Latest Drugwonks' Blog
If you give someone the tools they use to commit a crime, are you also responsible?
Consider the following news item from Reuters about pharmacy benefit managers and their rebate contracts with drug companies:
U.S. probes contracts between drugmakers, pharmacy benefit managers
“The U.S. Attorney's Office for the Southern District of New York is investigating contracts between drugmakers and companies that manage prescription benefits, according to regulatory filings… When drugs are knocked off their formularies, patients may have to pay full price for them. PBMs often keep or dump a product depending on whether they can obtain favorable pricing.”
As I have noted PBMs get and distribute about $110 BILLION in rebates each year. That’s a trillion over a decade. ICER plays, or seeks to play a role in setting prices and determining what products PBMs choose and insurers pay for that is central to enlarging and maximizing rebates. And the PBMs are working closely with ICER to develop the price and access parameters of the contracts the U.S. Attorney for the Southern District of New York is investigating:
“ICER’s new program will make a huge difference by providing what is sorely needed: an independent, trusted source of information about new drugs,” stated Steve Miller, MD, Chief Medical Officer of Express Scripts, the nation’s largest pharmacy benefits manager. “I believe many payers and policy makers will find this information of critical importance as they evaluate the new drugs, and we look forward to using it to help us improve the ability of patients to get access to new, innovative drugs at a price the system can afford.”
PBMs are also looking to ICER’s Steve Pearson to find reasons to pay less for cancer drugs depending on their indication. As a recent article noted: “ Express Scripts is using data from ICER, as well as the DrugAbacus, to inform its indication-based pilot.”
As I have noted before, indication pricing, based on average response and on a QALY measure reflecting PBM profit motives, can endanger patients and discourage companies from investing in treatments for the most difficult to treat tumors. More generally, first in class or first ever drugs to treat the most severe conditions -- particularly rare diseases -- are likely to show modest benefit on average. Such medicines will never meet ICER's devalued QALY measure.
The most recent example is ICER has already determined that most new multiple myeloma drugs approved to treat patients whose disease has returned are NOT cost effective, even at 90 percent of the list price of the drug.
People with myeloma will bear moral, economic and clinical consequences that ICER ignores and the media barely mentions. So two days before ICER meets to approve the report’s (foregone) conclusions I will be releasing a white paper that measures these essential values.
One important point to consider: ICER recommendations would lead to drug companies forking over billions in rebates in exchange for putting these drugs on their formulary. It does NOT mean that patients will get access. It does mean that ICER is enabling the rebate ripoff scheme that the US attorney is investigating. It may not be cutting the deals but ICER is supplying the PBMs the justification for the rebate enterprise.
The American Journal of Managed Care ran a Q&A with Express Scripts and ICER consultant Peter Bach about his " DrugAbacus, the importance of using value frameworks, and using the European market as a model to recalibrate the healthcare system in the United States.
Bach likes to claim that he trying to reduce the mismatch between value and price. That is a presumption without much basis in fact and is largely shaped by his Malthusian definition of value.
Let's once again prove that Bach has an ideological axe to grind that has nothing to do with reality.
In his interview, Bach claims that "it’s impossible to convince yourself that we are getting any incremental value, period, let alone any incremental value of the excess spending. If we compare ourselves with other countries, there does not seem to be any rationale, except that we simply spend more for all units of healthcare"
I will get to his inaccurate assertion about other countries in a bit. But first, let's look at his claim about incrementalism, one he has been repeating for several years. Today and yesterday, Bach has ignored how cancer survivorship and life expectancy steadily increased over the past 20 years. More recently, new drugs for lung cancer have doubled response rates and increased survival by 45 percent. The total drug cost per patient (which includes the part of the price going to PBM rebates, etc.) is estimated to be between $36000-98000.
He may believe that the additional increment of average survival (which ignores genomic variation) is not worth spending money on. But that ignores the fact that treatments are targeted to smaller populations that have fewer options than previous generations. And he decidely believes that being able to live long enough to benefit from future medicines is a waste of time and money.
Bach knows better. After all, one of his co-authors in the paper he cites in his NEJM oral hallucination about new drugs not adding more survival despite higher prices, makes that very point in another study: " In the absence of significant pricing and total oncology outlay flexibility by payers, our analysis suggests that private sector investment in small oncology segments, and in stratified medicine generally, may not prove economically sustainable, thus endangering the translation of scientific advances into bedside medicines. Beyond increasing reimbursement, decreasing development cycle time and costs, or both, would most directly improve the economic incentives facing developers. By contrast, extending exclusivity periods, or initiating advance market commitments and awarding prizes would likely have less impact and involve greater implementation challenges." (Trusheim, Berndt "Economics of Stratified Medicine" Personalized Medicine (2012) 9(4), 413–427)
2. Bach's main point: "The reality is that the drivers of healthcare spending in the US are unit price, not volume."
To prove his claim Bach asserts: So, if we want to manage healthcare spending, you can make the argument that the excess price above that, which is being paid ambiently in European countries, is actually wasted dollars. It does not make the pill any better by paying 4 times as much for it."
That is untrue on two levels with respect to drugs.
In developed markets, most growth is from new brands and increased volume, not price. As the chart (from the IHI Oncology Trend Report: 2015)
The IHI report notes: "Oncology drug spending has risen slightly as a percentage of total drug spending over the past five
years in all regions, most notably in the EU5 countries where oncology now represents 14.7% of total
drug spending, up from 13.3% in 2010, while the U.S. has seen oncology increase more modestly from
10.7% to 11.3% of total drug spending over the same period."
Indeed, the US rate of spending was lower compared to Europe even though US adopts new medicines more quickly than Europe and other developed countries.
Yet the share of oncology of total drug spend is lower and increased more slowly in the US.
The IHI report estimates total spending on cancer drugs in the US is $42 billion. Forty eight percent of that spend is for targeted therapies ($20 billion) Total drug spending was $425 billion (without rebates) so new therapies are about 4.7 percent or that amount, which is unchanged since 2010. Cancer drugs as a percent of total health care spending remains at about 1 percent.
But Bach claims cancer drugs cost four times as much here than in Europe.
As an aside, Bach’s claim that drugs are 6 times more expensive in the US than in Europe is an absurdity. I can find a drug on the UK NHS formulary that has been subject to price concessions and price controls for a decade and compare it retail price here. But that ignores the fact that in most cases the US is using generic drugs that are less expensive than the brand drug Bach has selected. And with respect to cancer drugs the acquisition price of new products are about the same. For instance, the retail price of a 50ml vial of Keytruda in the US is about $2200. In the UK it is $1900. A year supply of 40 mg crestor is (US dollars) is $4300 and the retail price in the US is $2280. A year’s supply of Januvia in the UK is 3326 pounds or $4800 while the retail price in the US is $4552.
Finally, he glosses over the inequities of applying a QALY to a class of drugs or indication without regard to genomic variation or the severity of the tumor being treated. That's because he has a vested interest in using QALY to devalue new medicines which in turn allows the PBMs and insurance companies he consults for to rake in billions more in rebates. And this devaluation will also hurt and even cause cancer patients to die.
As I noted in a previous blog reviewing another work of fiction by Bach, "In an article published last year in the Journal of the American Medical Association, he suggested that in an indication-specific arrangement, the monthly price for Eli Lilly & Co.’s cancer drug Erbitux (cetuximab) would plummet from $10,320 a patient to about $470 a patient for its least effective use, treating recurrent or metastatic head and neck cancer. The drug also is used to treat locally advanced head and neck cancer, as well as colorectal cancer."
Bach claims that the use of Erbitux for head and neck cancer is a "least effective use". Let's set side the curious math used to arrive at the $470 figure. It is more important to note that Bach ignores not only individual differences in response but the impact of Erbitux relative to existing need and treatment protocols. Bach uses an average 2.3 months more of survival as his benchmark.
Here's what we know about pre-Erbitux treatment of recurrent, metastatic squamous cell carcinoma of the head and neck (SCCHN):
"None of the trials performed in the past, even those with a reasonable sample size, have shown that aggressive platinum-based combination chemotherapy leads to survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil.
What difference does Erbitux makes?
After decades without real progress, a recent European randomized trial showed that adding cetuximab, the first clinically available EGFR-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil) leads to an important survival benefit and this, with support of an additional smaller study in the US, has changed practice." J. B. Vermorken and P. Specenier Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol (2010) 21 (suppl 7): vii252-vii261 doi:10.1093/annonc/mdq453
Hence, the Bach pricing approach would whittle away payment for the hardest to treat cancers for patients that have had no real advances in care for decades. Maybe Bach supports paying doctors less for people who are the farthest gone because the relative health gains are well, not worth it??
Bach never comes clean about who benefits from the discounts he proposes. In the US, it's the PBMs and insurers. Currently, these special interests rake in about $4-8 billion in rebates on targeted oncology drugs. Meanwhile patients are forced to use drugs that generate the most rebates and have to pay a large portion of the retail drug cost on top of everything.
I guess that's linking prices to one set of interests -- PBMs and insurers -- that Bach values more than what is best for patients.
Much ado about an article in Morning Consult by Ronald T. Piervincenzi (Chief Executive Officer of the United States Pharmacopeia) and Thomas E. Menighan, Executive Vice President & Chief Executive Officer of the American Pharmacists Association).
According to their commentary, Legislation Threatens Patient Confidence in Biologics, Slows Biosimilars, legislative language in the Senate’s FDA and NIH Workforce Authorities Modernization Act would impede “the one issue uniting policymakers” -- the need to improve our system for getting low-cost quality-assured therapies to patients quickly.” How? “… by exempting biologic medicines – including biosimilars, insulin, blood thinners, cancer treatments and other drugs – from having to comply with public standards for quality.”
That’s a pretty strong statement and a lot of people should (rightly) take offense. But it raises an important issue – why the vitriol?
It’s a complicated issue with many moving parts, all of them worth serious debate. For those in on the issue, the under-current renews the continuing tension between USP and FDA on many matters relative to biosimilars.
It’s important that these two institutions work together in many places and understand each other’s individual efforts -- not the least of which is the continuing evolution of the FDA’s new Purple Book.
The “Purple Book” lists biological products, including any biosimilar and interchangeable biological products licensed by FDA under the Public Health Service Act (the PHS Act). The lists include the date a biological product was licensed under 351(a) of the PHS Act and whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act.
The Purple Book will also enable a user to see whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already-licensed FDA biological product). Biosimilar and interchangeable biological products licensed under section 351(k) of the PHS Act will be listed under the reference product to which biosimilarity or interchangeability was demonstrated.
USP and FDA both have important roles to play. It’s a very small sandbox with very large public health implications.
According to their commentary, Legislation Threatens Patient Confidence in Biologics, Slows Biosimilars, legislative language in the Senate’s FDA and NIH Workforce Authorities Modernization Act would impede “the one issue uniting policymakers” -- the need to improve our system for getting low-cost quality-assured therapies to patients quickly.” How? “… by exempting biologic medicines – including biosimilars, insulin, blood thinners, cancer treatments and other drugs – from having to comply with public standards for quality.”
That’s a pretty strong statement and a lot of people should (rightly) take offense. But it raises an important issue – why the vitriol?
It’s a complicated issue with many moving parts, all of them worth serious debate. For those in on the issue, the under-current renews the continuing tension between USP and FDA on many matters relative to biosimilars.
It’s important that these two institutions work together in many places and understand each other’s individual efforts -- not the least of which is the continuing evolution of the FDA’s new Purple Book.
The “Purple Book” lists biological products, including any biosimilar and interchangeable biological products licensed by FDA under the Public Health Service Act (the PHS Act). The lists include the date a biological product was licensed under 351(a) of the PHS Act and whether FDA evaluated the biological product for reference product exclusivity under section 351(k)(7) of the PHS Act.
The Purple Book will also enable a user to see whether a biological product licensed under section 351(k) of the PHS Act has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already-licensed FDA biological product). Biosimilar and interchangeable biological products licensed under section 351(k) of the PHS Act will be listed under the reference product to which biosimilarity or interchangeability was demonstrated.
USP and FDA both have important roles to play. It’s a very small sandbox with very large public health implications.
Following the advice of Peter Bach, who holds the Express Scripts Chair for Rebate-Driven Outcomes Policy at Memorial Sloan Kettering, the Center for Medicare and Medicaid Services (CMS) has proposed paying cancer doctors less for administering the most expensive cancer drugs covered under Medicare part B. A lot of people -- including the oncologists themselves --have been complaining about the cut. But nobody has talked about the most unethical part of the experiment: As Drug Channel's Adam Fein explains:
"CMS wants to reduce reimbursement for buy-and-bill drugs—but for only half of the country's providers. The other half will retain current reimbursement levels. After five years, CMS will see what happened. .."
As only Adam has pointed out this is an unprecedented experiment on patients.
Did anyone ask Medicare consumers if they wanted to participate? Did CMS offer to pay moving costs to people who want to be in the control arm of this experiment?
Did anyone ask if this was even ethical? Here's what the NIH Office of Human Research Protection guidance on informed consent requires. You tell me if the Medicare Part B experiment comes within a light year of this moral galaxy:
" Disclosing the reasonably foreseeable risks of research to prospective subjects recognizes the ethical obligation to give prospective subjects sufficient information to make a knowledgeable decision about whether or not to participate. This reflects the ethical principle of respect for persons, which recognizes the importance of giving individuals sufficient information during the informed consent process to make a considered judgment about whether to participate in research that could affect their health or wellbeing—for better or worse."
The CMS notice does not address any of these issues. Indeed, the phrase informed consent doesn't even show up in the proposal.
Instead:
"Providers, suppliers, and beneficiaries who are included in the model will have access to the existing claims appeals process, as well as a proposed Pre-Appeals Payment Exceptions Review process, to resolve disputes arising from the policies implemented by this model. "
In otherwords, no informed consent, not even passive consent. Instead, patients are being hereded into an experiment that in my opinion, violates EVERY canon of the Nuremberg Code
To be fair, my guess is the position of CMS is that of many people like Peter Bach who believe that price-driven treatment selection does not required informed consent as long as you create a website for your cancer abacus. But even those who want limits on informed consent in comparative effectiveness trials would do so if patients were not assigned to the treatment arm.
CMS informs no patient. The guidance does not require doctors or hospitals to do so.
This is a deliberate attempt to side-step informed consent. And the Part B human experiment is just one part of a larger effort to limit patient choices in what are actually natural experiments by dressing them up as comparative effectiveness research.
I suggest anyone involved in the Part B human experiment read George and Catherine Annas' article on Therapeutic Ilusion to understand just how unethical the project is. The authors note:
"Historically, misleading and confusing terms such as “therapeutic research,” “experimental treatment,” and “invalidated
treatment” have been used to blur the distinction between research and treatment. Similar misleading terms are being deployed in an effort to make evidence-based medicine research (including comparative-effectiveness research) easier to do by dispensing with or watering down disclosure requirements."
By convincing themselves that the law of informed consent does not apply to treatment...The radically paternalistic result would be that physicians could not only set the “standard of care” for medical interventions—whether research or treatment—but also set the “standard of care” for informed consent for both. That quest is, we think, dangerous to the autonomy and dignity of patients and should be repulsed not only by patients, research subjects, and the public, but by physicians and researchers as well."
"CMS wants to reduce reimbursement for buy-and-bill drugs—but for only half of the country's providers. The other half will retain current reimbursement levels. After five years, CMS will see what happened. .."
As only Adam has pointed out this is an unprecedented experiment on patients.
Did anyone ask Medicare consumers if they wanted to participate? Did CMS offer to pay moving costs to people who want to be in the control arm of this experiment?
Did anyone ask if this was even ethical? Here's what the NIH Office of Human Research Protection guidance on informed consent requires. You tell me if the Medicare Part B experiment comes within a light year of this moral galaxy:
" Disclosing the reasonably foreseeable risks of research to prospective subjects recognizes the ethical obligation to give prospective subjects sufficient information to make a knowledgeable decision about whether or not to participate. This reflects the ethical principle of respect for persons, which recognizes the importance of giving individuals sufficient information during the informed consent process to make a considered judgment about whether to participate in research that could affect their health or wellbeing—for better or worse."
The CMS notice does not address any of these issues. Indeed, the phrase informed consent doesn't even show up in the proposal.
Instead:
"Providers, suppliers, and beneficiaries who are included in the model will have access to the existing claims appeals process, as well as a proposed Pre-Appeals Payment Exceptions Review process, to resolve disputes arising from the policies implemented by this model. "
In otherwords, no informed consent, not even passive consent. Instead, patients are being hereded into an experiment that in my opinion, violates EVERY canon of the Nuremberg Code
To be fair, my guess is the position of CMS is that of many people like Peter Bach who believe that price-driven treatment selection does not required informed consent as long as you create a website for your cancer abacus. But even those who want limits on informed consent in comparative effectiveness trials would do so if patients were not assigned to the treatment arm.
CMS informs no patient. The guidance does not require doctors or hospitals to do so.
This is a deliberate attempt to side-step informed consent. And the Part B human experiment is just one part of a larger effort to limit patient choices in what are actually natural experiments by dressing them up as comparative effectiveness research.
I suggest anyone involved in the Part B human experiment read George and Catherine Annas' article on Therapeutic Ilusion to understand just how unethical the project is. The authors note:
"Historically, misleading and confusing terms such as “therapeutic research,” “experimental treatment,” and “invalidated
treatment” have been used to blur the distinction between research and treatment. Similar misleading terms are being deployed in an effort to make evidence-based medicine research (including comparative-effectiveness research) easier to do by dispensing with or watering down disclosure requirements."
By convincing themselves that the law of informed consent does not apply to treatment...The radically paternalistic result would be that physicians could not only set the “standard of care” for medical interventions—whether research or treatment—but also set the “standard of care” for informed consent for both. That quest is, we think, dangerous to the autonomy and dignity of patients and should be repulsed not only by patients, research subjects, and the public, but by physicians and researchers as well."
At yesterday’s annual FDLI conference, FDA Commissioner Califf said that, “to achieve innovation, we must take risks.” And he wasn’t using the royal “we.”
He reiterated that one of his top priorities is to focus on staffing. (He also mentioned that he has about 100 “top priorities.”) There’s an important connection. The FDA’s ability to be an innovation enabler is directly linked to the issue of staff. Not necessarily more staff (although more is certainly better), but staff that is permitted, encouraged, cajoled, urged, directed, educated, and rewarded for taking risks – especially outside oncology and orphan diseases.
It’s slow going. There was solid momentum in the creative thinking of divisional staff in the early days of the new millennium, the McClellan years. But this nascent trickle of “entrepreneurial regulation” hit treacle in the face of the Vioxx imbroglio. It was a battle worth fighting – and winning. The agency is still recovering.
The good news is the agency has come a long way back. New pathways for approval are on the books with some notable clinical successes. New thinking on clinical endpoints and biomarkers, the patient-focused drug development initiative (with the patient voice evolving from tellers-of-sad-stories to allies in clinical development), and more robust programs on quality and pharmacovigilance have infused some inside the FDA to think outside the regulatory box. But entrepreneurial regulation must be more than the “some” of its parts. Proposed legislation could help advance and encourage these and other initiatives but, as the Commissioner commented at the FDLI event, new laws mustn’t allow drugs to enter the market that don’t provide therapeutic benefit. Amen and words to the wise.
Embracing the risks of expedited pathways and other aspects of 21st century entrepreneurial regulation requires better internal agency communication, collaboration, and coordination. If victory in that realm becomes the Califf legacy, it would be a hugely important one for both the FDA and the public health. Success rests, as FDA Chief Counsel Liz Dickinson so eloquently phrased it, “on the infusion of new people and novel ideas.”
The policy of being too cautious is the greatest risk of all. -- Jawaharlal Nehru
He reiterated that one of his top priorities is to focus on staffing. (He also mentioned that he has about 100 “top priorities.”) There’s an important connection. The FDA’s ability to be an innovation enabler is directly linked to the issue of staff. Not necessarily more staff (although more is certainly better), but staff that is permitted, encouraged, cajoled, urged, directed, educated, and rewarded for taking risks – especially outside oncology and orphan diseases.
It’s slow going. There was solid momentum in the creative thinking of divisional staff in the early days of the new millennium, the McClellan years. But this nascent trickle of “entrepreneurial regulation” hit treacle in the face of the Vioxx imbroglio. It was a battle worth fighting – and winning. The agency is still recovering.
The good news is the agency has come a long way back. New pathways for approval are on the books with some notable clinical successes. New thinking on clinical endpoints and biomarkers, the patient-focused drug development initiative (with the patient voice evolving from tellers-of-sad-stories to allies in clinical development), and more robust programs on quality and pharmacovigilance have infused some inside the FDA to think outside the regulatory box. But entrepreneurial regulation must be more than the “some” of its parts. Proposed legislation could help advance and encourage these and other initiatives but, as the Commissioner commented at the FDLI event, new laws mustn’t allow drugs to enter the market that don’t provide therapeutic benefit. Amen and words to the wise.
Embracing the risks of expedited pathways and other aspects of 21st century entrepreneurial regulation requires better internal agency communication, collaboration, and coordination. If victory in that realm becomes the Califf legacy, it would be a hugely important one for both the FDA and the public health. Success rests, as FDA Chief Counsel Liz Dickinson so eloquently phrased it, “on the infusion of new people and novel ideas.”
The policy of being too cautious is the greatest risk of all. -- Jawaharlal Nehru
How the mighty have fallen.
Once a newspaper of national importance, the Los Angeles Times has become a shadow of its former self. Consider it’s latest Page One investigation into Purdue Pharma. The drug manufacturer's malfeasance? Promoting on-label claims.
Really.
Here’s a link to the article and here’s a link to Purdue’s response.
According to Purdue, “In an attempt to resurrect a long-discredited theory, the paper ignores the clinical and regulatory data that directly contradicts their story.”
And they have the facts and citations to prove it. All of it.
Further, “Over the course of two years, Purdue Pharma provided the LAT with more than a dozen hours of briefings and discussions regarding the clinical evidence supporting OxyContin’s 12-hour dosing and the regulatory requirement that we promote the product as such. Unfortunately, the paper disregarded this information, instead publishing a story that’s long on anecdote and short on facts.”
Two years and the Times got the story so wrong? That’s bad news for the paper’s readers who expect and deserve better. Maybe it’s good news for the salivating tort bar. But before they start filing lawsuits, they better get the rest of the story.
For example (per Purdue):
CLAIM: OxyContin has a 12-hour dosing “problem” that puts patients at risk.
FACT: Nearly a decade ago, the FDA cited a lack of clinical evidence when it formally rejected the “fundamental premise” that patients receiving OxyContin at intervals more frequent than twice-daily are at increased risk of “side effects and serious adverse reactions.” In doing so, the agency reinforced the twice-daily labeling for OxyContin. The LAT omitted the findings of this report from its story.
Oops.
And my favorite:
CLAIM: Purdue should tell physicians to prescribe OxyContin for eight-hour use.
FACT: The FDA prohibits pharmaceutical companies from promoting their products for uses, including dosing, not approved by the agency. Given FDA has not approved OxyContin for eight-hour use, we do not recommend that dosing to prescribers. In fact, a State Attorney General recently cited a peer company for falsely claiming that OxyContin was an eight-hour drug. The LAT omitted this piece of information from its story, falsely claiming that OxyContin was an eight-hour drug. The LAT omitted this piece of information from its story.
Is there a fact checker in the house? Ouch.
There are so many serious issues surrounding opioids that the lack of professionalism by the LA Times is astounding.
I guess the Times ace I-Team can forget about that Pulitzer.
Once a newspaper of national importance, the Los Angeles Times has become a shadow of its former self. Consider it’s latest Page One investigation into Purdue Pharma. The drug manufacturer's malfeasance? Promoting on-label claims.
Really.
Here’s a link to the article and here’s a link to Purdue’s response.
According to Purdue, “In an attempt to resurrect a long-discredited theory, the paper ignores the clinical and regulatory data that directly contradicts their story.”
And they have the facts and citations to prove it. All of it.
Further, “Over the course of two years, Purdue Pharma provided the LAT with more than a dozen hours of briefings and discussions regarding the clinical evidence supporting OxyContin’s 12-hour dosing and the regulatory requirement that we promote the product as such. Unfortunately, the paper disregarded this information, instead publishing a story that’s long on anecdote and short on facts.”
Two years and the Times got the story so wrong? That’s bad news for the paper’s readers who expect and deserve better. Maybe it’s good news for the salivating tort bar. But before they start filing lawsuits, they better get the rest of the story.
For example (per Purdue):
CLAIM: OxyContin has a 12-hour dosing “problem” that puts patients at risk.
FACT: Nearly a decade ago, the FDA cited a lack of clinical evidence when it formally rejected the “fundamental premise” that patients receiving OxyContin at intervals more frequent than twice-daily are at increased risk of “side effects and serious adverse reactions.” In doing so, the agency reinforced the twice-daily labeling for OxyContin. The LAT omitted the findings of this report from its story.
Oops.
And my favorite:
CLAIM: Purdue should tell physicians to prescribe OxyContin for eight-hour use.
FACT: The FDA prohibits pharmaceutical companies from promoting their products for uses, including dosing, not approved by the agency. Given FDA has not approved OxyContin for eight-hour use, we do not recommend that dosing to prescribers. In fact, a State Attorney General recently cited a peer company for falsely claiming that OxyContin was an eight-hour drug. The LAT omitted this piece of information from its story, falsely claiming that OxyContin was an eight-hour drug. The LAT omitted this piece of information from its story.
Is there a fact checker in the house? Ouch.
There are so many serious issues surrounding opioids that the lack of professionalism by the LA Times is astounding.
I guess the Times ace I-Team can forget about that Pulitzer.
Yesterday I had the pleasure of attending and participating at the joint meeting of the FDA’s Drug Safety & Risk Management and Anesthetic and Analgesic Drug Products advisory committees.
The topics under discussion were the successes and failures of REMS programs for extended release (ER) and long-acting (LA) opioids. Many important presentations and discussion. Two statements that stood out as directional:
“REMS modifications shouldn’t unduly restrict patient access.” (Doris Auth, REMS Assessment Team Leader, Division of Risk Management, CDER)
“Education is not an event, it is a process.” (Graham McMahon, President & CEO, Accreditation Council for Continuing Medical Education)
In short – it’s important to move forward, weighing the risks and benefits of REMS programs not just for prescribers – but for patient too. Bravo.
I was chosen to offer public testimony, and here’s what I had to say:
To paraphrase Peter Drucker, the information revolution will shift -- from the generation of data, to figuring out the meaning and purpose of the data with the patient’s perspective in mind.
Nowhere is this more pertinent than in the discussion of the future of opioid pain medicine and the role of the FDA – and advancing both the science and regulatory approaches to appropriate pain care management. But cutting the Gordian Knot of what “appropriate” means demands more than current REMS programs. It requires working with the providers of continuing medical education to develop better curricula. It means ever better-validated risk evaluation and mitigation strategies with more thoughtful purpose.
It means enhanced and validated reporting tools for post-marketing surveillance. It means using real world data to provide real world advice. And it means using the tools of the 21st century century such as patient and physician apps.
The FDA can play an important role in working to develop and share (with a broad constituency) validated tools for physicians to use in determining which patients may be more prone to slide into abuse so they can choose their therapeutic recommendations more precisely.
One improvement will be to improve the accessibility of the ER/LA Opioid Analgesics REMS website, so that interested healthcare providers can more easily access accredited REMS-compliant material.
We must also work to continue expanding the to include the extended healthcare team. Education of team members beyond analgesic prescribers is critical for implementation of REMS learnings.
We should revise the FDA Blueprint for Prescriber Education to reflect stakeholder input and feedback
We should link Schedule II and Schedule III Narcotics DEA registration and re-registration to either completion of prescription opioid education or other acknowledgements, such as board certification in pain medicine. We should include IR opioids in the REMS modification discussion. It’s where the overwhelming volume is.
With the data collected from REMS programs, a logical next step is to utilize that real world data to amend product-specific labeling to indicate lessons learned outside of the rarified world of the randomized clinical trial environment to assist physicians in using the right product for the right patient. Real world evidence doesn’t just mean recognizing new risks, but also communicating new benefits learned through patient outcomes. And such evidence is both available and exciting.
Beyond the REMS programs discussed during the course of this meeting, the FDA has required all sponsors of brand name products with approved abuse-deterrent labeling to conduct long-term epidemiological studies to assess their effectiveness in reducing abuse in practice.
And then there’s the thorny question of FDA labeling. Product labeling is the basis for articulating the value proposition of a product. As you are aware, data definition and generation are very much still a work-in-progress – as is their relationship to clinical relevance. No absolute magnitude of effect can be set for establishing product characteristics. And the FDA continues to talk about the ambiguous totality of evidence standard – which really means using their best regulatory judgment.
One crucial question that deserves more conversation is the nature of the evidence used to decide whether or not a given product “works” to reduce abuse in the “real world.” Given the data challenges, it may be almost impossible to ever demonstrate a causal link between a new formulation and an impact on patient abuse – but is that because the product didn’t have an effect or our current measurement methodologies and data systems are inadequate to detect it?
The path forward is unclear. Is real world data reliable and robust enough? Should the FDA define and then assign various statistical weights to comparison and population studies? At the end of the day, the agency can’t only look to REMS for risk mitigation but must also seek out data that supports more aggressive labeling language.
Obviously, more work needs to be done in order to refine optimal data sources, study design, statistical methods, and epidemiologic outcomes of interest to developers, physicians, patients … and regulators. No one group can do it by themselves. We need a more, aggressive, creative, and collegial approach to the pain management ecosystem.
At the end of the meeting, the joint committee recommended mandating continuing education for doctors who prescribe opioids, ignoring American Medical Association calls for such requirements to be voluntary. The committee, which held no formal vote on the issue, also urged FDA to update its education materials by incorporating the new CDC guidelines on opioid prescribing and other material on alternative pain treatments. The committee suggested education be required for doctors seeking DEA registration to prescribe controlled substances.
The committee also urged the agency to update its risk evaluation and mitigation strategy to include shorter-acting opioids, amid criticism from some members that opioid manufacturers have too much influence over the strategy. The committee voted 30-0 to urge FDA to make changes to its entire opioid drug safety program. Some of the advisers said there was little evidence the current safety plan has had any effect, adding that it needed a greater emphasis on the drugs' risks.
The topics under discussion were the successes and failures of REMS programs for extended release (ER) and long-acting (LA) opioids. Many important presentations and discussion. Two statements that stood out as directional:
“REMS modifications shouldn’t unduly restrict patient access.” (Doris Auth, REMS Assessment Team Leader, Division of Risk Management, CDER)
“Education is not an event, it is a process.” (Graham McMahon, President & CEO, Accreditation Council for Continuing Medical Education)
In short – it’s important to move forward, weighing the risks and benefits of REMS programs not just for prescribers – but for patient too. Bravo.
I was chosen to offer public testimony, and here’s what I had to say:
To paraphrase Peter Drucker, the information revolution will shift -- from the generation of data, to figuring out the meaning and purpose of the data with the patient’s perspective in mind.
Nowhere is this more pertinent than in the discussion of the future of opioid pain medicine and the role of the FDA – and advancing both the science and regulatory approaches to appropriate pain care management. But cutting the Gordian Knot of what “appropriate” means demands more than current REMS programs. It requires working with the providers of continuing medical education to develop better curricula. It means ever better-validated risk evaluation and mitigation strategies with more thoughtful purpose.
It means enhanced and validated reporting tools for post-marketing surveillance. It means using real world data to provide real world advice. And it means using the tools of the 21st century century such as patient and physician apps.
The FDA can play an important role in working to develop and share (with a broad constituency) validated tools for physicians to use in determining which patients may be more prone to slide into abuse so they can choose their therapeutic recommendations more precisely.
One improvement will be to improve the accessibility of the ER/LA Opioid Analgesics REMS website, so that interested healthcare providers can more easily access accredited REMS-compliant material.
We must also work to continue expanding the to include the extended healthcare team. Education of team members beyond analgesic prescribers is critical for implementation of REMS learnings.
We should revise the FDA Blueprint for Prescriber Education to reflect stakeholder input and feedback
We should link Schedule II and Schedule III Narcotics DEA registration and re-registration to either completion of prescription opioid education or other acknowledgements, such as board certification in pain medicine. We should include IR opioids in the REMS modification discussion. It’s where the overwhelming volume is.
With the data collected from REMS programs, a logical next step is to utilize that real world data to amend product-specific labeling to indicate lessons learned outside of the rarified world of the randomized clinical trial environment to assist physicians in using the right product for the right patient. Real world evidence doesn’t just mean recognizing new risks, but also communicating new benefits learned through patient outcomes. And such evidence is both available and exciting.
Beyond the REMS programs discussed during the course of this meeting, the FDA has required all sponsors of brand name products with approved abuse-deterrent labeling to conduct long-term epidemiological studies to assess their effectiveness in reducing abuse in practice.
And then there’s the thorny question of FDA labeling. Product labeling is the basis for articulating the value proposition of a product. As you are aware, data definition and generation are very much still a work-in-progress – as is their relationship to clinical relevance. No absolute magnitude of effect can be set for establishing product characteristics. And the FDA continues to talk about the ambiguous totality of evidence standard – which really means using their best regulatory judgment.
One crucial question that deserves more conversation is the nature of the evidence used to decide whether or not a given product “works” to reduce abuse in the “real world.” Given the data challenges, it may be almost impossible to ever demonstrate a causal link between a new formulation and an impact on patient abuse – but is that because the product didn’t have an effect or our current measurement methodologies and data systems are inadequate to detect it?
The path forward is unclear. Is real world data reliable and robust enough? Should the FDA define and then assign various statistical weights to comparison and population studies? At the end of the day, the agency can’t only look to REMS for risk mitigation but must also seek out data that supports more aggressive labeling language.
Obviously, more work needs to be done in order to refine optimal data sources, study design, statistical methods, and epidemiologic outcomes of interest to developers, physicians, patients … and regulators. No one group can do it by themselves. We need a more, aggressive, creative, and collegial approach to the pain management ecosystem.
At the end of the meeting, the joint committee recommended mandating continuing education for doctors who prescribe opioids, ignoring American Medical Association calls for such requirements to be voluntary. The committee, which held no formal vote on the issue, also urged FDA to update its education materials by incorporating the new CDC guidelines on opioid prescribing and other material on alternative pain treatments. The committee suggested education be required for doctors seeking DEA registration to prescribe controlled substances.
The committee also urged the agency to update its risk evaluation and mitigation strategy to include shorter-acting opioids, amid criticism from some members that opioid manufacturers have too much influence over the strategy. The committee voted 30-0 to urge FDA to make changes to its entire opioid drug safety program. Some of the advisers said there was little evidence the current safety plan has had any effect, adding that it needed a greater emphasis on the drugs' risks.
Francis Bacon was perhaps the first scholar to note that we are all guilty of confirmation bias. He observed that “the human understanding when it has once adopted an opinion (either as being the received opinion or as being agreeable to itself) draws all things else to support and agree with it.”
Confirmation bias explains the synergistic relationship between so-called studies that look at drug pricing, the media attention paid to these articles and the virtual absence of reporting on studies looking at the ecosystem for treating cancer.
Two articles on the price of oral cancer drugs – one in JAMA and the other in Health Affairs are examples of this disease.
The articles look only at the list price of cancer drugs over 10 years.
They could have looked at the increase in the list price of non-drug cancer care (which has increased as well) but they didn’t.
Nor will you find any discussion of the fact the over the time periods studied, increased use of oral cancer drugs was associated with a decline in hospitalization and outpatient spending associated with increased use in oral oncology.
There are hundreds of articles reporting on these studies that with rare exception (Ed Silverman at STAT) note that the ‘studies’ do consider drug prices in context. In particular, confirmation bias has lead researchers and reporters alike to ignore other economic and clinical factors impacting the cost – and – value of cancer drugs:
A recent IMS Oncology report – largely ignored by the same journalists writing about the two articles -- found that utilization, not price, was the main driver of spending on cancer drugs with longevity of patients a key driver of use.
Targeted therapies (not including rebates, patient assistance support, etc. ) now account for almost 50% of total spending and they have been growing at a compound average growth rate of 14.6% over the past five years
Overall therapy treatment costs per month have increased 39% over the past ten years in in inflation- adjusted terms, similar to the 42% increase in overall response rates and 45% increase in months that patients are on therapy, which also contribute to higher overall spending levels associated with improved survival rates. http://www.imshealth.com/imshealth-web-aux/controller/getReport
2. The increase in use of targeted therapies w diagnostics are associated with an increase in duration of response and survival. In fact, the use of oral cancer drugs is associated with a 150 percent increase in treatment duration.
3. Neither article accounts for the fact that newest oral cancer drugs are targeting smaller groups of patients based on tumor subtype and mutational status.
4. Neither article noted that over the same period they were obsessing about drug prices, cancer costs increased at the same rate as overall health spending. Another well-ignored Milliman study found
Over the entire 2004 to 2014 study period, the average annual increase in cost was essentially the same in the actively treated cancer population and the non-cancer population.
Cancer prevalence increased from 2004 to 2014 more than the contribution of cancer patients’ cost to the total population spend.
For patients being actively treated, the portion of spending for cancer-directed pharmaceuticals increased from 2004 to 2014 while the portion of spending for inpatient care declined.
Finally, the articles ignored yet another study showing the increase in rebates as a percent of price increases. The chart below shows the rebates as a percent of gross sales for Bristol Myers as it introduced immunotherapies for cancer.
“As people's opportunities to succumb to confirmation bias increases online - only seeking out information that confirms their prejudices - ignorance, extremism and close-mindedness have continued to rise unabated.” Maajid Nawaz
I’ve just returned from a cold, blustery and wet London where I attended the annual Pharma Access Leaders Forum.
But the meeting was hot.
In fact, piping hot when you consider the tectonic changes being felt in the world of healthcare technology assessment (HTA) and their implications on both patient access and innovation. And the linkages couldn’t be more profound.
Wither HTA in the EU? A key red thread through a series of potent discussions was real world evidence (aka, “outcomes data”). Head honcho HTA officials from across Europe (including England and Scotland – both still in Europe as of last report) returned again and again to the value of outcomes not just for the evolving world of Risk Sharing Agreements, but for the acceleration of reimbursement science.
Reimbursement science? In July 2012, when Sir Michael Rawlins was chairman of NICE, he told the House of Commons that value, “is based on the collective judgment of the health economists we have approached across the country. “It is,” Sir Michael said, elusive.”
When it comes to HTA – the times they are a-changin'.
One key insight came from Finn Børlum Kristensen, Chairman of the Executive Committee, European Network for HTA (EUnetHTA), who reminded the conference of JM Eisenberg’s advice, “Globalize the evidence, localize the decision.”
Just as we’ve finally come to realize the urgency of regulatory science (adaptive clinical pathways, imaging, bioinformatics, biomarker validation, 21st century bioequivalence, etc.) to the future of healthcare, so too must we understand and encourage the development of reimbursement science. And high up on the list of items to consider is the validity and utility of outcomes data. We’ve come a long way from the 2007 NICE/Velcade risk-sharing arrangement. Today the stakes are higher and the battle has ratcheted up to a higher level.
When it comes to reimbursement science, we are still in early days. For example, while many HTA bodies in Europe have moved beyond accepting evidence exclusively “the old fashioned way” (via the traditional RCT “gold standard”), there are exceptions – such as Germany. As Detlef Parow (Head of Care Management at DAK-Gesundheit) pointed out, IQWiG will only look at outcomes data “only in exceptional cases.” (This is in keeping with the IQWiG “Principle of Prohibition,” where “Everything is forbidden if it is not expressly permitted.”)
The always-insightful Francois Meyer (Advisor to the President, Director of International Affairs for HAS -- France’s Haute Autorité de Santé) wisely suggested more formal early dialogues on scientific advice – similar to the regulatory science initiatives that drive the conversations between FDA and innovators. This would give HTA bodies the opportunity to identify key issues and receive draft company positions, discuss divergent views and try to reach consensus before any final submissions or decisions are made. Sometimes the most common-sense recommendations are the toughest to implement.
But, as with FDA and the advancement of regulatory science, much depends on willingness and ability to implement based on infrastructure, capabilities, and trust. The end goal is the same for all stakeholders -- ensuring optimal use of resources for healthcare systems; improving access to value-adding medicines for patients; and appropriate reward for innovation.
In a 2009 white paper, I wrote, “We need to develop proposals that modernize the information used in the evaluation of the value of treatments. Just as the key scientific insights guiding the FDA Critical Path program are genetic variations and biomedical informatics that predict and inform individual responses to treatment, we must establish a science-based process that incorporates the knowledge and tools of personalized medicine in reimbursement decisions: true evidence-based, patient-centric medicine.”
Today, right now, we need a Critical Path for Healthcare Technology Assessment to begin the process of developing a similar list of ways new discoveries and tools (such as electronic patient records) can be used to improve the predictive and prospective nature of clinical outcomes. In an era of personalized medicine, one-size-fits-all treatments and reimbursement strategies are dangerously outdated. Accepting real world evidence does not mean discarding the randomized “gold standard” – it means augmenting it.
It’s a complicated proposition—but such a goal is as simple as it is essential -- cost must never be allowed to trump care, and short-term savings must not be allowed to trump long-term outcomes. Just as we need new and better tools for drug development, so too do we need them for HTA.
A health technology assessment model for the 21st Century should reflect and measure individual response to treatment based on the combination of genetic, clinical, and demographic factors that indicate what keep people healthy, improve their health, and prevent disease. A rapidly aging society demands a new healthcare paradigm capable of providing for its needs in the 21st Century. Equality of care must be matched with quality of care.
But the meeting was hot.
In fact, piping hot when you consider the tectonic changes being felt in the world of healthcare technology assessment (HTA) and their implications on both patient access and innovation. And the linkages couldn’t be more profound.
Wither HTA in the EU? A key red thread through a series of potent discussions was real world evidence (aka, “outcomes data”). Head honcho HTA officials from across Europe (including England and Scotland – both still in Europe as of last report) returned again and again to the value of outcomes not just for the evolving world of Risk Sharing Agreements, but for the acceleration of reimbursement science.
Reimbursement science? In July 2012, when Sir Michael Rawlins was chairman of NICE, he told the House of Commons that value, “is based on the collective judgment of the health economists we have approached across the country. “It is,” Sir Michael said, elusive.”
When it comes to HTA – the times they are a-changin'.
One key insight came from Finn Børlum Kristensen, Chairman of the Executive Committee, European Network for HTA (EUnetHTA), who reminded the conference of JM Eisenberg’s advice, “Globalize the evidence, localize the decision.”
Just as we’ve finally come to realize the urgency of regulatory science (adaptive clinical pathways, imaging, bioinformatics, biomarker validation, 21st century bioequivalence, etc.) to the future of healthcare, so too must we understand and encourage the development of reimbursement science. And high up on the list of items to consider is the validity and utility of outcomes data. We’ve come a long way from the 2007 NICE/Velcade risk-sharing arrangement. Today the stakes are higher and the battle has ratcheted up to a higher level.
When it comes to reimbursement science, we are still in early days. For example, while many HTA bodies in Europe have moved beyond accepting evidence exclusively “the old fashioned way” (via the traditional RCT “gold standard”), there are exceptions – such as Germany. As Detlef Parow (Head of Care Management at DAK-Gesundheit) pointed out, IQWiG will only look at outcomes data “only in exceptional cases.” (This is in keeping with the IQWiG “Principle of Prohibition,” where “Everything is forbidden if it is not expressly permitted.”)
The always-insightful Francois Meyer (Advisor to the President, Director of International Affairs for HAS -- France’s Haute Autorité de Santé) wisely suggested more formal early dialogues on scientific advice – similar to the regulatory science initiatives that drive the conversations between FDA and innovators. This would give HTA bodies the opportunity to identify key issues and receive draft company positions, discuss divergent views and try to reach consensus before any final submissions or decisions are made. Sometimes the most common-sense recommendations are the toughest to implement.
But, as with FDA and the advancement of regulatory science, much depends on willingness and ability to implement based on infrastructure, capabilities, and trust. The end goal is the same for all stakeholders -- ensuring optimal use of resources for healthcare systems; improving access to value-adding medicines for patients; and appropriate reward for innovation.
In a 2009 white paper, I wrote, “We need to develop proposals that modernize the information used in the evaluation of the value of treatments. Just as the key scientific insights guiding the FDA Critical Path program are genetic variations and biomedical informatics that predict and inform individual responses to treatment, we must establish a science-based process that incorporates the knowledge and tools of personalized medicine in reimbursement decisions: true evidence-based, patient-centric medicine.”
Today, right now, we need a Critical Path for Healthcare Technology Assessment to begin the process of developing a similar list of ways new discoveries and tools (such as electronic patient records) can be used to improve the predictive and prospective nature of clinical outcomes. In an era of personalized medicine, one-size-fits-all treatments and reimbursement strategies are dangerously outdated. Accepting real world evidence does not mean discarding the randomized “gold standard” – it means augmenting it.
It’s a complicated proposition—but such a goal is as simple as it is essential -- cost must never be allowed to trump care, and short-term savings must not be allowed to trump long-term outcomes. Just as we need new and better tools for drug development, so too do we need them for HTA.
A health technology assessment model for the 21st Century should reflect and measure individual response to treatment based on the combination of genetic, clinical, and demographic factors that indicate what keep people healthy, improve their health, and prevent disease. A rapidly aging society demands a new healthcare paradigm capable of providing for its needs in the 21st Century. Equality of care must be matched with quality of care.
From the pages of the Buffalo News:
Insurers have incentive to keep plans affordable
A recent editorial called the provision that prohibits the government from negotiating Medicare Part D drug prices “a ruinously bad decision.” (“Panel offers a blueprint for dealing with ruinous cost of prescription drugs,” April 22 News.)
Yet keeping the feds out of price negotiations between private insurers and drug companies has worked wonders. Surveys indicate nine out of 10 seniors are satisfied with their Part D coverage; 96 percent report that their coverage works well. And because insurers have a financial incentive to attract enrollees by keeping plans affordable, the program cost $349 billion less than initially projected during its first decade.
With satisfaction and savings like that, it’s a shame the government doesn’t make “ruinously bad decisions” more often.
Peter J. Pitts
President, Center for Medicine in the Public Interest; Former Associate Commissioner, FDA
Insurers have incentive to keep plans affordable
A recent editorial called the provision that prohibits the government from negotiating Medicare Part D drug prices “a ruinously bad decision.” (“Panel offers a blueprint for dealing with ruinous cost of prescription drugs,” April 22 News.)
Yet keeping the feds out of price negotiations between private insurers and drug companies has worked wonders. Surveys indicate nine out of 10 seniors are satisfied with their Part D coverage; 96 percent report that their coverage works well. And because insurers have a financial incentive to attract enrollees by keeping plans affordable, the program cost $349 billion less than initially projected during its first decade.
With satisfaction and savings like that, it’s a shame the government doesn’t make “ruinously bad decisions” more often.
Peter J. Pitts
President, Center for Medicine in the Public Interest; Former Associate Commissioner, FDA
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.
