Latest Drugwonks' Blog
Important reporting from today’s edition of the Wall Street Journal:
“An unusual clinical trial involving four different drugs offered promise that guiding treatment based on the molecular traits of a tumor can improve survival from lung cancer. Researchers said the study amounted to "proof of concept" for a new approach to clinical trials that could improve the efficiency of cancer-drug development and eventually shorten the time it takes to get new treatments to market.”
The “Battle” study involved 255 patients with advanced lung cancer.
According to Edward S. Kim, a cancer researcher at M.D. Anderson and principal investigator of the Battle study, "This is a first step to find biomarkers that may help supplant existing toxic therapies and to find the right population for a particular drug," said.
The WSJ writes, “The adaptive design is gaining interest among researchers and drug companies because it could help identify drugs that don't work sooner, and identify biomarkers that would be used to enroll patients in late-stage studies required for market approval.”
Currently large clinical trials typically take all comers without evaluating their biomarker status. "The problem is that when you take a drug that has a specific target, but you treat everybody, you dilute the effect" of the drug, said Dr. Kim.
Researchers say that is why many targeted cancer drugs fail in late-stage or Phase III studies.
"This is the future," Tyler Jacks, a cancer researcher at Massachusetts Institute of Technology and president of the AACR, said of the Battle trial. "This is how drugs will be developed and clinical trials organized."
Important news. Good news. Potentially life-saving news. And interesting news considering that some are using the current PDUFA reauthorization debate to suggest the FDA demand comparative effectiveness studies as part of the agency’s drug approval process – something that no other drug licensing agency in the world does.
If the Battle study proves nothing else – it’s that we don’t know enough about how new medicines work once approved ("in the real world"). And that’s particularly true for cancer drugs. So what does “comparative effectiveness” really mean? And should it be applied to the global gold standard of safety/efficacy or, if you prefer, risk/benefit. Lung cancer is a good example, considering that average survival on chemotherapy is about eight months. What’s the value in asking about pre-approval “comparative effectiveness? Compared to what? "Best practice" treatment? And compared how?
Those who call for such a third leg are on a price jihad (cost effectiveness). That’s their privilege – but they had better understand the consequences such a move inside the FDA process would have on pharmaceutical innovation.
But first, there are some things they should understand, more generally about innovation itself:
Innovation is slow. As any medical scientist will tell you, there are few "
Innovation is expensive. In 2003, researchers at
Comparative effectiveness is an interesting health policy issue -- but the PDUFA reauthorization process is the wrong place for the conversation.
Memorial Service In Tribute of The Life of Rep. Bob Franks
A memorial service will be held in tribute of the late Former U.S. Representative Bob Franks. Below is information on the service:
Saturday, April 17, 2010, 11:00AM Cathedral Basilica of the Sacred Heart 89 Ridge Street Newark, NJ 07104 (973) 484-4600 Speakers: Governor Chris Christie Former Governor Jon Corzine Former Governor Tom Kean Former Governor Christine Todd Whitman Roger Bodman, Godfather to Abigail Franks Alfred Fasola, Godfather to Sara Franks Former Congressman John Kasich, Godfather to Kelly Franks Donations: The Franks family asks that in lieu of flowers, donations should be directed to the New Jersey National Guard State Family Readiness Council, http://www.nationalguardsfrc.org/.
WASHINGTON (AP) -- Opposition to President Barack Obama's health care law jumped after he signed it - a warning to Democrats running for re-election this fall that his victory could become their liability.
A new Associated Press-GfK poll finds Americans oppose the health care remake 50 percent to 39 percent. Before a divided Congress finally passed the bill and Obama signed it at a jubilant White House ceremony last month, public opinion was about evenly split. Another 10 percent of Americans say they are neutral.
Disapproval for Obama's handling of health care also increased from 46 percent before the bill passed to 52 percent currently - a level not seen since last summer's angry town hall meetings.
Nonetheless, the bleak numbers may not represent a final judgment for the president and his Democratic allies in Congress. That's because only 28 percent of those polled said they understand the overhaul extremely or very well, and a big chunk of those remain neutral.
Democrats hope to change public opinion by calling attention to benefits available this year for seniors, families with children transitioning to work and people shut out of coverage because of medical problems.
"There are some things I like, because I think that there are some people who need health care," said Jim Fall, 73, a retired computer consultant from Wrightwood, Calif.
But "I don't like the idea of the government dictating what health care should be like," added Fall. "Nor do I like them taking money out of Medicare. They are going to create more waste and they are going to take away benefits."
Seniors - reliable voters in midterm congressional races - were far more likely to oppose the law. Forty-nine percent were strongly opposed, compared with 37 percent of those 64 and younger. Seniors' worries that Medicare cuts to insurers, hospitals and other providers will undermine their care are a formidable challenge for Democratic congressional candidates this fall.
Analysts said such wariness on a major piece of social legislation is unusual.
"The surprise of this poll is that you would expect people to be more supportive of the bill now that it's the law of the land - and that's not the case," said Robert Blendon, a Harvard public health professor who follows opinion trends on health care. "The election for the House is going to be competitive, and health care is clearly going to be an issue."
The nearly $1 trillion, 10-year health care remake would provide coverage to nearly all Americans while also attempting to improve quality and slow the ruinous pace of rising medical costs.
Nonpartisan congressional budget analysts say the law is fully paid for. Its mix of Medicare cuts and tax increases, falling mainly on upper-income earners, would actually reduce the federal deficit. And people covered by large employers may even see a dip in their premiums.
The public doesn't seem to be buying it.
Fifty-seven percent said they expect to pay more for their own health care, contrasted with 7 percent who expect to pay less. And 47 percent said they expect their own medical care to get worse, compared with 14 percent looking forward to an improvement.
"Based on the little information we know, somebody's going to have to pay for it, so it makes sense that taxes would go up," said Lang Fu, 48, an oil and gas engineer from Houston.
Politically, Americans are polarized. Democrats support the overhaul by 68 percent to 18 percent, while Republicans oppose it 85 percent to 9 percent. Whites oppose it by 57 percent to 32 percent, while minorities support it 61-27.
Political independents are roughly even, with 44 percent opposed and 40 percent in favor - within the poll's margin of error. Some may be swayed by appeals from Obama and the law's supporters.
Donna Christian of Kingsport, Tenn., is an independent leaning in favor of the law. A bad heart forced Christian, 45, to leave her job as a supervisor at a wireless phone company a few years ago. She and her 10-year-old daughter make do on a limited income, and have coverage through Medicaid.
"I think Americans are going to be better off in the long run even if they don't see that now," Christian said. "More will have coverage, and they'll be able to go to the hospital when they need to."
Ron Pollack, head of Families USA, a liberal advocacy group that supports the overhaul, said it will be "a real task" to turn public opinion around, but he's confident.
"When you dig deeper, individual provisions of the law have enormous support," he said. Pollack believes current polls reflect public disgust with a "very lengthy and messy process."
But Rep. Dave Camp, R-Mich., says Democrats already lost their chance to persuade the public.
"They have had 16 months to explain this bill," Camp said. "Good luck trying to explain it in the next six."
The AP-GfK Poll was conducted April 7-12, 2010, by GfK Roper Public Affairs and Media. It involved interviews with 1,001 adults nationwide on landline and cellular telephones. It had a margin of sampling error of plus or minus 4.3 percentage points.
PS/ The Associated Press is not owned by Fox News.
While narrower bioequivalence margins might be necessary for certain categories of generic drugs, FDA's Pharmaceutical Science and Clinical Pharmacology Advisory Committee has determined that the specifications should not be tightened across the board for all generic drug approvals.
On April 13, the panel voted that current bioequivalence standards are not sufficient for generic versions of "critical dose" drugs, drugs where there is a narrow therapeutic index and deviations can result in therapeutic failure or adverse drug reaction. But on April 14, the committee pulled back from FDA's proposal to revise the bioequivalence margins for all generics, rejecting that idea in a 12-2 vote.
FDA officials presenting at the meeting signaled strong agency support for the move.
Here are the four component parts:
1. Information is presented in language that is readily understandable by consumers;
2. Audio information is understandable in terms of volume, articulation, and pacing used;
3. Textual information is placed appropriately and is presented against a contrasting background for sufficient duration and in a size and style of font that allows the information to be read easily; and
4. The advertisement does not include distracting representations (including statements, text, images, or sounds or any combination thereof) that detract from the communication of the major statement.
Subjective. Subjective. Subjective. Subjective.
Nothing new -- just more of the same old ambiguity. And more excuses to write warning letters that serve no purpose other than to satiate the hunger of those on the Hill who see volume of letters as equaling more robust oversight.
Really?
For a good overview of the issue and some top notch opinions, see this article from the RPM Report.
If you're wondering why "net impressions" has become "net neutrality" -- it's because the FDA doesn't do impressions.
(And don't call me Shirley.)
Former Senator (and almost HHS Secretary) Tom Daschle keynoted the opening of the 19th Annual Partnerships in Clinical Trials conference.
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Okay, once more with feeling – “generic” does not equal “identical.” That’s why the FDA wants to tighten the bioequivalence standards for generic drugs. Bravo!
The Pharmaceutical Science and Clinical Pharmacology Advisory Committee voted unanimously, with one abstention, that critical dose drugs do constitute a distinct group and voted unanimously that FDA should develop a formal list of those drugs - although the terminology of "narrow therapeutic index" may be more appropriate. And in an 11-2 vote, the committee concluded that current bioequivalence standards are not sufficient for drugs in the narrow therapeutic index group.
According to the agency, although that methodology is "statistically rigorous" and accepted as a valid way to establish bioequivalence in most of the world, "many consumers and health professionals do not understand these statistical methods and the approval standards based on confidence intervals … Many wrongly assume that the FDA places the standards ... on the mean or average of the study data rather than the confidence intervals."
"Since the public seems to have a basic understanding of averages, the proposal to be discussed is for an additional criterion to be placed on the geometric mean (average or point-estimate) of the data limiting it to 90-111 percent." The agency surveyed 12 years of generic approvals and found that only approximately 2 percent to 3 percent of approved generic drugs would not have passed with the additional criteria.
According to a report in the Pink Sheet, “There is regulatory precedent in the definition of narrow therapeutic ratio, where drugs that meet certain parameters of median lethal dose and median effective dose are required to have careful titration and patient monitoring. But that definition is not necessarily clinically practical, FDA states, because the relevant parameters are not always available during drug development. Thus, the agency is asking the advisory committee whether it should consider CD drugs to be a distinct class, and how it should be defined. The agency also wants to know whether if the current bioequivalence standards are appropriate for CD drugs.”
The agency has already set up specific requirements for one drug product, asking manufacturers of generic versions of Sanofi-Aventis's insomnia drug Ambien CR (zolpidem) to compare partial AUCs over clinically relevant time intervals. An appendix considers the role of partial AUC for generics of modified-release methylphenidate products as well.
Its good news that the FDA is taking a strong stance in favor of the public health – because there will be many who seek to undermine this important initiative.
In the words of John Stuart Mill,
“One person with a belief is equal to a force of 99 who have only interests.”
Biogen Idec is developing a test that can tell patients their odds of getting a deadly brain illness from Tysabri.
The screening tool could be marketed as early as 2011 if clinical trials involving 9,000 people show a low rate of false findings. The test is designed to detect the JC virus that causes progressive multifocal leukoencephalopathy, or PML, a brain-cell destroyer that can lead to disability and death. (Tysabri has been linked to 42 PML cases.)
If the test works, it is “absolutely a game changer,” said Patricia O’Looney, vice president of biomedical research at the National Multiple Sclerosis Society. With a false-negative rate of 2 percent, patients who are free of the virus would lower their risk of getting the brain disorder PML to 1 in 25,000 for the first three years of their Tysabri therapy.
And speaking of risk management, I’m chairing a panel on REMS today at the 19th Annual Partnerships in Clinical Trials conference.
A common question I get about REMS is – how is it different from what we used to call RiskMAPS? I see two main differences. The first, obviously and importantly, is that REMS has actual legislative language. And that’s an important detail – but it’s one-dimensional.
The second, more important and contentious difference is the environment into which REMS was birthed -- an environment in which there is growing realization that the 21st century FDA must add a third leg to its mission of safety and efficacy – and that third leg is safe use. The safe use of drugs. And the formulation, implementation and communication of plans – REMS plans -- that will assist physicians and patients achieve better outcomes through the strategies and tactics devised therein.
That being said, there are those in industry and in the broader healthcare policy arena who look at REMS and don’t see GEMS.
Many have looked at the FDAAA language on REMS and see it as an ill-advised green light for the FDA to inject itself into the practice of medicine.
While I agree that REMS does indeed represent an expansion of the FDA's authority, I do not agree that it is either ill advised or an over-extension of the agency’s purview.
The concept of "safe use" as an integral part of the FDA's 21st century mission and REMS as one of many tactics to achieve better patient care are contentious and crucial. And it is that debate which brings us together today.
REMS must be viewed as a “win/win” situation for the agency (which can now move forward to approve drugs with higher risk profiles and have a more direct path for post-market surveillance), for sponsors (who can have their drugs approved with greater alacrity), for physicians (who will – at least in theory) have a more complete view of risks and benefits, and patients (who will have additional therapeutic options and will now – at least in certain circumstances – become a more complete part of the compliance/adherence proposition).
There’s much debate and discussion over where in the drug development process REMS should surface. Acknowledgement that this cannot be done in the absence of data – and confusion as to how to deal with early (even Phase II information) that might be REMS relevant. And “confusion” meaning both scientific uncertainty and internal confusion and discomfort.
There’s evident frustration about validated tools (the absence thereof). But this was at least somewhat assuaged by the timely release of the FDA’s draft guidance on “Format and Content of Proposed REMS Assessments, and Proposed REMS Modifications.” And it was a cool and refreshing draft indeed.
And there’s continued discussion as to whether or not companies should wait until the agency asks – or if sponsors should preemptively (you should excuse the expression) provide an outline of a potential REMS plan. This is important not just as an issue of timeliness (as opposed to having the agency introduce the topic in a complete response letter), but also of responsibility. If, as we all want to believe, the FDA must be both regulator of and colleague to industry, then what are the responsibilities of a sponsor relative to (among many other things) surfacing the REMS issue – and at what point in the process. Nobody said it was going to be easy.
CDER Director, Dr. Janet Woodcock said that, “Safety means doing the right things for patients. FDA must consider post-approval issues as part of a drug’s lifecycle.”
Janet understands that there’s a real difference between “headlines and help.” In other words, REMS and other safety mechanisms can be viewed as either “headlines” about “unsafe” drugs or in a more appropriate context of “safe use.” Janet opts for “safe use,” while others (in the media and elsewhere) seem more predisposed to the other.
According to Woodcock, “FDA does not control the health care system, so our improving the use of marketed drugs, to a great extent, is going to involve influence rather than control.”
“Influence rather than control” is a savvy and sophisticated concept -- one that many of our elected members of Congress could learn from, and one in which REMS plays an important role.
The FDA’s "Safe Use" initiative is the patient-facing sibling of the agency’s “Safety First” pharmacovigilance program. But it's more than that -- it's the FDA reasserting ownership of safety from those who would use it only as a mallet of fear. I will not mention names.
It's important to note that when the FDA announced the warfarin label change the agency (and Larry Lesko in particular) came under attack from critics who asserted that this was the FDA, inappropriately, telling doctors how to practice medicine.
Jane Axelrad, the associate director for policy at CDER, had to say about REMS, “These safety plans allow patients to have continued access to certain medicines for which there are safety concerns that can be managed through appropriate use.”
Whether you say “appropriate” use or “safe” use – the principle is the same – making sure that the risk/benefit analysis of any given therapy is communicated in a lucid and (when required) strident manner.
Sometimes that requires a label change. Sometimes it requires a REMS plan, but it will always require the active participation and leadership of the FDA in partnership with the pharmaceutical industry, physicians, and yes – even patients.
Because no safe use program will succeed without the secret ingredient of patient responsibility.
But does it require additional agency authority. At a recent House Energy and Commerce Health Subcommittee hearing FDA’s Principal Deputy Commissioner Josh Sharfstein said that FDA could use more authority to bring negotiations over a drug's Risk Evaluation and Mitigation Strategy to a close. The agency can require a REMS, he commented, but not specify its contents.
Brand sponsors must implement such a plan, whereas FDA must pay for and operate a communication plan for generic drugs, he noted. Something to think about as we head into the PDUFA reauthorization debate.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
