Below is an informative and illuminating report in “The Pink Sheet” about the January 17 meeting of the Institute of Medicine Committee on Assessment of the U.S. Drug Safety System (i.e. FDA safety review process).
Dr. Steve Nissen, former chair of FDA’s Cardiovascular & Renal Drugs Advisory Committee noted: "The academic community needs to help the FDA by providing access to people who are unbiased, who are safety oriented…We need, the FDA needs, advisory panels that have some courage, that are willing to stand up when we need to stand up and say to the FDA, ‘we don’t think this drug is ready for approval,’ so that the FDA has the support of the academic community to do the right thing."
Dr. Curt Furberg (Wake Forest University) reiterated Nissen’s call for greater academic input and proposed that clinicians be replaced with safety experts. Furberg was a member of FDA’s Drug Safety & Risk Management Advisory Committee until May 2005. "My view is that we have too many clinicians….There are a couple of people who have said ‘I need those drugs for my patients.’ I found that very self-serving and offensive. The FDA’s role is not to provide drugs for doctors," Furberg said. "The FDA’s role is to protect the public from harmful drugs. We need to bring in experts in drug safety and people who understand public health."
The IOM committee was especially critical of two recent advisory panel approval recommendations— Bristol-Myers Squibb/Merck’s type 2 diabetes treatment Pargluva (muraglitazar) and GSK’s Serevent (salmeterol)—for which the safety data did not warrant approval.
An acknowledgement at the IOM meeting confirms that FDA advisory committees do not even examine the data submitted by industry! “The people who are on those panels have to look at the data."
How then, can the FDA or anyone claim that the safety review process has any integrity whatsoever?
A letter to The Washington Post by Dr. Henry Greenspan (University of Michigan) informs us that the Michigan courts have been following FDA’s preemption dictum which denies citizens the right to sue pharmacueical companies tha conceal safety hazards of its products with the inevitable result: "Michigan is the canary in their coal mine, and the canary is dying.”
Contact: Vera Hassner Sharav
FDC: “THE PINK SHEET”
January 30, 2006
Volume 68 | Number 005 | page 20
Drug Safety Issues Require "Courage" From Advisory Cmtes, Nissen Says
Advisory committees should be strengthened to better scrutinize safety data and improve advice given to FDA, Steve Nissen (Cleveland Clinic Foundation) said at the Jan. 17 meeting of the Institute of Medicine’s Committee on the Assessment of the U.S. Drug Safety System. "We need, the FDA needs, advisory panels that have some courage, that are willing to stand up when we need to stand up and say to the FDA, ‘we don’t think this drug is ready for approval,’ so that the FDA has the support of the academic community to do the right thing," Nissen said.
Nissen called for increased participation by academics and safety specialists in aiding advisory committees. "The academic community needs to help the FDA by providing access to people who are unbiased, who are safety oriented, so that they’re there," Nissen said. Nissen is a former chair of FDA’s Cardiovascular & Renal Drugs Advisory Committee and continues to serve as a consultant.
Curt Furberg (Wake Forest University) reiterated Nissen’s call for greater academic input and proposed that clinicians be replaced with safety experts. Furberg was a member of FDA’s Drug Safety & Risk Management Advisory Committee until May 2005. "My view is that we have too many clinicians….There are a couple of people who have said ‘I need those drugs for my patients.’ I found that very self-serving and offensive. The FDA’s role is not to provide drugs for doctors," Furberg said. "The FDA’s role is to protect the public from harmful drugs. We need to bring in experts in drug safety and people who understand public health."
Nissen criticized the September 2005 review of Bristol-Myers Squibb/Merck’s type 2 diabetes treatment Pargluva (muraglitazar) by FDA’s Endocrinologic & Metabolic Advisory Committee. Members noted potential cardiovascular safety risks with the diabetes therapy, but Bristol’s plans for a pharmacovigilance program with a 15,000 patient cohort and an outcomes trial swayed the committee to issue a favorable recommendation (1" The Pink Sheet" Sept. 19, 2005 <http://www.thepinksheet.com/fdcreports/story/viewStory.do?targetAN=00670380005> , p. 11).
"Panels sometimes perform very well and sometimes they perform very poorly, as in the case of muraglitazar. I think this panel put the FDA in a terribly risky situation….It’s very tough when a group of experts says to the FDA ‘we don’t see a problem.’"
Nissen authored a study, published October 2005 in the Journal of the American Medical Association, calling for a delay in the approval of Pargluva due to safety concerns. While Nissen’s study was based on the same Phase II/III trial results that were presented to the advisory committee, his analysis found a higher risk rate (2" The Pink Sheet" Oct. 31, 2005 <http://www.thepinksheet.com/fdcreports/story/viewStory.do?targetAN=00670440001> , p. 3).
"When I read that statement from the FDA safety officer, I’d seen enough. If I’d been on that panel, I would have almost certainly raised these questions and the panel would never have ended at two o’clock in the afternoon," Nissen said. " There would have been a lot of probing of the data… I’m going to guess there would have been a majority opinion not to approve."
Bristol/Merck received an "approvable" letter from FDA in October 2005 requesting additional cardiovascular safety information.
"I think what would have probably turned [the muraglitazar] panel meeting differently is one or two rigorous people who understand safety that would have explained to the other panel members why the signals here cannot be ignored and why the Phase IV trial was not even close to adequate," Nissen said. The Pargluva review did not include any cardiologists among the voting consultants at the meeting.
IoM committee member Bruce Psaty (University of Washington) also said that the advisory committee was wrong to accept the promise of Phase IV safety studies for Pargluva and when recommending approval of GSK’s Serevent (salmeterol). Post-marketing studies that were planned for Pargluva "could not answer important questions," Psaty said.
Nissen proposed randomized controlled trials instead of observational pharmacovigilance studies to address safety concerns. "When safety signals are observed, randomized trials are essential. A company came in with a proposal for a so-called ‘pharmacovigilance’ study. It just doesn’t cut it."
"If you’re looking at the first drug in a new class, particularly one that’s had problems with toxicity, let’s keep the bar high," Nissen urged. "We’ve got to have a high enough bar to avoid this kind of a problem in the future."
Several other competing peroxisome proliferator-activator receptor agonist programs were delayed or dropped prior to Pargluva’s review due to similar safety issues (3" The Pink Sheet" Oct. 11, 2004 <http://www.thepinksheet.com/fdcreports/story/viewStory.do?targetAN=00660410017> , p. 24). Genentech Senior
Director-Development James Nickas agreed with Nissen and called for more thorough committee consideration of post-marketing trials (see 4following story <http://www.thepinksheet.com/fdcreports/story/viewStory.do?targetAN=00680050012> ).
Nissen proposed prospective analyses of safety data to tackle risks early on in the drug development and approval processes.
"I wrote a letter to the sole remaining company that has a dual PPAR in development, which is AstraZeneca, and I suggested to them that they prospectively define cardiovascular safety and adjudicate these endpoints in their Phase III program," Nissen said. "If this signal is not there then that’s good, and if it is, they’ll find it out."
Nissen suggested that much of the responsibility for presentation of safety concerns to the committee rests with industry. "We’re dealing with an area where industry has all the power. I think that panels are often intimidated….They are often people that are involved somehow with industry and they’re worried about the appearance of being a crusader or a gadfly…so people will stay silent."
Nissen claimed that industry has a disproportionate advantage at advisory committee hearings because company representatives are better prepared than committee members. "I expect [the companies] to portray their drugs in the best light, but the panel has to step up and get it right. The companies are so much better prepared than anyone on the safety side," Nissen explained. "They have mock advisory panels….They also come to these panel meetings with prominent spokesmodels."
In comparison to the well-prepared industry representatives, Nissen claimed committee members do not have sufficient time to review the data. "We usually get [data] the night before. We would be glad to get them the week before. I think it would be very helpful."
Nissen said he had been told when joining an advisory committee that "the best prepared members of the panel were those with the longest flight to Washington." However, "I don’ t know if that is true in some panels. I like to believe that people who take on the public responsibility take it seriously."
Nissen singled out University of Washington biostatistician Thomas Fleming, who has served as a member and consultant to several committees. "I work a lot with Tom Fleming, who is extraordinarily rigorous. When you have people like that on there, you feel very comfortable that you haven’t missed anything."
Former FDAer and drug safety consultant Judith Jones (Degge Group) agreed with Nissen’s view on the panels’ preparedness and noted the lack of training given to committee members. Advisory committee members "currently are assigned to their committee and they come to their first meeting not necessarily having much orientation. There’s a need for a very clear orientation of these committees to their regulatory mandate and responsibilities," Jones said.
Jones proposed the National Institute of Health’s study section as a model for improving committee preparation. "The NIH study section has a very nice process of requiring people to review very large volumes of data and write down their opinions before they discuss them with other colleagues," Jones explained. "Such an effort would be very, very helpful in the decision making process of advisory committees who are currently given questions at a very short notice."
Members of FDA’s Oncologic Drugs Advisory Committee also expressed a desire for better training at a meeting in the fall (5" The Pink Sheet" Nov. 21, 2005 <http://www.thepinksheet.com/fdcreports/story/viewStory.do?targetAN=00670470007>, p. 13).
Nissen noted that the questions posed to a committee by FDA can also impact the outcome of the review. "I’ve seen some very aggressive questions from the agency, where it’s pretty clear from the questions that the agency does not want the drug approved and the panels will often get led in that direction," he said.
Overall, the agency is "trying to present a relatively neutral set of questions and a good panel will put the pieces together," Nissen said. "But people who are on those panels have to look at the data."
Contents copyrighted © F-D-C Reports, Inc. 2006; protected by U.S. Copyright Law.
THE WASHINGTON POST
Drugs and Liability
Monday, January 30, 2006; Page A16
New drug labeling guidelines from the Food and Drug Administration
include the doctrine of "preemption" ["FDA Tries to Limit Suits in
State Courts," Jan. 19]. This holds that labeled warnings provide
immunity from state tort liability.
The doctrine has been rejected recently by two federal district courts;
a chief justice in Minnesota called part of the argument for it
Meanwhile, in Michigan, the pharmaceutical industry has enjoyed full
legal immunity from lawsuits since passage of a preemption law in 1995.
However, a bipartisan group of state representatives is close to
rescinding the tort-immunity statute. That has put national "tort
reformers" in crisis mode. Michigan is the canary in their coal mine,
and the canary is dying.
Ann Arbor, Mich.
Henry ("Hank") Greenspan, Ph.D.
University of Michigan
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