Latest Drugwonks' Blog
When it comes to drug shortages, pounding Big Pharma isn’t the answer. Finally someone is focusing on the perverse economic incentives of Average Sales Price (ASP) as a key factor behind the problem. And that someone is Senator Orrin Hatch (R, UT.)
His Patient Access to Drugs in Shortage Act is out for comment through April 25, 2012. This proposed legislation is the only bill dealing with the economic causes of the shortages.
Some important codicils include:
* Price Stability — The draft would change the Medicare reimbursement rate for generic injectable products with 4 or fewer active manufacturers from Average Sales Price (ASP) + 6% to Wholesale Acquisition Cost (WAC) in order to achieve market price stability.
* Medicaid/340B Rebate Exemption — The draft exempts generic injectable products with 4 or fewer active manufacturers from Medicaid rebates and 340B discounts in order to achieve market price stability.
* Extended Exclusivity — Manufacturers who hold an approved application for a drug that would mitigate a shortage can extend by 5 years any period of exclusivity, even if the drug is eventually moved from drug shortage designation.
* Drug Shortage Database — The Secretary would establish a mechanism by which health care providers and other third-party organizations may report evidence of a drug shortage.
This last point may sound innocuous – but it’s crucial. There are many players in the drug shortage game – not just innovator pharmaceutical companies and the FDA. There are generics manufacturers, hospitals, Group Purchasing Organizations (GPOs), and physicians. (For more on the GPO issue, see this new op-ed in today’s Washington Examiner).
As the Japanese say – don’t fix the blame; fix the problem.
Earlier this week the Supreme Court heard arguments as to whether representatives of pharmaceutical companies are entitled to overtime. The answer, it seems, turns on whether those visits are actually sales calls.
According to Paul D. Clement, lawyer for the defendant, the pharmaceutical sales representatives plaintiffs, “ … were hired for a sales job. They were given sales training. They attend sales conferences. They are assigned to sales territory, and they are evaluated and compensated as salespeople.”
But, commented Chief Justice John G. Roberts Jr, “They don’t do sales. Your long list sort of stopped one step short. They don’t make sales.”
As the New York Times accurately reports, industry reps “do not sell products in the strict sense of the term. Rather, they encourage doctors to write prescriptions for patients to buy drugs from pharmacies.”
Interesting semantical and practical questions and it’ll be interesting to see how the Supremes rule. In the meantime here’s a related question – depending on the final judgment – will government detailers (aka “academic detailers”) qualify overtime pay? They’re not supposed to be “selling” anything either.
I like BIO CEO Jim Greenwood's proposal to give FDA a chief innovation officer who who would examine whether the number of drug rejections is reasonable, or whether it is stunting innovation and causing unwarranted delays.
“People who die because a product is not approved quickly enough are just as dead as those who die because a product is not safe,” Greenwood said. “It’s not just the job of the FDA to protect us, it’s also to promote innovation.”
My pick for the position: Janet Woodcock. No one (except for Bob Temple) could and has balanced these two missions better. And no one has done more to promote personalized medicine, which allows products to more efficiently embody safety and innovation.
There are a lot of important bi-partisan ideas to accelerate the innovation process. A chief innovation officer should not be a ceremonial add-on or be limited to reviewing product development after the fact. That official could report to the Commissioner, search out and encourage companies with innovation products for fast track approval, be in on the development of products from the beginning. That's something Dr. Woodcock would and could do effectively.
But the way to change FDA to promote those broader objectives is to hold it accountable to new standards for product approval and oversight reflecting dramatic changes in the science sustaining innovation. Congressman Rogers and others can help the FDA by getting them out of the comparative effectiveness business. Reauthorization of PDUFA will give the agency more resources and more direction with regard to increasing the predictability in the development process for drugs, devices, diagnostics and combination products. However, the FDA would get a boost if legislation stipulated that any products that use biomarkers or other tools to target treatments and improve the ability to monitor disease progression or response would be automatically approved for use in Medicare, Medicaid, etc.
The more we can defang what is an increasingly worthless CER enterprise the more FDA can achieve the mission the Congressman Rogers wants the agency to carry out. CMPI will be releasing a study, supported by the Kauffman foundation, that estimates how much innovation and health value our nation will forfeit if CER becomes the focus of commercialization instead personalized medicine. The estimates, even with conservative assumptions built in, are staggering.
Every time someone at FDA has to pay lip service to CER it is a signal to companies that all the work put in on diagnostics, combination products and targeted treatments will go to naught because they have to wait for a bunch of underachieving health economists and other professionals to conduct systematic reviews or horizon scams, I mean scans, or clinical trials. Then again, as I noted in my last post, it looks at though PCORI will be handing out dough to to figure out how to conduct patient-centered research and how to engage patients, though the last time I checked no one -- except the stakeholders who will also get the PCORI cash -- was asking for such government help.
You want to make medicine patient-centered? Produce patient-centered medicine. Tools and treatments that reduce hassles, improve life, increase health.
That's something FDA can, should and is trying to do in collaboration with companies. If you asked people should we spend $3 billion on medical decision making or the same amount making better medicines more quickly available to people who need them, I don't have any doubt that faster approvals would win.
The FDA could do a lot with $3 billion over the next decade and do much more for our health and nation than PCORI ever will. Just a suggestion if Congressman Rogers wants to amend his bill....
Yesterday the HELP Committee released a draft version of PDUFA legislation and plans a April 25 PDUFA mark-up.
The Senate draft creates a new pathway for review of "breakthrough" therapies, requiring FDA to work with sponsors to expedite approval of products to treat serious or life-threatening diseases based on "preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints."
On the other side of the Capitol, the House Energy and Commerce Committee released a discussion draft of PDUFA reauthorization legislation on Wednesday. Both the House and Senate bills incorporate the Generating Antibiotic Incentives Now (GAIN) Act, which would extend market exclusivity by five years for drugs that treat antibiotic-resistant pathogens. The E&C version includes an additional six month extension for drugs approved along with a companion diagnostic; this provision has been deleted from the Senate version.
The House draft also seeks to permanently reauthorize two laws that create incentives for conducting clinical trials in pediatric populations, the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Similar legislation, the Better Pharmaceuticals and Devices for Children Act, was introduced with bipartisan sponsorship in the Senate on Tuesday; it is likely to be incorporated into the Senate PDUFA reauthorization bill.
House lawmakers said they were optimistic that any outstanding issues in the GOP draft would be resolved in the coming days, and full committee Chairman Fred Upton (R, MI) said he was convinced the panel is on track to meet his goal of approving the legislation by the end of June.
That PCORI was able to get JAMA to publish two fluffy and self congratulatory editorials that explain how patient-centered reflects the extent to which PCORI, AHRQ and the consultants it funds will be able to disseminate about any crap that it produces through the 'major' medical media outlets. AHRQ, PCORI and cronies are able to get anything it produces published in medical journals. It is spending hundeds of millions of dollars peddling CER to doctors who in exchange get CME credit just for clicking on to a website. And PCORI will be spending hundreds of millions of dollars holding conferences, webinars, etc to explain to 'stakeholders' how patient-cetered they are.
But what exactly is PCORI producing?
In the JAMA puff piece, Joe Selby and colleagues note:
"The institute's first funding announcement solicited projects focused on methods for engaging patients and other stakeholders in all aspects of the research process. "
They conclude that "The proposition that greater involvement of patients, clinicians, and others in the research process could help reorient the clinical research enterprise, reduce clinical uncertainty, and speed adoption of meaningful findings holds great promise, but remains to be tested. PCORI will test this hypothesis. The underlying imperative is to improve patients' care experience, decision making, and health outcomes. Patients as well as the physicians and other health care professionals who care for and about them are invited and encouraged to join in this effort. "
http://jama.ama-assn.org/content/307/15/1583.full?ijkey=2UlGCXlTXheck&keytype=ref&siteid=amajnls
This sounds alot like maximum feasible participation encouraged in community action programs during the 1960s. In his book "Maximum Feasible Misunderstanding," Daniel Patrick Moynihan noted that the "war on poverty was not declared at the behest of the poor. It was declared in their interests by persons confident in their judgment on such matters."
The War on Poverty was not a war and did not do much about poverty. But it did employ and give out grants to the policy entrepreneurs who conceived the War on Poverty in the first place. That consisted of professional economists, professional social scientists, government officials and professional philanthropists.
Similarly, PCORI was not created in response to an outcry from patients about the lack of inclusion of their "voices" in medical decision making. It was a product of the same said professionals who supported PPACA and who believe that spending $3 billion on making sure the CER they produce is marketed and used is in the nation's interest.
The article by the Methods Committee on how it plans to spend money on grants reflects a similar disconnect between the needs of patients and the myopic goals of the CER community. See if you can figure out the punchline of this paragraph:
"Ms M is a 45-year-old woman with depression (Box 2), whose situation similarly highlights the gap between existing research and the characteristics and concerns of patients. Little evidence exists about which sequence of treatments is optimal for Ms M's constellation of symptoms, adverse effects, or initial response. Despite more than 1000 trials on antidepressants and related treatments, most studies include patients with narrowly defined characteristics who are followed up for short periods, do not take place in settings in which care is routinely delivered, and include a limited spectrum of comparators, including drugs and other therapeutic approaches.11 How can clinical research focusing on much larger, long-term issues trials yield more personalized guidance for patients like Ms M?12"
http://jama.ama-assn.org/content/307/15/1636.full?ijkey=419QnSMR.MBDU&keytype=ref&siteid=amajnls
The Methods Committee presumes that since all manner of studies have never been able to identify what treatment is right for Mrs M that the solution is to spend more money on methodologies that will be larger and more long term but at the same time yield more personalized guidance.
Does anyone believe that bigger studies that take longer to produce will, especially at a time when medical information is becoming digitized and atomized, yield personalized guidance that patients will abide by and obey? Am I the only one who sees a social science scam in all this? Is this too cynical on my part?
More later.
They’ve got a list. And they’re checking it twice.
The giant PBM Express Scripts is launching ScreenRx, a program that uses a computer to sift through hundreds of factors that affect patients and forecast who is most likely to forget a refill or simply stop taking their drugs. The company then plans to contact those patients to help them stick with their doctor's orders.
It’s estimated that about $317 billion in additional medical expenses were incurred by the U.S. health care system last year because people didn't comply with prescriptions. These additional expenses might include a heart attack for someone who stops taking cholesterol medicines or an amputation for someone who doesn't adhere to diabetes treatment.
The analysis, called predictive modeling sorts through more than 400 variables that could affect a patient to see which people have enough red flags to warrant concern.
Once a patient has been flagged, they receive a phone call. An Express Scripts representative will talk to the person to see if they need help. The PBM then might send the patient a pillbox if they have a hard time remembering their prescriptions or a special beeper that goes off when it's time to take medicine.
If the patient struggles to pay for the drugs, Express Scripts will provide information on assistance programs.
According to a report in the Washington Post, “Analysts say predictive modeling programs that aim to forecast patient behavior and improve care have been evolving in health care over the past few years, and the Express Scripts product is the latest evolution.”
Survival of the most compliant. Would Darwin have approved?
Eli Lilly’s John Lechleiter believes that the biopharmaceutical industry exists in an “innovation ecosystem.” A new study by the Tufts University Center for the Study of Drug Development (funded by PhRMA) confirms that notion by exploring the breadth and nature of partnerships between biopharmaceutical companies and academic medical centers (AMCs).
The full study can be found here.
The Tufts study examines a subset of public-private partnerships – more than 3,000 grants to AMCs from about 450 biopharmaceutical company sponsors. The Tufts report describes the various types of partnership models that exist, and recent trend as well as identifies next generation academic-industry collaboration models emerging from the public-private-partnership paradigm.
To add to Lechleiter’s phrase, the report discusses the importance for and a model of a sustainable innovation ecosystem. This is in keeping with the ethical and pragmatic policy of the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) regarding the disclosure of conflicts of interest:
“There is no inherent conflict of interest in the working relationships of physicians with industry and government. Rather, there is a commonality of interest that is healthy, desirable, and beneficial. The collaborative relationship among physicians, government, and industry has resulted in many medical advancements and improved health outcomes.”
Some findings from the Tuft’s study:
The partnerships examined in this report fall into three primary categories: joint clinical trials (75%), studies targeting public health priorities (14%), and health research and education projects (11%).
* 72 percent of the joint clinical trials are for pharmaceuticals.
* Studies targeting public health priorities cover a range of topics, including breakthrough-investigations involving multiple disciplines.
* Joint health research and educational activities ranged from basic medicine to translational research to new technologies, particularly nanotechnology and pharmacogenomics.
Tufts found that these relationships often involve company and AMC scientists and other researchers working side-by-side on cutting-edge science with advanced tools and resources, enabling the U.S. to rise to the challenge of various biomedical opportunities, such as personalized medicines and a growing understanding of rare diseases.
The report outlines the 12 primary models of academic-industry collaborations and highlights emerging models, which reflect a shift in the nature of academic-industry relationships toward more risk- and resource-sharing partnerships.
* Unrestricted research support has been one of the most widely used models. While these models have generally represented the most common form of academic-industry collaboration, Tufts research found that they are becoming less frequently used.
* The report found a range of innovative models emerging, from corporate venture capital funds to pre-competitive research centers to increasingly used academic drug discovery centers.
Examples of emerging academic-industry partnership models include:
* The Coalition Against Major Diseases, a consortium under the Critical Path Institute, involves biopharmaceutical companies, academic institutions, and others working together to facilitate the development of effective treatments for Alzheimer’s and Parkinson’s disease.
* Eli Lilly and Company launched the Open Innovation Drug Discovery program to facilitate research on molecules around the world that have the potential to ultimately be developed into medicines by allowing academic and other researchers to submit molecules for free screening as potential drug candidates.
* Sanofi has a strategic alliance agreement with the Massachusetts Institute of Technology’s (MIT’s) Center for Biomedical Innovation focused on advancing knowledge in the area of human health through basic and applied research and promoting scientific exchange between MIT and Sanofi researchers to support the development of health care solutions for patients.
The report highlights the mutual benefits of partnerships:
* Both academia and industry are facing increasingly complex scientific challenges. According to the report, as the scope of some of the scientific challenges is so large, collaboration is viewed as increasingly important to making significant progress.
* Partnerships benefit both industry and academia by providing the opportunity for the leading biomedical researchers in both sectors to work side-by-side to explore the promising new technologies and scientific discoveries that have the potential to treat the most challenging diseases and conditions facing patients today.
The report finds that the nature of collaboration occurs across all aspects of drug discovery. According to Tufts, companies are funding and working collaboratively with the academic component of the public sector on basic research that contributes broadly across the entire spectrum of biomedical R&D, not just for products in their portfolios.
The report concludes that academic-industry partnerships are growing in number and importance as “the translational gap between discovery and clinical development has become increasingly difficult to bridge.” The complementary nature of partnerships involving AMCs and biopharmaceutical companies increases synergies between the two sectors, ―enabling the nation’s R&D enterprise to tackle the most complex and challenging diseases and conditions.
How’s that for sunshine?
The official comment period is over and it's pretty clear that FDA’s February 9th biosimilar draft guidance has sparked resistance among some industry players – specifically over certain definitions and requirements. No surprises there.
Stakeholders sent criticisms over the suggested protocols as well as several recommendations for change. The draft guidance, contained in three documents, represent FDA’s interpretation of the Biologics Price Competition and Innovation (BPCI) Act of 2009.
Biosimilarity
Two drug developers said that the agency should tighten its proposed biosimilarity standards. While commending FDA for “an excellent job drafting guidance on quality considerations for demonstrating biosimilarity to a reference product,” Genentech took issue with FDA’s proposed wording that manufacturers “should” thoroughly assess the analytical similarity of their biosimilars to their reference products, and “should” perform in-depth chemical, physical, and bioactivity comparisons with side-by-side analyses of “an appropriate number of lots of the proposed biosimilar product and the reference product.” FDA also suggested that “where available and appropriate,” manufacturers compare their products with the reference standard for specific suitable attributes such as potency.
The assessment of the analytical similarity of a biosimilar product and the robustness of these methods are fundamental requirements for a biosimilarity assessment, and use of the word “should” implies that it does not necessarily need to be done, Genentech noted. “Please replace ‘should’ with ‘is expected to’ or ‘needs to,’” Genentech stated in a letter transmitted to the agency by Earl Dye, director of technical regulatory policy and strategy.
Novo Nordisk urged FDA to define biosimilars as products that are as similar as scientifically possible to their reference products, at least through sharing the same amino acid sequence, without exception, as their reference products. The company cited FDA’s emphasis on the importance the 3-D structures of proteins play in their biological functions and the ability of post-translational modifications to alter the proteins’ functions.
“FDA should never permit biosimilar applications for products that cannot be adequately characterized,” Novo Nordisk stated in its letter, signed by James C. Shehan, Novo Nordisk’s corporate vp, legal, government, and quality affairs.
Biosimilar producer Biocon counter-suggested that FDA should expect that the expression construct and/or the processing of a proposed product would result in the same primary amino acid sequence as the reference product. Some expression constructs may give a precursor protein that only after modification in the process will yield the same amino acid sequence as that of the reference product, Biocon noted in its letter, submitted by Siriam Akundi Ph.D., associate vp, quality, and regulatory.
Demonstrating Safety
Novo Nordisk also believes that biosimilar applicants “should always submit the results of comparative animal toxicity studies.” It added, “In the current state of science, some form of comparative safety and effectiveness testing will be necessary for almost all biosimilars.
“All biosimilar applicants should conduct at least one comparative clinical pharmacokinetic study and, where there is a relevant pharmacodynamic marker, at least one comparative clinical PD study,” Novo Nordisk added. “Similarly, a biosimilar applicant should always conduct at least one comparative clinical immunogenicity study.”
Two patient groups also called for FDA to promote greater safety. The Colon Cancer Alliance asked FDA to require “extensive” clinical testing of biosimilars, with a system capable of rigorously tracking and tracing them back to their product of origin. “It is critical to the safety of patients that these drugs be submitted to open and robust clinical studies and are marked with a unique and transparent product labeling system that will facilitate robust pharmacovigilance,” Global Healthy Living Foundation (GHLF) president Seth Ginsberg wrote in GHLF’s letter.
Interchangeability
Ginsberg noted that it is difficult to designate a biosimilar as interchangeable with their innovator products unless there is sufficient data. He expressed concern that decisions on interchangeability could be made by pharmacists or insurers through states’ automatic substitution policies. “We believe that the choice of product should be decided only by patients and physicians, who are ultimately responsible for patient care and have the full spectrum of a patient’s medical history,” Ginsberg added.
Novo Nordisk urged FDA to confirm that it would not designate a new biosimilar delivery device or container closure system as interchangeable with its reference product “where additional training on the new device or system is necessary to guide safe use, or where the proposed delivery device or container closure has inequivalent performance or critical design features.”
And miles to go before …
“The keys to success for the biosimilar pathway are informing and educating patients and physicians on the benefits and safety challenges of replicating biologic drugs, providing a unique and distinctive naming and labeling system, and understanding that the FDA’s approval of a biosimilar as a standalone therapy does not mean that it is interchangeable with its biologic counterpart,” the Colon Cancer Alliance stated in its letter to FDA written by CEO Andrew Spiegel.
The alliance urged FDA to adopt a system that uses individual nonproprietary names for biologics and biosimilars, enabling physicians, patients, and regulators to differentiate between products easily—a suggestion also made by Novo Nordisk and the National Association of Chain Drug Stores.
Biocon took issue with FDA’s requirement that sponsors provide “sufficient scientific justification” for extrapolating clinical data to support biosimilarity determinations for each condition of use for which a license is sought. “Once biosimilarity is established, and product is approved for one indication, no additional clinical studies should be expected for obtaining approval for other approved indications,” Biocon stated. “If the route of administration, dosing frequency, and dosage amount of the proposed biosimilar is identical to the reference product for each indication, any additional clinical studies should not be expected.”
Novo Nordisk also urged FDA to publish product-class specific guidance for biosimilar and bioequivalent applications for complex proteins, like the EMA has done. With all the discord that FDA’s draft biosimilar guidance has created, the agency will have to work to balance the interests of innovators, biosimilar developers, and patient groups. The agency will have to ensure that it does not tilt its final guidance toward developers of new drugs by rules that unduly impede biosimilars. Nor should it tilt its requirements toward biosimilar makers seeking less rigorous review. It won’t be easy, but balancing competing interests will ultimately benefit companies, researchers, and especially patients, by finally providing a biosimilar pathway in the U.S.
And that's assuming the law that makes biosimilars possible remains on the books after the Supreme Court ruling.
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.
