Latest Drugwonks' Blog
Do doctors need more and better information on how to get the right dose of the right drug to the right patient at the right time. Yes! But denying FDA approval to one drug because, in a large randomized controlled clinical trial, it may not be "as effective" as another is not only meaningless -- it's counterproductive. How can care be improved if physicians are denied access to new drugs that work? Hm.
What we DO need are more and better molecular diagnostics and more adaptive clinical trials to show what drugs work best in specific subpopulations. That's not comparative effectiveness, it's clinical effectiveness. And it's crucial to the advancement of 21st century medicine.
Here's the NPR story on the NEJM articles:
http://www.npr.org/templates/story/story.php?storyId=124516838
Watch for the issue of an FDA "third leg" to come up during the upcoming debate over PDUFA reauthorization. Watch "comparative" effectiveness morph into "cost" effectiveness. And remember -- what we need to discuss is "clinical" effectiveness.
http://www.whitehouse.gov/health-care-meeting/proposal/titleiii
Fast forward to the present. The RAND Corporation reviewed the ability of Britain's National Health Service -- the ultimate public option with centralized control over health spending, treatment practices, reimbursement levels and performance standards -- to keep people healthier and make sure qualiity of care drives all decisions. RAND looked at the NHS ability to deliver high quality care after increasing spending on health care during that time at a rate faster than spending in the US.
Here's what the study found:
A damaging rift between doctors and managers: “The GP and consultant contracts are de-professionalising, and have had the peculiar effect of simultaneously demoralising and enriching doctors. We’ve lost the volitional work of the doctors and far too many of us are now just working to rule.”
Pointless new structures. “Stop the restructurings. The only thing they generate is redundancy payments.” One body responsible for improving standards reported to five different ministers and had three different names in the space of 30 months.
A culture of fear and slavish compliance. “The risk of consequences to managers is much greater for not meeting expectations from above than for not meeting expectations of patients and families.”
http://www.timesonline.co.uk/tol/news/uk/health/article7052606.ece
RAND notes that the NHS has implemented all manner of quality commissions, practice guidelines, performance standards, value-based reimbursement contracts with doctors, etc. Sounds a lot like the Senate and House bills right? The RAND study noted that comparative effectiveness studies came in for particular criticism by everyone within the NHS:
"NICE is too focused on fiscal issues: This concern likely arises because NICE is simultaneously considering clinical effectiveness and cost effectiveness. Implementation of NICE technology appraisals is mandatory which underscores the focus on fiscal issues. Concerns were also raised about whether the thresholds are adequate (£30,000 per quality adjusted life year) and about the limited and somewhat weaker economic evidence relative to clinical evidence. This led some observers to suggest that the UK needed guidelines development that would not account for resource issues."
This concern about NICE -- the "group of doctors and health experts" President Obama refers to -- is related directly to the feeling among NHS managers and and GPs that they are simply instruments for carrying out the fiscal goals of the NHS at the expense of the needs and health of patients. And meanwhile, none of the new structures, measurements or studies have improved care. Instead, as the RAND study notes:
"Concerns have been raised about perverse incentives for treating multimorbidity patients imbedded in the financial incentives."
Or as the President said: "And to make sure that the quality of care for seniors drives all of our decisions, a group of doctors and health care experts, not Members of Congress, will be tasked with coming up with their best ideas to improve quality and reduce costs for Medicare beneficiaries."
Here’s a taste:
The firestorm over GlaxoSmithKline’s Avandia (rosiglitazone), which was rekindled two weeks ago with an incendiary Senate report, shows why people who live outside the Beltway are convinced that Washington is broken, and why they are right.
The politico-media outburst exemplifies the worst aspects of the American regulatory environment. It also exemplifies why business as usual in Washington must stop, and why the responsibility rests directly at the feet of the politicians and regulators who are failing their responsibility to put the public’s health before politics.
As with previous rounds in the Avandia circus, grandstanding members of Congress played gotcha with FDA, releasing their report to the agency and to the media simultaneously. Citing data from disgruntled FDA employees, Committee Chair Max Baucus (D-Mont.) and ranking member Chuck Grassley (R-Iowa) said in a Feb. 20 press release that “the FDA itself estimated that the drug caused approximately 83,000 excess heart attacks between 1999 and 2007.” The release gave the false impression that this represents FDA’s official position.
Unless the political leadership at HHS and FDA acts quickly and decisively, decision-making based on external political pressure and a paralyzing precautionary philosophy will become institutionalized.
Instead of being occasionally blown off course by recurring squalls, the very real risk is that permanent climate change will forever degrade FDA’s science-based over-sight process, eroding the public’s confidence in the agency and placing a stop sign on the path of biomedical innovation.
Avandia is the poster child for a culture that has evolved at FDA — encouraged by publicity-seeking politicians — in which agency employees who dislike a regulatory decision are able to keep raising the issue, and if they don’t like the results, to go outside established agency procedures for resolving scientific disputes to enlist support from members of Congress and their enabling lapdogs in the media.
There’s more. A lot more. Names are named. And punches aren’t pulled.
The complete BioCentury commentary can be found here.
The issue is – the few versus the many.
"It really isn't the average that matters to people most. For various reasons - analytical, historical and others - we use mean results. But that's not what happens to individual people. ...Of greater interest, this is true for a lot of situations, are the effects on individuals or the distribution of those effects, which we are not so used to measuring."
Even if a drug only has a 10 percent effect, Temple said, "it might have a rather large effect in a fraction of the population," so a look at distribution is useful. "We do think about that, mostly though," he conceded, "when you have context that has a safety problem or the effect is particularly important."
There are increasing opportunities in early studies to identify the responders and incorporate that information into the design of later-phase trials, Temple noted. If sponsors find a likely response predictor, "genomic or some other kind of finding, there's nothing that stops the later trials from stratifying that predictor and analyzing the groups separately or even making the result in the responder subgroup the primary analysis."
Temple's remarks came during a debate on whether clinical trials for PAH drugs should be required to show that patients in the treatment arm improve their distance by a minimum amount during the six-minute walk.
The question, he noted, is what is a big enough improvement? The answer can come from the patients themselves, in how they feel about walking or their life activities, he suggested, "We're very interested in looking more at well-validated patient reported outcomes."
Let's remember and embrace that last comment, "well-validated patient reported outcomes."
Bob’s comments, coming on the heels of the FDA’s recent documents regarding clinical trial designs (Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics), seem to reinforce the agency’s Critical Path philosophy of broadening decision-making criteria about a drug based strictly on generalized results from large scale RCTs. Trial designs that focus on patient selection for ideal response is a key tenet of the personalized medicine approach that industry and FDA are hoping to create and for which the Critical Path’s Reagan Udall Foundation was created to foster.
That being the case, perhaps we should take the Wisdom of Temple to our nation’s Temple of Wisdom and suggest to Congress that a certain percentage of PDUFA fees be used to fund the FDA’s Critical Path program.
The bill is essentially the same as the amendment, also sponsored by Welch, included in the health care reform legislation passed by the House last summer. However, a price negotiation provision is not part of the Senate bill on health reform, which has become the primary vehicle for passing health reform through Congress.
The Welch bill does not provide HHS with the authority to establish a national formulary. The Congressional Budget Office has consistently concluded that empowering HHS to negotiate prices, without also providing the secretary with authority to set up a national formulary, would not produce savings to the government.
As Stanford economists Alain Enthoven and Kyna Fong have explained, when discussing Medicare Part D, “Government price negotiation could leave people without drugs that manufacturers decide aren’t sufficiently profitable under the plan.”
That’s exactly what has happened under the health insurance program run by the Department of Veterans Affairs, which is already empowered to directly negotiate prices with drug producers.
Of the 300 most prescribed drugs among Americans 65 and older, the VA only covers 65 percent of them, according to a study from the Lewin Group. By contrast, the two most popular plans in the Medicare Part D drug benefit — where private insurers compete for customers — each cover 94 percent of those medicines.
In fact, over a third of retired veterans supplement their VA coverage by enrolling in Part D
The Part D model hasn’t sacrificed cost-savings for choice, either. The competitive pressures among participating insurers have lead to a 17 percent drop in out-of-pocket spending for seniors who enrolled in the program in 2006 — that’s equivalent to 14 extra days of medicine a year.
Moreover, Part D’s total expenses over the next decade are expected to be nearly $120 billion less than originally estimated when the program was created.
Mr. Welch and friends are hoping to have the bill move in tandem with the final push to pass health care reform legislation or be added to the package of "fixes" being planned for the Senate bill.
Add this to the growing list of reasons why “reconciliation” is both phony and dishonest.
FDA has issued two new draft guidance documents regarding clinical trial designs: Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, and Guidance for Industry: Non-inferiority Clinical Trials.
Adaptive Design Guidance: This draft guidance is designed to provide sponsors and the review staff in both the drugs and biologics divisions with information regarding adaptive design clinical trials when used in drug development programmes, including aspects of adaptive design clinical trials that deserve special consideration and how a sponsor should interact with FDA while planning and conducting such a study.
An "adaptive" design has been described as a clinical study design that allows users to adapt or modify a trial during its progress based on examination of the accumulated data at an interim point without affecting the validity and integrity of the trial.
The FDA defines an adaptive clinical trial design as one that "includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study". By allowing modifications, the FDA states, there is the possibility that one can make the study more efficient (eg, shorter duration, fewer patients), or have the study be more likely to demonstrate an effect of the drug if one exists, or be more informative (eg, by providing broader dose-response information). The regulator adds, "FDA shares the interest of drug developers in these advantages, but is also concerned with several aspects of such approaches, notably the possible introduction of bias and the increased possibility of an incorrect conclusion."
The guidance notes that such prospectively planned modifications can be submitted with the written study protocol, or in a statistical analytic plan, if used.
The FDA has invited comments on some recommended reporting requirements. It has stated that, in the drug development process, it is important to protect study blinding of an adaptive design study. To this end, it recommends that, where the design is modified after examination of unblinded interim data, and to avoid the introduction of bias (and to maintain confidence in the validity of the study's result), sponsors include in the adaptive design protocol written standard operating procedures (SOPs) that define who will implement the interim analyses and adaptation plan, and all monitoring and related procedures to accomplish the plan, providing for strict control of access to unblinded data. Other information to be included in the SOPs: who would perform the interim analyses and would have access to unblinded data; how compliance with SOPs would be documented; and what information, and under what circumstances, would be permitted to be passed from the Data Monitoring Committee to the sponsor or investigators.
In one part of the guidance document, it is stated: "Adaptive design studies may work best, and with least risk, when there truly are just a few issues (eg, dose, population subsets, endpoints) that need to be examined and are built into an adaptive design."
The document also states: "The greatest interest in adaptive design clinical trials has been in the adequate and well-controlled setting intended to support marketing a drug. Because these studies have the greatest regulatory impact, this guidance is generally oriented toward the use of adaptive design methods in adequate and well-controlled studies, where avoiding rates of false positive study results (increased Type 1 error rate) is critical, and introducing bias should be minimised. Many adaptive methods, however, are also applicable to exploratory studies. This guidance encourages sponsors to gain experience with the less well-understood methods in the exploratory study setting."
According to the guidance, the range of possible study design modifications is described as "broad". The guidance includes both familiar and less familiar approaches in the use of such adaptive designs – as the regulators state that "the less familiar design methods incorporate methodological features with which there is little experience in drug development at this time." Early interaction with the FDA is encouraged on any adaptive design.
Non-Inferiority Clinical Trials Guidance: This guidance provides the FDA's view of how a sponsor can use non-inferiority study design to provide evidence of a drug's effectiveness. This includes the agency's advice on how a sponsor can choose an appropriate non-inferiority margin and how to analyse the results. As stated by the agency in the guidance, a non-inferiority trial compares two treatments and seeks to demonstrate that "any difference [between the treatments] is small enough to allow a conclusion that the new drug has at least some effect or, in many cases, an effect that is not too much smaller than the active control." (These trials contrast with the more common superiority trials, specifically a placebo-controlled trial, where the intent is to show that the new drug is more effective than the control.)
The guidance states: "The usual reason for using a non-inferiority active control design instead of a study design having more readily interpretable results (ie, a superiority trial), is an ethical one. Specifically, this design is chosen when it would not be ethical to use a placebo, or a no-treatment control, or a very low dose of an active drug, because there is an effective treatment that provides an important benefit (eg, life-saving or preventing irreversible injury) available to patients for the condition to be studied in the trial."
Part of the guidance includes five examples of successful and unsuccessful efforts to define non-inferiority margins and conduct non-inferiority studies.
The Food and Drug Administration plans to increase prosecutions of pharmaceutical and food industry executives as part of an effort to refocus its criminal division, which has been under attack in Congress and is criticized in a new government report.
In a letter to Sen. Chuck Grassley (R., Iowa), the FDA says an internal committee has recommended that the FDA and its Office of Criminal Investigations "increase the appropriate use of misdemeanor prosecutions, which allows responsible corporate officials to be held accountable and is a valuable enforcement tool."
An FDA official said the agency has the authority to prosecute corporate executives for criminal actions within their companies under a provision called "strict liability." He said the government doesn't have to show intent to defraud in order to get a conviction. He added that the provision is an important tool that hasn't been used much in recent years.
A report set to be released Thursday by the Government Accountability Office, Congress's watchdog arm, says the Office of Criminal Investigations has operated autonomously for years with little or no accountability to top FDA officials. The criminal office doesn't have to explain what it is investigating or how it using funds, according to the report. It said the office's budget rose 73% between 1999 and 2008 to $41 million, and the number of employees increased by about 40%.
But nowhere in the article does it actually discuss what the OCI does. The reporter, Alicia Mundy, is at fault for only telling one side of the story. Let’s correct that bit of shoddy journalism.
OCI pursues cases that present a danger to the public health and have an FDA nexus. The diverse background of OCI agents gives the FDA the ability to aggressively address issues ranging from mail and financial fraud, to smuggling, forfeiture, and counterfeiting. OCI agents do this with talent, devotion, skill – and success.
OCI is a career destination of choice for the cream of the crop of Federal law enforcement agencies such as the FBI and the Secret Service – and they come to the FDA with an average of 12.5 years of Federal law enforcement investigatory experience. That’s why Terry Vermillion, the director of OCI and a former Secret Service agent himself, refers to his agents as “a taskforce of talent.” And they play a crucial role in protecting the safety of America’s prescription medicines and food supply.
In a typical year, FDA's Special Agents will investigate about 1,000 criminal cases resulting in the arrests of hundreds of suspected violators of public health laws.
On average, 200 criminal suspects are convicted each year as the result of OCI investigations. From 1993 to present, OCI has made 4,593 arrests that resulted in 3,546 convictions and more than $5.7 billion in fines and restitutions.
The article also takes some cheap shots at Vermillion. I worked with Terry – and no one at the FDA is more committed to protecting the public health.
Consider the words of Teddy Roosevelt:
“It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood, who strives valiantly; who errs and comes short again and again; because there is not effort without error and shortcomings; but who does actually strive to do the deed; who knows the great enthusiasm, the great devotion, who spends himself in a worthy cause, who at the best knows in the end the triumph of high achievement and who at the worst, if he fails, at least he fails while daring greatly. So that his place shall never be with those cold and timid souls who know neither victory nor defeat.”
Terry Vermillion and the agents of the FDA’s Office of Criminal Investigations are the Roughriders of 21st century drug safety.
And they deserve our respect.
That quote, from an Tom Bethell essay about the state of climate science, also applies to statements and studies used by the elite to push for health care reform... If a consensus for reform exists -- in the form that is currently approved by the NEJM, Health Affairs, the Kaiser Foundation, the Commonwealth Fund, Families USA, AARP, AMA, then the underlying statistics and studies must be right. RIght?
Lest one needs a refresher course in the demise of the UN clmate change report, let me point you to Andrew Neil's BBC blog.
The IPCC 2007 report claimed that global warming was leading to an increase in extreme weather, such as hurricanes and floods. Like its claims about the glaciers, this was also based on an unpublished report which had not been subject to scientific scrutiny -- indeed several experts warned the IPCC not to rely on it.
The author, who didn't actually finish his work until a year after the IPCC had used his research, has now repudiated what he sees has its misuse of his work.
His conclusion: "There is insufficient evidence to claim a statistical link between global warming and catastrophe loss."Yet it was because of this -- now unproved -- link that the British government signed up to a $100 billion transfer from rich to poor countries to help them cope with a supposed increase in floods and hurricanes.
It was also central to many of the calculations in Britain's Stern Report, which might now need to be substantially revised.
Now after Climate-gate, Glacier-gate and Hurricane-gate -- how many "gates" can one report contain? -- comes Amazon-gate. The IPCC claimed that up to 40% of the Amazonian forests were risk from global warming and would likely be replaced by "tropical savannas" if temperatures continued to rise.
This claim is backed up by a scientific-looking reference but on closer investigation turns out to be yet another non-peer reviewed piece of work from the WWF. Indeed the two authors are not even scientists or specialists on the Amazon: one is an Australian policy analyst, the other a freelance journalist for the Guardian and a green activist.
The WWF has yet to provide any scientific evidence that 40% of the Amazon is threatened by climate change -- as opposed to the relentless work of loggers and expansion of farms.
Every time I have questioned our politicians about global warming they have fallen back on the mantra that "2,500 scientists can't be wrong", referring to the vast numbers supposedly behind the IPCC consensus. http://www.bbc.co.uk/blogs/dailypolitics/andrewneil/2010/01/the_dam_is_cracking.html
That should sound familar (and you know who you are) to the self proclaimed healthcare experts who have shaped the consensus with factoids, overstatements and formulas for "bending the health cost curve" by simply eliminating care that actually makes patients sicker....
Most recent case in point. The resurrection of Obama's big lie, repeated by Senator Dodd and Cong. Debbie Wasserman-Schultz that uncompensated care is a $1000 tax on every American family...
First question: Will our taxes go down by $1000 under Obamacare? Will we have $1000 more to spend by 2016. Did CBO score that. I don't think so.
Second, here is the reality behind that mythical number, courtesy of AEI's Tom Miller:
[ An Urban Institute] study concluded that attributing increased private health insurance premiums to any expanded costs of treating the uninsured is a misperception; particularly when a net balance of only about $14.5 billion was arguably financed by the privately insured in the form of higher (cost-shifted) private payments for care and, ultimately, higher insurance premiums. Indeed, they estimated that the amount of uncompensated care potentially available for private cost-shifting is most likely even lower, at about $8 billion in 2008, which was less than 1 percent of private health insurance costs ($829.9 billion).
http://www.american.com/archive/2009/july/healthcare-dreams-healthcare-realities
The $1000 lie is just part of the patchwork of falsehoods stitched together to push through a government takeover of healthcare. It is hard to follow them all. But we will try.
Counterfeit versions of Pfizer Inc.’s Viagra for erectile dysfunction, Bristol-Myers Squibb Co.’s blood thinner Plavix and Teva Pharmaceutical Industries Ltd.’s morning-after pill Plan B were among the products seized, an Interpol officer who coordinated the raids, said Jan. 26 in an e-mail from Jakarta. The haul also included fake aspirin, antibiotics, malaria treatments and hair-loss medicines, she said.
The seizures and arrests, part of an investigation called Operation Storm II, are the second round of raids in two years in Asia as international and local police crack down on widening sales of fake medicines. Sales in the counterfeit-drug industry will jump more than 90 percent to $75 billion this year from 2005 levels, according to the New York-based Center for Medicine in the Public Interest.
Asia is the world’s biggest producer of all counterfeit products, the Organization for Economic Cooperation and Development said in 2007 report. About 40 percent of 1,047 arrests related to fake drugs worldwide in 2008 were made in Asia, according to the Washington-based Pharmaceutical Security Institute.
Counterfeits can account for more than 30% of all drugs sold in developing nations and less than 1 percent of all medicines in developed nations such as the U.S., the International Medical Products Anti-Counterfeiting Taskforce, or IMPACT, said in 2006.
The complete story can be found here:
http://www.latinamericanpost.com/index.php?mod=seccion&secc=5&conn=5950
But his recent "research" report -- "New Jobs Through Better Health Care" explaining how health care reforms pushed by the Obama administration will save billions and create nearly 3 million jobs (as a result) is nothing short of hack work. I am waiting for his next study: "How Obamacare Will Turn The NJ Nets Into A Playoff Contender"
http://www.americanprogress.org/issues/2010/01/new_jobs_health.html
I won't go through chapter and verse -- yet -- on what a shoddy cut and paste piece of propaganda Cutler lent his name to. And I will ignore the fact that there is no methodology section that allows someone to look at how Cutler arrived at his conclusion or explains how 1) premiums will actually decline by 12 percent by 2019 (without subsidies) and how, assuming that is the case, even with higher taxes on business, earnings and income, that decline alone will bring back the 26 percent of American workers who just leave the work force altogether. Let me just focus on one amazing statement and deconstruct:
"we demonstrate a less emphasized point about the health care reform legislation currently before Congress—if successful, its provisions can lower the costs of business and increase both the number of jobs by 250,000 to 400,000 annually over the next decade and increase wage growth. "
Really? An analysis of the premium and tax burden imposed by the provisions David says will save money reveals:
- An average family who receives health insurance through a small employer and earning between $20,000 and $200,000 would be paying, on average, a range of $82 to $892 more. In the large group market, an average family making between $30,000 and $200,000 would be paying, on average, a range of $116 to $724 more.
- An average head of household who receives health insurance through a small employer and earning between $20,000 and $200,000 would be paying, on average, a range of $383 to $1,587 more. In the large group market, an average head of household also making between $20,000 and $200,000 would be paying, on average, a range of $185 to $1,419 more.
There is also "a payroll tax increase that will permanently sever the link between the Medicare Payroll tax and its contributions to Medicare. This payroll tax increase of .5% on earnings above $200,000 for singles and $250,000 for joint couples will contribute money to the general fund for health care instead of directly for Medicare payments."
That would affect nearly 80 percent of all small businesses and somehow that provision lowers business costs....
http://www.heritage.org/research/taxes/bg2203.cfm
What is David Cutler thinking? More to the point, was he thinking? Certainly there are many factors that influence job creation apart from health care costs, especially if someone is claiming the jobs created are replacing those eliminated for reasons having nothing to do with health care costs!! Cutler knows that from his own research and from a quick scan of the research on labor economics. One thing is certain, adding mandated coverage to the cost of being an American or running a business is a tax just as providing a subsidy or third party payment of health care services is a non-cash form of income (tax free) that substitutes for income or lower taxes. However the effect of each will differ. A one size fits all approach to providing health care does not work. And trying to prove that the one size fits all approachh solves every problem is intellectually dishonest. Americans know a con job when they see it. And the Center for American Progress study on how better healthcare will create jobs that were destroyed during the recession is exactly that.
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.
