PDUFA Follies

04/19/2010 09:12 AM |

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 "Eureka!" moments in health research. Progress comes step-by-step, one incremental innovation at a time. Companies more often profit by improving existing chemicals and making processes more efficient than by revolutionizing the whole field with new products.

Innovation is hard.  Today it takes about 10,000 new molecules to produce 1 FDA-approved medicine. And if that's not frightening enough, only 3 out of 10 new medicines earn back their research and development costs. And here's the kicker -- unlike other R&D-intensive industries, pharmaceutical investments generally must be sustained for over two decades before the few that make it can generate any profit.

Innovation is expensive.  In 2003, researchers at TuftsCenter for the Study of Drug Development estimated the costs to bring a new medicine to market to be $802 million, and others suggest that the total cost is closer to $1.7 billion

Innovation is under attack.  From accusations of the “me-too” variety, to crackpot schemes to replace pharmaceutical patents with a “prize” system, life for innovator pharmaceutical companies is rough and tough.  Israel Makov (formerly the Big Abba of generics giant Teva) once told me that he wasn’t really in the pharmaceutical business, but rather “in the litigation business.”

But innovation is important – and not just for pharmaceutical industry profits. Increases in life expectancy resulting from better treatment of cardiovascular disease from 1970 to 1990 have been conservatively estimated as bringing benefits worth more than $500 billion a year. In 1974, cardiovascular disease was the cause of 39 percent of all deaths. Today it is about 25 percent. Cerebrovascular diseases were responsible for 11 percent of deaths back then. In 2004 they caused 6.3 percent of deaths. Kidney diseases were linked to 10.4 percent of deaths and now they are associated with 1.8 percent. And that’s just for the United States.

As Harvard University health economist (and Obama healthcare advisor) David Cutler has noted: "The average person aged 45 will live three years longer than he used to solely because medical care for cardiovascular disease has improved. Virtually every study of medical innovation suggests that changes in the nature of medical care over time are clearly worth the cost."

Comparative effectiveness is an interesting health policy issue -- but the PDUFA reauthorization process is the wrong place for the conversation.

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Congressman Bob Franks

04/16/2010 10:29 AM |

Bob Franks was my congressman and my friend.  As a public servant, candidate and leader of the Healthcare Institute of New Jersey he brought enthusiasm, humor and decency to his every endeavor.  His untimely death from an aggressive form of cancer this past week reminds us not only how too short life is but how we should never take for granted indiviudals of Bob's caliber.  

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:

Rep. Bob Franks Memorial 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/.

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Not so APpy together

04/16/2010 08:07 AM |

Oddly -- not covered widely (at all?) by the MSM:

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.

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But not too narrow

04/15/2010 10:35 AM |

From the Pink Sheet:

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.

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What's Old is Neu(tral)

04/15/2010 09:47 AM |

"Net Neutrality?" Really?

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.)


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The 100-Yard Daschle

04/15/2010 09:28 AM |

Former Senator (and almost HHS Secretary) Tom Daschle keynoted the opening of the 19th Annual Partnerships in Clinical Trials conference.

He spoke at length (and in very laudatory terms) about the recent healthcare reform legislation.  Pretty much party-line material, but three things to share:

(1) Senator Daschle made the point that the US has a “healthcare market” while the rest of the developed world has a “healthcare system.” He prefers the latter. No surprise there.  But …

(2) “This reform legislation only puts us “on the 30-yard line.” I found this peculiar since he had initially referred to the new law as “comprehensive.” But then I realized that he was being honest. Draw your own conclusions, but remember -- the healthcare debate isn’t over. It’s only the beginning. And the scary thing is that the component that’s over is the transparent part.

(3) Daschle suggested, as one of the things that need to happen to advance America’s health, “a less risk-averse FDA.”  Hm.

Smart guy.  Savvy remarks.  Attention must be paid.

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Navigating the therapeutic narrows

04/14/2010 09:12 AM |

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.

Critical dose drugs have a narrow therapeutic index, meaning that "small changes in blood concentration have the potential to result in serious therapeutic failures and/or serious adverse drug reactions." FDA is consulting the committee on the need to establish separate bioequivalence criteria for these drugs given continuing debate about whether critical-dose drugs require special consideration, the agency explained.

Currently, the "sameness" of a brand product and a generic version is evaluated based on two-treatment crossover study to prove bioequivalence, the aim being to show that the 90 percent confidence intervals of the geometric mean test/reference ratios for both maximum plasma concentration and the area under the plasma concentration-time curve fall within a range of 80 percent to 125 percent.

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.”

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New CMS Director Loves NHS

04/13/2010 05:40 PM |

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CRO Choice

04/13/2010 06:53 AM |

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. That’s 21^st century risk management.

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 21^st 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.

Another area that needs to be addressed, Sharfstein suggested, is the different treatment of brand and generic drugs when it comes to imposing a REMS with a communication plan for alerting health care professionals and patients about a drug's risk.

 
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.

While some see REMS as mission creep, others see it as the natural and logical extension of FDA responsibility in our new age of more precise diagnostics and personalized medicine.

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In Vivo In LapDog Wonderland

04/12/2010 04:33 PM |

The IN VIVO blog folks, who seem to find nothing bad about comparative effectiveness research -- without pointing to any clinical or scientific evidence that it improves health outcomes or economic studies that show it does not reduce investment in innovation -- have found yet another great thing about CER:  It can be used to diss alternative medicine.  

Comparative Effectiveness Research and Alternative Medicine: Bring it On

"..Isn’t it at least possible that CER will focus on determining whether other commonly used therapies meet even that baseline standard?

So rather than thinking of CER as a threat to big pharmaceutical brands, maybe there is an alternative vision for how it might work. Literally: as a tool to test the value of so-called “alternative” medicine."


Wow.   As if that is the primary purpose of the $600 million a year the Agency for Healthcare Research and Quality will be receiving.   

The In Vivo folks note:  "Sebelius diplomatically avoided taking a stand on the value of alternative medicine, and stressed that private plans—not the feds—will decide what to cover."

I have a suggestion for In Vivo:  Less sucking up to Sebelius and more reporting.   Here is what the legislation actually has the feds deciding and using CER in making these decisions on behalf of consumers, doctors and private plans:

1. Development of a national health quality strategic plan that will be used for improving Federal payment policy with an emphasis on " quality and efficiency" (as in payments to health exchanges)
2.  Establishment of annual benchmarks for each relevant agency to achieve national priorities.  (see number 1)
3.   Establishment of a " process for regular reporting by the agencies to the Secretary on the implementation of the strategic plan.
4.  Strategies to align public and private payers with regard to quality and patient safety efforts.
5.  Incorporating quality improvement and measurement (using CER)  in the strategic plan for health information technology required by the American Recovery and Reinvestment Act

Just to make it clear (and maybe the In Vivo folks might want to break away from their fawning to check this out), the legislation requires: ‘quality
measure’ means a standard for measuring the performance and  improvement of population health or of health plans, providers of services, and other clinicians in the delivery of health care services.

Then too,  the legislation requires" A group health plan and a health insurance issuer offering group or individual health insurance coverage shall, at a minimum provide coverage for and shall not impose any cost sharing requirements for— ‘‘(1) evidence-based items or services that have in effect a rating of ‘A’ or ‘B’ in the current recommendations of the  United States Preventive Services Task Force; ‘‘(2) immunizations that have in effect a recommendation from the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention with respect to the individual involved; and ‘‘(3) with respect to infants, children, and adolescents, evidence-informed preventive care and screenings provided for in the comprehensive guidelines supported by the Health Resources and Services Administration. "

How is this evidence developed?  Through the application of comparative effectiveness research within the context of development of the quality strategic plan.

But of course " private plans—not the feds—will decide what to cover."

Which is why CER is required to be used to determine the the effect of new technologies on " national expenditures associated with a health care treatment, strategy, or health conditions....priorities in the National Strategy for quality care established under section 399H of the Public Health Service Act that are consistent with this section. "

But of course " private plans—not the feds—will decide what to cover."

In Vivo makes fun of those who worry about CER being used for rationing when it is obvious to them that all the CER dough will be allocated comparing flu shots to massages from chiropractors or aromatherapy.   Of course it will.  So we should ignore the fact that the legislation gives AHRQ significant authority in setting CER and quality agenda, control over dissemination of CER findings and preference in conducting and controlling CER research, especially as it pertains to coverage decisions for health plans, Medicaid and the Independent Medicare Advisory Board.  And we should ignorestatutory language stating:

The Secretary may only use evidence and findings from research conducted under section 1181 to make a determination regarding coverage under title XVIII if such use is through an iterative and transparent process which includes public comment and considers the effect on subpopulations.

Paragraph (1) shall not be construed as preventing the Secretary from using evidence or findings from such comparative clinical effectiveness research in determining coverage, reimbursement, or incentive programs under title XVIII based upon a comparison of the difference in the effectiveness of alternative treatments in extending an individual’s life due to the individual’s age, disability, or terminal illness.

‘‘(d)(1) The Secretary shall not use evidence or findings from comparative clinical effectiveness research conducted under section 1181 in determining coverage, reimbursement, or incentive programs under title XVIII in a manner that precludes, or with the intent to discourage, an individual from choosing a health care treatment based on how the individual values the tradeoff between extending the length of their life and the risk of disability.

‘‘(2)(A) Paragraph (1) shall not be construed to— ‘‘(i) limit the application of differential copayments under title XVIII based on factors such as cost or type of service; or ‘‘(ii) prevent the Secretary from using evidence or findings from such comparative clinical effectiveness research in determining coverage, reimbursement, or incentive programs under such title based upon a comparison of the difference in the effectiveness of alternative health care treatments in extending an individual’s life due to that individual’s age, disability, or terminal illness.

Which if you flip it around means you can use CER to steer people to what you think is best using copays and limit coverage of new technologies if you think treatment A raises fewer questions about "safety" (and risk of death) than treatment B which is newer.  

And in the final analysis, has anyone asked what the additional cost and time will mean to patients in terms of life expectancy, morbidity, cost of care?
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The UnCERtainty Principle

04/12/2010 08:11 AM |

The soundbite about AHRQ and CER is that it’s “non-political.” That remains to be seen. Previous examples of Uncle Sam as CRO (CATIE, ALLHAT) speak otherwise.

Consider this – NICE (the National Institute for Health and Clinical Excellence) is suspending publication of all decisions until after the U.K. general elections on May 6th.  According to the Pink Sheet, “The decision reflects just how controversial the organization is in the U.K., where it has become a lightening rod for political debate.”

Something to think about.

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No Mas

04/09/2010 11:35 AM |

According to a study in the May issue of Pediatrics, many Spanish-speaking people in the United States receive prescription instructions from the pharmacy so poorly translated that the medications are potentially hazardous to their health. (The errors occur largely because of deficiencies in computer programs that most pharmacies rely on to translate medication information from English to Spanish.)

This is an important issue that should be immediately addressed by the FDA as part of the agency’s Safe Use initiative.

This is a real health disparity that can and must be fixed inmediatamente.

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Creating Social Networks To Discuss Healthcare Reform

04/08/2010 05:01 PM |

I spent about 40 minutes on the Handsoffmyhealth.org  Facebook page answering questions about the impact of health care reform from about 500 people who signed in.   

People wanted to know how much control the government will or would have over medical decisions.  And many people with cancer wrote in, wanting to know how the health plan might affect them and their ability to get insurance. 

I said that the key issue going forward is to preserve individual choice and the ability to get medical treatment based on need, not cost.

That said, the first steps being taken to implement health care legislation are as follows:

1.   Allocate $10 billion to the IRS and 17000 more IRS agents to review value of health care, whether you have it and to determine if your source of healthcare exempts you from paying a fine. 

2.   Allocate $250 million and add FBI agents to increase the number of Strike Teams swooping into the offices of physicians who seem to be overbilling based on an audit of claims data and not based on material evidence.

3.   Give the Agency for Healthcare Research and Quality an additional $600 million a year to develop guidelines for determining what technologies, services and treatments should be covered in a "quality" health plan and for how doctors should practice medicine based on comparative effectiveness benchmarks that ignore individual differences.

4.   Medicare cuts to hospice and home health care services. 

People at the lower end of the income scale with cancer and serious disabilities will be forced in Medicaid.  By 2014 the current rush of primary care doctors retiring and opting out of Medicaid will create "hollow health care" access.  For speciality care and cancer treatment, Medicaid will have the right to restrict access to care and drugs based on comparative effectiveness.   If a medicine is not on the Medicaid formulary you are out of luck. 

I also predicted that at some point in time a health plan will go under, prompting the administration to take it over like it did GM and the banks.  A very cheap way of creating a public option.   Expect a lot of bailing out of the "too big to fail" health plan.  ERs will be the place of last resort for millions and millions of other people will pay the fine, get coverage when they are sick, drop it when they are well again.   This churning takes places in Medicaid all the time and it will spread to health care insurance in general because the incentive to game the system is built into the bill.

Finally,  I suggested that just as people pay taxes and send their kids to public schools, people who want decent health care will pay up and buy into private health associations or go off-shore, paying out of pocket when they need or with the help of new gap insurance products. 

It may all that we can do is create escape routes and underground railroads to let people secure the care they want and when they need it. 

In America that is called market opportunity. 



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Dosing Dilemma

04/07/2010 01:47 PM |

We often talk about the four rights – the right medicine for the right patient at the right time in the right dose.  But that fourth “right” – dosing – often gets forgotten.

Today’s news, from the May edition of the American Journal of Preventive Medicine, finds that U.S. hospitalizations for poisoning by prescription opioids, sedatives and tranquilizers have jumped 65 percent from 1999 to 2006. That number is almost twice the increase in hospitalizations for poisonings by all other drugs and medicinal substances. “People are seeing headlines...and thinking 'it's sad and tragic but maybe it's just Hollywood,’ said lead author Jeffrey H. Coben, M.D., a professor and director of the Injury Control Research Center at the West Virginia University School of Medicine. “It's widespread throughout the U.S. and involves serious hospitalizations and is escalating at a rapid pace."

For those who don’t think that proper dosing isn’t an issue – think again.

It’s a killer.

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Rounding Third

04/06/2010 09:01 AM |

Lilly CEO John Lechleiter: "I believe China will make a significant contribution to medical innovation in this century.”

Sales too (the Chinese market for pharmaceuticals is currently ranked the 7th largest in the world - and could jump to number three as soon as next year) – but that’s not the point.  Lechleiter is thinking outside the box and it’s not the marketing and sales box.

According to the Pink Sheet, “Lilly has also begun linking an expanding array of Chinese scientists into its globe-spanning virtual research network. Eli Lilly's Robert Armstrong, one of the earliest advocates of replacing the R&D silos of traditional pharmaceutical companies with research networks that stretch from West to East, said in an earlier interview that Lilly is racing to construct a "dynamic matrix of partnerships across the globe aimed at R&D."

Lechleiter: "China is uniquely situated to play a key role in global pharmaceutical research and development … A growing number of Chinese scientists educated in other countries are returning home, adding to the tremendous human capital of this country and setting the stage for further innovation-driven growth. The 'brain drain' has become the 'brain gain' here in China.”

And, “As China seeks to expand its R&D base, what can this nation do to build its great potential to participate in the global innovation economy of the future?"

His primary suggestion involves IP rights – and rightfully so.

Leichleiter: "Above all there must be strong protection of intellectual property. China has made significant progress in intellectual property protection, developing a patent regime aligned with international systems. This is an essential first step to help foster innovation, but it is indeed just the first step.”

And without question there’s work to be done.  In December 2009 China passed a new patent law that will allow domestic Chinese pharmaceutical manufacturers to manufacture knock-offs of on-patent medicines – and export them to third countries.  According to Yin Xintian, director the regulations department of China’s State Intellectual Property Office, the new law will “ensure patients can get the drugs they need when they need them.”

Intellectual property rights are the fertile soil that facilitates the tree of pharmaceutical innovation to grow in the first place. To borrow an over-used adjective from the world of global climate change -- we must protect "sustainable" innovation. Jamie Love and Company may very well say, "A world without patents, amen." And they're right, because minus pharmaceutical IPR we'd all better start saying our prayers -- because that's the only way we're going to battle disease and improve the health of our global fraternity. That's a Silent Spring we cannot afford.

Leichleiter then issued a more general call for “conditions.”

"Creating and maintaining the conditions for innovation to flourish is challenging and complicated work - work that is never finished.”

Indeed.

Might this call for more “flourishing” conditions also include a regulatory “third way” to counterbalance both the FDA and EMEA? (Oops, I meant EMA).

Stay tuned.

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NHS' Wilde Card

04/05/2010 08:12 AM |

According to a report in the Sunday Telegraph, David Cameron, the leader of the British Conservative Party, wants all patients with cancer to have broader access to all approved medicines – whether or not their use is backed by the National Institute for Health and Clinical Excellence (NICE), the NHS' rationing body.

Last month, research found that up to 20,000 lives may have been shortened by decisions taken by the NICE in the past year.

The Telegraph writes that, “Handing decisions back to patients and their doctors is a significant dismantling of the current system … In making yesterday's pledge Cameron chose local decision-making – and its inherent risks – over state control.”

Oscar Wilde quipped, “Experience is the name everyone gives to their mistakes.”

If that’s the case, then we should learn from the experience of our trans-Atlantic cousins.

The complete Telegraph article can be found here.

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Big Sky. Bad Idea.

04/02/2010 09:54 AM |

According to a report in the Helena Independent Record:

Gov. Brian Schweitzer, who last month asked the federal government to approve a “waiver” so Montana could import prescription drugs at lower cost for state-funded health plans, has not submitted any of the usual documentation that accompanies a waiver request, his administration acknowledges. Instead, the governor wrote only a letter to U.S. Health and Human Services Secretary Kathleen Sebelius, asking that her agency grant Montana a “Medicaid waiver” allowing importation of lower-cost drugs from Canada.

“We have to work through the secretary’s office,” says Anna Whiting Sorrell, director of the state Department of Public Health and Human Services. “There is not another state that has requested this. We think the governor is forging a new path.”

News must travel slowly in Montana.

There have been numerous requests for such waivers.  And they’ve all been denied – for good reason.

Let’s look at the record.

Minnesota

During pre-announced visits by Minnesota State officials, Canadian Internet pharmacies were observed engaging in dangerous practices. For example:

• One pharmacy had its pharmacists check 100 new prescriptions or 300 refill prescriptions per hour, a volume so high that here is no way to assure safety.
  
  

• One pharmacy failed to label its products and several others failed to send any patient drug information to patients receiving prescription drugs.
  
  

• Drugs requiring refrigeration were being shipped un-refrigerated with no evidence that the products would remain stable.
  
  

• One pharmacy had no policy in place for drug recalls.  Representatives of the pharmacy allegedly said that the patient could contact the pharmacy about a recall “if they wished."
  
  

• One of the Canadian internet pharmacy presidents said, “We won’t have any problems getting drugs.  We have creative ways to get them.” 
  

• The FDA launched an investigation confiscating thousands of drug shipments headed for the U.S. Some of them were headed for Minnesotans who ordered them over the state’s Web site. When opened, nearly half claimed to be of Canadian origin, but “85 percent of them were from 27 other countries including Iran, Ecuador and China. And 30 of them were counterfeit. One Minnesota resident discovered that one of his “Canadian” drugs came from Greece, and another came from Vanuatu, a small island in the South Pacific. "I never heard of the place,” he said.

According to its latest statistics, Minnesota RxConnect fills about 138 prescriptions a month. That's for the whole state -- population: 5,167,101.

Wisconsin

Modeled on the Minnesota program, the Wisconsin site hawks its promise and hides its dangers. All of the legalese buries the fact that the state doesn’t except any responsibility for the safety or effectiveness of any medicines bought on the State’s website.  For example, the State won’t even guarantee that the drugs ordered are what the customer will receive. Not only that, but the State also says that they will not accept any legal responsibility or liability should any of the drugs cause a problem.  The Governor is hiding the fact that his website puts any user into a dangerous buyer beware situation.  Here’s the exact verbiage from the Wisconsin site:

“In no event shall the State Portal or its employees be liable for any direct, indirect, incidental, special, exemplary, or consequential damages (including, but not limited to, procurement of substitute goods or services; loss of use, data, or profits; or business interruption) however caused and on any theory of liability, whether in contract, strict liability, or tort (including negligence or otherwise) arising in any way out of the use of this system, even if advised of the possibility of such damage. This disclaimer of liability applies to any damages or injury, including but not limited to those caused by any failure of performance, error, omission, interruption, deletion, defect, delay in operation or transmission, computer virus, communication line failure, theft or destruction or unauthorized access to, alteration of, or use of record, whether for breach of contract, tortious behavior, negligence or under any other cause of action.”

Illinois

Remember Wrong-Way Rod Blagojevich’s swagger over his “I-Save-RX”program? Over 19 months of operation, a grand total of 3,689 Illinois residents used the program -- which equals approximately .02% of the population.

The City Experience

Remember Springfield, MA and “the New Boston Tea Party?” Well the city of Springfield has been out of “drugs from Canada business” since August 2006.

And speaking of Boston tea parties, according to a story in the Boston Globe, “Four years after Mayor Thomas M. Menino bucked federal regulators and made Boston the biggest city nationally to offer low-cost Canadian prescription drugs to employees and retirees, the program has fizzled, never having attracted more than a few dozen participants.”

And then, of course, there are those pesky safety issues.

Attention Governor Schweitzer -- The drugs being sent to U.S. customers from Canadian internet pharmacies are not “the same drugs Canadians get.” That bit of rhetoric is just plain wrong. Canadian internet pharmacies – by their own admission – are sourcing their drugs from the European Union. And while they may say their drugs come from the United Kingdom, let’s not conveniently forget that 20% of all the medicines sold in the UK are parallel imported from other nations in the EU – like Spain, Greece, Portugal, and Lithuania.

Last month Governor Schweitzer said that Montana could buy some of the drugs directly from wholesalers in Canada or place the orders and have them delivered to pharmacies around the state, for purchase by people covered by publicly funded health plans.

Someone should refer the Governor to Bartlett's Familiar Quotations:

“Those who cannot learn from history are doomed to repeat it”

And if that familiar quote from Santayana doesn’t get the point across, here’s a related one – “Remember the Alamo.”

The Montana state slogan is “the last best place.”  Maybe so.

But not for drug importation.

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Unleavened Thoughts About the Healthcare Regime

04/02/2010 07:28 AM |

I don't want to think in terms of repeal. Rather, I would prefer to use a medical or scientific analogy in describing how to respond to the effects of the legislation.The bill itself is a virus and we the people are the host if you will. Or consider it an experiment with every American forced into participation. Either way, we will be subject to new "solutions" that will have unknown consequences and side effects.  As with any social experiment or massive program of social engineering, we will experience the end product in ways much different than promised.  (If anyone has used on-line dating services, you know what I am talking about.) 

Strategically, demanding outright repeal or defunding of health care reform sounds great to a small group. To build support for fundamental changes in what is now law will require exactly what the supporters of the current bill engaged in, nothing less and probably more:

1.    Consistent and persistent evaluation of the performance of health care delivery systems. These standards should be easily grasped by most people and communicated easliy in visual form too.   Are doctors leaving the system? Are people paying more or less for insurance? Are people any healthier?  

2.    Warning signs. The other side is hell bent on using health care reform to reduce our long term debt. Debt will rise because of spending unrelated to health care reform.To turn health care reform and by extension, every doctor and hospital, into any agent of deficit reduction first and foremost is a rationale for rationing care. And it is an immoral one at that. 

3.    An increasing reliance on the use of comparative effectiveness research to shape policy and health care coverage decisions. Increasiningly, to justify the need to avoid financial Armageddon,  policymakers will rely upon CER to help make hard choices to slow health care spending in order to avoid “financial catastrophe.” If that sounds a lot like the narrative of the climate change crowd who used self-serving and secretive studies to support policies that also would lead to a decline in economic growth in order to save the planet, you are right. The “science” of CER demonstrating that a half to a third of health care spending is wasteful  has much in common with the that of the hockey stick project about the atmosphere evaporating. It is not empirical or biological, it is speculative and has never been evaluated for it’s real impact on public health or human well-being. Should we take prescriptions that are not tested or are not based on an accurate representation of human or biological mechanisms? Yet CER is precisely that and it may be used to determine what preventive services are covered and what new benefits will qualify for reimbursement.  It is possible to opt out of government run care because of conscientious objection to CER? I hope so..

4.    Impact on innovation. Largely unnoticed, drug companies are filling up pipelines with new products.More and more of them are based on  novel targets and rely on biomarkers linked to specific pathways and small populations. The number of molecular diagnostics to help predict,  diagnose and monitor the progression of diseases or response to medicines are growing as is the business capacity to provide doctors and hospitals the ability to use this information. The progress will be incremental but it will come. The question is will future policies add to the cost and pace of progress or not?  CER is only one such challenge.  And alone it’s proponents will be left looking foolish and backwards. However changes to the FDA regulatory process can easily increase the time and cost of bringing new products to market and reduce the effective patent life of niche medicines.  Demands to have a new center for drug safety review all NDAs before they go to market and for CER studies as a condition for approval would impose huge costs on innovation and the pubic health.   Similarly, CER requirements can add more delay and uncertainty to the R&D process.    

These are substantive concerns about the new health care bill that can be  addressed through the writing of regulation and new legislation.  We intend to track these issues as we have in the past.   I don’t care if someone wants to call this approach repeal or reform or a do-over.  I would like to think of restoring and improving the health of the system and all Americans.

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Sunshine Supermen (and women)

04/01/2010 02:13 PM |

From the Pink Sheet:

Pfizer is the fifth pharma company to post its payments to healthcare professionals but the first to include payments to principal investigators and institutions for conducting clinical trials.

The company posted the information on March 31, announcing that it paid a total of $35 million to 4,500 health care professionals for speaking, consulting and research services. The figure also includes meals and travel reimbursement. Of this sum, approximately $15.3 million went to research organizations for new clinical trials initiated after July 1, 2009, and for ongoing or new research between July 1 and December 31, 2009.

Pfizer said the clinical trial payments cover participant recruitment, coordinating and conducting the clinical trails and completing compliance activities to ensure regulatory requirements are met.

Pfizer was required to post all payments or transfers of value to physicians, including those relating to research, under a corporate integrity agreement with HHS' Office of Inspector General. The CIA accompanied Pfizer's $2.3 billion settlement with the Department of Justice to resolve allegations of off-label marketing of four drugs and kickbacks to healthcare providers involving nine other drugs.

The company's payment report also specifies non-cash payments, such as for meals or educations items worth $25 or more and totaling $500 or more during the six-month period. Pfizer is the first company to report these non-cash expenditures.

Lilly was the first to post payments to healthcare providers for consulting and speaking engagements, followed by Merck, GlaxoSmithKline and Cephalon. Cephalon was the first to do so under a CIA, which required it to report figures for a full year. The other three posted data for a single quarter.

Lilly's Top Speakers Earn $150,000 In Six Months

Cephalon has been the only company to clearly designate its highest-paid doctors, breaking out payments in $10,000 increments as required under its CIA. Pfizer's CIA gave it the option of listing the payments in $10,000 increments or in the actual amount paid and the company chose to report individual sums for 4,856 entities.

A Pfizer spokesperson said nine individuals received $50,000 to $150,000 and the remainder received less than $50,000. The company set a cap of $50,000 per year for individual speakers. But those with particular expertise can be cleared to receive a maximum of $150,000.

By comparison, Cephalon paid three doctors more than $140,000 in speaking fees during the year. And in a one quarter period GlaxoSmithKline's top speaker earned $99,375, Lilly's highest paid physician received $70,050 and Merck's top earner received $22,600.

Companies are now required to post payments to healthcare professionals under a provision included in the health care reform legislation signed into law last week. The law requires reporting of payments for consulting and speaking engagements, the value of certain meals and non-cash items like educational materials.

Pfizer said it will post its next report on March 31, 2011, which will include a full year of data for 2010 and include the value of all financial transactions, regardless of value. The company will post payment reports quarterly beginning in June 2011.

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Janet Woodcock and the King of Siam

03/31/2010 11:17 AM |

To repeat that quote from Theodore Roosevelt, “When you’re in a hole, stop digging.”

Note to Amphastar Pharmaceuticals – stop digging.

Back in August Amphastar was so unsatisfied with the way the FDA was dealing with their file for generic Lovenox, they decided to claim unfair treatment at the hands of CDER Director Dr. Janet Woodcock.

Amphastar claimed that its rival, Momenta, had a "leg up" and was getting "special access."  And yet both companies were in the same place in the regulatory process and both companies are being asked for the same data sets.  And this is unfair why?

According to Amphastar it's unfair because CDER Director, Dr. Janet Woodcock co-authored a paper with one of Momenta's founders, MIT biological engineering professor Ram Sasisekharan, on how the FDA taskforce (on which they both served) identified and contained the cause of contaminated Chinese heparin imports.

Well, to nobody’s surprise, the inspector general of the Department of Health and Human Services has cleared Janet of all allegations of conflict of interest.

Not satisfied to acknowledge a boner of monumental proportions, Amphastar's general counsel, Jason Shandell, said that the FDA narrowly tailored its review to legal issues. "We never asserted she got any money—that would be illegal. Our focus was on the appearance of impropriety and its impact on the approval system.”

Remove foot from mouth, right?

Um – not so fast.  According to Politico: “For more than two months in late 2008, private investigators working for a drug company gathered information on a high-ranking official at the Food and Drug Administration – unearthing details about her husband, two daughters, and in-laws, and re-tracing her steps on a business trip she took to Thailand.

The drug company, Amphastar Pharmaceuticals Inc., paid more than $100,000 to Kroll, the New York-based private investigative firm, to uncover the information about Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, who oversees the agency’s new-drug approvals.”

And it gets worse. At one point, the investigators hired a freelance reporter to file Freedom of Information Act requests, using her status as a journalist to request Woodcock’s emails, phone records, voicemails, calendar and expense reports, among other documents – without mentioning that she was being paid for her efforts by a private investigative firm. Oops.

And worse.

According to Politico, “On behalf of the drug company Kroll also investigated a second FDA official – Moheb Nasr, director of the FDA’s Office of New Drug Quality Assessment, creating a file on him that included his birth date, the price he paid for his home, and details of his education and professional background.”

And here’s a lesson to all of you drugwonks out there – do NOT let your lawyer act as spokesperson.

 “I feel like as a citizen you have a right to question your government and a right to look at public information,” said Amphastar’s general counsel, Jason Shandell. “There was no impropriety here.”

So now the conversation has moved Amphastar’s boner.  Solid PR.

And to make things even worse for Amphastar, they’re now squarely in the crosshairs of Senator Max Baucus (D, MT), who said it was “an outrage,” and has demanded that Kroll tell him how often private detectives target public officials.

“Pharmaceutical companies should be focusing on getting their drugs approved based on health research and science rather than wasting their resources hiring private investigators to snoop around the lives of FDA regulators and their families,” said the Senator.

An apology is in order.  Read More & Comment...