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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.
During a past episode of Mad Men, the creative team at Sterling/Cooper is hard at work ideating on a “women’s product” campaign when someone asks, “What do women want?”
Strolling by, Roger Sterling quips, “Who cares!”
Well, when it comes to social media, what does pharma want -- and who cares?
Many will say “regulation from the FDA -- in fact, a great many. But is that really what pharma wants?
Yesterday I participated in a small roundtable (sponsored by AstraZeneca) on “Examining the Roles of the FDA and the Pharmaceutical Industry in Social Media.”
(Full disclosure: I ate two small eggplant and tomato tea sandwiches and drank 2.5 cups of organic coffee. I did not offer to reimburse AZ for the “gift.”)What does pharma want? One of the opening comments was that pharma wants the “ability to engage” in social media. My response to that was to ask whether pharma has the “will” to engage – because they certainly have the ability if they choose to use it. And where there’s a will, there’s a way.
Another issue that came up early – and that generated a lot of conversation – was the need to bifurcate the discussion of digital advertising from that of social media. There are rules for digital advertising, paid digital advertising. Social media, on the other hand, is the New Frontier. It’s the crucial gray zone that exists between regulated speech and user-generated content. It’s where the rubber meets the road.
What pharma wants (or should want) is specific areas of clarification from the FDA on this new and exciting zone of opportunity.
What of the empowered digital healthcare consumer that we hear so much about? Well – there were a few of them in attendance at the AZ confab and they had some interesting things to say.
What struck a chord for me was when one of the civilians in the room (by which I mean a patient) said that she really had no idea why pharmaceutical companies chose to absent themselves from disease-related social media conversations. She assumed it was because Big Pharma is afraid of mixing it up with real people in real time dialogue.
And she’s right, of course – but for reasons she didn’t suspect. The ensuing explanations of adverse event reporting and other compliance-related issues didn’t cause her to nod her head, but rather to say (indeed, almost insist) that “pharma should explain to people why they’re not there.”
Blame the FDA! was the knee-jerk reaction. But that’s not fair and it’s not true. How can the agency be blamed for industry’s reluctance to push the boundaries – even a little? Fear of warning letters? Fear of unearthing adverse events? I say, where there’s a will, there’s a way. If you won’t blaze the path – even a little -- then don’t expect anyone to know where you want to go.
Unfortunately, blazing new territory through real-time learning is not, shall we say, historically a tradition of the pharmaceutical industry. Everyone wants to do new and exciting things – second.
Here’s an even more basic question – what’s the right thing to do? I submit that it’s irresponsible to actively avoid participating in the social media healthcare conversation. It is, to directly quote CDER Director Dr. Janet Woodcock, “where the people are." Healthcare begins at search.
But, someone pushed back, that’s why we need more directive regulation from the FDA. I fundamentally disagree (1) that’s what’s needed and (2) that’s what’s coming. Let me explain.
(1) IMHO, “We need more regulation” just doesn’t cut it. Since there is no direct “ask” from industry, it’s impossible to expect the FDA to offer direct guidance. It’s not like requesting guidance for DTC advertisements. That was a precise request for a tangible deliverable that resulted in direct and specific rules and regulation. More regulation? Be careful, that may be precisely what you get. Also, “more” guidance means nothing without a more precise reference. “More” relative to what aspects of social media? These details were lacking at last November’s Part 15 hearing and (alas) equally so in the lengthier (but equally non-specific) docket submissions.
(2) What are the odds, lacking direction, expertise and experience, that DDMAC will deliver some kind of deus ex machina solution? Expecting the Holy Grail will only lead to disappointment and frustration. And blaming the FDA when that happens won’t make anything better or move the social media agenda any further ahead. If industry is expecting to climb the steps of White Oak on its knees, kiss an FDA relic and miraculously throw away the crutches hobbling their ability to participate in social media, well, there had better be a Plan B.
Where there’s a will there’s a way.
Then there’s the question of language and syntax. For example, what does “sponsored” mean? Let’s do a brief thought experiment. Consider a televised PGA tour event. When a product logo for an erectile dysfunction medicine appears on the screen and the announcer intones, “This portion of the Masters is sponsored by DRUG NAME HERE,” nobody out there in the viewing audience takes that to mean the “sponsor” has chosen the speed of the greens, the height of the rough, or the pairing of golfers in the tournament. But say “sponsored” on a social media site and watch the sparks fly at internal regulatory review. Fore! This also leads to the still vague regulatory distinction between property owner and property user – an issue in dire need of FDA clarification. Discussion of this important social media issue in FDA docket submissions? Try and find it.
Of course, there’s the subtle but crucial differentiation between “permissible” and “appropriate.” And this returns us to where we started. What does pharma want? Do they want social media, primarily, as a new channel for marketing or do they see it as a new and exciting and robust and dynamic mechanism for advancing the public health through real-time interactive communications?
Indeed – why not both? Where there’s a will, there’s a way.
And AZ – thanks for the sandwiches and kudos for a job well done.
The FDA has approved a clinical trial of Botox as a treatment for vaginal spasms that can block sexual intercourse and gynecological examinations.
clinicaltrials.gov also lists a similar study that already is under way at the University of Tehran in Iran.
The full article can be found here.
I leave the rest to your imagination.
As Harry Truman opined, “I have found the best way to give advice to your children is to find out what they want and then advise them to do it.”
If only it were that easy with FDA advisory committies.
Matt Herper (Forbes) reports that an analysis of FDA advisory committee recommendations compared to actual FDA actions (from 2007 through 2010) shows that FDA followed adcomm advice 74% of the time. The study, by Concept Capital, looked at a total of 120 product-specific advisory committee votes and the ensuing FDA actions.
Interestingly, the FDA overruled “no” votes only three times: (Tarceva for maintenance therapy in lung cancer, Avastin for breast cancer, and Micardis to lower blood pressure.)
As Herper writes, “In other words, a no vote from an advisory panel is likely to stick, but a yes vote does not mean the product will be approved.”
“Advice is judged by results, not by intentions.”
-- Cicero
"Securing funding for "Regulatory Science" has been a top priority for Commissioner Margaret Hamburg, highlighted most recently during an October 6 luncheon address to the National Press Club, coinciding with a white paper outlining the agency’s vision for enhancing its science base.
The initiative may be the last hope for the agency to play a central role in encouraging drug development as a core part of its mission, after the underwhelming results from prior efforts like the Critical Path Initiative and the Reagan/Udall Foundation. For industry, "Regulatory Science" funding may be the only hope to secure a pool of resources for the agency to craft policy in areas like companion diagnostics, surrogate markers, etc. without another significant step-up in user fees."
The problem is what money that has been spent is being steered to academic institutions that are not collaborating with either other, with other industry consortium or things on the Critical Path opportunities list. Further, lip service is being paid to adoption of new tools and pathways even as the FDA puts out guidances that ignore or fail to encourage their use. The muddled 510k guidance discussion and recent FDA guidance on submission of Phase I safety data are examples of guilt by omission.
I find myself agreeing with Senator Tom Harkin who expressed concerned about the FDA's increasing set of duties and inability to establish common protocols to speed development of anti-infectives and vaccines within the bio-defense sphere:
Stressing that he was “just thinking out loud,” Harkin suggested that maybe “we need to take something out of FDA, something out of Defense, that would be put under BARDA, and let BARDA be the lead agency.” (Harkin previously noted the “hard work” he and others in Congress put into creating BARDA, and wondered how the new HHS initiative fit within that framework.)
Harkin noted his ongoing frustration with the failure to achieve licensure of cell-based flu vaccines. “FDA just—institutionally, I don’t know if they can do it,” he said. “It is just that they have so much to do and they have other responsibilities, and mostly they are focused on drugs that we take for illnesses.”
That's quite a statement. Unfortunately the organized interests in Washington are more interested in rent-seeking than getting things done.
Just thinking out loud...maybe everyone needs to redirect efforts towards the development of collaboration to produce the science and regulatory culture required to sustain advances in clinical development and the goal of increasingly effective use of products once on the market. That's what the Critical Path is and was about. Discussions about what can be done with fees collected under The Prescription Drug User Fee Act are starting.
www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/default.htm
That might be a good time and place to introduce changes in priority and purpose.
www.nature.com/news/2010/101012/full/467766a.htm
Cancer-gene testing ramps up
Thousands to get personalized medicine in Britain's National Health Service.
Ewen Callaway
In an approach that many doctors and scientists hope will form the medical care of the future, Massachusetts General Hospital in Boston has for the past year and a half been offering people with cancer a novel diagnostic test. Instead of assessing tumours for a single mutation that will indicate whether a drug is likely to work or not, the hospital tests patients for some 150 mutations in more than a dozen cancer-causing genes, with the results being used to guide novel treatments, clinical trials and basic research. This form of personalized medicine tailors treatments on the basis of the molecular and genetic characteristics of a patient's cancer cells, potentially improving the treatment's outcome.
Now Britain is set to test whether an entire health-care system is ready for the approach. Plans were unveiled this week to deploy broad genetic testing for selected cancer patients in Britain's government-run health-care provider, the National Health Service (NHS). This form of 'stratified medicine' uses genetic information to group patients according to their likely response to a particular treatment.
"The United Kingdom is really the ideal place to do this," says James Peach, who heads the programme for Cancer Research UK, the charity that is leading the effort. As the NHS treats millions of people each year, unprecedented numbers of suitable patients could be enrolled in the genetic-profiling programme. "The idea is to scale this up to every patient in the NHS," says Peach. In its first phase, the programme will be rolled out to as many as 12,000 NHS cancer patients over two years, beginning in early 2011. By contrast, Massachusetts General has tested about 1,600 patients, and other hospitals' efforts each number in the hundreds.
The tests, which will look for several dozen mutations in about a dozen genes linked to cancer, will be carried out on people with lung, breast, colorectal, prostate or ovarian cancers, or metastatic melanoma, who are being treated at six NHS hospitals. Therapies that target specific tumour-causing mutations have already been approved, or are on the verge of approval, for most of these conditions, says Peach.
Testing a clinical sample for so many mutations at once is a challenge in itself. Because most existing clinical tests probe individual genes, the NHS programme is working with the Technology Strategy Board, a government agency that supports technology development, and several companies to design a customized test that detects all of these mutations in one go. The partnership, which includes the pharmaceutical multinationals Pfizer and AstraZeneca, will also design software to make the results useful to researchers and clinicians. By genotyping patients for a broad array of cancer-causing mutations, the new tests will make it easier to assign subjects to clinical trials, Peach says.
That is already happening at Massachusetts General, where the test is helping to establish clinical trials that wouldn't otherwise have happened, says Leif Ellisen, a geneticist who helps lead the hospital's cancer testing programme. For example, its broad genetic test detects a mutation in a gene called BRAF that is already known to be commonly mutated in metastatic melanoma. Finding such mutations in people with lung and colon cancer made it possible to put them in a trial of an experimental treatment targeting that gene, Ellisen explains.
Basic research should also benefit from the NHS programme, says Peach. Researchers will have access to consenting patients' genetic data as well as to medical records of the outcomes of the treatment. These data could reveal how drugs targeting one molecular pathway are affected by mutations in another gene, says Andy Futreal, a cancer geneticist at the Wellcome Trust Sanger Institute in Hinxton, UK, and an adviser to the programme.
Peach hopes that the first phase of the cancer programme will pave the way for expanding genetic testing to more patients and other conditions, such as diabetes, AIDS and even psychiatric disorders. Cancer offers a good testing ground for personalized medicine, because numerous targeted therapies already exist, but "there's no reason why this should be restricted to cancer", says Peach.
Fabrice André, who runs a similar cancer diagnostic programme that has so far been offered to about 100 patients at the Gustave Roussy Institute in Villejuif, France, says the NHS programme could point the way to implementing personalized medicine across an entire population. "It can really change the landscape of how molecular testing is being done for cancer," he says. "If they succeed, then it's going to be a major step forward."
The Office of Personnel Management (OPM) is planning a new database that will store health care claims information from three federal programs - the Federal Employees Health Benefits Program, the National Pre-Existing Condition Insurance Program and the forthcoming Multi-State Option Plan.
OPM (in a 10/5 Federal Register notice, says the database will allow OPM to "actively manage all three programs to ensure the best value for the enrollees and taxpayers." The database will be effective Nov. 15 "unless comments are received that would result in a contrary determination."
OPM? Healthcare “value?” This raises two issues: (1) expertise and (2) mission creep. Are people being hired to do this? Who are they? Who’s choosing them? Transparency is required – if not a Congressional hearing.
Information collected will include personal identifying information, address, dependent information, employment information, health care provider details including debarred provider information, health care coverage information, health care diagnosis information and provider changes and reimbursement on the aforementioned coverage, procedures and diagnosis.
OPM? Really? Sounds like a CMS program – or even AHRQ. Also, will this data be shared with other federal agencies? And if so, to what end.
Per the FR notice, "the data will be de-identified for specific analysis that provide flexible queries of the data set for general demographic queries, risk-adjusted profiles, and comparison of chronically ill patients and other useful analytics; and engage in econometric modeling of, among other things, health trends, risk adjustment methodologies, pharmacy pricing and negotiation."
Hm – “econometric modeling?” That sounds menacing.
Yes – definitely Congressional hearing material.
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.
