Latest Drugwonks' Blog
Per a new report in BioCentury, rather than pave new ground, industry and FDA have agreed PDUFA VI will be more about fixing potholes that have been persistent impediments to modernizing the agency’s oversight and review of drugs, and providing more resources to promote the expansion of projects started under PDUFA V.
The most important outcomes are steps that are intended to improve FDA’s ability to recruit, hire and retain scientific staff, measures to improve the agency’s financial transparency and accountability, and extensions of ongoing efforts to integrate patient perspectives and real-world data into regulatory decision making.
Completion of the goals letter, expected in March, and review by HHS and the White House over the summer, will mark the end of the first phase of the PDUFA reauthorization process. But it only will launch the start of the much more arduous portion of the PDUFA reauthorization journey: congressional approval.
I. Fixing HR
FDA’s ability to meet user fee review goals, and to go beyond them by implementing new regulatory ideas and proactively supporting product development, depends almost entirely on its ability to recruit, retain and develop talented and dedicated staff.
At the start of PDUFA VI negotiations, PhRMA and BIO told FDA that industry would not support increases in user fees to hire new staff unless CDER demonstrated that it had put procedures in place that would fill staffing holes and provide confidence it could hire to fill new positions funded by PDUFA VI. According to industry negotiators, CDER and FDA have met the challenge, in part by taking some steps that are common in the private sector, such as hiring external head hunters.
Unlike previous user fee agreements, which paid for FTEs even if they were never hired, the agency will only receive the additional money if it meets recruitment and retention goals. FDA has also agreed to hire an external organization to assess and continuously evaluate its hiring and retention efforts.
Other nuts-and-bolts activities covered in PDUFA VI include improving the reliability of the electronic filing process for new drug applications, steps to improve the management of meetings between FDA and sponsors, and revamping a formula that is used to increase user fee payments based on estimated workload.
II. Breakthroughs and Biomarkers
Some of the new hires will work on improving FDA’s review of products that combine drugs and devices, and on the breakthrough therapies program. The breakthrough process is resource-intensive, and the largest allocation of new staff in PDUFA VI, about 60 employees, will be dedicated to breakthrough reviews. PDUFA VI will also include additional money and mandates for FDA to review drug development tools, including surrogate endpoints, biomarkers and patient-reported outcomes (PROs).
Alas. industry dropped attempts to establish review time goals for biomarker qualification.
Advancing FDA’s patient-focused drug development (PFDD) initiative is another priority for patient groups as well as for industry and FDA. FDA has already started expanding PFDD by encouraging patient groups to hold their own meetings modeled on meetings the agency has held. PDUFA VI will include a series of guidance documents that are intended to lead to PFDD version 2.0, which could include establishing standards for conducting and analyzing patient-preference research, and taking steps to formally integrate patient preferences into regulatory decisions.
FDA created structured benefit-risk frameworks during PDUFA V, and will expand their use in PDUFA VI.
Advancing the use of real-world evidence to make regulatory decisions will be another major emphasis of PDUFA VI. This will include enhancing the Sentinel Initiative, a system that allows investigators to monitor and query electronic medical records, health claims databases and other sources. Projects under consideration for Sentinel include monitoring the safety of biosimilars, and broadening its focus from safety to efficacy.
Biopharmaceutical companies are looking to PDUFA VI to open legal avenues to communicating with payers and possibly other parties about real-world data on off-label uses of approved drugs.
Finalization of the draft PDUFA VI goals letter will set in motion a series of reviews by HHS and the White House Office of Management and Budget that are slated to be completed by September. Following publication of the draft agreement in September, and a final public meeting in October or November, the deal should be formally submitted to Congress in mid-January.
PDUFA VI AT A GLANCE
* Improve FDA recruitment, hiring, retention: Implement HR improvements, hire outside HR contractors, contract for external analysis and monitoring of progress
* Funding for about 200 additional full-time employees (FTEs): Funding contingent on FDA meeting recruitment, retention goals
* Increased funding for breakthrough reviews: Largest portion of new FTEs
* Modification of the “workload adjustor” formula used to increase user fee payments based on anticipated submissions: Annual user fee increases expected to be smaller; FDA to gain more predictable funding
* Patient-focused drug development 2.0: Issue a series of new guidance documents on patient-focused drug development
* Research on the integration of real-world evidence into product reviews: Expand Sentinel Initiative, a system for postmarket monitoring and querying of electronic health records, insurance claims and other records to track medical product safety; Implement other efforts to use real-world evidence to study and communicate about safety and efficacy
* Increased funding for review of drug development tools: Add resources to qualify surrogate endpoints, biomarkers, patient-reported outcomes; Expand use of benefit-risk framework to guide drug development activities; Enhance FDA capacity to analyze innovative clinical trial designs
* Increased transparency regarding spending PDUFA funds
* Information technology improvements: Increase reliability of the electronic submissions system, upgrade CDER's IT system
The most important outcomes are steps that are intended to improve FDA’s ability to recruit, hire and retain scientific staff, measures to improve the agency’s financial transparency and accountability, and extensions of ongoing efforts to integrate patient perspectives and real-world data into regulatory decision making.
Completion of the goals letter, expected in March, and review by HHS and the White House over the summer, will mark the end of the first phase of the PDUFA reauthorization process. But it only will launch the start of the much more arduous portion of the PDUFA reauthorization journey: congressional approval.
I. Fixing HR
FDA’s ability to meet user fee review goals, and to go beyond them by implementing new regulatory ideas and proactively supporting product development, depends almost entirely on its ability to recruit, retain and develop talented and dedicated staff.
At the start of PDUFA VI negotiations, PhRMA and BIO told FDA that industry would not support increases in user fees to hire new staff unless CDER demonstrated that it had put procedures in place that would fill staffing holes and provide confidence it could hire to fill new positions funded by PDUFA VI. According to industry negotiators, CDER and FDA have met the challenge, in part by taking some steps that are common in the private sector, such as hiring external head hunters.
Unlike previous user fee agreements, which paid for FTEs even if they were never hired, the agency will only receive the additional money if it meets recruitment and retention goals. FDA has also agreed to hire an external organization to assess and continuously evaluate its hiring and retention efforts.
Other nuts-and-bolts activities covered in PDUFA VI include improving the reliability of the electronic filing process for new drug applications, steps to improve the management of meetings between FDA and sponsors, and revamping a formula that is used to increase user fee payments based on estimated workload.
II. Breakthroughs and Biomarkers
Some of the new hires will work on improving FDA’s review of products that combine drugs and devices, and on the breakthrough therapies program. The breakthrough process is resource-intensive, and the largest allocation of new staff in PDUFA VI, about 60 employees, will be dedicated to breakthrough reviews. PDUFA VI will also include additional money and mandates for FDA to review drug development tools, including surrogate endpoints, biomarkers and patient-reported outcomes (PROs).
Alas. industry dropped attempts to establish review time goals for biomarker qualification.
Advancing FDA’s patient-focused drug development (PFDD) initiative is another priority for patient groups as well as for industry and FDA. FDA has already started expanding PFDD by encouraging patient groups to hold their own meetings modeled on meetings the agency has held. PDUFA VI will include a series of guidance documents that are intended to lead to PFDD version 2.0, which could include establishing standards for conducting and analyzing patient-preference research, and taking steps to formally integrate patient preferences into regulatory decisions.
FDA created structured benefit-risk frameworks during PDUFA V, and will expand their use in PDUFA VI.
Advancing the use of real-world evidence to make regulatory decisions will be another major emphasis of PDUFA VI. This will include enhancing the Sentinel Initiative, a system that allows investigators to monitor and query electronic medical records, health claims databases and other sources. Projects under consideration for Sentinel include monitoring the safety of biosimilars, and broadening its focus from safety to efficacy.
Biopharmaceutical companies are looking to PDUFA VI to open legal avenues to communicating with payers and possibly other parties about real-world data on off-label uses of approved drugs.
Finalization of the draft PDUFA VI goals letter will set in motion a series of reviews by HHS and the White House Office of Management and Budget that are slated to be completed by September. Following publication of the draft agreement in September, and a final public meeting in October or November, the deal should be formally submitted to Congress in mid-January.
PDUFA VI AT A GLANCE
* Improve FDA recruitment, hiring, retention: Implement HR improvements, hire outside HR contractors, contract for external analysis and monitoring of progress
* Funding for about 200 additional full-time employees (FTEs): Funding contingent on FDA meeting recruitment, retention goals
* Increased funding for breakthrough reviews: Largest portion of new FTEs
* Modification of the “workload adjustor” formula used to increase user fee payments based on anticipated submissions: Annual user fee increases expected to be smaller; FDA to gain more predictable funding
* Patient-focused drug development 2.0: Issue a series of new guidance documents on patient-focused drug development
* Research on the integration of real-world evidence into product reviews: Expand Sentinel Initiative, a system for postmarket monitoring and querying of electronic health records, insurance claims and other records to track medical product safety; Implement other efforts to use real-world evidence to study and communicate about safety and efficacy
* Increased funding for review of drug development tools: Add resources to qualify surrogate endpoints, biomarkers, patient-reported outcomes; Expand use of benefit-risk framework to guide drug development activities; Enhance FDA capacity to analyze innovative clinical trial designs
* Increased transparency regarding spending PDUFA funds
* Information technology improvements: Increase reliability of the electronic submissions system, upgrade CDER's IT system
Yesterday the new Duke-Margolis Center for Health Policy (headed by Mark McClellan), held a conference titled, “Off Label Communication in 2016: Meeting Information Needs through New Policy Options.”
Those new options are detailed in an important new paper:
Policy Options for Off-Label Communication: Supporting Better Information, Better Evidence, and Better Care
I am honored to be one of the co-authors and to have had the opportunity to speak at the event.
Just about every speaker pointed to the need for FDA leadership – though bold action and … clarity.
This is urgent for many reasons: different federal agencies (FDA, FTC, DOJ) with different views on pathways and jurisdiction, and the extreme danger of allowing federal judges dictate regulatory policy. If existing policy has evolved to protect the public from snake oil, the recent Amarin decision is precarious precedent for communications about fish oil – and beyond.
The paper lays out what we refer to as Guiding Principles for Lasting Solutions. They are:
Promote well-informed clinical decision-making to improve public health.
Support FDA’s central role in reviewing, approving, and enforcing efficacy claims.
Reduce inconsistencies across agencies’ enforcement decision-making.
Avoid continued cycles of litigation through greater policy clarity.
Promote more evidence development and data submission to FDA.
Nature abhors a vacuum. All of the participants in the conference and all the authors of the white paper were in complete agreement that, absent strong and forward-looking FDA leadership, the off-label debate will result in public health chaos.
And, as many management gurus have written, one of the key tenets of successful leadership is the ability to delegate in order to get things done.
To that end, one of the more contentious policy recommendations made in the paper is for the FDA to pursue a strategy that embraces third party sanctioned communication.
This alternative, which did not have universal support within our working group, involves a more intramural approach based on the FDA’s partnering with an external entity charged with accrediting certain types of communication.
This organization could focus its efforts on reviewing not an NDA, but an NDI – New Drug/Device Information, consisting of a sponsor’s evidence and associated communications about off-label use, and then potentially approve them for broader distribution.
An NDI review could be given within a rank, score, or grade system that confers greater weight to better evidence, and could be given contingent upon continued evidence generation and resubmission to the clearing body.
For example, an off-label communication may be approved and given an initial grade or rating that sunsets within a specified number of years barring updated submission of relevant evidence. Continued off-label communication at the current evidentiary grade and after the specified date would then be subject to additional evidence development by the sponsor.
The proposed reviewing body would operate outside of FDA but with FDA participation. To avoid First Amendment and other legal concerns, the body’s conclusions could not bind the FDA or otherwise hinder FDA’s ability to pursue enforcement action. While the reviewing body would not provide certainty to the regulated community, its recommendations could offer useful guidance to drug manufacturers.
An approach that involves an outside reviewing body might enable FDA to advance a model that more clearly differentiates between types and levels of communication, without modifying the FDA-approved product labeling. For example, the reviewing body might treat communication around off-label use that has become standard of care in a different manner than more tailored or less-well-established evidence on an off-label indication or within a specific patient subpopulation. Such a system could potentially play a more directed and focused alternative or supplement to the current role of peer-reviewed communications.
Any such entity will need to have participation from the FDA, and potentially other relevant agencies and will need to include a robust peer-review capacity. Incentives in the form of more rapid and predictable review and action would need to be in place to encourage sponsors to develop evidence and submit communication materials.
The end goal would be a process that augments the FDA’s capacity to review a diversity of communication types reflective of rapidly emerging evidence -- but does not change FDA’s ability to pursue enforcement action.
Such a third-party approach has precedents. In Canada, for example, the Pharmaceutical Advertising Advisory Board (PAAB) serves as an independent preclearance review agency for assessing the accuracy and evidentiary basis for promotional information on prescription, non-prescription, biologic, and homeopathic products. The PAAB process works within the Canadian regulatory framework with Health Canada as an ex-officio member of board leadership, conferring “approval” of advertising materials through a logo incorporated on cleared materials.
There also may be useful lessons for a third-party off-label communication entity from the Center for Disease Control’s Advisory Committee on Immunization Practices (ACIP), which develops recommendations on how and when to use vaccines within the United States. With FDA as a party to committee deliberations, ACIP relies on the body of clinical evidence, sponsor labeling, and data sources to issue formal, non-binding advice for immunization best practices – including potential off-label uses of vaccines.
While these examples differ in important ways from a third-party review system for off-label materials, they illustrate features and feasibility concerns that would need to be addressed to ensure a trustworthy, collaborative, and science-based process.
Might the USP be a good home for such a program. They already have a time-tested intramural relationship with the FDA. It's a thought worth further discussion.
All this to say that off-label communication is now on the health policy front burner and the flame is on high. As Everett Dirksen used to say, “When I feel the heat, I see the light.”
Those new options are detailed in an important new paper:
Policy Options for Off-Label Communication: Supporting Better Information, Better Evidence, and Better Care
I am honored to be one of the co-authors and to have had the opportunity to speak at the event.
Just about every speaker pointed to the need for FDA leadership – though bold action and … clarity.
This is urgent for many reasons: different federal agencies (FDA, FTC, DOJ) with different views on pathways and jurisdiction, and the extreme danger of allowing federal judges dictate regulatory policy. If existing policy has evolved to protect the public from snake oil, the recent Amarin decision is precarious precedent for communications about fish oil – and beyond.
The paper lays out what we refer to as Guiding Principles for Lasting Solutions. They are:
Promote well-informed clinical decision-making to improve public health.
Support FDA’s central role in reviewing, approving, and enforcing efficacy claims.
Reduce inconsistencies across agencies’ enforcement decision-making.
Avoid continued cycles of litigation through greater policy clarity.
Promote more evidence development and data submission to FDA.
Nature abhors a vacuum. All of the participants in the conference and all the authors of the white paper were in complete agreement that, absent strong and forward-looking FDA leadership, the off-label debate will result in public health chaos.
And, as many management gurus have written, one of the key tenets of successful leadership is the ability to delegate in order to get things done.
To that end, one of the more contentious policy recommendations made in the paper is for the FDA to pursue a strategy that embraces third party sanctioned communication.
This alternative, which did not have universal support within our working group, involves a more intramural approach based on the FDA’s partnering with an external entity charged with accrediting certain types of communication.
This organization could focus its efforts on reviewing not an NDA, but an NDI – New Drug/Device Information, consisting of a sponsor’s evidence and associated communications about off-label use, and then potentially approve them for broader distribution.
An NDI review could be given within a rank, score, or grade system that confers greater weight to better evidence, and could be given contingent upon continued evidence generation and resubmission to the clearing body.
For example, an off-label communication may be approved and given an initial grade or rating that sunsets within a specified number of years barring updated submission of relevant evidence. Continued off-label communication at the current evidentiary grade and after the specified date would then be subject to additional evidence development by the sponsor.
The proposed reviewing body would operate outside of FDA but with FDA participation. To avoid First Amendment and other legal concerns, the body’s conclusions could not bind the FDA or otherwise hinder FDA’s ability to pursue enforcement action. While the reviewing body would not provide certainty to the regulated community, its recommendations could offer useful guidance to drug manufacturers.
An approach that involves an outside reviewing body might enable FDA to advance a model that more clearly differentiates between types and levels of communication, without modifying the FDA-approved product labeling. For example, the reviewing body might treat communication around off-label use that has become standard of care in a different manner than more tailored or less-well-established evidence on an off-label indication or within a specific patient subpopulation. Such a system could potentially play a more directed and focused alternative or supplement to the current role of peer-reviewed communications.
Any such entity will need to have participation from the FDA, and potentially other relevant agencies and will need to include a robust peer-review capacity. Incentives in the form of more rapid and predictable review and action would need to be in place to encourage sponsors to develop evidence and submit communication materials.
The end goal would be a process that augments the FDA’s capacity to review a diversity of communication types reflective of rapidly emerging evidence -- but does not change FDA’s ability to pursue enforcement action.
Such a third-party approach has precedents. In Canada, for example, the Pharmaceutical Advertising Advisory Board (PAAB) serves as an independent preclearance review agency for assessing the accuracy and evidentiary basis for promotional information on prescription, non-prescription, biologic, and homeopathic products. The PAAB process works within the Canadian regulatory framework with Health Canada as an ex-officio member of board leadership, conferring “approval” of advertising materials through a logo incorporated on cleared materials.
There also may be useful lessons for a third-party off-label communication entity from the Center for Disease Control’s Advisory Committee on Immunization Practices (ACIP), which develops recommendations on how and when to use vaccines within the United States. With FDA as a party to committee deliberations, ACIP relies on the body of clinical evidence, sponsor labeling, and data sources to issue formal, non-binding advice for immunization best practices – including potential off-label uses of vaccines.
While these examples differ in important ways from a third-party review system for off-label materials, they illustrate features and feasibility concerns that would need to be addressed to ensure a trustworthy, collaborative, and science-based process.
Might the USP be a good home for such a program. They already have a time-tested intramural relationship with the FDA. It's a thought worth further discussion.
All this to say that off-label communication is now on the health policy front burner and the flame is on high. As Everett Dirksen used to say, “When I feel the heat, I see the light.”
I am all for “transparency in drug pricing.” The question is transparency proponents have to answer is: why are they only focusing on how drug companies set their prices when the effective price consumers pay is set by PBMs, insurers and hospitals??
Take this story from Minneapolis.
A major company has rolled back the price of a potentially life-saving prescription drug after a KARE 11 News investigation.
But the decision has some people asking how often we’re being overcharged on other medicines.
Curt’s Story
It started with Curt Burshem.
Back in November he told us CVS Caremark had jacked up the price for a prescription drug a family member needed for a kidney disorder.
Curt Burshem discovered that CVS was overcharging him on prescription drugs.
"When I see a company doing this crap, it makes me insane,” he said.
But, now, CVS has reversed the price high.
"Justice had been served,” Curt told us.
When Curt originally went to the CVS pharmacy in Maple Grove last Spring, the initial 30-day supply cost about $.87 per pill.
But when he followed his insurance company’s advice and ordered a 90-day supply through the mail, CVS Caremark increased the price to more than $6 a pill.
After KARE 11 called CVS they rolled the price back and gave Curt a refund.
Which raises the question: If transparency proponents were intellectually honest (some are, most are not) they would demand the same openness from every health care institution that shapes access to and the price of medicines.
Will PBMs and insurers reveal how they move from drugs that they acquire at 40-60 percent below pharmacy retail prices to charging consumers 30 percent of that retail price?
Will PBMs and insurers reveal how and why they decide when their customers are forced to fail first on medicines?
We need to know. They claim drug costs are climbing at an unsustainable rate. That doesn’t square with data since 2000, spending on drugs has remained at 9-10 percent or HHS projections that overall drugs will remain at about 9 percent of total health spending through 2030. So why are copays and co-insurance rates increasing??
Will hospitals reveal how they go from drugs acquired at the same rate to charging up to 700 percent of retail prices? And while they are at it, will they explain why charges for hospital care increased faster than drugs, even as the use of these new medicines reduce hospital costs? Why has hospital spending increased 6 times faster than drug spending between 2010-2013?
If I am a pharmaceutical company, I’d be for transparency for everyone. I’d show them mine, if they showed theirs. Let’s have the Full Monty for all.
Take this story from Minneapolis.
A major company has rolled back the price of a potentially life-saving prescription drug after a KARE 11 News investigation.
But the decision has some people asking how often we’re being overcharged on other medicines.
Curt’s Story
It started with Curt Burshem.
Back in November he told us CVS Caremark had jacked up the price for a prescription drug a family member needed for a kidney disorder.
Curt Burshem discovered that CVS was overcharging him on prescription drugs.
"When I see a company doing this crap, it makes me insane,” he said.
But, now, CVS has reversed the price high.
"Justice had been served,” Curt told us.
When Curt originally went to the CVS pharmacy in Maple Grove last Spring, the initial 30-day supply cost about $.87 per pill.
But when he followed his insurance company’s advice and ordered a 90-day supply through the mail, CVS Caremark increased the price to more than $6 a pill.
After KARE 11 called CVS they rolled the price back and gave Curt a refund.
Which raises the question: If transparency proponents were intellectually honest (some are, most are not) they would demand the same openness from every health care institution that shapes access to and the price of medicines.
Will PBMs and insurers reveal how they move from drugs that they acquire at 40-60 percent below pharmacy retail prices to charging consumers 30 percent of that retail price?
Will PBMs and insurers reveal how and why they decide when their customers are forced to fail first on medicines?
We need to know. They claim drug costs are climbing at an unsustainable rate. That doesn’t square with data since 2000, spending on drugs has remained at 9-10 percent or HHS projections that overall drugs will remain at about 9 percent of total health spending through 2030. So why are copays and co-insurance rates increasing??
Will hospitals reveal how they go from drugs acquired at the same rate to charging up to 700 percent of retail prices? And while they are at it, will they explain why charges for hospital care increased faster than drugs, even as the use of these new medicines reduce hospital costs? Why has hospital spending increased 6 times faster than drug spending between 2010-2013?
If I am a pharmaceutical company, I’d be for transparency for everyone. I’d show them mine, if they showed theirs. Let’s have the Full Monty for all.
Within days of being given a diphtheria jab during a school vaccination drive, 5-year-old Meraj Shabbir Khan's leg became so swollen that he was hospitalised.
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.
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.”
Today the FDA’s Arthritis Advisory Committee heard presentations on whether or not the agency should approve a BLA from Celltrion Inc. for CT-P13, a biosimilar of Remicade infliximab from Johnson & Johnson.
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.
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.
If you’re following the opioids debate and want to cut through the political rhetoric and get right to the meat of the policy debate, here’s a conference you should plan on attending the Abuse-Deterrent Formulations Summit.
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.
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.
From the pages of Drug Information Daily:
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.
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.
On Friday, FDA posted briefing documents ahead of the Feb. 9 meeting of its Arthritis Advisory Committee to discuss a BLA from Celltrion Inc. for its CT-P13, a biosimilar of Remicade infliximab from Johnson & Johnson. What's just as interesting is what's not in the package.
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.
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.
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.
