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In a cramped Mumbai paediatric ward, third-year pharmacology student Nitin Shinde opens the boy's file and notes the vaccine, his age and the doctor's diagnosis of a skin infection. That information is later logged into a computer programme linked to a national database, part of India's fledgling efforts to track, analyse and ultimately warn patients about unknown side effects of drugs on the market.
India's six-year-old pharmacovigilance programme, which collects and submits suspected adverse drug reactions to a World Health Organisation (WHO) database, is key to improving drug safety in a country where medicine consumption is high, experts say.
But insufficient staff and equipment, and a lack of awareness among medical professionals mean many potentially dangerous drug reactions go unrecorded, hospital personnel across India told Reuters.
Gaps in the system mean the government has less data to determine whether drugs might have harmful side effects. Also, relatively little information flows from one of the world's largest pharmaceutical markets to the WHO database of over 12 million suspected adverse drug reactions.
"In a country of 1 billion people consuming so much medicine, obviously safety is a concern," said G. Parthasarathi, dean of the pharmacy school at JSS University in Mysore, adding the pharmacovigilance programme is still gaining traction. "We've made a good start," he said.
Last year, India contributed 2 percent of the 2.1 million suspected reactions added to VigiBase, the WHO's global database. China, with a comparable population, contributed 8 percent.
Indian health officials say the monitoring programme is a "high priority" and a $14.5 million annual budget is sufficient.
"We are going to develop a better pharmacovigilance system in India in due course," said G.N. Singh, India's drug controller. "Patient health will be assured."
Regarding doctors' lack of engagement, "the culture of reporting is improving," said V. Kalaiselvan, principal scientific officer at the Indian Pharmacopoeia Commission.
The full Reuters article can be found here.
Much of what passes for journalism or commentary about the biotechnology/pharmaceutical industry is click driven hate mongering. Want to write about drug companies. Start with this theme: Everything drug companies do is disgusting. Nothing they do is beyond reproach. Use h one example of unseemly behavior and claim every company does the same thing. Add some anger and sarcasm.
Pharma sucks. Ha-ha.
Press send or post.
Here’s some recent examples in order (mostly) of idiotic magnitude:
Here’s what White House Chief of Staff Denis McDonough said in the wake of a Super Bowl commercial to raise awareness of opioid-induced constipation run two companies marketing a drug to treat it: “Next year, how about fewer ads that fuel opioid addiction and more on access to treatment.” commercialized and misused pharmaceutical knowledge,” he told a United Nations agency.
Apparently McDonough never got the memo that people – including millions of cancer patients and individuals with digestive tract paralysis who safely use opioid based drugs to control searing pain – should have the same right to poop as White House staffers.
Bill Maher tweeted (and this is evidence of why humor should be left to humorists) “Was that really an ad for junkies who can't shit? America, I luv ya but I just can't keep up.”
In between the harsh sarcasm of the White House and Maher’s tweet is the much needed gap created by Samantha Allen of the Daily Beast:
Martin Shkreli Is Just One of Many Pharma A-Holes
Nancy Retzlaff is not Martin Shkreli. She won’t inspire hundreds of news articles nor will she become the subject of any Internet memes. She won’t threaten Ghostface Killah and it seems unlikely that she will ever flirt with a minor on a YouTube livestream.
But the chief commercial officer for Turing Pharma is just as responsible for keeping the price of the life-saving drug Daraprim 5,000 percent higher than it used to be. And as long as the public eye is still trained on the Shkreli sideshow, she’ll get away with it.
….There are more Martin Shkrelis out there, and not all of them are acting like assholes on Twitter. And if the Shkreli Show overshadows the people who still need easy access to a once-affordable treatment, everyone loses. The Pharma Bro started out as a poster child for a pressing problem. He may end up being a red herring.”
Samantha Allen seems eminently qualified to cover the relationship between being an asshole and drug pricing. She has a PhD in Ph.D. in Women’s, Gender, and Sexuality Studies from Emory University. She In 2013, she received the John Money Fellowship for Scholars of Sexology from the Kinsey Institute. She used the money to “research a wide range of media (books, photos, videos, graphic art, tabloids, etc.) on several different sexual fetishes (shoe, foot, nylon, pantyhose, breast, spanking, hair, etc.) dating from across the 20th and 21st centuries.”
Is this a great country or what?
But Dr. Allen is also an asshole expert because she is a misandrist. In case you are wondering, that means she hates men:
“i hate men because it’s not my job to fix masculinity; it’s my job to heal from it and to be together with my sisters as we try to make it through a hostile world. and yet i am expected to patiently educate men on how not to be an asshole. here’s my only tip: stop spending so much time around men. they’re assholes.”
Finally, here’s someone attacking drug companies for changing all human and cultural concepts in the world so widely that treatment is completely considered as a business in the world today..We should revive our traditional medicine which is in harmony with our culture and is naturally cheaper and more useful.”
That last statement is from former Iranian President Mahmoud Ahmadinejad who blamed “Zionist medicine” for polluting our planet with profitable but useless medicines.
You knew it had to come down to the Jews controlling Big Pharma this:
“Martin Shkreli (pictured) is a Jewish businessman (he has relatives living in Albania, and is often referred to as an Albanian). Though his Wikipedia page says he is Albanian and Croatian, he was born and raised in Brooklyn, went to Baruch College, worked for uber-Jewish hedge fund manager Jim Cramer in his teens — and had his own hedge fund by the time he was 21.
When the Jews want to profit more from selling a drug needed to treat sick people, who otherwise would die, they don’t just raise the price by a factor of five or ten. They send someone to raise it by a factor of fifty, wait for the reaction to hit the press, then they pretend to back down… yessir, all the way down to where they had planned to put the price from the beginning.
… This is a Jewish business strategy. Whenever they want to do something that they know will antagonize the public, they have one of their own, or someone under their control, do something even worse, and then they pretend to “correct” their own agent by telling him to stop doing it, and start doing something that isn’t quite so bad instead.”
Or as Dr. Allen put it:
Martin Shkreli became the public face of price gouging because he was so transparent. But Retzlaff’s cool, calm, and collected attempt to spin the same exorbitant price increase for an HIV drug as a net good is arguably more dangerous because it is less obvious.”
There’s no underlying similarity binding these anti-pharma and anti-Semitic rants except varying degrees of paranoia and this observation by George Orwell: “If thought corrupts language, language can also corrupt thought.”
From the very beginning of the hearing, it was clear the expert members of the committee didn’t understand what biosimilars really are, nor the pathway the agency uses to review them.
And yet, at the end of a long day they were asked to vote on this question:
Does the Committee agree that based on the totality of the evidence, CT-P13 should receive licensure as a biosimilar product to US-licensed Remicade for each of the indications for which US-licensed Remicade is currently licensed and CT-P13 is eligible for licensure (RA, AS, PsA, PsO, adult CD, pediatric CD, adult UC)?
Despite open public comment from patients and physicans concerned about extrapolation issues, the vote was 21-3 in the affirmative. It was the vote the FDA wanted. And they got it.
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.
What does the FDA know that our European and Canadian regulatory cousins do not?
There was also much chatter amongst the panel members about this vote helping to lower prices. Maybe so. Maybe not. Either way it’s not an appropriate discussion for an FDA panel.
The event’s lead-off hitter is Dr. Doug Throckmorton, CDER’s Deputy Director for Regulatory Programs and the FDA’s point-man for opioids. His talk, “The Future of Abuse-Deterrent Formulations,” is a timely must-hear presentation.
Does Califf’s Opioid Announcement Go Far Enough?
Sens. Joe Manchin (D-W.Va) and Edward Markey (D-Mass.) will maintain their holds on the nomination of Robert Califf for the top job at the FDA, despite the agency’s announcement Thursday that it would overhaul its opioid policies.
Specifically, the FDA said it would reexamine its approval, REMS and postmarket policies for opioids in response to a growing abuse epidemic and calls to action from lawmakers.
The senators — along with Sen. Bernie Sanders (I-Vt.) — in January placed holds on Califf’s nomination, with all three citing the FDA’s handling of approving prescription opioids.
A spokeswoman for Manchin tells DID that the senator’s plans have not changed, and he still plans to filibuster and hold Califf’s nomination. Manchin said the FDA’s announcement that it would re-evaluate its risk-benefit framework for the drugs will only “slightly improve” the agency’s response to the opioid epidemic, and that “sweeping changes” are still necessary.
Markey said in a statement that the FDA’s actions are “some important steps” but “fall short of what is needed.”
Andrew Kolodny, director of Physicians for Responsible Opioid Prescribing and the chief medical officer of Phoenix House, tells DID that many of the FDA’s “speaking points” are “meaningless.”
He criticized the agency’s announcement that it would convene an advisory panel before approving any new opioids that lack abuse-deterrent properties, asserting that these meetings should be held for all approvals regarding opioids.
Senator Markey also made that point: “By refusing to convene advisory committees to inform all of its opioid approval decisions, the FDA continues to ignore outside experts who could help stem the tide of tragic deaths and overdoses plaguing the country,” Markey said in a statement. He also said he would continue to hold off on Califf’s nomination “[u]ntil the FDA commits to convene advisory committees of outside experts for all its opioid approval decisions.
Peter Pitts, president and founder of the Center for Medicine in the Public Interest and a former FDA associate commissioner, tells DID that he thinks the FDA’s approach could make a difference, saying it will make the approval process “more complete.” “I think there will be a higher evidentiary standard on the one hand, but on the other hand there will be a clearly explained pathway as to how to achieve it. They're taking ambiguity out of the process.”
Pitts added that the approach is going to provide guidance on how to develop abuse-deterrent opioids and how to use real-world data to impact post-approval labeling.
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.
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.
Tricky Road Ahead For Safe Approval of Biosimilars
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.
Quality Attributes
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.
Pharmacovigilance
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.
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.
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.
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.
