Vol. 9 No. 142
As the FDA works to finalize and implement a classwide opioid risk evaluation and mitigation strategy (REMS), the agency is also considering ways to expand its oversight of drugs outside of the REMS.
For example, while the proposed REMS would require drugmakers to set up an agency-approved prescriber education program, the FDA is also considering using its Safe Use Initiative to push for further measures such as patient-provider agreements, Karen Weiss, associate director for medical affairs at CDER, said Thursday at a joint meeting of the Anesthetic and Life Support Drugs and Drug Safety and Risk Management advisory committees.
The voluntary agreements, written documents signed by both providers and patients that outline each party’s responsibilities upon dispensing and receiving the drugs, would be coupled with an agency-backed education campaign designed to increase awareness of the REMS.
Such measures would “expand where REMS is not appropriate,” Weiss said.
While the REMS proposed by the FDA would apply only to long-acting and extended-release brand-name and generic drugs containing fentanyl, hydromorphone, methadone, morphine, oxycodone and oxymorphone, the agency considered expanding it to all opioids.
Ultimately, however, there was not enough evidence of safety concerns to justify such a move, Bob Rappaport, director of the FDA’s division of anesthesia and analgesia products, said.
In addition, the agency avoided requiring physician and patient training because it would have been “extremely burdensome for the healthcare system,” Rappaport said.
What the FDA instead included in its REMS proposal, which was released last month after more than a year in development, was a requirement that drugmakers set up an agency-approved prescriber education program developed and implemented by an independent third party (DID, June 30).
This training will be subject to strict oversight by the FDA, Rappaport said.
“We have the final say in the content of the training, we will have complete oversight of that training and we will make sure that it is appropriate and that it is not in any way biased or inadequate,” Rappaport said.
The joint advisory committee meeting is scheduled to conclude Friday with a vote on the agency’s REMS proposal. — David Belian
While drugmakers say more flexible standards could help spur the development of drugs for rare diseases, one senator concedes lack of federal funding may be part of the problem.
While considerable money has been allocated to research into treatments for major diseases, the federal government has been “less generous and less successful” with funding for rare diseases, Sen. Tom Harkin (D-Iowa), chairman of the Senate Health Education, Labor and Pensions (HELP) Committee, said during a hearing Wednesday on developing drugs for pediatric rare diseases.
He asked for suggestions from NIH and FDA officials on how to get companies to develop drugs for orphan diseases, when development typically involves greater risk and less reward.
Drugmakers, in public comments to the FDA, have asked for additional guidance, more flexible standards and coordination with foreign regulators to create harmonized standards, reducing the need for multiple clinical trials for an already small trial pool (DID, July 1).
While patients with rare diseases are particularly vulnerable, it is important that the FDA ensure the safety of drugs, Jesse Goodman, FDA deputy commissioner for science and public health, said. However, part of the problem is that “there are simply not [enough] products being developed,” he added.
The agency is prepared to be more flexible in its review of rare disease drugs, he noted, citing the FDA’s approval of several products based on small clinical trials — sometimes with as few as 10 patients — and often on one trial. The agency also is open to the use of surrogate endpoints and biomarkers as measures of efficacy.
Conducting clinical trials in rare disease populations presents additional challenges for drugmakers because the number of available patients is small, especially in pediatric populations, and knowledge about the diseases often is limited, Goodman said.
In addition, because the impact of therapy can differ on a child depending on age, Goodman said, it may be difficult to determine whether a child’s response during a clinical study is related to a drug or the result of the natural course of the disease.
In an effort to improve development, the FDA has created a rare diseases review group and added a director for rare diseases in the Office of New Drugs to help drugmakers with regulatory requirements. Last month, Sen. Sam Brownback (R-Kan.) said the agency should develop a system to prioritize the top 100 rare diseases to spur development (DID, June 28).
Current incentives for drugmakers are outlined in the Orphan Drug Act, passed in 1983, which provides seven years of market exclusivity, tax credits and a dedicated path of approval. However, a lack of additional incentives may have discouraged drugmakers from further investing in rare diseases, some experts say.
An FDA report on orphan drugs is due to Congress by March 2011, with a new guidance document on orphan drug development expected in September 2011. — LaCrisha Butler
Tibotec’s experimental non-nucleoside reverse transcriptase inhibitor TMC278 slightly outpaced Bristol-Myers Squibb’s Sustiva in suppressing HIV to undetectable levels, according to data presented Thursday at the international AIDS conference in Vienna.
However, a higher number of patients in the TMC278 (rilpivirine) group showed no viral drop or an increase when compared with patients taking Sustiva (efavirenz) — 9 percent versus 4.8 percent.
In two pivotal trials, 84.3 percent of patients receiving TMC278 reached an undetectable viral load, compared with 82.3 percent of patients who were given Sustiva, Tibotec said.
The trials reached their primary goal, which was to show noninferiority of TMC278 to Sustiva in the number of patients achieving an undetectable viral load at week 48.
Grade 2 to 4 adverse events (moderate, severe and life-threatening) possibly related to treatment were observed in 15.9 percent of TMC278 patients versus 31.1 percent in the Sustiva arm, Tibotec said.
The ongoing ECHO and THRIVE studies involve 1,368 previously untreated HIV-1 infected adults. — Meg Bryant
The FDA has rejected NicOx’s non-steroidal anti-inflammatory drug (NSAID) candidate naproxcinod over adverse event concerns.
The FDA, in a complete response letter, recommended that NicOx conduct one or more long-term clinical trials to determine cardiovascular (CV) and gastrointestinal (GI) effects, the company said Thursday.
NicOx plans to discuss the letter and possible next steps with the FDA as soon as possible.
The action follows an FDA advisory panel’s recommendation against approval. The committee also recommended that the company assess CV and GI events, especially in high-risk populations such as the elderly (DID, May 13).
Naproxcinod is designed to alleviate osteoarthritis pain without GI upset or increased blood pressure seen with other NSAIDs. In Phase III studies, naproxcinod showed a similar blood pressure profile to placebo. However, the drug had a higher rate of GI events compared with placebo, but lower than Roche’s Naprosyn (naproxen).
NicOx’s naproxcinod application to the European Medicines Agency is currently under review. In May, the Paris-based company announced that it was delaying a Phase II study of a heart drug candidate as the company waits for regulatory decisions on naproxcinod (DID, May 21). — LaCrisha Butler
The European Medicines Agency (EMA) will reach a decision on whether to continue to permit sales of GlaxoSmithKline’s (GSK) diabetes drug Avandia by September, the agency said Thursday.
The announcement follows a July 19 to 22 meeting of the EMA’s Committee for Medicinal Products for Human Use to discuss two recent studies authored by FDA drug reviewer David Graham and the Cleveland Clinic’s Steven Nissen that highlight the risk of cardiovascular problems with the drug. The European Commission requested the review earlier this month.
According to Graham’s study, the adjusted hazard ratio for Avandia (rosiglitazone) compared with Takeda’s Actos (pioglitazone) in elderly patients was 1.18 for the composite of acute myocardial infarction, stroke, heart failure or death. Results from Nissen’s meta-analysis also showed an increased risk of heart attack, but not cardiovascular death or all-cause mortality, with Avandia (DID, June 29).
The EMA approved Avandia in July 2000 as a second-line treatment for Type 2 diabetes. It later authorized the drug in combination with metformin as Avandamet and with glimepiride as Avaglim. All three medications carry warnings against use in patients with heart disease.
Worldwide sales of Avandia totaled about $1.2 billion in 2009. However, GSK just announced that sales dropped 26 percent in the second quarter of 2010 compared with the prior-year period (DID, July 22). — Meg Bryant
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