Pharmacy Best Practices:Post-marketing surveillance brings added drug safety
Initial clinical trials can’t reveal all risks, but better data collection and FDA involvement can help
By Mari Edlin
January 1, 2009
THREE INITIATIVES HAVE converged to place the spotlight on drug safety: the Sentinel Initiative, which is a long-term effort to create a national electronic system for monitoring medical product safety; mandating manufacturers to develop a Risk Evaluation and Mitigation Strategy (REMS) for certain drugs and biological products to ensure the benefits outweigh the risks; and the Nationwide Health Information Network (NHIN). The first two strategies are the results of the U.S. Food and Drug Administration Amendment Act of 2007 (FDAAA).
The Act also establishes a timetable for inclusion of new safety information on drug labels and requires post-approval studies of clinical trials to assess a known risk or signals of a serious risk, and to identify an unexpected serious risk.
"Clinical trials, which typically study only several thousand patients, do not reveal all of the risks," says Paul Seligman, MD, associate director of safety policy and communication for FDA's Center for Drug Evaluation and Research (CDER). "A rare problem may only come to light after the drug is used in millions of people. Post-marketing surveillance is one way to monitor a drug's safety on an ongoing basis."
He says that better data, science and communication are the basis of post-marketing drug safety. The data is provided by the new Sentinel Initiative, a public-private partnership. It will enable FDA to query specific adverse event data in large databases - including patient registries, claims and Medicare data - to verify if reported data from professionals and patients match up with what has been found.
Understanding the science behind why certain people adversely react to medications and ensuring providers and patients receive risk information advance the safety efforts in the post-marketing phase of a drug's life-cycle.
Most of the post-marketing safety reports are submitted to drug manufacturers by physicians, nurses, pharmacists or other healthcare providers. Once they are assessed, the drug companies turn the reports over to FDA.
Information is derived from clinical trials, adverse event reports, post-approval studies, peer-reviewed biomedical literature and the post-market risk identification and analysis system. The post-market risk system is mandated under the FDAAA to improve FDA's ability to track products that are already on the market.
FDA expects to link data among 100 million patients by 2012.
When a safety issue is discovered, the agency determines if a drug's benefits still outweigh its risks. If so, a manufacturer may be required to add certain side effects to the drug label or develop a Medication Guide - part of REMS, the risk mitigation strategy - for patients, families and caregivers when drugs are dispensed.
FOUR LABEL CHANGES IN 2008
Between March 25 and September 9, 2008, FDA issued 21 letters calling for post-marketing studies or clinical trials to address safety issues. The letters resulted in four label changes, including a boxed warning on conventional antipsychotic medications because of a risk of mortality in elderly patients treated for dementia-related psychosis.
"There needs to be a paradigm change in the way clinical trials are conducted to discover risks earlier on," says Annette Stemhagen, vice president, epidemiology and risk management for United BioSource Corp. in Bethesda, Md. "Once a drug hits the market, there are many more people taking a drug with more opportunity to find safety problems."
Under section 909 of FDAAA, drugs that already were associated with specifically identified elements to assure safe use, as enumerated in the Act, were "deemed to have REMS," but those risk mitigation strategies required formal review and approval. In March 2008, FDA published a Federal Register Notice identifying those drugs "deemed to have REMS." FDA required that those REMS reports be submitted for approval by September 21, 2008.
Some of the elements to assure safe use included in FDAAA are: 1) prescribers must be specially trained and certified to prescribe; 2) pharmacies, practitioners and healthcare settings that dispense those drugs must be certified; 3) drugs must be dispensed with evidence of safe use conditions, such as lab test results; or 4) drugs must be dispensed in specified healthcare settings.
Those submitted proposals are in the process of formal review and approval. As of November 20, 2008, FDA had approved 21 REMS, while 28 other REMS await review.
SERIOUS REACTIONS
Dr. Seligman says FDA receives about 450,000 reports of drug reactions a year with about one-third of those considered serious, resulting in hospitalization or death.
The agency evaluates whether the safety issue was discovered during pre- and post-marketing trials, whether the issue can be prevented and if drug's benefits outweigh risks. About 900 of the 450,000 reports result in safety-related label changes.
"All drugs are inherently risky," says Peter Pitts, president and cofounder of the Center for Medicines in the Public Interest. "They can be made safer by ensuring that the right people get the right drug, and that a diagnosis supports use of a specific medication."
That is why Pitts prefers to use the terminology "safe use of drugs" rather than "drug safety."
SAFETY ALERTS ARRIVE BY EMAIL
The traditional "Dear Doctor" letter notifying physicians about patient safety information through the U.S. mail may be a thing of the past. The Health Care Notification Network (HCNN) is an online service that delivers patient safety alerts to physicians and other healthcare professionals via email.
"HCNN provides safety information immediately without the delay of regular mail and the interference of junk mail that physicians often receive," says Edward Fotsch, MD, CEO of San Francisco-based Medem Inc., which provides network operations for HCNN under contract with iHealth Alliance.
Dr. Fotsch adds that the network mitigates the problem of liability for manufacturers, sends alerts based on medical specialties and decreases alert "weariness" because physicians receive the electronic alert from only one source rather than from many health plan sources.
This first HCNN alert went out in October for the fluoroquinolone class of antibiotics, as the FDA recently stated that this class is associated with an increased risk of tendonitis and tendon rupture. Manufacturers have updated their warning labels to include this information. Bayer (Cipro, Avelox) was the first manufacturer to issue a Patient Safety Alert via the HCNN, which included a Box Warning for tendonitis and tendon rupture and a plan to develop a REMS.
MHE Executive View
--Between March 25 and Sep-tember 29, 2008, the FDA issued 21 letters calling for post-marketing studies or clinical trials and biologics to address safety issues
--FDA receives 450,000 drug-reaction reports per year, and one-third are considered serious.
--HCNN online service delivers patient safety alerts to physicians and other clinicians via email.