Latest Drugwonks' Blog
Former Senator (and almost HHS Secretary) Tom Daschle keynoted the opening of the 19th Annual Partnerships in Clinical Trials conference.
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Okay, once more with feeling – “generic” does not equal “identical.” That’s why the FDA wants to tighten the bioequivalence standards for generic drugs. Bravo!
The Pharmaceutical Science and Clinical Pharmacology Advisory Committee voted unanimously, with one abstention, that critical dose drugs do constitute a distinct group and voted unanimously that FDA should develop a formal list of those drugs - although the terminology of "narrow therapeutic index" may be more appropriate. And in an 11-2 vote, the committee concluded that current bioequivalence standards are not sufficient for drugs in the narrow therapeutic index group.
According to the agency, although that methodology is "statistically rigorous" and accepted as a valid way to establish bioequivalence in most of the world, "many consumers and health professionals do not understand these statistical methods and the approval standards based on confidence intervals … Many wrongly assume that the FDA places the standards ... on the mean or average of the study data rather than the confidence intervals."
"Since the public seems to have a basic understanding of averages, the proposal to be discussed is for an additional criterion to be placed on the geometric mean (average or point-estimate) of the data limiting it to 90-111 percent." The agency surveyed 12 years of generic approvals and found that only approximately 2 percent to 3 percent of approved generic drugs would not have passed with the additional criteria.
According to a report in the Pink Sheet, “There is regulatory precedent in the definition of narrow therapeutic ratio, where drugs that meet certain parameters of median lethal dose and median effective dose are required to have careful titration and patient monitoring. But that definition is not necessarily clinically practical, FDA states, because the relevant parameters are not always available during drug development. Thus, the agency is asking the advisory committee whether it should consider CD drugs to be a distinct class, and how it should be defined. The agency also wants to know whether if the current bioequivalence standards are appropriate for CD drugs.”
The agency has already set up specific requirements for one drug product, asking manufacturers of generic versions of Sanofi-Aventis's insomnia drug Ambien CR (zolpidem) to compare partial AUCs over clinically relevant time intervals. An appendix considers the role of partial AUC for generics of modified-release methylphenidate products as well.
Its good news that the FDA is taking a strong stance in favor of the public health – because there will be many who seek to undermine this important initiative.
In the words of John Stuart Mill,
“One person with a belief is equal to a force of 99 who have only interests.”
Biogen Idec is developing a test that can tell patients their odds of getting a deadly brain illness from Tysabri.
The screening tool could be marketed as early as 2011 if clinical trials involving 9,000 people show a low rate of false findings. The test is designed to detect the JC virus that causes progressive multifocal leukoencephalopathy, or PML, a brain-cell destroyer that can lead to disability and death. (Tysabri has been linked to 42 PML cases.)
If the test works, it is “absolutely a game changer,” said Patricia O’Looney, vice president of biomedical research at the National Multiple Sclerosis Society. With a false-negative rate of 2 percent, patients who are free of the virus would lower their risk of getting the brain disorder PML to 1 in 25,000 for the first three years of their Tysabri therapy.
And speaking of risk management, I’m chairing a panel on REMS today at the 19th Annual Partnerships in Clinical Trials conference.
A common question I get about REMS is – how is it different from what we used to call RiskMAPS? I see two main differences. The first, obviously and importantly, is that REMS has actual legislative language. And that’s an important detail – but it’s one-dimensional.
The second, more important and contentious difference is the environment into which REMS was birthed -- an environment in which there is growing realization that the 21st century FDA must add a third leg to its mission of safety and efficacy – and that third leg is safe use. The safe use of drugs. And the formulation, implementation and communication of plans – REMS plans -- that will assist physicians and patients achieve better outcomes through the strategies and tactics devised therein.
That being said, there are those in industry and in the broader healthcare policy arena who look at REMS and don’t see GEMS.
Many have looked at the FDAAA language on REMS and see it as an ill-advised green light for the FDA to inject itself into the practice of medicine.
While I agree that REMS does indeed represent an expansion of the FDA's authority, I do not agree that it is either ill advised or an over-extension of the agency’s purview.
The concept of "safe use" as an integral part of the FDA's 21st century mission and REMS as one of many tactics to achieve better patient care are contentious and crucial. And it is that debate which brings us together today.
REMS must be viewed as a “win/win” situation for the agency (which can now move forward to approve drugs with higher risk profiles and have a more direct path for post-market surveillance), for sponsors (who can have their drugs approved with greater alacrity), for physicians (who will – at least in theory) have a more complete view of risks and benefits, and patients (who will have additional therapeutic options and will now – at least in certain circumstances – become a more complete part of the compliance/adherence proposition).
There’s much debate and discussion over where in the drug development process REMS should surface. Acknowledgement that this cannot be done in the absence of data – and confusion as to how to deal with early (even Phase II information) that might be REMS relevant. And “confusion” meaning both scientific uncertainty and internal confusion and discomfort.
There’s evident frustration about validated tools (the absence thereof). But this was at least somewhat assuaged by the timely release of the FDA’s draft guidance on “Format and Content of Proposed REMS Assessments, and Proposed REMS Modifications.” And it was a cool and refreshing draft indeed.
And there’s continued discussion as to whether or not companies should wait until the agency asks – or if sponsors should preemptively (you should excuse the expression) provide an outline of a potential REMS plan. This is important not just as an issue of timeliness (as opposed to having the agency introduce the topic in a complete response letter), but also of responsibility. If, as we all want to believe, the FDA must be both regulator of and colleague to industry, then what are the responsibilities of a sponsor relative to (among many other things) surfacing the REMS issue – and at what point in the process. Nobody said it was going to be easy.
CDER Director, Dr. Janet Woodcock said that, “Safety means doing the right things for patients. FDA must consider post-approval issues as part of a drug’s lifecycle.”
Janet understands that there’s a real difference between “headlines and help.” In other words, REMS and other safety mechanisms can be viewed as either “headlines” about “unsafe” drugs or in a more appropriate context of “safe use.” Janet opts for “safe use,” while others (in the media and elsewhere) seem more predisposed to the other.
According to Woodcock, “FDA does not control the health care system, so our improving the use of marketed drugs, to a great extent, is going to involve influence rather than control.”
“Influence rather than control” is a savvy and sophisticated concept -- one that many of our elected members of Congress could learn from, and one in which REMS plays an important role.
The FDA’s "Safe Use" initiative is the patient-facing sibling of the agency’s “Safety First” pharmacovigilance program. But it's more than that -- it's the FDA reasserting ownership of safety from those who would use it only as a mallet of fear. I will not mention names.
It's important to note that when the FDA announced the warfarin label change the agency (and Larry Lesko in particular) came under attack from critics who asserted that this was the FDA, inappropriately, telling doctors how to practice medicine.
Jane Axelrad, the associate director for policy at CDER, had to say about REMS, “These safety plans allow patients to have continued access to certain medicines for which there are safety concerns that can be managed through appropriate use.”
Whether you say “appropriate” use or “safe” use – the principle is the same – making sure that the risk/benefit analysis of any given therapy is communicated in a lucid and (when required) strident manner.
Sometimes that requires a label change. Sometimes it requires a REMS plan, but it will always require the active participation and leadership of the FDA in partnership with the pharmaceutical industry, physicians, and yes – even patients.
Because no safe use program will succeed without the secret ingredient of patient responsibility.
But does it require additional agency authority. At a recent House Energy and Commerce Health Subcommittee hearing FDA’s Principal Deputy Commissioner Josh Sharfstein said that FDA could use more authority to bring negotiations over a drug's Risk Evaluation and Mitigation Strategy to a close. The agency can require a REMS, he commented, but not specify its contents.
Brand sponsors must implement such a plan, whereas FDA must pay for and operate a communication plan for generic drugs, he noted. Something to think about as we head into the PDUFA reauthorization debate.
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?
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.
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.
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.
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.
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.
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.
