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And speaking of PDUFA reauthorization – wait, time out.
FDA has proposed a new application review model that would allow it to call a time-out, which could be used to resolve mid-cycle issues.
The idea seems to be an admission by the agency that the six and ten month review times for priority and standard applications, respectively, are no longer sufficient to actually complete a review.
So, it’s not really an issue of “time out” as it is “time on” – as in “time added” at the agency’s discretion.
Minutes of the Sept. 27 industry and FDA Prescription Drug User Fee Act reauthorization negotiation revealed the agency proposed the time-out solution in an effort to create more application review time that will, among other things, allow more feedback to sponsors.
The proposal also could be used to address industry requests for a formal mid-cycle meeting to gain agency feedback on an application’s direction.
But will more feedback result in greater predictability? The length of the review clock stoppage would be fixed, but was not specified in the minutes of the 9/27 meeting.
Industry representatives called for a mid-cycle review in a previous PDUFA negotiating session, but FDA said comprehensive feedback likely was not possible at the midpoint of an application review because its process is not complete. Hm.
An agency willingness to add more meetings to the process is a change from previous discussions with industry, where the agency argued allowing for more meetings could lead to more sponsor questions and create more work for reviewers.
But FDA maintains its previous position that it cannot provide additional application support with the resources it has -- and so its offer for more sponsor-requested meetings means the review time must be extended. Hm.
REMS, FDA, FDAAA, FTC, ANDA ...
The Federal Trade Commission is looking into whether companies are using REMS to thwart generic competition.
Markus Meier, assistant director of the Health Care Division in FTC’s Bureau of Competition, said he had seen two ways a company may use REMS to block generics: preventing generic companies from getting samples of the drug for bioequivalence testing, or making it difficult for a generic to participate in its REMS program.
“Some systems are so restricted that there is nowhere to buy the product except to buy it from the branded company,” he said. If the branded company refuses to sell it then the generic cannot do bioequivalence testing and therefore cannot file an ANDA and “potentially there will never be generic competition for the product.”
Hm. “Spirit” of FDAAA notwithstanding, can a company be “forced” to sell its product to a competitor? Interesting IP question.
Meier said FTC has also seen some instances in which the generic company got sufficient samples and filed an ANDA and then had to come within the branded company’s REMS to start marketing their product. At that point “the branded company tries to impose onerous requirements for participation in the program so that it makes it difficult for the generic to actually qualify,” he stated.
Hm. But don’t all REMS have to be approved by the FDA? Minus more directive practices from the agency, well, if you’re not part of the solution …
“I’m not saying that’s been proven,” Meier added. “I’m not saying we’ve made that accusation of anybody but we’re looking at it. And one of the reasons we’re looking at is because the statute (FDAAA) expressly prohibits participants in these programs from using REMS to erect barriers to competition.”
As for dealing with potential REMS abuse, Meier said FDA does not believe it has any mechanism to enforce the FDAAA provision prohibiting a company from using a REMS to block or delay approval of an ANDA. But “onerously prescriptive” is certainly in the eyes of the beholder. Is a REMS that’s tough for the proper public health reasons somehow wrong if it restricts entry of a generic and/or follow-on product?
Certainly not.Will FDA tighten standards for generic drugs? According to CDER Director, Dr. Janet Woodcock – the answer is “yes.” Good call.
At a meeting of the Generic Pharmaceutical Association in Bethesda, Maryland, Janet said the agency is discussing tightening the limits "so there is less variability.”
Less variability equals better predictability.
Dr. Woodcock commented that patients have complained about generic anti- seizure medications not working as well as brand-name counterparts.
This strikes a very personal note for me. One of my sons has Juvenile Myoclonic Epilepsy. His condition is wonderfully controlled via his meds – and I’d like it to stay that way.
Woodcock said that industry executives have approached her with concerns that some generic drugs have spurred quality concerns that went unnoticed in the approval process because clinical testing includes too few patients.
“They say, ‘I know there are products out there that aren’t equivalent,’ and typically they’re manufacturing folks,” Woodcock said in her speech. “I’ve heard it enough times from enough people to believe that there are a few products that aren’t meeting quality standards.”
Woodcock said she didn’t know when the agency would come to any conclusions about generic standards of equivalence. The standards assure the generic is absorbed at the same rate and extent as the brand-name version.
The absorption problems aren’t necessarily harmful, Woodcock said. FDA permits generic drugs to absorb at a 25 percent different rate and extent than the originals they copy.
In April, a group of outside FDA advisers, the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, voted 11-2 that the agency’s equivalence requirements aren’ sufficient for certain medicines. They didn’t offer an alternative, and suggested the FDA list “critical dose drugs,” or drugs where a small difference in concentration can change patients’ reaction, that may need new standards.
The Pharmaceutical Science and Clinical Pharmacology Advisory Committee voted unanimously, with one abstention, that critical dose drugs do constitute a distinct group and voted unanimously that FDA should develop a formal list of those drugs - although the terminology of "narrow therapeutic index" may be more appropriate. And in an 11-2 vote, the committee concluded that current bioequivalence standards are not sufficient for drugs in the narrow therapeutic index group.
Critical dose drugs have a narrow therapeutic index, meaning that "small changes in blood concentration have the potential to result in serious therapeutic failures and/or serious adverse drug reactions." FDA is consulting the committee on the need to establish separate bioequivalence criteria for these drugs given continuing debate about whether critical-dose drugs require special consideration, the agency explained.
Currently, the "sameness" of a brand product and a generic version is evaluated based on two-treatment crossover study to prove bioequivalence, the aim being to show that the 90 percent confidence intervals of the geometric mean test/reference ratios for both maximum plasma concentration and the area under the plasma concentration-time curve fall within a range of 80 percent to 125 percent.
It’s good news that the FDA is taking a strong stance in favor of the public health – because there will be many who seek to undermine this important initiative.
For those of you waiting for FDA to reveal the magical regulations that will unleash the power of healthcare social media – don’t hold your breath.
According to DDMAC Director Thomas Abrams, some social media guidance might be released by the end the year and will address issues related to Internet drug promotion --not how to use specific social media tools like Facebook, YouTube and Twitter
“What we’re going to do is address questions like how to respond to unsolicited requests for information, what’s the corporate responsibility for correcting and monitoring third party sites for misinformation, what’s the corporate accountability for having people post promotional videos and things like that,” Abrams said during a Food and Drug Law Institute conference on enforcement.
And things like that.
In other words, and as predicted, the low hanging fruit.
Since last November’s Part 15 hearing, DDMAC has communicated that efficacy claims must be accompanied by risk information and cast doubt on the concept of a “One-Click Rule.” So much for regulations setting pharma free.
“In an instant all will vanish and we'll be alone once more, in the midst of nothingness!"
-- Waiting for Godot
For more on why industry shouldn’t wait for regulatory holy writ, see here.
Peter has written a lot on comparative effectiveness research and has some suggestions about how to encourage it and conduct it in ways that promote better care and less cost. As the Economix blog put it: "using the research not to decide whether to cover a procedure but instead to decide how much to pay for it. If there isn’t research showing that a more expensive treatment is more effective than a cheaper treatment, then the reimbursement rate for the cheaper treatment applies to both." Of course if a more expensive treatment is more effective than it should be paid for.
I don't trust the motives of many who make up the CER community and believe that CER research contributes nothing to the goal of improving clinical decisionmaking. Uwe Reinhardt's fippant assertion that differences in clinical pratice can't be controlled for is completely wrong and self serving since Reinhardt endorses using average outcomes of average populations with minimal risk adjustment to decide who gets what. For Reinhardt's smug analysis: economix.blogs.nytimes.com/2010/10/15/basing-pay-for-performance-on-outcomes/
I believe Peter is the exception. The links to his articles and those written about his work are below. He offers a sensible starting point for developing an alternative to the CER slush fund.
jama.ama-assn.org/cgi/content/short/304/15/1719
www.theledger.com/article/20101020/ZNYT01/10203007
economix.blogs.nytimes.com/tag/us-health-care-costs/
content.healthaffairs.org/cgi/content/abstract/29/10/1796
Day 2 of the Third Annual Risk Management and Drug Safety Summit focused on the future from a policy perspective -- and why.
A few points to share and consider:
After the 65 presentations made at the FDA's public meeting and over 2000 docket submissions, it's becoming increasingly clear that not only is the agency's REMS initiative confusing to industry and stakeholders -- but that the problem is, in many ways, one of the FDA's own making.
Not that the there's anything wrong with the REMS concept, to contrary, the recent Avandia decision (and, notably, Tysabri) shows the value of a program that provides avenues for both approving and maintaining products with high risk profiles on the market. The problem is that the excesses of the post-Vioxx inquisition have inured many -- specifically practicing physicians -- to any kind of safety warnings.
When important safety warnings become ambient noise, we're facing a dangerous public health situation.
Consider the rash of black box warnings proliferated by the agency since the recall of Vioxx. It's the Precautionary Principle come home to roost. Despite the best intentions, early safety signal communications has resulted in a rash of negative unintended consequences: tabloid media reporting, patients scared into non-compliance, labels being increasingly "lawyered-up," and ever-more defensive medical practices that add costs to our already over-burdened healthcare system and birth ever-more (and more obnoxious) 1-800 ambulance-chaser ads. At a certain point, prescribers just stop listening. And that's not good.
Someone raised the issue of REMS and federal preemption. The laughter took a few minutes to subside. Bad decisions have negative unintended consequences. The implications of Wyeth v. Levine will be with us for years to come.
A related issue is that of product knowledge. What is the real level of understanding physicians have about the products they prescribe -- especially since they are spending less and less time with pharmacy field staff (often by politically-correct dictate).
Isn't it time that sales reps begin to "detail the label" to their physician audience? That would be a real public health service -- and also has positive marketing potential. A solid double play.
And perhaps it's time for the FDA to measure how the New Labeling Rule (not so new anymore) has impacted prescriber understanding. Such a study would be a whole lot more useful to protecting and promoting the public health than yet another study on the viewing public's understanding of fair balance and adequate provision. (And maybe its time for industry to step up to the plate and rewrite their existing labels in the new format.
Relative to PDUFA V reauthorization, it's going to be a tough slog for the FDA to ask for new things when it still has much to deliver on from PDUF IV. And that certainly includes many risk management issues, REMS included.
This becomes even more interesting when you consider the likelihood of different members of Congress wielding the gavel on some committees pretty crucial to the reauthorization process. One issue raised, relative to reauthorization, is the need for the FDA to clarify the when, where and how of the OSE in the review process.
The conference ended on a positive and thoughtful note. Rather than a laser beam focus on REMS, perhaps what is required (from both regulator and regulated) is a broader focus on the appropriate spirit of risk management -- of which REMS is only a piece.
Perspective. It's a wonderful thing.
CDER Director, Dr. Janet Woodcock gave the opening keynote at yesterday’s third annual Risk Management and Drug Safety Summit. And it was an address to reckon with.
Some selected comments:
“Safety issues aren’t headlines – they’re biology; a scientific puzzle.”
“The CDER mission is to promote and protect the public health by assuring that safe and effective drugs are available to Americans.”
“Safe does not mean risk-free. Effective does not mean equally for all. We do not have a legislative mandate to consider pricing issues and I doubt we ever will.”
Her four-part definition of “safety”: (1) risks are managed, (2) quality is assured, (3) health fraud is pursued, and (4) advertising is appropriate.
She announced that in “the Fall,” FDA would release several FDAAA-related guidance documents:
– Guidance that should reduce burdens on the healthcare system of “Medication Guide-only” REMS, while preserving use of Medication Guides to present important information to patients as part of patent labeling
– Guidance on safety related labeling changes
– Guidance on Postmarketing Studies and Clinical Trials
Relative to advancing the science of drug safety Janet discussed:
• In silico modeling
• Systems biology
• Animal models
• In-vitro models
• Benefit-risk assessment
She also announced that the agency was creating a new group within CDER’s existing biostatistician office to focus on safety.
She discussed failure modes and effects analysis (FMEA). Some in the audience whispered that, hopefully, FMEA would do a better job than FEMA.
Janet also shared that morale within CDER “despite what you may read in the press,” is high and has improved since more staff has been hired to more fairly address the workload.
She addressed the FDA’s participation in the Observational Medical Outcomes Partnership, and many more issues -- all which can all be found in her PowerPoint here.
And it’s definitely worth a look to any and all interested and/or concerned about the future of REMS specifically and risk management more generally.
Next up was Sir Alasdair, who shared the MHRA’s “pharmacovigilance toolkit. (Note, this toolkit can be found as part of his PowerPoint presentation here.) It’s elegance and simplicity is in stark contrast to the FDA’s approach, which seems to be “let 1000 initiatives bloom.”
He made an interesting observation that, in the 1950s, thalidomide was drug safety’s first historical moment and that Vioxx was it’s “second coming.”
He spoke to the Avandia issue by stating that EMA and FDA had reached the same conclusion by reviewing the same data simultaneously. However, since the regulatory tools of MHRA (as part of EMA) and FDA are different, the results were different. To wit, while Avandia remains on the market in the US with a REMS, in the EU the drugs license has been suspended.
Sir Alasdair also adroitly addressed the need to move from data management to risk management – a finesse that many in the audience also viewed in contrast to the current FDA approach.
Specifically, he discussed the need to move from reactive to proactive methodology and harness more robust sources of data, moving “up the evidence hierarchy. And that “regulatory actions should be linked with measurable public health benefit.”
It was an information-packed presentation that is worth careful examination by those interested in how the EU is approaching various risk management issues.
The highlight of the morning was a brief, heated (but friendly) Q&A debate Drs Woodcock and Breckenridge on the topic of HbA1c as a legitimate biomarker for Avandia. (Sir Alasdair’s point was that, if Avandia was being reviewed for approval today, HbA1c would not be an acceptable marker.) It was a collegial exchange that should only slightly impact the Special Relationship.
A video of this point/counterpoint will soon be available on www.drugwonks.com.
Juergen Schmider (Corporate Safety Officer and Vice President of Global Pharmacovigilance & Epidemiology at Cephalon) was up next and made some very interesting points about, among other things, off-label promotion – about which he commented, “It used to be a gentleman’s offense, but no longer.
Indeed.
Herr Schmider’s presentation can be found here.
There were a series of other presentations, all of which can be found at www.fdanews.com/RMDSSpresentations.
The day ended on a hopeful and thoughtful note with the following comment from Gary Appio (US Safety Director, Novartis): “We need to advance towards thinking not about risk management, but benefit/risk management.
Amen.
Today I chaired the third annual Risk Management and Drug Safety Summit where I was joined by (among others) CDER Director, Dr. Janet Woodcock and MHRA Chairman, Sir Alasdair Breckenridge.
It was a risk management bar mitzvah in the sense that it felt like REMS was finally coming-of-age – although not yet entirely mature.
Here’s how I kicked off the conference and introduced Janet:
It’s been quite a year on the REMS watch. As Walter O’Malley – the man who moved the Brooklyn Dodgers to Los Angeles once commented, “The future is just one damn thing after another.”
During the course of 2010 there have been both bouquets and brickbats.
Last month the Infectious Diseases Society of America suggested that overuse of antibiotics could be controlled via a REMS-like approach – or even an actual REMS. If it takes a REMS to drive the safe and appropriate use of antibiotics, then so be it. Burdensome on docs, yes – but you know the drill.
In July -- Janet Woodcock said “We don't have the kind of standardization and consistency of REMS programs that would be ideal." Then she announced that the FDA would begin to develop a standard REMS system. Perhaps this will even include a Periodic Table of the Elements to Assure Safe Use.
In June -- John Jenkins, director of the Office of New Drugs -- and the best dressed man at the FDA – admitted that having to develop and then assess the impact of medication guides as part of the REMS program is a burdensome administrative task for the agency.
He said, "We are looking to try and be creative in how we interpret that part of the statute, so stay tuned to see if we're able to find some creative ways around this," he said.
In the meantime, said Dr. Jenkins, "until we work through this further, there are a lot of medication guide-only REMS - a lot of burden on us, a lot of burden on you - that we'd like to try to get out of."
As of June 3rd, FDA had listed 123 REMS on its website. Eighty-four consist only of a MedGuide, while another 25 involve a medguide and communication plan. The other 14 REMS require sponsors to adopt elements to ensure safe use. Five of those also involve a MedGuide; three also have a communication plan; and the other six also require both a MedGuide and a communication plan.
If FDA does not find a solution to the current MedGuide Malaise, the next reauthorization of the Prescription Drug User Fee Act in 2012 offers an opportunity for legislative change. Industry and other stakeholders already have cited REMS as an area for focus during PDUFA V.
In May -- FDA began designing a five-item grid as a management tool to explain its risk-benefit decisions in a new more concise format.
The grid has five basic factors that need to be addressed. The top two are the seriousness of the condition addressed and the need for a new treatment of the condition. Then comes the traditional heart of the NDA package: analyses of clinical data on the benefits of the drug and the risks associated with its use.
Significantly, the fifth fundamental factor is explicitly the level of risk management associated with the product. FDA is going to take it into consideration in every decision; and sponsors who ignore or underplay the identification of who should use the product and who might use it will have a gap in their filings.
The grid proposal does not call for a fixed mathematical formula behind each approval. Net/Net, the agency has not tried to reduce the role of judgment in approval decisions.
Judgment? You mean FDA decisions aren’t black and white? Egad! Someone had better tell Congress.
In the words of John Jenkins, disagreement "happens a lot in the decisions that we have to make. Very few of the decisions that we make on drugs are easy. Very few of the drugs we see have a dramatic overwhelming benefit with relatively no risk. We see that most drugs have marginal to moderate benefits on a population basis and they have general safety but they have the risks of serious toxicities at some low levels." In other words, every decision is "very complex."
Really?
Key take-away is that the FDA is officially moving risk management into the list of key factors affecting new products. And, for better or worse, "judgment" is in the eye of the beholder.
In April -- Biogen Idec announced that it is developing a test that can tell patients their odds of getting PML from Tysabri.
The screening tool could be marketed as early as 2011 if clinical trials involving 9,000 people show a low rate of false findings.
With a false-negative rate of 2 percent, patients would lower their risk of getting the brain disorder PML to 1 in 25,000 for the first three years of their Tysabri therapy. That’s 21st century risk management. REMS par excellence.
In March -- Josh Sharfstein suggested, during a House Energy and Commerce Health Subcommittee hearing, that FDA could use more authority to bring negotiations over a drug's Risk Evaluation and Mitigation Strategy to a swifter conclusion.
Josh said, "It's very important for us to work with companies to come up with something that works. There's no question there's a lot we learn from the interchange with companies, but it sometimes can take a long time to come to agreement. Well – that’s a bit of the pot calling the kettle black – but at least it’s an acknowledgement of the problem.
And, of course, there was Avandia.
Let me introduce our first keynote speaker, CDER Director, Dr. Janet Woodcock, by reminding you of what she told this conference last year. Janet said that, “Safety means doing the right things for patients. FDA must consider post-approval issues as part of a drug’s lifecycle.”
Importantly, Janet understands that there’s a real difference between “headlines and help.” In other words, REMS and other safety mechanisms can be viewed as either “headlines” about “unsafe” drugs or in a more appropriate context of “safe use.”
According to Janet, “FDA does not control the health care system, so our improving the use of marketed drugs, to a great extent, is going to involve influence rather than control.”
“Influence rather than control” is a savvy and sophisticated concept -- one that many of our elected members of Congress could learn from, and one in which REMS plays an important role.
I believe we can also hear the voice of Janet Woodcock in the white paper the agency released a few weeks ago on “Advancing Regulatory Science for the Public Health.
“There is no single discovery — no magic bullet — to address our unique set of modern scientific regulatory challenges. But one thing is clear: if we are to solve the most pressing public health problems we face today, we need new approaches, new collaborations and new ways to take advantage of 21st century technologies. And we need them now.
Ladies and Gentlemen, I am pleased to introduce Dr. Janet Woodcock.
It cost $33 million to rescue 33 Chilean miners. Each made $12000 a year. If we use the QALY approach and assume $50000 per QALY it was obviously a waste of Chile's time and money to undertake the successful operation. Couldn't that money be better spent on disease management programs? There would be money left over to pay the families of the miners after the mine had been sealed up. Too bad that Health Dialog didnt have a shared decision making tool to discourage the miners from asking for such an expensive, invasive and untested procedure. At least Chile should have waited to let AHRQ conduct a CER review before deciding to pay for the rescue.
When it comes to mandated health insurance exchanges, state officials must strive to ensure that they don’t crowd out free market mechanisms. Preserving a vibrant private insurance market will maximize choice and enable people to find the insurance plan that best fits their needs.
Healthcare coverage isn’t a one-size-fits-all proposition.
When President Obama said that people who are happy with their insurance “can keep it,” we should keep him to his word. Policymakers and private healthcare stakeholders need to work together so that state exchanges don’t become the only way to get health insurance.
Choice is crucial.
See here for a more detailed examination of the slippery slope towards a single payer system.
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.
