FDA, JAMA, PV, RWE and other relevant acronyms

05/09/2017 02:54 PM | Peter Pitts

Via Medscape:

Safety Events Common in Newly Approved Drugs

Nearly one third of drugs newly approved by the US Food and Drug Administration (FDA) are affected by safety issues that were not known at the time of approval, a study has shown.

Biologic and psychiatric drugs, as well as those that received accelerated approval or were approved within 60 days of the statutory decision deadline, are the most vulnerable to postmarket safety events, Nicholas S. Downing, MD, from the Department of Medicine at Brigham and Women's Hospital in Boston, Massachusetts, and colleagues report. Their study was published online May 9 in JAMA.

The findings "are not surprising to those of us who have been following this for a while, but they do reflect a growing realization by the mainstream medical community that there are important differences between efficacy in randomized controlled trials and effectiveness once a drug hits the real world," Peter J. Pitts told Medscape Medical News. Pitts is a former FDA associate commissioner and current president of the Center for Medicine in the Public Interest, New York, New York. "It reinforces the basic truth that when you give people medicine, interesting things will happen — good and bad. Postmarket research is the continual search for understanding what these interesting things are in the real world," he added.

To determine the prevalence of postmarket safety events and the characteristics associated with the likelihood of their occurrence in newly approved drugs, the researchers used the Drugs@FDA database to identify all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010. They then separated the drugs on the basis on seven prespecified features: class (pharmaceutical, biologic), therapeutic area, priority review, accelerated approval, orphan product, near–regulatory deadline approval, and total review time.

Of 222 novel therapeutics identified, including 183 pharmaceuticals and 39 biologics, 71 (32%) were affected by a total of 123 postmarket safety events over a median 11.7 years of follow-up. The safety issues led to three drug withdrawals. The irritable bowel syndrome drugs valdecoxib and tegaserod were withdrawn in 2005 and 2007, respectively, as a result of adverse cardiovascular events. The psoriasis drug efalizumab was withdrawn in 2009 as a result of an observed increased risk for progressive multifocal leukoencephalopathy.

The approved drugs were also associated individually and class-wide with 61 incremental boxed warnings (43 drugs) and 59 safety communications (44 drugs).

Although safety events leading to market withdrawals were rare, "new boxed warnings, indicating that potentially life-threatening or preventable safety events had been observed in the postmarket period, and safety communications, which describe serious but non-life-threatening postmarket safety events, each occurred for approximately one-fifth of the novel therapeutics," the authors write.

The median time between drug approval and the first postmarket safety event was 4.2 years, and nearly one in three of the drugs had one or more safety events at 10 years, the authors write.

The researchers performed multivariate analyses looking at the relationship between each of the prespecified characteristics and postmarket safety events. They found an increased risk for safety issues among biologics compared with pharmaceuticals (incidence rate ratio [IRR], 1.93; 95% confidence interval [CI], 1.06 - 3.52; P = .03) and among drugs used to treat psychiatric conditions compared with cancer and hematologic therapeutics (IRR, 3.78; 95% CI, 1.77 - 8.06; P < .001). In addition, postmarket safety events were more prevalent among drugs that received accelerated approval (IRR, 2.20; 95% CI, 1.15 - 4.21; P = .02) and those approved near their regulatory deadline (IRR, 1.90; 95% CI, 1.19 - 3.05; P = .008).

Of interest, safety events were significantly less common among drugs with the shortest regulatory review times. This finding "conversely raises the possibility that some approval packages provide clearer evidence of safety, allowing for more rapid regulatory approval," the authors write. "An analysis of regulatory review documents from the European Medicines Agency indicated that safety risks that would ultimately prompt a postmarket safety event were not always evident in the premarket period, suggesting that additional premarket review might only delay approval without identifying therapeutics that pose a future safety concern."

"I agree with the authors' main point, which is that there are major gaps in our knowledge about the safety of drugs at the time that they are approved," Sean Hennessy, PharmD, PhD, told Medscape Medical News. Dr Hennessy is from the Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, and Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

"This isn't necessarily a bad thing, since requiring drug companies to perform the much larger studies that would need to be done to learn about rare adverse effects prior to approval would further increase the cost of drug development, which is already very expensive. Rather, we need to develop more robust systems to assess the safety of drugs after they are approved," Dr Hennessy explained.

Additional research is warranted to gain insight into the approval timeline and drug safety, the authors state. Further, they call for collaboration between stakeholders and the FDA "to develop and maintain an effective system for detecting postmarket safety events."

Stakeholder engagement is essential, Pitts told Medscape Medical News. "Although it's not taught in medical school, it's up to physicians and pharmacists to report adverse events, which is critical from a risk perspective and to mitigate potential problems with the use of approved medicines in everyday practice."

The good news, according to Pitts, is that "the FDA is taking this challenge to heart," by enhancing the capacity of its postmarket safety surveillance programs, and improving interactions with industry to achieve a better understanding of the performance of new drugs once they get into the market.The FDA's Sentinel Initiative, an integrated, national electronic monitoring system for active postmarket risk identification and analysis, is an important step in this direction, as is the sharing of premarket clinical trial data, the authors write. "[T]he integration of multiple data sources that include observations among large and diverse patient populations can facilitate the detection of postmarket safety events."

Previously, as reported by Medscape Medical News, the Government Accountability Office has questioned the sufficiency of the FDA's reporting of postmarket studies of approved drugs.

"I'm not as optimistic as the authors that the current system is working…. Sentinel, which I'm part of, is a great system, but has limited bandwidth. There aren't enough resources to use Sentinel as the only way to study the safety of every approved product, nor does FDA have the human resources to be primarily responsible for studying the safety of all products," Dr Hennessy explained.

"Industry needs to play a role. Unfortunately, FDA is limited by law in their ability to require companies to perform their own safety studies. Changing this would require an act of Congress," he added.

The authors acknowledge that even the most careful regulatory review and surveillance systems may not prevent all postmarket safety events. "[I]t may be impossible to detect other less common events until several years after approval, once the therapeutics are in broad use."

Dr Downing has disclosed no relevant financial relationships. One coauthor reports receiving personal fees from Cepton, OliverWyman, Roland Berger, McCann Health, Omnicom, Grey Healthcare, Saatchi & Saatchi, Sudler, TBWA, Havas, Agipharm, Mayoly Spindler, Teva, Menarini, Pierre Fabre, Merck, and AbbVie. One coauthor reports receiving a grant from the FDA; research agreements with Medtronic and Johnson & Johnson (Janssen) through Yale University; serving as chair of a cardiac scientific advisory board for UnitedHealth, being a founder of Hugo, being a participant and participant representative of the IBM Watson Health Life Sciences Board; and serving as an advisory board member of Element Science. One coauthor reports receiving grants from the FDA, Medtronic, Johnson & Johnson, the Centers for Medicare & Medicaid Services, Blue Cross Blue Shield Association, and the Laura and John Arnold Foundation. Mr Pitts serves as chief regulatory officer for Adherent Health Strategies. Dr Hennessy has disclosed no relevant financial relationships.

JAMA. 2017;317:1854-1863.  Read More & Comment...

BCBSA BS on Rx

05/09/2017 01:26 PM |

The policy shop of BCBS has released a report about drug costs that is deliberately deceptive and misleading.   It focuses only on the contribution of innovative drugs to total drug spending, ignoring other facts that underscore the important role new medicines play in reducing the rate of health care spending and hiding the rebates they, along with PBMs pocket. 

The report claims that “since 2010 prescription drug spending has increased 10 percent annually for Blue Cross and Blue Shield (BCBS)members since 2010, an overall rise of 73 percent.This upward trend is due to a small fraction of emerging, patented drugs with rapid uptake and large year-over-year price increases that are more than offsetting the continued growth in utilization of lower-cost generic drugs. These higher costs are being incurred by consumers and payers alike; while consumer out-of-pocket costs have risen just three percent annually for prescription drugs in total, they have risen 18 percent annually for patented drugs.”


You might wonder how it is possible for consumer out of pocket costs to rise 3 percent annually if the increase in patented drug spending has increased 18 percent? Is it because health plans are sucking up the difference in cost for our sake? A closer look at the findings suggests answers. 

1    BCBS compared apples – the average increase in out of pocket costs – which includes the increase in the use of generic drugs – to oranges, namely the pre-rebate increase in spending on drugs for Hepatitis C, autoimmune diseases and cancer for less than 1 percent of chronically ill patients.  Indeed, the BCBS ‘study’ acknowledges that the drug spending data they use is pre-rebate.  But let’s stick with sticker prices for now and ask: how does the increase in the use of a small number of new medicines affect drug spending and total health expenditures.

2    It turns out that employer-sponsored health plans are spending LESS on brand or innovator drugs as a percent of total health care spending.  And total drug spending is about the same as it was in 2007:


Sources: Health Care Cost and Utilization Reports for 2010-2015





3.       Since 2007, brand drugs as a percent of total drug spending has DECLINED


    Sources: Health Care Cost and Utilization Reports for 2010-2015




4. If brand spending is down and total drug spending as a percent of all health expenditures are flat, why is cost sharing for drugs going up by 3 percent a year? 

BCBS notes: “Utilization is down for all brand drugs, but the unit price has increased by an average of 17 percent each year, leading to a total increase in spending of 10 percent.”
 
In other words, health plans are charging the retail, not the rebated price, in determining copays and coinsurance even as brand drug spending as a percent of total Rx dollars has declined.  Indeed, the spread between the rebated and retail price has been increasing.  


Source: IMS Data

What's more, these rebates are not used to reduce the out of pocket costs of patients And plans use the retail price to fatten their margins with rebates AND the out of pocket spending of consumers.  Reports about rebate revenues are hard to come by.  However, an NAIC report suggests that rebates industry-wide are at least $30 billion which is more than the total underwriting gain of all health insurers.   

The BCBS policy report hides the fact that drug spending as a percent of total health care spending is flat.  It hides the fact that it is using rebates and retail prices to pad the bottom line.  And it is using innovator drug prices as scapegoats.  

A final thought: The Healthcare Cost Institute reports show that the utilization of all inpatient and outpatient services has declined since 2007 even as the use of both new and generic medicines has increased.   And yet health plans have rarely considered or acknowledged that the use of prescription drugs reduces the reliance on more expensive forms of care. 
  Read More & Comment...

From the FDA.ke News Desk

05/06/2017 03:31 PM | Peter Pitts

In the wake of the unraveling scandal surrounding the agency’s television viewing habits, CDRH spokesperson Teng Kay has denied allegations they have been instructed by “unconfirmed alien contact” to reclassify TV remotes as Class II Medical devices. In a related story, Acting FDA Commissioner Rupert Murdoch has issued a list of “breakthrough therapy” entertainment for recommended viewing. The list is said to include: ANDA and the King of Siam, Complete Response Letters from Iwo Jima, and Fahrenheit 453. All programming has been deemed truthful, accurate, and non-misleading by the Shkreli Institute for Ethical Studies.  Read More & Comment...

ICER’s GIGO

05/05/2017 03:58 PM | Peter Pitts

ICER’s new report, to no one’s great surprise, has found abuse-deterrent opioids provide neither financial nor societal benefits.

GIGO. Garbage In. Garbage Out.

For example:

The ICER analysis specifically does not include diversion – even though the majority of the problem arises from this community.

ICER also changed its model at the last minute to be include all abuse-deterrent formulations (ADFs) and not just Oxycontin -- despite preliminary results that showed that, over 5 years, OxyContin ADF prevented 4,300 cases of abuse, >12,000 abuse years, saved $300 million in medical costs against $387 million in incremental pharmacy costs. These results alone are within the realm of cost effectiveness: $20,500 per abuser avoided, $7100 per abuse year avoided for the most successful ADO introduced into the market.

Societal costs are not included despite ICER’s promise they would be.

Heroin switching is included, despite the fact that it is an incident cohort. Per ICER, “We did not include the effects of increasing heroin use that might result from opioid abusers being switched to ADF opioid, as we are considering only incident and not prevalent opioid abuse in the model.” Hm.

ADF benefit is reduced by 25% because of the author of the original paper (Rossiter) conducted a sensitivity analysis to see how such a reduction would effect the model.

ICER is calling for ADFs to be “cost-neutral.” But how is this possible since the overwhelming cause of the problem are inexpensive, non-ADF generics?

What the ICER report ignores entirely is that one of the factors driving abuse and addiction is the inappropriate use of generic opioids for conditions that have non-opioid, on-label options. (52 percent of patients diagnosed with osteoarthritis receive an opioid pain medicine as first line treatment as do 43 percent of patients diagnosed with fibromyalgia and 42 percent of patients with diabetic peripheral neuropathy.)

Payers often implement barriers to the use of branded, on-label non-opioid medicines, relegating these treatments to second line options – along with new abuse-deterrent opioid formulations. The result is a gateway to abuse and addiction. An unintended consequence of the ICER analysis will be more of this inappropriate behavior.

According to Harvard health economist David Cutler, Virtually every study of medical innovation suggests that changes in the nature of medical care over time are clearly worth the cost.  But, as Aldous Huxley reminds us, ““Most human beings have an almost infinite capacity for taking things for granted.”

Abuse-deterrent opioids are precision medicines. They are not for everyone. As Dr. Charles Inturrisi, professor of pharmacology at the Weill Cornell Medical College, said at a 2013 Center for Medicine in the Public Interest Capitol Hill conference on opioids, “Personalized medicine can reduce the non-responder rate because you can focus in on individuals who are highly associated with being responders and you can eliminate the trial and error inefficiencies that inflate healthcare cost.”

One of the consequences of the ICER report is that it will deter investment in more and more creative abuse deterrent programs. The phrase, “strangling the baby in the crib” comes to mind.

Remember – ICER is the organization that found the new class of Hepatitis C therapeutics failing their cost/benefit litmus test -- another example of this organization being on the wrong side of history. Alas, it’s totally understandable considering that, on September 3, 2016, Dan Ollendorf (ICER Chief Scientific Officer) told the Pink Sheet, “It’s difficult to really understand how these [abuse deterrent opioids] are going to be of benefit if the non abuse-deterrent formulations are still out there.”

Talk about Confirmation Bias!

   Read More & Comment...

QunitilesIMS Data to Digest

05/05/2017 08:06 AM | Peter Pitts

The QuintilesIMS Institute has issued a very interesting new report, “Medicines Use and Spending in the US: A Review of 2016 and Outlook to 2021.” It’s a must-read for many reasons – not the least of which is its plethora of data. Many items to peruse and digest.

Here are four of the reports conclusions – as an appetizer …

* The outlook for spending has been revised downward as expectations for new products and price increases have moderated.
* Invoice price growth for protected brands is projected to be between 7-10% down from 8-11% in the prior outlook.
* Net price growth for protected brands is forecast to be 2-5% through 2021.
* The impact of losses of exclusivity are expected to be 50% greater in the next five years, including the impact of biosimilar introductions.

With the caveat that statistics are like swimwear (what they show you is interesting but what they conceal is essential), have a look and draw your own conclusions.  Read More & Comment...

Dear Colleague: Let's Put Off-Label on the Legislative Table

05/04/2017 06:03 PM | Peter Pitts

Representative Morgan Griffith (R/VA) has introduced HR 1703, the Medical Product Communications Act. It’s legislation that would take a lot of the ambiguity out of the FDA’s biggest conundrum – regulatory clarity on the sharing of truthful accurate, and non-misleading off-label information.

As Mr. Griffith writes in a Dear Colleague letter, “Doctors should have the most up-to-date information when caring for their patients and, when done responsibly and in an appropriate context, manufacturers should be able to provide it.”

Amen.

For more detail on the issue, have a look at this new article from the Therapeutic Innovation and Regulatory Science (the official journal of the Drug Information Association), “Using Off-Label Communications to Responsibly Advance the Public Health.”  Read More & Comment...

The Dubai Declaration

05/03/2017 08:58 AM | Peter Pitts

When it comes to 21st century pharmacovigilance, sometimes it’s important to look …  backwards. According to the 10th century Arab physician, Ibn Sina, “The time of action must be observed, so that essence and accident are not confused.”

At the United Arab Emirates’ Sixth National Pharmacovigilance Conference” held last month in Dubai, specific recommendations (known as “the Dubai Declaration”) were released by the Ministry of Health and Prevention (MoHP).

According to Dr. Amin Hussain Al Amiri (MoHP- Assistant Undersecretary for Public Health Policy & Licensing Sector, the Declaration will be submitted to the regional Gulf Health Council for Cooperation Council States and the 22-member Arab League with the hope that this “would benefit the Arab World.”

The complete list of recommendations can be found here.

A few stand out from the rest, specifically:

1- Build trust in the critical role of testing medicines following registration and testing random sample from the field.

2- Enhance of pharmacovigilance education programs among HCPs in the region.

3- Include pharmacovigilance education in the academic curricula of medical and scientific schools and making it among the basics of education.

4- ADRs reporting must become a “culture of HCPs” who must not be embarrassed in doing so.

5- Enhance health education to raise public awareness on expected ADRs.

6- Reported ADRs to be categorized and separated according to originator medicine, generic, and the biological view of the difference in chemical compositions.

7- Focus on the educational role of pharmacovigilance officers among the various healthcare establishments in the region.

When it comes to the quality of medicines, remember the words of Dr. Janet Woodcock, (CDER Director, USFDA), “The spark that ignited the flame was when we asked ourselves, Do we know enough about the quality of drugs that are sold in the United States? And the answer was … no.”

We would all do well to learn not just from the past – but from other parts of the world. The West doesn’t have a monopoly on good ideas.
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Scott Gottlieb: Hope Over Hate

04/27/2017 11:18 AM |

Today (we hope) the Senate HELP Committee will vote to confirm Dr. Scott Gottlieb as the next FDA commissioner.

Three things stand out about his nomination:

1.    Dr. Gottlieb has garnered the support of a wide range of patient organizations and medical associations.  The same coalition supported Dr. Rob Califf’s nomination in 2016.
2.    The same groups and individuals who oppose Dr. Califf’s nomination are opposing Scott.  Apart from the Senators who opposed both individuals to demonstrate frustration with the FDA’s response to the opioid addiction problem, the critics are the self-important and self-serving hacks from Public Citizen along with smug academics whose names I will not repeat. 
3.    Both Dr. Gottlieb and Dr. Califf are deeply committed to changing the paradigm of FDA approval by working with talented individuals inside the agency.  

Dr. Gottlieb’s nomination reflects a bi-partisan consensus about the role of the FDA that originated with President Obama and the nomination of Dr. Peggy Hamburg:   When it comes to evaluating the risk and benefit of innovations that determine not only whether we live or die but how we live and die, patients and their loved ones have as much of say on the basis for approval and regulation as any expert.  

Dr. Gottlieb will carry on that tradition.  His opponents want to destroy that tradition.  Hope vs. hate. Remember that the next time you see a hateful, angry tweet about the next FDA commissioner.  
  Read More & Comment...

Making Drug Manufacturing Great Again

04/21/2017 01:25 PM | Peter Pitts

From the pages of Investor’s Business Daily …

Making Drug Manufacturing Great Again

President Trump wants to lower drug prices and reinvigorate domestic pharmaceutical manufacturing.  Bravo. But standing in the way is the inside-the-Beltway gospel that preaches that regulators love ambiguity.

As a former FDA associate commissioner, I can affirm that's true. Vagueness gives the agency almost unlimited authority to do whatever it wants.
But, when it comes to the FDA, it's predictability in pursuit of the public health that's important. And nowhere is this truer or more timely than when it comes to the oversight of drug manufacturing.

Drug manufacturing isn't sexy to the general public and rarely makes headlines — unless something goes wrong. Recalls make headlines. Adherence to current good manufacturing practices (GMPs) do not.

A few years ago I had the chance to visit Pfizer's Kalamazoo production facility. What impressed me more than the gee-whiz production aspects of the facility (of which there were plenty) was the dedication of the people who work there — top to bottom.

It actually reminded me a lot of the FDA. Long-term employees dedicated to serving the public health through dedication to quality. And they all took it very personally. Just like at the FDA, the Pfizer folks were on personal missions of quality. There was a lot of pride on display.

Mr. President — there hasn't been an exodus of pharma manufacturing to foreign shores. In fact, when I visited the Kalamazoo facility they were exporting (among other things) the active pharmaceutical ingredient (or API, the actual drug substance) for methyl prednisolone (a corticosteroid long off patent) to both China and India.

A U.S. manufacturing facility of an innovative biopharmaceutical company that exports drugs to China and India for profit?  What's wrong with this picture? Well, as it turns out, it's what's right — innovation through manufacturing prowess, organic chemistry smarts and green technology. Better. Faster. Cheaper.

Pharma's always bragging about its ever-growing investment in R&D. But when was the last time you heard about investments in domestic manufacturing? Probably never.

And when was the last time you read about enhanced drug safety through good manufacturing processes and cooperation between industry and the FDA? Not recently. That's a shame because they're both important stories.

The president's nomination of Dr. Scott Gottlieb to be the next FDA commissioner likely portends a more holistic view of drug regulation. I served with Scott for two years at the agency. Not only is he a voice for greater regulatory predictability, he's also a silo-buster.

Having previously served as deputy commissioner, he understands the need for greater interdepartmental cooperation. In other words, it's not just about better utilization of expedited review pathways or better use of real-world data, or enhanced post-market surveillance, or more robust off-label communications. It's about making the process work for patients.

But manufacturing is all about process. Modernized pharmaceutical manufacturing isn't only about ensuring and enhancing quality for finished medicines, it's also about making America's pharmaceutical factories globally competitive players in the production of API (like Pfizer's plant in Kalamazoo) and excipients (the ingredients other than the API that are included in the manufacturing process or are contained in a finished pharmaceutical product.)

And the more complicated the drug, the more complicated the active pharmaceuticals and other ingredients. American know-how and dedication to GMPs present a wonderful opportunity for our domestic facilities to thrive. Quality manufacturing is our unique proposition vis-a-vis less expensive operations overseas.

FDA regulation of medicine manufacturing is also a crucial piece of the solution to preventing future drug shortages. According to a 2012 report from the House Committee on Oversight and Government Reform, by hastily ramping up manufacturing enforcement actions, the FDA "effectively shut down 30% of the total manufacturing capacity at four of the country's largest producers of generic injectable medications."

Resolving this problem will require the FDA to work with manufacturers to find practical, science-based solutions to quality-control issues that neither compromise safety nor slow down production. Regulatory discretion is often the better part of valor.

Enforcement of savvy manufacturing quality control is crucial, but an equally important (and often ignored) aspect of the FDA's mission is to advance America's pharmaceutical production acumen by being both regulator of and partner with industry.

That's a winning combination: the best and the brightest from industry and government together with the best production capabilities in the world. The keys to the kingdom are on the table.

Pitts, a former FDA associate commissioner, is president of the Center for Medicine in the Public Interest.  Read More & Comment...

DTC Fair Balance ... for Lawyers!

04/17/2017 09:19 AM | Peter Pitts

House Judiciary Committee Chairman, Rep. Bob Goodlatte (R/VA.) wants drug side-effect ads that are run by lawyers to include a warning that patients should talk with their doctors before adjusting medication, the Wall Street Journal reports. Along with the American Medical Association and some drug companies, he contends the ads are to blame for patients suffering harm or even dying after dropping treatment.
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PDUFA Reauthorization. Discuss.

04/14/2017 05:54 PM | Peter Pitts

House, Senate Health Committee Leaders Release Discussion Draft of FDA User Fees Reauthorization

WASHINGTON, DC – The leaders of the Senate and House health committees today released a discussion draft of bipartisan legislation reauthorizing the Food and Drug Administration user fee agreements.

The Food and Drug Administration (FDA) Reauthorization Act of 2017 renews FDA's authority to collect user fees from the makers of prescription brand drugs, medical devices, generic drugs and biosimilars, and several vital programs at the FDA. The 2012 prescription drug user fee amendments (PDUFA), medical device user fee amendments (MDUFA), generic drug user fee amendments (GDUFA), and biosimilar user fee amendments (BsUFA) all must be updated and reauthorized by Congress before the current user fee agreements expire on September 30.

If the agreements are not reauthorized before the August work period, the agency will be forced to send layoff notices to more than 5,000 FDA employees. A delay in reauthorizing these agreements would delay the reviews of critical drugs and devices.

“We are fully committed to a timely reauthorization of the agreements and are well on our way,” said Energy and Commerce Committee Chairman Greg Walden (R-OR). “This represents another opportunity to help expedite the review and approval of new cures and treatments for patients, and we must prioritize it. As this process proceeds, I look forward to continued discussions with my colleagues in the House on other member priorities that could strengthen this important legislation.”

"The swift reauthorization of these user fee agreements is critical to making sure FDA has the resources and personnel it needs to ensure timely review and approval of safe and effective medical treatments,” said Energy and Commerce Committee Ranking Member Frank Pallone, Jr. (D-NJ). “These carefully negotiated agreements encourage innovation, improve our regulatory review process, and provide certainty to both patients and industry. I look forward to working with my colleagues to move this legislation through Congress and to the President's desk.”

“If we do not move quickly to reauthorize these agreements, in late July, the FDA will be forced to begin sending layoff notices to more than 5,000 employees to notify them that they may lose their job in 60 days,” said Senate Health, Education, Labor and Pensions Committee Chairman Lamar Alexander (R-TN). “The sooner we reauthorize the agreements, the better – to give patients, reviewers, and companies certainty. In addition to harming patients and families that rely on medical innovation, a delay in reauthorizing the user fees would threaten biomedical industry jobs and America’s global leadership in biomedical innovation.”

“I’m encouraged by our bipartisan work to reauthorize these agreements to advance safe, effective, and innovative medical products,” said Senate Health, Education, Labor and Pensions Committee Ranking Member Patty Murray (D-WA). “Patients and families nationwide are relying on us to ensure FDA can continue its vital work without interruption. I hope that we can continue to put partisanship aside and advance this important legislation.”

The FDA Reauthorization Act of 2017:

Updates and reauthorizes the user fee programs, which, in Fiscal Year 2016, accounted for 70 percent of the brand drug review budget, 36 percent of the medical device review budget, 75 percent of the generic drug review budget, and 29 percent of the biosimilar review budget.

Reflects the recommendations sent by FDA to Congress in January, which were based on over a year of negotiations and discussions with industry, Congress, patients, and other stakeholders.

Implements the four user fee agreements authorized by FDARA, which support the goals of the 21st Century Cures act and advance key bipartisan priorities:

Prescription Drug User Fee Amendments (PDUFA VI): Enhances patient-focused drug development, supports biomarker development and qualification, dedicates staff to assist in the development and review of rare disease drugs, sets clear timelines and improves guidance for drug and device combination products, and evaluates ways to modernize the clinical trial process.

Medical Device User Fee Amendments (MDUFA IV): Enhances the patient voice in the device development process, supports the collection of real world evidence on the safety and effectiveness of devices, and improves the review process for  “de novo” devices—low- to moderate-risk devices that are the first of their kind.

Generic Drug User Fee Amendments (GDUFA II): Improves the fee structure to support small businesses, provides goal dates for all outstanding generic applications, and establishes priority review timelines.

Biosimilar User Fee Amendments (BsUFA II): Continues to build the biosimilars program, and supports guidance for product developers.

CLICK HERE for the text of the discussion draft, HERE for a section-by-section summary of the discussion draft, and HERE for a one-pager. Health committee leaders ask that stakeholders who wish to comment on the contents of this draft please submit to FDAuserfees2017@help.senate.gov by April 28th.  Read More & Comment...

PIE Day

04/12/2017 07:47 AM | Peter Pitts

It's time to go beyond FDAMA 114.

Representative Brett Guthrie (R/KY) introduced the Pharmaceutical Information Exchange (PIE) Act of 2017 (H.R.2026). The bill incorporates the multi-stakeholder consensus recommendations developed during a forum sponsored by the Academy of Managed Care Pharmacy. The legislation would allow biopharmaceutical manufacturers to proactively share clinical and economic information with population health decision makers on emerging therapies in advance of Food and Drug Administration (FDA) approval, an area that is significantly restricted by current federal laws and FDA regulations.
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Expediting Complex Geneics

04/06/2017 09:18 AM | Peter Pitts

It's not about speed, it's about predictability.

The way to expedite complex generics is by making the process predictable. Predictability = more development programs = competition = lower prices.
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PV in the EU: Can the Doctor See You Now?

04/06/2017 06:57 AM | Peter Pitts

European, national, and regional authorities should invest in awareness-raising campaigns to increase public knowledge about medicinal safety and adverse drug reaction (ADR) reporting.
 
This is one of the main findings of the study “Pharmacovigilance in the European Union: Practical implementation across Member States” from the University of Duisburg-Essen which assesses the functioning of EU pharmacovigilance legislation.
 
The report focuses on adverse drug reaction (ADR) reporting of biologicals in six EU Member States - the UK, Finland, France, Poland, Portugal, and Germany. Since the 1990s, legislation at the EU level has strengthened medicinal safety in general, and particularly the reporting of ADRs. However, transposition problems remain in some EU Member States when it comes to medicinal safety.
 
ADRs account for 5% of all hospital admissions, cause around 200,000 deaths per year in the EU, and cost roughly €80 billion.
 
Almost 85% of EU rules are not transposed on time, and occasionally come with a delay of more than two years. Although patients are given a strong role within the new EU pharmacovigilance legislation, they lack awareness, and this leads to ADRs going unreported.
 
The report argues that ADR reporting should be viewed as a key responsibility for healthcare professionals and not as a failure or lead to reputational damage. They should also be properly trained and targeted by awareness-raising campaigns to ensure they are aware of the importance of medicinal safety to public health and feel comfortable in reporting ADRs without fear of liability and/or failure.
 
Patients also have a critical role to play, and Member States should enable patients to report ADRs online, and connectivity of IT systems between general practitioners, hospitals, pharmacies, and the national competent authority should be improved.
 
A key solution identified by the report is to put in place awareness raising programmes aimed at both patients and healthcare professionals to increase knowledge about medicinal safety and highlight the role it can play to ensure public health.
 
The report will be shared with EU Member States, the EU Institutions, and key stakeholders, with the aim of ensuring the recommendations are taken up by governments, and that the EU legislation can be properly implemented across Europe.  Read More & Comment...

Scott STAT!

04/05/2017 10:05 PM | Peter Pitts

“I think Scott is very much for good regulation, and very much against bad regulation,” Pitts said. “Importantly, he recognizes where FDA core mission stops, and where mission creep begins — and that’s an important finesse he’d bring to the commissioner’s chair.”
 
Via STAT News:
 
 Gottlieb’s pledge to uphold ‘gold standard’ raises red flags
 
When Dr. Scott Gottlieb pledged at his confirmation hearing to uphold a “gold standard of safety and efficacy” at the Food and Drug Administration, he raised an important question:

What exactly does he mean by that?
 
Traditionally, “gold standard” refers to robust, randomized controlled clinical trials. But there’s enormous pressure on the FDA — from pharma companies and Congress, for starters — to accept other kinds of evidence, perhaps even patient anecdotes, to determine whether experimental drugs work. And President Trump is promising to speed drug approvals.
 
So when Gottlieb said: “I think there are ways to modernize clinical studies without sacrificing the gold standard,” he raised red flags.
 
“I don’t think he was using the phase ‘gold standard’ in the way that most of us who think about the agency for a living understand it,” said Rachel Sachs, an associate professor of law at Washington University in St. Louis.
 
“I think he views adaptive clinical trial design as in keeping with that gold standard,” Sachs said.
 
And that’s the rub, because modifying clinical trial standards has many people concerned. Reshma Ramachandran, co-chair of the National Physicians Alliance’s FDA task force, says she, too, doesn’t know what Gottlieb meant by “gold standard” — but isn’t optimistic about his interpretation.
 
She pointed out that Gottlieb has criticized the use of adequate and well-controlled Phase 3 trials in the past, saying they’ve needlessly delayed access to important drugs.
 
“That seems to indicate that his idea of ‘gold standard’ means sacrificing safety and efficacy you’d expect from FDA in favor of expediting an approval pathway,” Ramachandran said.

Joshua Wallach, a research fellow at Yale’s Collaboration for Research Integrity and Transparency, had similar worries.

“I’m concerned: I don’t want a complete erosion of the quality of clinical trial evidence that’s required from industry,” Wallach said. “There’s definitely a movement still toward deregulation — and lowering of evidentiary standards.”
 
Wallach is afraid, in particular, of changes to clinical trial endpoints. Modernizing the clinical trial process might force trials to lean on surrogate endpoints. That could mean assessing an experimental drug based on whether it has some interim effect (like improving a dementia patient’s performance on a memory test) rather than whether it meets more significant long-term goals (like prolonging that patient’s ability to complete daily tasks). It could also open the door to pharma companies scouring their clinical trial data to find metrics that look good — and presenting those to the FDA, even if the trial was originally designed to answer an entirely different question.
 
“I’m worried about seeing more small, crappy trials that don’t actually tell you anything about efficacy and safety — which are extremely important before drugs can be approved or marketed,” Wallach said.
 
Part of upholding the FDA’s gold standard could involve respecting and keeping on career staff, Sachs said. And for that, she gives Gottlieb high marks.
 
“I think he understands the importance of a strong, well-resourced FDA,” Sachs said. “I don’t think he will burn it all down. I don’t think he’s inclined to destroy the agency from within.”
 
Peter Pitts, president of the nonprofit Center for Medicine in the Public Interest, saw another glimmer of good news in the confirmation hearing: He said he thinks Gottlieb’s definition of “gold standard” includes keeping FDA funding strong.
 
“The president and his team understand that you can’t get more for less — and that’s especially true on staffing,” said Pitts, who was a former associate commissioner of FDA and worked with Gottlieb at the agency for two years. “And Scott came pretty close to saying he was against a reduction of budget.”
 
Pitts added that he was impressed by Gottlieb’s performance at the hearing.
 
“I think Scott is very much for good regulation, and very much against bad regulation,” Pitts said. “Importantly, he recognizes where FDA core mission stops, and where mission creep begins — and that’s an important finesse he’d bring to the commissioner’s chair.”  Read More & Comment...

Arizona and Off-Label. Heart in the right place. Brain -- not so much.

03/30/2017 10:11 AM | Peter Pitts

Arizona is first state to pass a law allowing drug makers to promote off-label uses

Ed Silverman @Pharmalot

In what some observers are calling a misguided effort, Arizona has become the first state in the nation to pass a law allowing drug makers to promote their medicines for so-called off-label uses — so long as the information given doctors is truthful.

Interestingly, the law was hatched by the Goldwater Institute, the same think tank that spearheaded the controversial Right to Try laws designed to give patients early access to experimental medicines. And the think tank is vowing to duplicate that campaign by introducing off-label bills around the country.

This move comes amid rising pressure on the Food and Drug Administration to loosen regulations for off-label promotions, which is one of the most contentious issues to roil both the agency and the pharmaceutical industry. At issue is a fierce debate over patient safety and free speech.

Doctors can prescribe a medicine for an off-label — or unapproved — use, but drug makers have battled restrictions on their ability to distribute such information, such as reprints of medical studies. The companies believe free speech is being curtailed and have lobbied Congress and the FDA to loosen regulations. For its part, the FDA worries public health can be jeopardized by promotions that go too far.

Significantly, drug makers were emboldened by a pair of court rulings in recent years that determined companies can disseminate off-label information, so long as it is truthful and not misleading. However, one of those decisions, which was issued by a federal appeals court, only extends to Connecticut, New York, and Vermont, creating uncertainty about whether the issue would be tested elsewhere.

The FDA, meanwhile, has not yet taken any action.

In fact, the agency held a two-day, public meeting last November. But two months ago, the FDA issued a memo that, instead of suggesting possible solutions, simply summarized key points framing the long-running debate and carefully rebuffed many of the suggestions made by drug makers and others that support expanding pharmaceutical marketing.

And so the Goldwater Institute is trying to force the issue with the Free Speech in Medicine Act.

“Curbing the exchange of information about off-label treatments by those with the most knowledge about the drug’s uses, risks, and side effects not only prevents patients from receiving the best possible care; it violates the constitutional right to free speech,” said Christina Sandefur, the executive vice president of the Goldwater Institute, in a statement.

While the Goldwater Institute plans to take its “model law” to other state legislatures, so far, similar bills have not yet been introduced elsewhere, according to Richard Cauchi, health program director at the National Conference of State Legislatures.

Meanwhile, though, one former FDA official, who has publicly urged the FDA to loosen its regulations, believes such state laws would be useless, because they would be preempted by federal law that allows the FDA to issue guidance documents and rules about various activities and requirements.

“It’s nice that the Arizona legislature thinks disseminating off-label information is a good thing, but it’s not their jurisdiction to say so,” said Peter Pitts, a former FDA associate commissioner who heads the Center for Medicine in the Public Interest, a think tank that is funded, in part, by the pharmaceutical industry. “I don’t think a challenge in court would last more than five minutes.”

Nonetheless, one consumer advocate, who opposes widening the ability of drug makers to promote off-label uses, fully expects the Goldwater Institute to persist.

“I don’t think the law will change the landscape, but they’re seeking to gin up public attention and become a stepping-stone to try to get Congress to pass laws that would accomplish the same thing on a national level,” said Michael Carome, who heads Public Citizen.  “I suspect that’s the ultimate goal.”

As for the Right to Try campaign, 33 states have so far passed such laws and, recently, bills were introduced in the US House and the Senate. Critics say these bills are wrongheaded for trying to cut the FDA out of the process, since regulatory oversight would be removed and drug makers are actually the ultimate gatekeepers for deciding access to their drugs.
   Read More & Comment...

STAT News Tangled Treatment of Scott Gottlieb

03/29/2017 12:29 PM |

STAT News is one of my favorite sites for medical and health news.   The reporting is great and the journalists are open, thoughtful and smart.   

Every once in a while there will be clunker like the following article about Scott Gottlieb:

Trump’s FDA nominee pledges to untangle his ties to 25 biopharma companies

"President Trump’s pick to lead the Food and Drug Administration has promised to recuse himself from agency decisions on more than 25 companies to which he has ties.

Dr. Scott Gottlieb, who is deeply entrenched in the industry he may soon regulate, plans to resign from his roles in investment banking, venture capital, and as a consultant to drug companies within 90 days of his Senate confirmation. At the same time, he’ll sell off his shares in a host of biotech companies.

And for one year after those resignations, Gottlieb will stay out of any FDA deliberations related to those companies, which include GlaxoSmithKline, Bristol-Myers Squibb, and Vertex Pharmaceuticals."

Deeply entrenched?  Untangling of ties?  From 25 -- count em, 25 -- companies? Sounds suspicious.  Should we ask Carrie Matheson to get to the bottom of Gottlieb's consulting activities?  

A less breathless and narrative driven article could have noted that Scott's recusals and divesting of industry related investments and associations are no different than what any other nominee for FDA commissioner has done, including Rob Califf and Peggy Hamburg.   And no one was keeping score of how many companies they consulted for or held stock in.  Or that Gottlieb has made increasing the number of generic drugs that compete against medicines made by companies he advised a top priority? 

To be fair,  when I wrote to STAT News editor Rebecca Robbins raising my belief that the article was more narrative than reporting she responded that the intent was not to reinforce a narrative peddled those who regard Dr. Gottlieb as a pharma pawn.  

But there is this as well: "The 44-year-old physician has traced an unusual career path, pivoting from Wall Street to a role at the FDA and then embarking on a lucrative career as an investor and adviser." 

Who else thinks that this article will spur more attacks and spawn similar pieces from other news outlets that will include quotes from anti-industry critics such as Public Citizen who have already smeared Scott?


   Read More & Comment...

ICER Devalues People With Rheumatoid Arthritis

03/28/2017 01:05 PM |

 

ICER recently had a meeting to discuss its latest study: "Targeted Immune Modulators for Rheumatoid Arthritis: Effectiveness & Value." It is no different than any other ICER report:  It concludes no medicine is cost effective and it uses methodology that no economist can replicate.   ICER reports are the cold fusion experiments of health care economics. 

I have released a report discussing the impact of ICERs approach on patients.  It concludes that applying ICER's cost-effectiveness standard to all biologics developed for RA since 2000 (none are cost-effective according to ICER) would have harmed a lot of people with RA.

Between 1999 and 2014 there would have been 46689 more deaths under an ICER regime.   Additionally, research suggests that since 1999 the life expectancy of people with RA who used new medicines could expect to live 10 years longer than those not treated.   Hence under an ICER regime people with RA would have 466894 fewer life years (46689 x 10).  

Going forward, ICER claims new RA drugs are not cost effective either.  

ICER estimates that only 97000 people year for five years (486000) with RA would get two new drugs it reviewed: baricitinib and sarilumab.  Both medicines were tested in people with RA whose disease didn’t respond to any other treatments or couldn’t tolerate any other medicines.  

ICER fails to disclose how they arrived at the estimate that 97000 people a year would use new drugs. Further, it assumes – without any support – that 70% of new users on baricitinib would come from patients using sarilumab and 30% would come from another biologic -- adalimumab--that it claims isn't cost effective either. 

In doing so, ICER assumed that 50% of these patients were moderate-to-severe cases, and 50% of this subset had failed initial treatment with non-biologic RA drugs such as methotrexate.  ICER states: "Applying these proportions to the projected 2016 US population resulted in an estimate of approximately 486,000 patients in the US over a five-year period.”

But this assumption is flawed. A recent study found that 50 percent of all RA patients failed to respond to their second-line biologics. Further, many other patients will stop responding to any therapy.   Finally, ICER did not consider that many people with RA do not benefit from any other medicines.  So, there is little basis to assume that two new medicines would not be used more widely as well as claim that one would replace the other.  

If the 97000 limit is applied, 398000 people with RA a year would be denied medicines that improve their condition and could likely increase their life expectancy. ICER limits would cost RA patients up to 250900 life years over that time. 

You can access the entire study here.   Read More & Comment...

Limpid Lipids

03/28/2017 10:25 AM | Peter Pitts

Nothing is more illustrative of the price/value discussion than PCSK9s. Just what are they worth? What's innovation worth?

At a recent Galen Institute forum, cardiologists, patient organizations, and policy wonks sat down to discuss the relative merits of PCSK9s both as a therapeutic choice and a reimbursement imbroglio. Issues ranged from physicians’ frustration with pre-authorization, to best practice beyond familial hyperlipidemia. What value should be assigned to PCSK9s for patients who are non-compliant with their statin therapy? Providers want to have the freedom to deliver the best clinical outcomes. How can payers become a more symbiotic part of that therapeutic journey?

Galen Institute President Grace-Marie Turner commented, "As I travel the country, I have become increasingly concerned as doctors say that their hands are being tied by bureaucrats who second-guess their clinical decisions. At this critical moment in the health care debate, I believe policymakers need to hear the physician point of view." She noted that, typically, physicians are so busy caring for patients that they do not have much opportunity to take part in discussions of health care policy. "For this reason, we decided to bring this group together to begin a national conversation about this crisis in the medical profession, and ensure that policymakers and patients alike understand the barriers doctors are facing as they attempt to deliver the best care possible to their patients."

According to Dr. Seth Baum, fellow of the American College of Cardiology, the American Heart Association, the American College of Preventive Medicine, the National Lipid Association, and the American Society for Preventive Cardiology, "Patients should not have to wonder who is deciding which medicines they take -- their doctor, or their insurer … In my case, I am forced to complete intricate, 17-page documents so that insurers will allow my patients access to lifesaving new cholesterol medications, only to see them turned down, repeatedly."

Baum also pointed to "fail first" policies, which require doctors to prescribe older, cheaper medicines for patients until those patients "fail" on those drugs, before being allowed to prescribe breakthrough treatments that would be more effective. "These decisions are best made between doctor and patient, not by bureaucrats," he added. "Insurance should help ease health care worries, not tie doctors and patients up in red tape."

Another speaker at the conference, Dr. Hal Scherz, a pediatric urologist, said, "Third-party interference has become endemic in the U.S. health care system, and is increasingly destructive to the patient-physician relationship. A recent survey by the Physician's Foundation found that 53.9% of physicians surveyed claim that some of their decisions are compromised due to their current level of clinical autonomy. I am glad to take part in this discussion, and hope it will increase public awareness of the restrictions doctors encounter in their daily work."

Disease is the enemy. Practicing physicians know this, but their professional association -- the American Medical Association -- seems in need of some education. The AMA's new program, "truthinrx.org," is entirely silent on the actual metrics of healthcare spending and the value of pharmaceutical innovation. Ignorance is not bliss.

Medicines lower health care costs by improving patient health and warding off more serious complications, government interventions that discourage drug development will increase health care spending, not cut it.

The current inquisition of the pharmaceutical industry is meant to justify government restrictions on drug pricing. If facts still matter, free-market competition will be exonerated and upheld as the best way to contain health care spending while delivering quality care. If they don't matter, and legislators insist on imposing innovation-killing price controls, future health care savings will go up in smoke.

Healthcare innovation saves lives, saves money, promotes economic growth, and provides hope for hundreds of millions of people (both patients and care-givers) in the United States and around the world. It deserves respect -- or at least honest reportage.

Does this sound naïve? Perhaps, but as Schopenhauer said, "All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident."

How’s that for a tweet?  Read More & Comment...

Fake DTC news mustn't drive the healthcare debate

03/27/2017 09:57 AM | Peter Pitts

Policy development by sound bite is becoming a chronic disease. Exhibit A: “Pharma spends more on marketing and sales than on R&D.”

The Washington Post wrote about it.

John Oliver talked about it.

Legislators are fixated on it.

Letters to the Wall Street Journal complained about it.

Let’s look at the record – because the devil is in the details – and it starts with what “sales and marketing” means.

When pundits, politicians, and policymakers speak about “sales and marketing,” the picture they are painting is of direct-to-consumer pharmaceutical advertising – the public face of Big Pharma. So, let’s set the record straight on that straight away. In 2016 $5.6 billion was spent on DTC. Same period R&D spending is roughly $70 billion. Amorous middle-aged couples in claw foot bathtubs are a lot sexier than excel spreadsheets, but facts are pesky things. Surprised?

Here’s another eye-opener, the category of “marketing and sales” also includes product sampling and communications to physicians, legal and accounting fees, salaries, rent and utilities, and all post-licensure programs deemed necessary by the FDA. Nuts and bolts aren’t cheap. It’s also important to understand that the R&D reported investment is only for pre-approval investment and doesn't take into consideration post approval R&D expenditures, which were $20 billion in 2011 and most likely, much higher today.

But let’s address the elephant in the room – DTC advertising. Yes – it’s good for business (otherwise it wouldn't exist) but it’s also good for the public health. And, no, it doesn’t make medicines more expensive.

The good news is that an informed healthcare consumer is a healthier citizen.  And while information comes from many sources outside of the physician’s office – one of the most pervasive channels is through direct-to-consumer advertising.

Properly done, pharmaceutical advertising helps to de-stigmatize certain diseases and encourages people to talk with their doctors about problems previously considered taboo -- like depression. Other research demonstrated little or no correlation between a brand's DTC spending and it's cost. In other words, brands that spend more heavily on DTC advertising do not necessarily cost more than their less-advertised competition.

FDA research, of patients who visited their doctors because of an ad they saw, and who asked about that prescription drug by brand name, 87 percent actually had the condition the drug treats. And in 6 percent of those DTC-generated visits, a previously undiagnosed condition was discovered. Why is that so important? Because earlier detection combined with appropriate treatment means that more people will live longer, healthier, more productive lives without having to confront riskier, more costly medical interventions later on.

Only 7 percent of doctors said they felt "very pressured to prescribe" a particular advertised drug. When the FDA panel probed into the question of "pressure to prescribe," what we found out was that the real pressure was time pressure. More patients are coming in armed with more questions. A study in Health Affairs arrived at a similar conclusion. According to the study, ad- inspired doctor visits resulted in the advertised medicine being prescribed in only about 47 per cent of cases. Put another way, patients didn't get a prescription for the medicine they came in to discuss on more than half their visits. Even with advertising, doctors exert appropriate judgment when they prescribe drugs.

According to the FDA study, a majority of doctors feel that DTC advertising increases patient awareness and involvement, improves compliance, and enhances the overall doctor-patient relationship. But we can - we must - do better. Health care information is the consumer's Rosetta Stone, and the FDA, public policy institutes, pharmaceutical firms, communications professionals, health care providers, disease organizations, patient advocates, academics along with state and federal legislators must help design 21st century DTC advertising that not only helps to sell product, but also advances the public health.  Read More & Comment...