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FDA has issued two new draft guidance documents regarding clinical trial designs: Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, and Guidance for Industry: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Adaptive Design Guidance: This draft guidance is designed to provide sponsors and the review staff in both the drugs and biologics divisions with information regarding adaptive design clinical trials when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.
You probably wouldn’t put Microsoft on the list of companies in the market to hire former FDA officials, but the software giant snagged a top medical-device regulator today.
Donna-Bea Tillman, head of the office of device approvals, says her jump to Microsoft isn’t as unusual as it may seem. She told colleagues in a memo she has long had “a love for all things computer.”
Tillman elaborated in an interview with the Health Blog, saying she moonlighted writing software programs for engineering and biomedical experiments when she was in graduate school at Johns Hopkins doing biomedical engineering. “This is a match made in heaven,” she said of her new job.
Microsoft, Google and other technology companies are trying to get in on the medical information-technology bonanza, which was given a boost with $20 billion in last year’s economic stimulus package. Microsoft is also trying to get its Washington health group a higher profile.
IT can play a big part in comparative effectiveness research for medical treatments, Tillman said, adding, “If you want to buy a car, you can get information comparing everything in Consumer Reports, but I can’t get that if I get a disease.”
Jim Pinkerton (one of the smartest --- and tallest – players in the healthcare policy arena) has penned some very nice words about CMPI’s second annual Odyssey Awards dinner on his blog Serious Medicine Strategy.
And his focus is on one of our favorite four-letter words: Hope.
Hope in New Jersey
The Center for Medicine in the Public Interest (CMPI) held its second annual Odyssey Award Gala Thursday night, and amidst all the discussion of health policy and medicine, here was one mega-topic on the program: Hope.
Sadly, hope is in short supply in Washington these days. On healthcare, which was supposed to be the signature agenda item of the Obama administration, as well as the Democratic majority in Congress, we now see that both the executive and legislative branches are thoroughly bogged down in unpopular bureaucratese. Leaders on both ends of Pennsylvania Avenue are still trying to pass healthcare "reform" that the American people manifestly do not want. What the American people do want health, but health is not what Washington is interested in advancing. Yes, that seems strange, but Washington is a strange town.
Jim’s complete post can be found here:
http://seriousmedicinestrategy.blogspot.com/2010/02/httpwww.html
In the continuing saga of social media guidance ...
AstraZeneca (NYSE: AZN) today asked the U.S. Food and Drug Administration (FDA) to adopt guidance that will enable AstraZeneca and others to fully engage in real-time, social media conversations that responsibly provide accurate, balanced information on medicines from a known, identifiable and reliable source.
AstraZeneca’s proposal was in response to the FDA's September 2009 Call for Comments on their public notice: Promotion of Food and Drug Administration-Regulated Medical Products Using the Internet and Social Media Tools.
“AstraZeneca understands the value of social media to engage key stakeholders in today’s technology-driven world,” said Bob Perkins, Vice President, Public Policy and Promotional Affairs. “While we have developed a corporate presence in the digital space, we believe it is increasingly important to participate in online channels to provide accurate and regulated information about our branded products in conversations with patients, caregivers, and health care providers.”
AstraZeneca believes that five principles should be at the core of any company engagement in social media:
- Truth and Accuracy: Content must be created, developed, or made available that is truthful, balanced, accurate, and not misleading.
- To Be Respectful: Encourage product sponsor participation that respects the interests of patients, caregivers, and health care providers, particularly related to matters of privacy and the primacy of the patient/physician relationship.
- Protect and Advance Patient Health: Facilitate patient access to quality information for use with their physician to improve their health and protect patients through encouraging accurate and timely reporting on medicine safety.
- Transparency: Any product sponsor participation should be accomplished in a manner that, at all times, is entirely transparent to other participants as to the role of product sponsors as participants in online discussion.
- Respect the Views of Others: Acknowledge that patients, caregivers, clinicians and others who participate in social media have their own opinions and that, when they differ from those of the product sponsor, it is not the role of a product sponsor to censor or limit these views but to add the product sponsor’s own views to the discussion.
In its comments to the FDA, AstraZeneca proposed a regulatory framework that is consistent with these principles and defines, distinguishes, and distinctly regulates three types of communications on the Internet and in social media:
- Company-controlled, hosted online communications
- Company-controlled communications
- Real-time, social media participation communications
The company also noted that, “Without guidance, our activities are limited in a manner that we believe is not in the best interests of informed health care decision making. In our absence, consumers will turn to information sources that are not regulated and not always well informed.”
AstraZeneca believes the company has an obligation to participate in social media in a responsible way to help educate and empower patients, caregivers and prescribers to make informed decisions about its products.
Click here to view AstraZeneca’s full submission: http://www.astrazeneca-us.com/_mshost795281/content/media/FDA-2009-N-0441.pdf
On 2/25, AARP announced that it would refrain from further public advocacy of healthcare reform to help, "lower the external political pressure."
Hm.
Please sir, may I have (Sir Thomas) more.
Whatever happened to “there’s no place for politics at the FDA?” Steve Nissan’s shades-of-Watergate “secret tapes” notwithstanding, the debate over Avandia must be decided based on science and the best judgment of FDA career professionals.
Secret tapes? David Graham? We’ve been down this road before. Let’s get real here folks and let the FDA do its job without political interference.
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.
