Vol. 8 No. 192
The FDA is considering switching to a universal patient leaflet to replace medication guides as part of a risk evaluation and mitigation strategy (REMS) because the guides don’t effectively protect patients from medication errors and serious adverse events, a top agency official says.
The potential change would be part of a broader FDA initiative designed to improve the agency’s understanding of the real-world outcomes of drug use, instead of relying solely on traditional measures such as probable outcomes generated by clinical trials, Janet Woodcock, CDER’s director, said at the Second Annual Risk Management and Drug Safety Summit in Washington, D.C., Thursday.
The guides are proving confusing, Woodcock said, adding that the agency plans to look at ways to quickly learn what is happening after a drug is on the market.
Woodcock also said the agency has fallen short on some goals, including an adverse event reporting system in need of reform, a continued failure to meet Prescription Drug User Fee Act dates and difficulty recruiting advisory committee members due to an increased focus on eliminating conflicts of interest.
Still, the agency plans to take steps to resolve the issues in the next year, including a “mini-launch” of the Sentinel Initiative for adverse event reporting and the release of guidances on adaptive design and noninferiority, she said at the conference sponsored by United BioSource and the Center for Medicine in the Public Interest.
“Guidance for Industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications” is available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf. — David Belian
The FDA and stakeholders face a number of challenges in implementing the agency’s first draft guidance on risk evaluation and mitigation strategies (REMS), agency officials and industry experts say.
The use of REMS may require the FDA to expand its reach to include complex plans that require physician and patient enrollment and involve several pharmacy systems when monitoring and control of patient use is a part of the plan, Kathleen Frost of CDER's Office of Surveillance and Epidemiology, said Thursday at the Second Annual Risk Management and Drug Safety Summit. The draft guidance was published in the Federal Register Oct. 1 (DID, Oct. 1).
The FDA might request that REMS assessments include information about how the drug is actually used among patients or a survey of healthcare providers to see if they comprehend and remember information about a drug’s risks, Frost said. The information would be used to help determine whether the REMS “is doing its job in mitigating the risks of a specific adverse event,” she added.
A future development to watch for is “a classwide REMS for long-acting and extended-release opioids” from the agency, Frost said. “As part of that process, we are getting information and data on various risk management tools and their effectiveness, and on existing systems for providing elements of a REMS.”
In addition, 13 of the approved REMS include a stand-alone communication plan, Frost said. This may include letters to healthcare professionals, educational materials mailed directly to providers, dissemination of information about the REMS to encourage its implementation, and distribution of information through professional societies about any serious risks of the drug and any protocol to assure safe use.
“We anticipate that in many cases, the communication plans will be of short duration,” Frost said at the conference, sponsored by the Center for Medicine in the Public Interest, United BioSource and FDAnews. “If they are imposed [as part of a REMS] for an NDA for a drug without generic competition, they may only be for a year or two, until the industry gets used to the drug and how to handle it.”
Another example of REMS complexity Frost cited is that six of the 78 REMS programs approved as of Sept. 14 involve “elements to assure safe use” (ETASU), as do many of the pre-2007 risk minimization action plans (RiskMAPs), which the FDA has deemed to be equivalent to REMS. ETASUs are a challenge for the FDA; the agency is trying to standardize them while allowing flexibility of sponsor input, she said.
“We will be evaluating the impact of our actions to determine whether they are having the beneficial effects we expect and whether there are any unintended adverse consequences,” Frost said.
The FDA already has significant experience in facing challenges with REMS. For example, statistics posted to the FDA website Wednesday show that 59 REMS imposed between March 25, 2008, and Sept. 14 involve medication guides only. Medication guides were not part of the RiskMAP program, Frost noted.
From the industry’s standpoint, companies faced with a requirement to develop a REMS should first verify a long-term communications process and schedule with the FDA, Brian Harvey, vice president for regulatory policy at Sanofi-Aventis, said. This means giving the agency the names of sponsor stakeholders, roles and contact information, as well as a proposed communications schedule, he said.
He also cautioned sponsors not to be rigid about target review deadlines under the Prescription Drug User Fee Act (PDUFA). For example, he said, Sanofi-Aventis was willing to be flexible about PDUFA timelines for the REMS the FDA required for its anti-arrhythmic drug Multaq (dronedarone HCl). Without that flexibility on the company’s part, he said, the FDA would probably have been forced to send the company a complete response letter, delaying the drug’s approval. — Martin Berman-Gorvine
A required change in heparin manufacturing controls is expected to lessen the potency of the blood-thinner by roughly 10 percent and will result in products with varying strengths being sold at the same time, the FDA says.
The U.S. Pharmacopeia adopted the new manufacturing controls for heparin, including harmonizing the unit dose with the World Heath Organization’s (WHO) unit dose definition, the FDA says in an emailed statement Thursday. The change includes a testing method for potency and to detect impurities in the blood-thinner, the FDA says.
The FDA-approved labeling for heparin, including recommended doses, has not changed because there are not enough data to make new recommendations, John Jenkins, director of CDER’s Office of New Drugs, said during a media call Thursday.
The monograph was revised, in part, in response to a 2007 to 2008 incident of heparin contamination involving a manufacturing step in China (DID, April 22, 2008). The change also includes a test for the contaminant.
Heparin manufacturers already are making heparin using the new standard, which took effect Thursday. But the FDA has asked them to delay shipping the new product until Oct. 8 to give healthcare providers time to adjust dosing practices.
The agency is working with manufacturers to conduct in vitro and animal studies to better understand the impact of the change. Jenkins said in response to a DID question that it’s too early to speculate on potential labeling changes after the studies are complete. He added that the in vitro testing should be completed within the next few weeks and in the vivo testing could be finished in the next month or two.
Until the current supply of heparin is used up — which could take months or longer — both “old” and “new” heparin will be available on the market, Jenkins said. This transition period is necessary to prevent a shortage of the drug. Some patients may require dosing adjustments, most likely when heparin is administered as a bolus intravenous dose.
The FDA has asked companies that market heparin in the U.S. to identify the products that follow the WHO unit dose definition. Three of the companies, APP, Baxter and B. Braun, will place the letter “N” next to the lot number or expiration date of the product labeling, Jenkins said on the call.
Hospira will use a numeric code in the lot number to identify the new product because adding a letter would require a complete overhaul of Hospira’s lot number coding process, company spokesman Dan Rosenberg told DID. He added Hospira believes its method is clear and easily understood. — April Hollis
The FDA’s Oncologic Drugs Advisory Committee will consider the risk-benefit profile of GlaxoSmithKline’s (GSK) Votrient kidney cancer drug candidate next week, after hearing an FDA staff review cite the drug’s potential association with liver risk and a lack of statistically significant improvement in overall survival.
Three deaths in clinical studies of Votrient (pazopanib) were associated with or likely to be related to hepatic injury, according to briefing documents released before the Oct. 5 advisory committee meeting. The deaths and other adverse events strongly suggest Votrient may be associated with a significant risk of severe unusual hepatic injury in a larger patient population after marketing, the FDA says.
The risk of severe and fatal hepatotoxicity is important because there are other products approved to treat advanced renal cell carcinoma (RCC), the briefing documents say. Since 2005, five products have received FDA approval for advanced RCC — Bayer HealthCare’s Nexavar (sorafenib tosylate), Pfizer’s Sutent (sunitinib malate), Wyeth’s Torisel (temsirolimus), Novartis’ Afinitor (everolimus) and Genentech’s Avastin (bevacizumab). Nexavar and Sutent are tyrosine kinase inhibitors (TKIs) like Votrient.
The safety data for Votrient patients, compared with results from those on a placebo, showed an excess incidence of abnormal levels of liver enzymes, plus adverse events including hypertension, hemorrhage, arterial and venous thrombosis, gastrointestinal perforation and proteinuria.
The FDA staff note many adverse events including bleeding, visceral perforation, hypertension and arterial thrombosis appear common for TKIs but it is difficult to compare the safety and efficacy of Votrient with the two other TKIs without randomized trials. GSK is conducting a Phase III study comparing it with Sutent in patients with advanced RCC, but results will not be available for at least a couple of years, GSK spokeswoman Sarah Alspach told DID Thursday.
The briefing documents mention recent citations of a few cases of hepatic failure and deaths that may be associated with Nexavar or Sutent after three to four years of marketing, which may suggest a class effect, the FDA says. No hepatic safety signals appeared during the reviews of the two drugs. The premarketing hepatic safety profile of pazopanib may predict a significant risk of severe hepatic injury, the document says.
Results from a key Phase III trial of Votrient showed a five-month improvement in progression-free survival but no statistically significant improvement in overall survival, the document says. GSK filed the NDA for the drug last December, and the action date for the drug is Oct. 19, Alspach said.
The agency issued a guidance several months ago on laboratory measurements for use in clinical trials to assess a product’s potential to cause severe drug-induced liver injury during product development (DID, July 31).
Votrient will be discussed in the afternoon session of the panel’s meeting, following a discussion of Schering-Plough’s Pegintron (peginterferon alfa-2b), a melanoma treatment. — April Hollis
Merck KGaA has submitted an NDA for cladribine tablets, an investigational oral formulation of cladribine for reducing relapses of multiple sclerosis (MS), and discontinued trials of another MS drug candidate.
Cladribine has have the potential to become the first oral disease-modifying therapy for patients with relapsing forms of MS, as current therapies are parenteral, Germany-based Merck says in a statement this week.
Merck Serono, a division of Merck, submitted an application in July to the European Medicines Agency for the tablets.
Merck also is discontinuing studies for MS drug atacicept after an independent data monitoring committee found the risk-benefit ratio did not justify continuation of the research, ZymoGenetics says in an SEC filing this week. Merck Serono is a ZymoGenetics licensee.
In one of the studies, the committee observed an increase in MS disease activity in the atacicept treatment arms compared with the placebo arm. Two ongoing studies of atacicept, one in rheumatoid arthritis and one in systemic lupus erythematosus, will continue, according to the filing. — April Hollis
GlaxoSmithKline (GSK) has filed an sNDA for its drug Avodart to reduce the risk of prostate cancer among men with an increased risk of developing the disease.
The company also has filed for regulatory approval of the indication in the EU through the European Mutual Recognition Variation Procedure, GSK says in a statement Thursday.
Avodart (dutasteride) had 27 percent growth in worldwide sales last year to $578 million, according to the company’s SEC filings. The drug is indicated to treat urinary symptoms of enlarging prostate and reduce the risk of acute urinary retention and prostate-related surgery, GSK says.
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