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Pharmaceuticals
Statin Makers Bet Big On Imaging Technique
ORLANDO, FLA. - Trying to get a leg up in the $22 billion market for cholesterol medicines, drug companies increasingly are turning to an imaging technique that allows researchers to see how much plaque is building inside arteries. Several of the biggest players are funding major research studies, and--in an unusual twist--many of these clinical trials are being run by the same cardiologist: Steven E. Nissen.
In retrospect, we realize that it is not unusual at all just...business as usual.
www.forbes.com/2003/11/10/cx_mh_1110merck.html
From today's WSJ:
"Cardiologist Steven Nissen of the Cleveland Clinic said the FDA should require companies to prove their drugs don't raise risks of cardiovascular disease before they are approved.
Dr. Nissen said there are more than enough diabetes drugs on the market that lower blood-glucose levels, and now is the time for the FDA to raise its standards.
"Merely lowering blood-glucose levels in diabetes is too simplistic," Dr. Nissen said. "We must reduce the complications of diabetes, including cardiovascular disease."
online.wsj.com/article/SB121495996433621583.html
Dr. Nissen suggested that in addition to requiring more preapproval studies, companies should have large, long-term studies in place when a drug is approved to monitor whether the drug increases the risk of cardiovascular disease.
Why stop at diabetes drugs? If you apply Nissen's logic to any illness "there are more than enough drugs" out there to treat everything under sun. And since every drug has some cardiac risk, why not subject them all to increased long term clinical trials (that Nissen would conduct of course) to look at the problem.Let's set aside diabetes which is not just killing people here but worldwide. And let's set aside Nissen's failure to acknowledge that by claiming there are more than enough drugs he is ignoring the fact that diabetes requires individualized treatment but that new medicines will be developed (we hope) around more particular and preventive approaches, etc., etc. and that diabetes is not just a cardiovascular disease but part of a larger disorder that must be treated with as many tools as possible. Would you want an FDA commissioner who would say "we have enough drugs for...."? I am sure there are some who believe that, including Marcia Angell, but not many real physicians and scientists.
I would love to see that statement thrown back at him.
Next, what are the implications of his approach to access to medicines for patients?
Here's what the lead medical officer who reviews diabetes drugs at the FDA said according to a reporting in Bloomberg News
"Conclusive evidence of cardiovascular benefit hasn't been established for any drug for Type 2 diabetes, despite several large, long-term trials," Hylton Joffe, lead medical officer in the FDA's Division of Metabolism and Endocrinology Products, told the FDA panel yesterday.
Requiring heart assessments, especially before FDA approval, would add years to drug development because it takes that long for damage to show up. There also are ethical and logistical questions about how to organize studies because patients don't want to be in a comparison group getting a dummy pill and usually require multiple medicines as their disease progresses, Joffe said."
www.nj.com/business/ledger/index.ssfFrankly, I don't think Nissen -- who simply engaged in fearmongering over Avandia and drugs for ADHD -- couldn't care about the ethics of the matter.
If Nissen were FDA Czar, here's what patients could expect:
Add years and billions to the cost of new drug development.
Say good-bye to the Critical Path.
Let millions of people who are dying of and suffering from any illness with a drug in development that may have a cardiac side effect that can be found in any amount of any correlation wait while some pet meta-analysis is verified. So that includes drugs for:
Cancer
Alzheimer's
Schizophrenia
Parkinson's
HIV
Diabetes
And stem cell research of any kind...
I hope at least patients are paying attention.
FDA Steps Up Security for Advisory Committees
By Kate Rawson
FDA advisory committee meetings are not supposed to be like episodes of the Jerry Springer show. And for good reason: One is a scientific discussion of the benefit-risk profile of new drug or indication. The other is a television tabloid talk show with topics in such poor taste that our own corporate content filters won’t even let us access the website.
But it was Springer-like behavior at a recent meeting (featuring a threatening rant by an apparently intoxicated speaker during the open public hearing) that led FDA to impose new security measures to protect the agency’s expert panelists. While FDA hasn’t made a formal announcement of the policy changes, Office of New Drug Director John Jenkins discussed the new procedures at the Drug Information Association’s annual meeting last week.
“We have put in place some new measures to help improve security at meetings,” Jenkins said. “If we anticipate that there may be an increased need for security at a particular meeting because it is a particularly controversial topic, we may have additional security procedures.”
Those procedures include:
1) Creating a physical barrier by roping off the committee from the public. The intent, Jenkins said, is “to put some separation between those who might become agitated in the audience and committee members.” (For taxpayers, it carries another benefit—preventing the public from sneaking pastries off the committee’s breakfast tray.)
2) Increasing the presence of security guards in the committee room—both in uniform and street clothes.
3) Reading a statement at the start of the meeting about “good rules of behavior.”
There have been kerfuffles at advisory committees before, especially when the drug under review would be used to treat a rare or life-threatening condition. The heckling of FDA commissioner David Kessler during the 1996 advisory committee review of Abbott’s ritonavir, the first protease inhibitor for HIV, comes to mind.
And in very rare cases, FDA takes extraordinary steps to protect committee members. That same year, the review of the abortifacient RU-486 was held in an unused warehouse in the middle of a remote industrial park in
But this is the first time that FDA has felt the need for a comprehensive plan to ensure the security of advisory committee members. And it’s the biggest change to the advisory committee process since the agency altered its conflict of interest guidelines last year.
The trigger was a May 2007 review of IDM’s mifamurtide (Junovan) for the treatment of osteosarcoma. During the open public meeting, an apparently intoxicated individual made threatening statements to
Later in the meeting, Hussain and other committee members pointedly suggested that FDA establish greater security measures. (Hussain, it should be noted, has had her share of controversy in committee rooms. Last year, she was also one of four votes against the approval of Dendreon’s Provenge, a decision that led to threatening e-mails, phone calls and letters.)
For drug sponsors, the new procedures aren’t likely to have significant practical implications. But they are indicative of the intense public interest in drug development, and the pressure to discover new cures and keep unsafe products off the market.
We should note that the majority of meetings aren’t controversial and hence don’t require significant security procedures. But, as Jenkins noted, “there have been some incidents where that decorum has not sustained itself, and we’ve felt the need to institute procedures to maintain the safety of our advisors.”
Hence the rope. Of course, roping off the public isn’t the only way FDA can ensure the safety of those present at advisory committee meetings. Given some of the disputes between FDA officials on drug safety issues (remember the Arcoxia meeting? The Avandia meeting?), perhaps that rope could be put to better use elsewhere.
Wouldn’t that make a good Springer show?
From World Health Advocacy... www.whadvocacy.com.
Consumers in Canada spend the same percentage of their income on prescription drugs as consumers in the United States.
Government policies surrounding the pricing and reimbursement of prescription drugs in Canada do not produce lower costs for Canadians compared to Americans. Despite major differences between the Canadian and American healthcare systems, the results of a recent study show that consumers in both countries are spending the same percentage of their incomes on prescription drugs.
The price of generic drugs in Canada is more than double U.S. prices for identical drugs, while brand-name drugs are comparatively cheaper. In currency-equivalent terms, Canadian retail prices for brand-name pharmaceuticals decreased slightly between 2003 and 2007. In the same time frame, generic drug prices in Canada increased by 34% compared to U.S. prices.
The authors of the study state that Canadian government policies insulate generic drug companies and pharmacy retailers from normal market forces that would put downward pressure on prices for generic drugs. A relatively freer market in the United States produces lower prices for generic drugs to encourage consumers to substitute these generics in place of brand-name drugs.
This is all from a Financial Times article entitled: "Why the UK's Cancer Survival Rates Look Bad"
www.ifpma.org/PressReviewEmail/PressReviewDetail.aspx
"Of the 20-plus countries in the Eurocare survey, only 10 look at the entire population. In 1998, the starting point for the latest five-year figures, Germany's figures covered just 1 per cent of the population, the Czech Republic 8 per cent, Poland 9 per cent and Spain and France 16 and 17 per cent respectively.
Prof Richards says that for instance in Italy, the figures cover only 28 per cent of the population, mainly in the affluent north "so it is almost certain their figures overestimate survival rates".
That's the good news. And Professor Richard's makes a fair point if he can prove that the smaller slice of cancer patients surveyed are more likely to be over-represented by people who are more likely to survive. Gee, that's just like infant mortality rates where some countries only count babies as alive if they live for 30 days while in the US we count them from the time they leave the womb.
Now the bad:
The UK has 100 per cent coverage, as do the Nordic countries. "Sweden, Norway and Finland do have appreciably better survival rates than we do, while Denmark looks remarkably like the UK across a whole range of factors," he says. "There is a real gap between us and the Nordic countries, and our task is to narrow that."
While the UK is slower than some other European countries to adopt newer cancer drugs, late diagnosis seems to be the real culprit. "Most of it is accounted for by our one-year survival rates," Professor Richards says. "If you get past that, our survival rates look much more like the European average. And one-year survival is most often correlated with advanced disease. There are relatively few cancers that will kill you in a year if they are diagnosed early". Smaller-scale studies also suggest that when patients in the UK seek help their disease is more advanced.
Does anyone have any idea why UK patients get help later when new drugs are less effective? Anyone?
Prof. Richard suggests:
Some of that may be cultural: stoical Britons may delay seeing a doctor. The government's cancer plan aims to tackle that through better education and better screening, backed by large investments in radiotherapy.
Stoical? Hardly. Resigned and outraged is more like it. But Richards also believes the Eurocare survey understates advances in survival because it is based on old data:
'Prof Richards believes that the reason Britain's figures are not better, despite the huge resources ploughed into tackling the problem, is that the numbers used for international comparisons are out of date, relating to cancers diagnosed in 1999 and 2000. "They predate the UK's big surge in spending after 1999, and any impact from the national cancer plan. We have a problem, but we are tackling it. I am pretty sure we are narrowing the gap".
In fact, many of the methodological problems with the Eurocare survey have been addressed in other articles, notably by Dr. Franco Berrino who took note of them in earlier surveys and adjusted for both over and under estimation of survival by weighting five year survival rates of all countries studies based on limitations deriving from the quality of registry data. Berrino, et al also use period analysis instead of the traditional cohort analysis provides long-term survival estimates that also take into consideration survival of more recently diagnosed patients. By every measure the UK lags behind Western health systems in Europe and the US in particular which has more heterogeneity in its cancer population.
www.thelancet.com/journals/lanonc/article/PIIS1470204507702462/fulltext
This afternoon Dr. Nissen has been invited to give a talk at a two day hearing of the Endocrine and Metabolic Drugs Advisory Committee designed to “discuss” the role of evaluating cardiovascular disease and/or risk in diabetes drugs. His topic? The need for cardiovascular assessment.
He will make the case that the way to determine whether diabetes drugs prevent or reduce heart attacks is to conduct experiments in which certain people are prevented from taking a drug that will reduce them.
Or will he? Depends on which way the political winds blow and the money is wired.
I as have noted on many occasions, Dr. Nissen uses surrogates – the media – and surrogate measures to get what he craves, exposure and a reputation as some sort of crusader that neither the FDA nor drug companies dare cross. In point of fact, he is mostly best shakedown artist this side of Al Sharpton.
We know that Dr. Nissen never lets science or statistics get in the way of a good soundbyte or payday. Apparently two large studies of diabetics – ACCORD and ADVANCE – which measured whether drastically reducing and controlling glycemic indexes and used reduction of CV risk, as an endpoint are not enough for him. The two large studies used different strategies and drug combinations to get people below a certain A1c level. ACCORD did so more rapidly than ADVANCE. Both used Avandia extensively (ACCORD more so) – and found no reduction in heart attacks. ACCORD had a slight increase in heart attacks but at the end of the day, Avandia was use in combination with other drugs in both studies. Some benefited, some did not. Overall there was no reduction in heart attacks. And there is no evidence that Avandia was associated with either.
www.theheart.org/article/874809.do
So what will even longer and larger clinical trials show? And should such studies, which take years to complete, be a precondition not only of drugs for diabetes but – as that Nobel Prize winning scientist Charles Grassley has noted, for every medicine for every disease?
I am sure Dr. Nissen has a better answer.
And I bet it will be coronary intravascular ultrasonography (IVUS), which involves the insertion of a catheter into the coronary artery in order to measure the size of an atherosclerotic plaque.
IVUS is the "imaging technique that is the hottest and most important right now in anti-atherosclerotic drug development.”
www.pharmaasia.com/article-6017-imagingsharpensdiseaseresearch-Asia.html
Who said that? Dr. Nissen. And who conducts most of the IVUS studies in the US.
Dr. Nissen.
Indeed, Dr. Nissen says that a number of drugs currently in clinical trials are aiming to use imaging as a primary endpoint for registration.
I am sure they are and I wonder who is conducting those trials?
Not that there is anything wrong with tooting your own horn so to speak as long as you don’t seek to infer from ”surrogate measures” studied in Phase I anything conclusive about how the drug will work…..
Nissen regarded the surrogate measures in ENHANCE as unreliable. So why in 2003 did he propose to Merck and Schering-Plough a IVUS study of Vytorin called QUEST: "short for Quantitative Ultrasound Ezetimibe and Simvastatin Trial. Ezetimibe and simvastatin are the generic names for Zetia and Zocor, respectively."
That study, according to Nissen’s Boswell, Matt Herper of Forbes.com, would have been an 800-patient study to see if adding their new cholesterol drug, Zetia, to Merck's cholesterol-lowering blockbuster Zocor can prevent plaque from collecting on the artery wall better than Zocor alone. The patients would be followed for 18 months.
www.forbes.com/2003/11/10/cx_mh_1110merck.html
Merck nixed the study and went with another group and IVUS approach to run what became ENHANCE. Same method, different bank account.
Nissen pounced, saying there was no reason to use Vytorin at all.
But if Nissen, as he most recently claimed, believes in an individual approach to reducing LDL and glycemic levels why ban a drug because it doesn’t work IN GENERAL or because it make aggravate risk because of meta-analysis. Why not promote the Critical Path and more patient specific approaches to life cycle management of drugs including adaptive trials designs and biomarkers. Could that be competition for IVUS perhaps?
Will Nissen promote larger trials that keep important drugs away from people to promote IVUS in favor of a path that target safer more effective therapies using tools other than those he is paid to operate?
It is hard to stay on message when you are trying to stay in the headlines.
Or line your pockets.
Different people have different opinions. We side with former FDA Chief Counsel Dan Troy.
Here's a new video podcast that features Dan telling it like it is:
Dan Troy on FDA Preemption
And you know what they say, an ounce of preemption ...
"…the Vioxx debacle, which sparked harsh criticism of both drug companies and their chief regulator, appears to have led to a climate shift. The drug industry largely has itself to blame for allegedly manipulating clinical data, concealing dangerous side effects and aggressively promoting risky products, which created widespread mistrust…."
online.wsj.com/article/SB121476772560213981.html
First, can one be blamed for alleged behavior. Second, where is the evidence of all these actions?
Well, it was largely generated by the same cast of characters:
“Outspoken scientists, watchdog groups, medical-journal editors and politicians have fanned worries about safety. The wave of post-Vioxx drug scares included concerns that GlaxoSmithKline PLC's widely used diabetes drug, Avandia, could raise heart-attack risk, and that Pfizer Inc.'s smoking-cessation drug, Chantix, may be connected to suicides. More than 80 U.S. deaths linked to contaminated heparin from China have further ratcheted up public anxiety. The FDA has been battered by criticism that it wasn't vigilant enough, including from Cleveland Clinic cardiologist Steven Nissen, Sen. Chuck Grassley of Iowa and Rep. John Dingell of Michigan.”
And when you want to keep fanning fears it helps not to be has vociferous in alerting the public when subsequent studies show Avandia has no heart attack risk or that multiple factors might associated Chantix to suicides (such as an increase in the number of addicts with mental illness taking the drug.) Ditto when drug safety vigilantes like Nissen and Grassley (I would not put Congressman Dingell in that camp) engage in fearmongering about Ritalin, SSRIs and Ketek because they know an unquestioning media fails to put the risks and reasons in context….
All of which begs the question, does any of this have any impact on drug approval rates and times?
The short answer: Sometimes it does but increasingly -- I hope – science-based regulation will not just shape drug development times but also who gets what drug, i.e. personalized medicine.
It is true that time is money, especially in drug discovery and development (same for devices and diagnostics). But the truth is the reaction to Vioxx could have been avoided with a post market system in place that could identify who was at greatest risk. Many of the product delays discussed – while in part due to the fact that the Office of New Drugs is overwhelmed and kicking everything back to the detriment of the public health -- would be overcome by the routine use of regulatory tools to speed up and improve the accuracy of toxicity screens, by wider use of combinations of drugs and diagnostics that measure and predict patient response to medicines and disease progression, etc.
To be sure, much of the information FDA reviewers are requesting could be obtained in the “real world.” But I believe that the questions they are asking are legitimate ones. Indeed, they are often the questions that companies themselves face but do not know the answer to or afraid to find out. To conduct an in-depth study of a safety issue absent large clinical trials and reliable assays would kill and drug and likely deny large number of patients who would benefit from a medicine access even as researchers were trying to establish the mechanism causing toxicity for a small percentage of people.
If we wait for drugs to be perfect and confer no risks, there will be no new drugs. No one wants that. Which is why we are developing predictive tools and should insist upon patient-centered real time updates of how well drugs and devices are performing.
I think rather than whining about how slow the FDA has become, pharma CEOs should demonstrate that they are putting their shoulder to the wheel to make better, safer medicines more quickly available. There are many such initiatives and partnerships focusing on these efforts. The recent efforts of the Predictive Safety Testing Consortium (PSTC) in developing safety biomarkers are great example. The PSTC, whose members consist of scientists from 16 institutions, including 13 major pharmaceutical companies, was organized and led by the Critical Path Institute (C-Path).
Talking about these programs and increasing support for them might not change the story line of reporters who want to write about “fast” and “slow”, “safe” and “dangerous”, drug safety “advocates” and Big Pharma, but it will change medicine for the better. Fast or slow will be replaced by what drug for which person.
According to the NHS release:
“The first of its kind in the world, the Constitution follows extensive discussions with staff, patients and the public over the last year. It reaffirms the rights to NHS services, free of charge without discrimination of any kind. For the first time, it will bring together in one place and clarify for staff and patients their rights and responsibilities to ensure the NHS operates fairly and effectively.”
The draft Constitution can be found at www.dh.gov.uk/consultations
"measures that offer the opportunity to effect a seismic change in patients' right to access the best and most modern medicines based on clinical need."
Others disagree.
Antoine Clark, international editor of Pharma Marketletter, commented,
"Seismic? I don't feel the Earth move!"
Here’s his read on what “free of charge without discrimination of any kind” means in NHS parlance:
Health care except in the case of:
1) week-ends and Mondays;
2) smokers;
3) drinkers;
4) fat people;
5) grumpy old people;
6) people living in the wrong post code;
7) people living in England;
8) people who don't know how to make a noise and kick up a fuss;
9) people who require the latest medical care;
10) people who want to have dental care;
11) foreigners (except when it is politically inconvenient to deny them or they vote Labour; and
12) people who have the nerve to pay extra for private care, as in "Please Sir, can I have some more?
The Wall Street Journal reports that, “Last year, the FDA approved just 19 new medicines, the fewest in 24 years, and announced about 75 new or revised "black-box" warnings about potential side effects -- the agency's strongest -- twice the number in 2004.”
True. But numbers are just numbers. The story is somewhat different when you put those numbers in perspective.
According to the Journal story, “Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, denies that the agency has become "more conservative" about drug safety. Rather, she says, the industry's faltering research efforts are mostly to blame for the fewer product approvals. She says the agency continues to base its decisions on science, not outside pressures. New methods, she adds, have helped it become more vigilant about side effects. She attributed the increase in black-box warnings primarily to a few large groups of medicines that were relabeled."
Reality bites.
Bringing new drugs to market has always been a scientifically challenging and expensive proposition – and it remains so. But the big difference today isn’t (gasp!) politics – it’s that, while discovery and development embrace 21st century science, regulatory science lags behind. At present, the FDA is using 20th century tools to review 21st century medicines.
This is why the agency’s Critical Path Program and the Congressionally-mandated Reagan/Udall Foundation are so crucial to our 21st century healthcare future -- as well as to the future of the pharmaceutical industry.
The comments of Schering-Plough CEO Fred Hassan (courtesy of the Journal article) are instructive:
“Mr. Hassan believes an intensifying focus on safety and a diminished tolerance for side effects at the Food and Drug Administration have dramatically lowered the odds that the drugs would make it to market -- at least not without a lot of extra time and money.”
Not so fast. It is today as it has been in the past and must be in the future – the quest for appropriate risk/benefit balance. Side effects are “tolerated” insofar as the benefits are appropriate. As to the “extra time and money” comment – there’s no benefit from wishing for the “good old days.” Time marches on and so does science. Perhaps a better focus would be on more innovative clinical trial designs – and on the FDA’s promised guidance on adaptive clinical trial designs.
The past is prologue.
"What will it take to get new drugs approved?" Mr. Hassan asks. "The point is, we don't know."
Yes we do. Better development science and better regulatory tools for the FDA.
Here's the full Journal story:
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.
