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U.S. Department of Health and Human Services

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Drug Safety Oversight Board Meeting, October 20, 2011

Public Summary

The following is a list of the Drug Safety Communications (DSC) posted since the September 15, 2011 meeting and relayed to the Drug Safety Oversight Board (DSB or Board) via memorandum:

  • October 11, 2011: Sprycel (dasatinib) and risk of pulmonary arterial hypertension: FDA issued a communication discussing the rare but serious risk of pulmonary arterial hypertension. This information has been added to the Warnings and Precautions section of the product labeling.
  • September 26, 2011: Safety review of possible increased risk of blood clots with birth control pills containing drosperinone: FDA issued a communication to update the May 31, 2011, DSC regarding an ongoing safety review of possible increased risk of blood clots in women who use these products. The most recent update states that the FDA remains concerned about the possible increased risk of blood clots in women who use drosperinone-containing birth control pills. Preliminary data from an FDA-funded study that evaluated the risk of blood clots in users of several different hormonal contraceptives suggests an approximately 1.5-fold increase in the risk of blood clots for women who use these birth control pills compared to users of other hormonal contraceptives. Given the conflicting nature of the data from six published studies that evaluated this risk, as well as the preliminary data from the FDA-funded study, there will be a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee meeting on December 8, 2011.
  • September 15, 2011: Abnormal heart rhythms may be associated with use of Zofran (ondansetron): FDA issued a communication informing the public of on ongoing safety review of Zofran. Zofran may cause QT prolongation, and the Warnings and Precautions section of the product labeling was updated to state that use should be avoided in patients with known congenital long QT syndrome. GlaxoSmithKline, the manufacturer of Zofran, is being required to conduct a thorough QT study to assess the potential for the drug to prolong the QT interval; these results are expected in the summer of 2012.

The DSB discussed two topics:

  1. Drug Shortages
  2. Risperdal Consta and Needle Detachments

The views expressed by non-Center for Drug Evaluation and Research (CDER) employees are those of the individual and not necessarily the opinion of their respective government agency or institution.

Drug Shortages

The Board heard a presentation from CAPT Valerie Jensen, R.Ph., Associate Director, CDER Drug Shortage Program, Office of New Drugs, on drug shortages.

Ms. Jensen provided background on and history of the CDER Drug Shortage Program, drug shortage trends in the United States, reasons for drug shortages, the industry’s role as FDA perceives it, and CDER’s approach to prevention/mitigation of drug shortages (including drugs, therapeutic proteins, and monoclonal antibodies).

Ms. Jensen stressed that FDA has very limited authorities directly related to drug shortages, and in fact, the only requirement is to notify FDA six months prior to discontinuation of a sole source of a drug product (without consequence for failure to notify) (Section 506C [21 U.S.C. 356c] DISCONTINUANCE OF A LIFE SAVING PRODUCT, see also 21 CFR 314.81(b)(3)(iii)). As such, the drug shortage program largely operates on the voluntary participation of industry, which in some cases has prevented drug shortages. In addition, FDA cannot mandate manufacturing capacity/production quantity.

Ms. Jensen remarked that drug shortages are at an all-time high (178 in the year 2010 with over 200 as of October 2011), with 74% of shortages involving sterile injectable drug products, especially older drugs products. In addition, in 2010, the most common reason for drug shortages (54%) were product quality/significant current good manufacturing practice issues (e.g., particulates, contamination, impurities). Product quality issues are also the most common reason for shortages thus far in 2011. She also explained why older sterile injectable drug products are vulnerable to experiencing shortages.

Ms. Jensen reviewed FDA’s approach to prevention/mitigation of drug shortages, which includes consideration of medical necessity; the risk-benefit profile of the drug; working cooperatively with the firm, other firms, professional organizations, and others within FDA; expediting certain issues (e.g., review, new manufacturing site, new raw material); temporary importation from unapproved sources (rarely); employing flexibility and creativity in addressing the issue; and performing outreach to healthcare professionals, consumers, and manufacturers.

The Board discussed the following:

  • The initial appeal but practical difficulty of developing and maintaining lists of medically necessary or vulnerable products. However, there are drugs (e.g., oncology, insulin) that the FDA has determined are medically necessary and has proactively notified firms and manufacturers of that determination.
  • The evolving nature of inventory control to one now which is “just in time” (e.g., only one month of product on hand).
  • Price control/lower prices for drugs via contractual obligations with group purchasing organizations and Federal agencies.
  • The role of “mom and pop”/gray market distributors in exacerbating drug shortages and their extremely high profit margins.
  • The collaborative relationship between the CDER Drug Shortage Program and the American Society of Health System Pharmacists (ASHP), and ASHP’s comprehensive website for drug shortages.
  • The unintended consequence of posting a drug in pending shortage on FDA’s website and purchasers “buying up” these drugs, thus creating a shortage or exacerbating a shortage. The same thing may occur at the end of the fiscal year with Federal agencies attempting to spend their funds.
  • Purchase of unapproved drugs outside of free trade agreements is prohibited by Federal agencies.
  • Manufacturers assume liability for those patients who import unapproved drugs.
  • The testing of filters for drugs with particulate matter, data review of this testing by FDA, and co-packaging of the filter with the drug.
  • The occurrence of global shortages: EMA and Health Canada are having similar experiences to the United States, while Australia is not as affected. The military is not permitted to enter into local economies to obtain drug products in shortage; it may only use FDA-approved drugs and manufacturers, and CMS may only pay for FDA-approved drugs.
  • Discussion of potential legislation to address this issue can be categorized into “carrot” (e.g., monetary, tax incentives) and “stick” (e.g., forced increased production) buckets.

Risperdal Consta and Needle Detachments

The Board heard a presentation from Robert Levin, M.D., Clinical Team Leader, Division of Psychiatry Products, Office of New Drugs, CDER on needle detachments occurring with Risperdal Consta use.

Dr. Levin discussed the regulatory history of Risperdal Consta and the components of the drug’s dose pack kit (vial, pre-filled glass syringe containing diluent, needle-free vial access device, one gluteal needle and one deltoid needle, fixed safety shields on needles). He stressed that the drug’s instructions for use (IFU) are complex and contain 18 steps (which have additional steps within them).

Dr. Levin described the history of needle detachments, when during administration detachment occurred, and whether it occurred with the gluteal or deltoid needle. The sponsor issued a Dear Health Care Professional (DHCP) letter in April 2010, performed a root-cause analysis, and is currently redesigning the drug’s kit components. In the interim, the sponsor will continue to assess the device components and will notify and train healthcare professionals (DHCP letter, visits to clinical sites, and IFU video).

Carl Fischer, Ph.D., Biomedical Engineer, Office of Compliance, Center for Devices and Radiological Health circulated the kit and the IFU to Board members. He also performed a demonstration on how to properly assemble the drug for use, emphasizing the complexity of the instructions and the potential for detachment at certain steps during assembly.

The Board discussed the following:

  • Clarifying questions about the device’s design; the drug’s use as a maintenance, rather than acute, therapy; and to whom, with which needle, and in what practice setting were needle detachments occurring.
  • Comparison of the Invega Sustenna plastic pre-filled syringe versus the Risperdal Consta BD Hypak syringe.
  • The VA, DoD, IHS, and HRSA discussed the incidences of needle detachments and the dissemination of the April 2010 DHCP letter within their respective Agencies.