated with hearing loss in children receiving cisplatin chemotherapy
- Educational and psychosocial impact of minimal to greater sensorineural hearing loss in children
- Management strategies for hearing loss in children
- Communicating about drug safety issues when there is incremental information about genomics.
Issues surrounding the heparin potency issue
Unfractionated heparin (UFH) is an injectable anticoagulant drug used to treat and prevent blood clots in the veins, arteries, or lungs. It is also used before surgery to reduce the risk of blood clots. On October 1, 2009, the United States Pharmacopeia (USP) changed the standard used to define UFH’s anticoagulant potency. Specifically, the "USP unit" reference standard was changed to match an international standard set by the World Health Organization (WHO). USP recognized that the reference standard change resulted in approximately a 10% loss in potency of a "USP unit." Thus, heparin manufactured after October 1, 2009 would be approximately 10% less potent than heparin manufactured before October 1, 2009. The Board discussed whether the 10% change in potency impacts the safe use of heparin and what additional information FDA should provide to health care professionals and the public about its safe use.
The Federal Partners with hospitals and clinics presented information on how the heparin potency change impacted their health care systems and what steps they may have taken to lessen any potential confusion with the available heparin products.
The Board discussed the following:
- An overview of UFH use in clinical practice
- A brief history of the heparin contamination situation of 2007-2008
- Heparin monograph changes and how they resulted in heparin potency changes
- The specific USP changes in the heparin assay and reference standard used to determine heparin activity
- USP and WHO reference standards
- FDA risk communications and consumer information issued on October 1, 2009 regarding the heparin potency change
- An overview of the nonclinical studies initiated as a result of the heparin monograph change
- A proposed study to evaluate any clinical consequences of the heparin potency change