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Celltrion conducted clinical studies of CT-P13 in rheumatoid arthritis (RA) and ankylosing spondylitis (AS), and is seeking extrapolation of CT-P13 across all seven of Remicade's approved indications including Crohn's disease, pediatric Crohn's disease, ulcerative colitis (UC), pediatric UC, psoriatic arthritis and plaque psoriasis.
In the briefing documents, FDA reviewers said the preclinical, clinical and manufacturing data submitted by Celltrion suggest that it is "highly similar" to Remicade. Agency officials noted that while there were differences in the binding of the Fc regions between Remicade and CT-P13, "it is reasonable to extrapolate conclusions regarding the similar efficacy and safety of CT-P13 and U.S.-licensed Remicade to IBD."
In brief, the FDA recommends approval for all indications mostly based on analytical studies along with some clinical (primarily for RA and AS data). Emphasis on analytics is not surprising based on the FDA biosimilar pathway – but what is interesting (and disturbing) is the absence of available real world data. More on this important patient safety issue shortly.
Infliximab is particularly relevant to the overall conversation regarding indication extrapolation because structural differences have been identified as potentially related to the treatment of inflammatory bowel diseases. The EMA has granted the product full extrapolation including inflammatory bowel diseases, while Health Canada did not, citing uncertainty regarding the clinical impact of observed structural differences.
AdComm members will be asked to discuss the similarity of CT-P13 to Remicade, whether there are clinically meaningful differences between the two mAbs, and whether there are sufficient data to support extrapolation to the approved indications beyond those studied in clinical trials. The panel will vote on whether CT-P13 should be approved as a biosimilar of Remicade for each of the seven indications.
Interestingly, the FDA has will not ask the panel to discuss any of the comparative real world data available that speaks to relevant clinical outcomes. This is particularly disturbing since (on page 11 of the briefing package) the agency FDA made statements on switching (per RA and AS) that would support the safety of a one-time switch from innovator to biosimilar. This is particularly important since Celltrion is NOT seeking interchangeability.
Should “defacto interchangeability” be an acceptable regulatory pathway?
Specifically absent from the FDA AdComm package is data from a study, from Mercy University Hospital, University College Cork, Centre for Gastroenterology, Mercy University Hospital, Cork, Ireland, which studied the clinical impact of both the innovator product (Remicade) and CT-P13, the Celltrion biosimilar. The findings are important. Specifically, the rates of surgery of the groups were significantly different.
80% of biosimilar patients required hospital readmission versus 5% of the Remicade) group. (p=0.00004). 60% of patients in the biosimilar group needed steroid augmentation of standard steroid tapering protocol with 50% requiring multiple increases in steroid dose versus 8% of those patients on Remicaide (p-value = 0.0007). Over the course of 8 weeks, 93% of patients in the biosimilar group had an increase in CRP with 7% remaining unchanged whereas 100% of patients in the Remicade group had a decrease in CRP (p=<0.001).
The study’s conclusion is not ambiguous, “Our results suggest that biosimilars may not be as efficacious as the reference medicine. The results found reflect the ECCO statement position that the use of most biosimilars in IBD will require testing in this particular patient population and cannot be extrapolated from other disease populations."
The complete poster can be found here.
An American College of Rheumatology abstract of CT-P13 data shows important differences between adverse events in patients with rheumatoid arthritis and those with ankylosing spondylitis depending on whether or not they were switched.
The ACR abstract can be found here.
The efficacy data was good. But the safety data is concerning. But the FDA AdComm won’t be discussing this study either.
Biosimilarity and measurement of efficacy is only one dimension. Attention must be paid to effectiveness relative to real-world patient outcomes data. Regulatory sins of omission are dangerous when it comes to the public health. Read More & Comment...
The FDA has announced a far-reaching action plan to reassess the agency’s approach to opioid medications. The plan will focus on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief.
Importantly, the FDA’s strategies and tactics are not adverse to the well-being of pain patients and avoid measures (such as mandatory advisory committees for abuse deterrent formulations) that would have the negative consequence of chilling investment in the science of abuse deterrence.
The FDA will:
• Re-examine the risk-benefit paradigm for opioids and ensure that the agency considers their wider public health effects;
• Convene an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;
• Assemble and consult with the Pediatric Advisory Committee regarding a framework for pediatric opioid labeling before any new labeling is approved;
• Develop changes to immediate-release opioid labeling, including additional warnings and safety information that incorporate elements similar to the extended-release/long-acting (ER/LA) opioid analgesics labeling that is currently required;
• Update Risk Evaluation and Mitigation Strategy requirements for opioids after considering advisory committee recommendations and review of existing requirements;
• Expand access to, and encourage the development of, abuse-deterrent formulations of opioid products;
• Improve access to naloxone and medication-assisted treatment options for patients with opioid use disorders; and
• Support better pain management options, including alternative treatments.
As one of the cornerstones of this plan, the FDA will seek guidance from outside experts in the fields of pain management and drug abuse. For example, the FDA has already asked the National Academy of Medicine to help develop a framework for opioid review, approval and monitoring that balances individual need for pain control with considerations of the broader public health consequences of opioid misuse and abuse.
“We are determined to help defeat this epidemic through a science-based and continuously evolving approach,” said
Per Rob Califf, the FDA’s Deputy Commissioner for Medical Products and Tobacco “This plan contains real measures this agency can take to make a difference in the lives of so many people who are struggling under the weight of this terrible crisis.”
In addition, the FDA will convene independent advisory committees made up of physicians and other experts when considering for approval any new opioid drugs that do not contain abuse-deterrent properties. The FDA will also convene a meeting of its standing Pediatric Advisory Committee to make recommendations regarding a framework for pediatric opioid labeling and use of opioid pain medications in the pediatric population.
The FDA is also strengthening the requirements for drug companies to generate postmarket data on the long-term impact of using ER/LA opioids. The agency expects this to result in the most comprehensive data ever collected in the field of pain medicine and treatments for opioid use disorder. The data will further the understanding of the known serious risks of opioid misuse, abuse, overdose and death.
The FDA’s full announcement can be found here.Read More & Comment...
On February 9th, the FDA’s Arthritis Advisory Committee will discuss biologics license application (BLA) 125544, for CT-P13, a proposed biosimilar to Janssen Biotech Inc.'s REMICADE (infliximab), submitted by Celltrion, Inc.
If the Adcomm gives a thumbs up and the agency approves the product, this will be the second biosimilar approved in the U.S., but the very first monoclonal antibody, a much more complex molecule than filgrastim.
Apart from the product issues, there are many important policy issues that should be discussed. For example:
Labeling, naming, coding, substitution, non-medical switching and interchangeability are all-important policy issues that FDA has the authority to impact and are appropriate to raise at a high level AdComm.
While extrapolation was allowed for filgrastim, the questions of extrapolation for this product are not as simple or straight forward for the following reasons:
Complexity and Stability
Filgrastim is generally not used as a long-term product for a life-long, chronic disease like infliximab and is much less complex than infliximab, which is nearly eight times larger. Monoclonal antibodies are used in patients with moderate to severe diseases like Crohn’s or ulcerative colitis and disease stability is critical. With biosimilar entry the risk of switching the patient to a new, similar product must be carefully considered due to the complexity of the product and disease state.
Regulatory Authorities Split
Because biosimilars are not identical copies of their reference products, even slight differences in structure can affect the biosimilar’s mechanism of action. Without clinical data in each therapeutic area, it may be challenging to understand the impact of these differences on clinical outcomes. Infliximab is particularly relevant to the overall conversation regarding indication extrapolation because structural differences have been identified which are thought to be potentially related to the treatment of inflammatory bowel diseases. The EMA has granted the product full extrapolation including inflammatory bowel diseases, while Health Canada did not, citing uncertainty regarding the clinical impact of observed structural differences.
Biosimilar sponsors compare the structure and function of their products to the reference product using a range of laboratory (i.e., analytical tests) tests. Because of the complexity and uncertainty with regard to monoclonal antibodies, we can’t always tell which product attributes (or parts of the structure) will be relevant to ultimate clinical outcome and which won’t be. This is why it’s critical that FDA take a conservative approach and ensure that the biosimilar and reference product are as highly similar as possible, across a wide variety of structural and functional attributes.
Studies Suggest Different Response in Different Disease States
An American College of Rheumatology abstract of infliximab biosimilar data shows difference between adverse events in patients with rheumatoid arthritis (RA) and those with Ankylosing Spondylitis (AS) depending on whether or not they were switched with a 22.5% difference in AS patients that were switched:
* Ankylosing Spondylitis (AS) TEAEs - 48.9% on biosimilar; 71.4% switched from innovator to biosimilar
* Rheumatoid Arthritis (RA) TEAEs – 53.5% on biosimilar; 53.8% switched from innovator to biosimilar.
Regulatory authorities recognize the importance of robust post-marketing safety monitoring for all drugs including biosimilars. What make biosimilars different from other drugs however is that unlike generic small molecule medicines where safety can be assumed to be identical as its branded counterpart, a biosimilar is not identical to its reference drug. Another defining difference with biosimilars is that all biologic medicines may trigger the human immune system to react in undesirable ways such as rendering the medicine ineffective. Small difference between products may result in different effects on the body’s immune system.
* Post-marketing safety monitoring is heavily dependent upon voluntary reporting of adverse events by health care professionals and patients. Unfortunately, this system does not have the capability to effectively monitor and accurately identify adverse events as a result of triggering the body’s immune system. It is unclear how regulators can or will implement robust ways to compare the safety of a biosimilar to its reference product once approved.
It may be February in Maryland – but the heat is on the FDA.Read More & Comment...
BIO released a set of voluntary principles that include a set of commitments by the trade group and its member companies to support "comprehensive and sustainable solutions to improve patient access to and affordability of innovative medicines." The principles include a commitment to work with payers, healthcare providers and policy makers to maximize patient benefit and drive "smarter" healthcare spending via "value-based and outcomes-based contracting arrangements, patient adherence and education programs, alternative financing and payment mechanisms, or other similar options."
Thee BIO PRINCIPLES ON THE VALUE OF BIOPHARMACEUTICALS begins as follows:
BIO member companies are committed to investing in, developing, and delivering innovative biopharmaceuticals that are transforming how we treat and cure patients with once-devastating diseases – giving them hope, extending survival, and saving millions of lives. The value that these innovative medicines offer to patients and their caregivers, the healthcare system, and society at large is truly a game-changer. The critical issue is how best to ensure that these medicines are accessible to patients in need, while continuing to foster the risk-taking required to sustain the promise of future treatments and cures. This issue is the subject of vigorous public policy debate, and we welcome it.
Per a report in BioCentury, Ron Cohen, president and CEO of Acorda Therapeutics Inc. and chairman of BIO, the trade group is putting the final touches on a media and lobbying campaign emphasizing the value of biopharmaceuticals and the high costs of other healthcare products and services. BIO's new principles also include a commitment to work with policy makers to "remove legal barriers that currently limit the ability to engage in value-based contracting and communications."
Stakeholders also told BioCentury that regulatory barriers to outcomes-based pricing contracts include FDA's prohibition on discussion of off-label uses of drugs and agency regulations that prevent companies from working with payers prior to approval to develop creative payment strategies. The FDA has listed these issues as key topics for the agency to address in its 2016 guidance agenda process.Read More & Comment...
Well sort of. As Adam Fein has noted, most generic drug price increases are a response to shortages, of which we have way too many. In most cases, the price increases can be blamed on drug shortages. "For example, the NADAC per unit for doxycycline hyclate (100 mg tab) increased from 5.6 cents to $3.65 (+6,351%). The increase is most likely due to a nationwide shortage. I presume there’s also an active gray market, as in generic injectables. For context, see Drug Shortages and Gray Market Profiteering."
And the retail price, once again, is not the real price. Again, Adam (drug)channels Mr. Spock in his logical analysis of the gap between retail and acquisition cost.
Adam's columns on pricing are more educational and authoratative than the turgid reports from some members of Congress.
Read More & Comment...
Two new lows were hit by Robert Langreth (with Rebecca Spalding) at Bloomberg and USA Today's Jane O’Donnell.
Langreth and Spalding wrote a predictably predictable article on the eve of Martin Shkreli’s no show congressional flogging. Predictable and derivative since it recycled the same stuff written by other low achieving reporters. The headline says it all: Shkreli Was Right: Everyone's Hiking Drug Prices.
So I will respond by recycling a previous blog on a ‘me-too’ pricing article in noting that Langreth fails to put drug price increases (net price or otherwise) into perspective. Langreth states that U.S. prescription-drug spending rose 12.2% in 2014, accelerating from 2.4% growth in 2013. But “price increases for protected brands increased spending by $26.3 billion, contributing 8.2% to total market growth on an invoice price basis; estimated net price growth was substantially lower as rising off-invoice discounts and rebates offset incremental price growth and reduced net price contribution to growth to 3.1%.”
That’s an increase in spending of about $7.1 billion. Total US health care spending increased by $100 billion from 2013-2014. So brand drugs were 7 percent of that amount.
O’ Donnell takes reporting on drug prices to a new low in "Patient groups funded by drugmakers are largely mum on high drug prices" She accuses patient groups that receive support from biotech firms from blocking efforts to impose price controls. The headline is the tipoff. To be more precise, she let’s Zeke Emanuel do the smearing. If you want a job done well, hire a pro:
"It is worrisome because it is a conflict of interest even if you can’t prove it changes their position," says Ezekiel Emanuel, an oncologist and professor who chairs the University of Pennsylvania's department of medical ethics and health policy. "The patient voice carries a disproportionate amount of weight."
So if someone alleges it changes your position, that’s a conflict of interest.
By that standard, the patient groups she cites as conflict free should also be suspected of conflict. More specifically, the Patient Voice Institute works with the Leapfrog Group which also gets money from large employers, health purchasing groups and AARP. All three are quoted in the article. But applying Zeke’s conflict benchmark, the fact that I can’t prove any connection means it is a conflict.
The j’accuse of getting funding from corporations is a diversion. O’Donnell, like many of her colleagues fail to look at the cost of new drugs relative to what insurance companies spend. It’s about 3 percent. And that spending makes treating illness less expensive by reducing hospitalization, saves lives and improves quality of life.
The question O’Donnell ignores is the one the Leukemia and Lymphoma Society answered about a year ago: How much would it really cost to pay for the drugs insurers scream are too expensive?
They commissioned a Milliman study and found that it would cost on average about 50 cents per patient per month. If drugs were driving up overall costs (as opposed to reducing them, which they do) why such a small increase to make people whole?
O’Donnell had the opportunity and column space to look at this issue. Instead she went down a darker, more deceptive road. What a shame. Then again, it's not surprising. Read More & Comment...
Mark Baum’s self-serving op-ed in the Wall Street Journal (New Prescription for Lower Drug Prices) that compounded-drug makers can bring inexpensive, off-patent medicines to market, “if the FDA will let them” omits a key issue in the debate – public safety.
Just last week, two Alabama pharmacists agreed to plead guilty to criminal charges in connection with the 2011 deaths of nine Birmingham-area patients who allegedly received a contaminated compounded drug.
According to federal prosecutors, the drugs were contaminated from being prepared, packed or held in unsanitary conditions. The Centers for Disease Control and Prevention found the same bacteria on a water faucet in an open container of amino acid powder, and on the surface of mixing equipment that had been used to make the drug, according to federal prosecutors.
Also last week, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said she has ruled out the use of compounding to combat spikes in generic drug prices.
Woodcock told the U.S. Senate Health, Education, Labor and Pensions (HELP) Committee that "there are very great risks" from FDA allowing mass production of compounded drugs to reduce the cost of a generic drug. Woodcock said that while recent legislation gives FDA additional power to enforce quality standards on pharmacies that compound sterile injectable drugs, FDA has limited oversight authority over compounding of tablets and pills. She said FDA has recently withdrawn compounded vitamin and hormone products after pharmacies distributed potentially fatal super-potent formulations.
Despite Mr. Baum’s rosy commercial projections, compounded drugs may be sub- or super potent, contaminated, or otherwise adulterated. Additional health risks include the possibility that patients will use ineffective compounded drugs instead of FDA-approved drugs that have been shown to be safe and effective.
His company, Imprimis, has had challenges with its compounding facilities in New Jersey and Southern California, both of which have been issued letters from the FDA citing Common Good Manufacturing Practices (CGMP) violations that could call into question the safety and effectiveness of the drugs compounded there.
Putting price before patient safety is bad medicine and worse policyRead More & Comment...
Sleeping with the Enemy? Hardly. Eli Lilly & Co. has announced an important collaboration with an unlikely bedfellow – their Hoosier neighbor, Anthem. The goal is to help develop common ground on policy solutions related to cost and value. Finally – two important players understand that they are, in fact, on the same team.
More information can be found here.Read More & Comment...
FDA finds Indian drug maker Wockhardt hid failed tests
MUMBAI | BY ZEBA SIDDIQUI
Indian drugmaker Wockhardt hid the results of failed tests and deleted data from its systems at a plant in western India, according to a report by the U.S. Food and Drug Administration sent to the company earlier this month and seen by Reuters.
Issues around "data integrity", maintaining accurate and consistent databases, are key to the U.S. watchdog, which regulates the world's largest market for generics producers.
Wockhardt is the latest of several major players in the $15 billion Indian drugs industry to be hit by U.S. regulatory action over the past few months.
It makes around a fifth of its $670 million in annual revenues from the United States and had said the Shendra plant, the site that prompted the FDA report, would boost its U.S. business. Shendra makes lucrative injectable medicines, which analysts say are key to Wockhardt’s U.S. plans.
Wockhardt did not return several telephone calls and emails requesting comment on the detailed report.
The FDA did not immediately respond to a request for comment on its report. It issues such reports, known as a 'Form 483', when its staff believe that conditions at a manufacturing site could lead to products that are harmful to human health.
In the report, dated Jan. 12, the FDA said that among other violations, the audit showed that the results of 22 failed tests had not been recorded. It also found multiple data files had been deleted from some machines.
The FDA did not detail whether the files or tests related to specific drugs, or whether the violations could impact the quality of medication produced at a plant which still exports to Britain and Ireland.
FDA inspectors also reported finding pharmaceutical ingredients that were not stored or labeled properly. A rejected drug batch was stored in the "approved material" area, and some batches did not carry expiry dates, the report said.Read More & Comment...
Citing his “extensive ties to the pharmaceutical industry,” Senator Bernie Sanders has placed a hold on the nomination of Rob Califf to be FDA Commissioner.
What are those “extensive ties?” Working to design and field innovative clinical trials for FDA review. You want the best and the brightest to work with industry on such matters – because industry is the one that does them. Not academia. Not NIH. Not physicians. And not the FDA. The pharmaceutical industry. And well-designed and executed clinical trials provide important insights into the benefits and risks of potential new therapies. To those reading this column this isn’t a surprise – but to many others it is.
If Senator Sanders thinks that having one of our nation’s keenest clinical trial design experts working with industry is a reason to place a hold on his nomination, then it’s time for him to step back and reconsider his position. When it comes to clinical trials that investigate safety and efficacy, we can't afford to use only the second best and almost brightest.
Yes, Bernie has other things on his mind at the moment, but facts as pesky things.Read More & Comment...
Somewhat different (but similar) from the FDA's "Filgrastim SNDZ" naming decision, the World Health Organization has posted a final version of its proposed biologics naming policy. It proposed that each biologic, including biosimilars, would be assigned a four-letter “biological qualifier” (BQ) that would make it possible to trace the compounds globally. BQs could be used for pharmacovigilance and to facilitate transferring prescriptions among countries.
WHO would generate BQs. The qualifiers would consist of random consonants, would be separate from non-proprietary names, and could be assigned retrospectively or prospectively.
It's BQ IQ.
A new report by the Pharmacy Benefit Management Institute (PBMI) makes some very interesting points about the value of PBMs to employers and employees. Some highlights include:
* PBM generic copays are in line with overall inflation, only increasing from $9.85 to $10.85 over a 15-year period in inflation-adjusted dollars.
* Preferred and non-preferred brand copays (preferred brand from $19.43 to $31.08 and non-preferred from $37.58 to $56.65) have outpaced inflation considerably.
* Plan sponsors increased use of prescription drug benefit deductibles by 157% in 2015 compared to 2014.
* In 2014, only 14% of plan sponsors reported having a deductible for prescription drugs compared to 36% in 2015.
* There is considerable opportunity for employers who are willing to implement additional strategies to control costs and utilization without shifting additional costs to members.
* Mail order in particular can save members an average of over four monthly copayments per prescription per year (annualized). For a member taking a preferred brand in a three-tier plan design, this equates to yearly savings of $138.88 for a single maintenance medication.
The complete report (sponsored by Takeda Pharmaceuticals) can be found here.Read More & Comment...
Shaywitz writes he was delighted to see the editorial:
"Not because I agreed with it–my heart is truly with the data scientists–but because I was grateful that someone had the courage to articulate a perspective I’ve come to believe is shared by the vast majority of academic researchers, but publicly voiced by no one–until now.
The result: a classic case of stated preference vs. revealed preference, where every academic researcher dutifully claims to be interested in sharing their data widely and freely, but somehow, tend not to actually do this."
David is right. But there is even more reason to ‘cheer’ the NEJM article. It reveals that scientist think it is “their” data when in fact it is the patient’s data. The researcher is entrusted with that data by us to use it to advance science and promote cures.
And the self-interested way such data is used – or shared – often abrogates the social contract in many ways.
Let me focus on one in particular, from the research article in the NEJM -- CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer -- that was the subject of the editorial. The researchers used data collected from cancer patients by the National Cancer Institute. Drazen and Longo call this “symbiotic collaboration.” I would call it another permutation of an approach that betrays patients.
The article notes: “Given the exploratory and retrospective design of our study, these results will need to be further validated. We advocate for these findings to be confirmed within the framework of randomized, clinical trials, in conjunction with genomic DNA sequencing studies.”
In other words, the symbiotic collaboration first and foremost will be used to fund randomized trials and sequencing studies support by the same programs that were paid to put together the tissue bank. As Stuart Kauffman, Colin Hill, Sui Huang and Lee Hood have noted: the methods used to generate so-called evidence-based medicine -- the basis for medical practice and reimbursement—randomized clinical trials (RCT) and comparative effectiveness research—are dangerously broken.
Data-sharing that respects the needs and hopes of patients is defined by how broadly data is shared and the degree to which researchers use data to tailor cancer treatment combinations to achieve the best outcomes possible.
So by definition, companies that use data from a variety of sources to establish biomarkers independent of the researcher who extracted tissue from patients in single person trials and based on powerful machine learning derived algorithms are supporting mutualistic relationships.
Researchers that boldly push for the Drazen model are, in my opinion, the true data parasites.
I think lots of researchers become researchers because they want to change the world for the better. You can check out the LabTV YouTube channel and see short videos of hundreds of researchers with such an ethos. The Drazen model merely reinforces the control of a small elite that are both disdainful of people like Eric Topol who is paving the way for a consumer led data revolution and fearful that the transformation means they will be out of jobs. Lee Hood’s P4 medicine vision is based on collecting and sharing data generated by patient activated social networks. Would Drazen call Dr. Hood a parasite??
To those who say that sharing will reduce incentives for innovation, just the opposite is true. Establishing the relationship between molecular insights and meaningful changes in disease progression depend heavily on collaborations that leverage the digitization of biology to its fullest.
As Shaywitz points out, now that we know the true motives of researchers, we can define the parasite problem and tackle it head on. Read More & Comment...
The recent mega-storm allowed many of us drugwonks to curl up with a new work of action non-fiction … from the FDA:
It’s worth perusing in its entirety, but here are a few items to tickle your regulatory palate:
For those of you following the debate over off-label communications
Manufacturer Communications Regarding Unapproved, Unlicensed, or Uncleared Uses of Approved, Licensed, or Cleared Human Drugs, Biologics, Animal Drugs and Medical Devices
The New Gold Standard
Adaptive Design Clinical Trials for Drugs and Biologics; Revised Draft
Meta-Analysis of Randomized Controlled Clinical Trials to Evaluate the Safety of Human Drugs or Biologic Products
Multiple Endpoints in Clinical Trials
The broader sharing of pharmacoecomonic data
Health Care Economic Information in Promotional Labeling and Advertising for Prescription Drugs Under Section 114 of the Food and Drug Administration Modernization Act
And the continuing saga of “Emerging Electronic Media” (aka: “Social Media”)
Internet/Social Media Advertising and Promotional Labeling of Prescription Drugs and Medical Devices – Use of Links to Third-Party Sites
The evolution of discussing risk information
Presenting Risk Information in Prescription Drugs and Medical Devices Promotion; Revised Draft
For the Biosimilar Brotherhood, three things to consider
Considerations in Demonstrating Interchangeability With a Reference Product
Labeling for Biosimilar Products
Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity
Attention NORD Horde
Guidance for clinical Investigators and Sponsors Natural History Studies for Rare Disease Drug Development
Women and Children First?
Measuring Treatment Benefit in Pediatric Populations: Use of Clinical Outcome Assessments
Pediatric Oncology Product Development; Revised Draft
Pregnant Women in Clinical Trials – Scientific and Ethical Considerations
Pharmacokinetics During Pregnancy and the Postpartum Period – Trial Design, Data Analysis, and Impact on Dosing and Labeling; Revised Draft
Postmarketing Safety Reporting for Human Drugs and Biological Products Including Vaccines
REMS Assessment: Planning and Reporting
Postmarketing Safety Reporting for Human Drugs and Biological Products Including Vaccines
Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn
General Principles for Evaluating Abuse - Deterrent Properties of Generic Solid Oral Opioid Drug Products
What’s on CDER’s list is interesting … as well as what is not.
2016 is going to be an interesting year.Read More & Comment...
Senator Edward Markey (D, MA) is using Senate rules to block the nomination of Rob Califf in an attempt to force the agency to rescind its approval of a prescription opioid for children and change its regulatory practices.
Markey, in Boston Globe interview said he is demanding that the FDA agree to reverse its 2015 decision allowing the pediatric use of the prescription painkiller OxyContin. He also wants the agency to commit to convening expert advisory panels to provide advice whenever considering the approval of an opioid drug, and to ensure that the risks of drug addiction and abuse are taken into account whenever the agency considers approving a prescription opioid.
We call Senator Markey’s attention to the FDA’s new “Guidance Agenda” for 2016.
Prominent on the list are plans to release a new draft guidance on: “General Principles for Evaluating Abuse-Deterrent Properties of Generic Solid Oral Opioid Drug Products.” That’s important.
Senator Markey is rightly concerned about opioids remaining atop the FDA’s list of “must address” items. But his “hold” on the Califf nomination will, if anything, hold back the agency from making progress on this urgent issue.Read More & Comment...
Terrific article in this week’s BioCentury, “Pricing Politics,” by one of our favorite reporters, Steve Usdin.
Here’s the opening paragraph:
Presidential candidates from both parties are tapping into public anger over prescription drug prices and responding by repeating old proposals, like controlling prices or lowering FDA approval standards, that won’t be enacted and probably wouldn’t work if they were put into practice.
Usdin writes about the “corrosive political environment” and “unrealistic prescriptions (aka: Bernie Sanders). He speaks of schadenfreude over our favorite “Pharma Bro” and how the Turing imbroglio has ignited the always-smoldering fire of public discontent over the way the pharmaceutical industry conducts its business.
How to manage this out-of-control Turingfreude? One way is for the innovative pharmaceutical industry to do a better job communicating the value message (I know, this is a recording) and, per Usdin, both PhRMA and BIO are preparing to ramp up their messaging efforts.
This is important beyond the rhetoric of a political season since many states have transparency initiatives that can only be successfully argued through the lens of relentless science and the potency of value.Read More & Comment...
Cohen was quoted in several articles on drug pricing (at least he was taken out of context and misquoted). And yesterday he was part of a CNBC panel discussion on the cost of medicines.
The headline for the video blares “Rising drug costs only 'getting worse': Expert”
The expert being Peter Bach. The definition of an expert is a person who has a comprehensive and authoritative knowledge of or skill in a particular area.
Bach first claimed that drugs are 20 percent of health care spending. Then he every study shows that drugs like Sovaldi are more expensive than the care it replaces. He then went on to claim such drugs that Sovaldi aren’t a cure because people can get re-infected with Hepatitis C,
1. Sovaldi is a medical miracle and do ‘really’ cure. Beating the virus into submission is the same as NOT having the disease.
2. The insurer funded Institute for Clinical and Economic Review (ICER) shows that even at list prices, Hep C drugs are cost effective. (Other studies come to the same conclusions.)
3. List price is not what drug companies get. Part of that price become rebates to payers and therefore support a whole posse of PBMs, insurers and oncologists (who get 6 percent of the drug cost as a fee for administering them).
As for the the 20 percent claim, Cohen said that the bigger issue is how to reduce the total cost of care overall and increase value. Who cares if drugs are 90 percent of the cost of a treatment if it leads to more productivity, longevity and lower spending than would be the case in the absence of such medicines?
It was one of the first times that a media outlet allowed a balanced discussion of drug prices. And when given the chance to respond, Cohen nailed it.
Bach made claims that belied a lack of authoritative knowledge.
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An article by STAT journalist Rebecca Robbins on drug pricing could use a lot of re-editing for balance and depth. Or maybe should could find another job.
She contrasts public ‘outrage’ (as represented by some well-dressed protestors) about drug pricing with an orgy of greedy indifference on the part of biotech CEOs.
Public anger at drug companies is “an abomination,” Ron Cohen, chairman of the big industry group BIO (my note: you see, even a trade group of small, money losing companies spending billions on medical research is now BIG as in powerful and dangerous), said at the Biotech Showcase. All the talk about pharma profiteering, Cohen said, is “a perversion of reality.”
Which can also describe Ms. Robbins reporting because of what is NOT included.
She follows Cohen’s comments (which were taken out of context: Cohen actually said that to smear everyone in the biopharma industry as all being “greedy profiteeers” is an abomination and perverse) with context free narrative about drug prices:
“Many drug makers have raised prices in the past year. And a slew of new drugs have (sic) hit the market with eye-popping price tags: cancer drugs at more than $11,000 a month; cholesterol drugs at more than $14,000 a year. Then there’s Martin Shkreli, the pharma executive who bought up a decades-old drug and hiked the price 5,000 percent, turning himself into a target of nationwide protests before he was arrested last month on securities fraud charges.”
Yes, linking Turing turd Shkreli who used the Daraprim price hike to short biotech stocks for the sake of his own portfolio, is now lumped in with companies developing new and important medicines that save lives, reduces health care costs and increase well-being is now part of the narrative.
Robbins is not alone in this perversion of reality. The WSJ’ Peter Loftus runs a me-too story that portrays price hikes as disregarding “mounting criticisms of prescription costs in the U.S”
Loftus claims companies “have raised U.S. prices for dozens of branded drugs since late December, with many of the increases between 9% and 10%, according to equity analysts. The increases are on list prices, before any discounts or rebates that manufacturers sometimes provide insurers and other payers. Some of the increases add thousands of dollars to the cost of already expensive drugs, and come on top of repeated price hikes in recent years.”
Let’s look at the price ‘hike’ in context. I will limit this discussion to the deceptive way in which prices are used. I won’t discuss the fact that neither writer discusses the value of new treatments relative to existing therapies for payers and patients.
Since Ron Cohen , CEO of Acorda Therapeutics,Inc. is one of the main characters of these stories, let’s look at how Loftus reports on the pricing of it’s main product Ampyra, which is used to help multiple-sclerosis patients improve walking. Loftus reports that Acorda raised Ampyra’s price by 11% on Jan. 1, to an annual cost of more than $23,650 a patient.
Ampyra revenues (unaudited) in 2015 were about $ 436 million.
When discounts and rebates to PBMs etc are taken into account, Accorda will gain only about 60% of the price increase.
That does NOT take into account that Acorda provides 2 months of free drug to people with new prescriptions, through our First Step program. At this point, 75% of all new prescriptions are First Step (and a higher percent of all commercial Rxs, as we are not allowed by law to give First Step to Medicare/Medicaid patients). The 10-K notes that 38-43% of patients respond to the treamtment, so First Step ensures the physicians and patients have determined that the patient is a true responder before asking the system to pay for the drug.
It also provides a generous PAP program, giving free drug to a significant portion of the population who are uninsured or underinsured
It also provides co-pay assistance so that no commercially insured patient pays more than $40 for an Rx.
All this an Acorda is not yet not profitable as a company since it is investing 1/3 of net sales n 6 clinical programs for innovative drugs to treat, Parkinson’s, epilepsy, stroke, MS and migraine.
Which means that the money given to PBMs and insurers aren't spent on more R&D. Yet neither Loftus or Robbins acknowledge that PBMs and insurers pocket the rebated portion of these prices. Nor do they note that these organizations then force patients pay to up to 30 percent of the price of the drug which is often marked up by insurers and such pharmacy benefit firms as Express Scripts. Payers know that companies will – after forking over rebates – also pay a big share of the patient’s drug bill. (Which explains why per patient sales are way below list price in many cases.) Indeed, Acorda's copay assistance is provided regardless of where insurers price the drug to patients.
Robbins points to a Senate report claiming Gilead priced drugs so that many people and Medicaid programs could not afford Solvaldi. In fact, payers were pocketing the rebates and deny access to the drugs. The Senate report notes a Gilead memo that states: “While many payers responded to these discounts by opening access broadly, some payers have continued to restrict access despite the discounts. “
Moreover, the Senate report, like Robbins and Loftus, ignored the rebates to the states. A report based on Medicaid data showed that Medicaid rebates for HCV brand medications “typically increased over time and averaged roughly 60% during 2014 across all brand medications.”
Medicaid requires companies to provide rebates (to states) of at least “23.1 % of the Average Manufacturer Price (AMP) per unit” or “the difference between the AMP and the best price per unit” to commercial payers if that rakes in more rebates.
On average, AMP is 59 percent lower than Average Wholesale Price, the so-called ‘retail’ price journalists like Robbins and Loftus use. That means the price used to calculate Sovaldi rebates is $49560 per patient. ($84000 x 59%). Gilead then provided rebates of 33 percent of that price according to the Senate report. That comes out to $33205 per person which is a 60 percent cut from retail price. Which means that drug prices are a vehicle for redistributing income to private and public payers.
Finally, neither Robbins or Loftus put drug price increases (net price or otherwise) into perspective. Loftus states that U.S. prescription-drug spending rose 12.2% in 2014, accelerating from 2.4% growth in 2013. But “price increases for protected brands increased spending by $26.3 billion, contributing 8.2% to total market growth on an invoice price basis; estimated net price growth was substantially lower as rising off-invoice discounts and rebates offset incremental price growth and reduced net price contribution to growth to 3.1%.”
That’s an increase in spending of about $7.1 billion. Total US health care spending increased by $100 billion from 2013-2014. So brand drugs were 7 percent of that amount.
I believe the incremental benefit of this spending is, a Donald Trump would say, huge. But first things first. Reporters should not report on drug prices in a context free zone. Doing so, especially since the factual context is easily available, is a deliberate perversion of reality.
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GAO Asked to Assess Viability of FDA’s Complex Generics Pathway
The House Energy & Commerce Committee is calling on the GAO to evaluate whether the FDA’s regulatory pathway for generic versions of complex drugs is sufficient.
Specifically, the committee sent a letter Dec. 10 asking the GAO to assess whether generic versions of nonbiologic complex drugs that are not fully characterized present challenges in meeting generic approval standards.
If the agency concludes that meeting approval standards presents challenges, then the GAO should consult with public and private groups to analyze the following questions:
- What requirements should be established regarding the comparability of the manufacturing process?
- What degree of characterization of the proposed generic version and the reference product should be required to determine safety and efficacy?
- What degree of similarity should be required for the active ingredient of the generic version to be deemed the same as the active ingredient in the reference product?
- What types of evidence should be required to demonstrate bioequivalence?
- How much clinical evidence is needed?
Once those questions are answered, the agency should determine whether current ANDA pathways can address the use of reference products. The study also should make recommendations for the FDA, such as developing policy documents and establishing general principles on evidence needed.
Read the letter here: www.fdanews.com/12-15-15-FDAGenerics.pdf.Read More & Comment...
Compare the approach ASCO takes to the one shaping the Cancer Moonshot 2020 effort.
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