Latest Drugwonks' Blog

Es ist nichts schrecklicher als eine thatige Unwissenheit…That’s Goethe for “There is nothing scarier than an active ignorance.” Case in point, the most recent post on The Health Care Blog by someone named Maggie Mahar who managed to write over 800 words arguing that there too many cancer drugs in development. How does she come to this conclusion? By ignoring medical science and simply applying the old attacks on big Pharma to cancer research:namely that every single one of those drugs is simply a me-too medicine that offers no real survival benefit (note no mention of quality of life) Here’s what Maggie concludes about cancer drugs:

“As each drug company races to fill its own pipeline, a fragmented industry spawns a dizzying array of half-way cures. Too many drugs shrink tumors-but don’t bring any mortality benefit. Meanwhile, too much competition and too little collaboration makes it difficult for oncologists to sort out which drugs are most effective alone, which should be used together-and in what sequence. “

So in otherwords the explosion of targeted cancer drugs — which may or may not be used in combination — is causing too much choice and opportunity. And if the drug does not provide an everage survival benefit based on randomized clinical trials — regardless of whether subpopulations are helped or whether quality of life is enhanced — get rid of them. So the right response is to just cut down the number of drugs in development?

Let’s be clear, the rate limiting factor here is not that too many drugs for cancer, Alzheimer’s, Parkinson’s or infectious disease in development (is 100 too many? 50? What about phase III failures?) but the need to better understand underlying disease mechanisms and pathophysiology and link it to dose and drug response. Do you get the sense that Maggie understands any of this? She has written a book that makes the earth shattering discovery that medicine is fraught with….uncertainty!!!! Well ,targeted therapies are a direct result of how science provides the tools to do so, particular by eliminating the one size fits all approach to evidence based medicine that Maggie swoons over. A dizzying array of drugs? Only to those who fail to use new tools of analysis and are too lazy to advance the state of care. Or to journalists who think that average response to drugs is good enough or the only measure of well-being.

I am so sick and tired of health policy wannabes recycling the same old accusations about drug development and health care without even paying attention at the impact technological transformation plays in shaping the future. You can see that there have come to a conclusion shaped by ideological biases and then work backward.. Maggie Mahar is just one more uninformed health care conspiracy theorist who trashes medical progress without knowing of what it consists….

A Blogger's Banquet

  • 07.10.2006

Wither pharmaceutical blogging? Have a look at the attached article on the “New Frontier” of pharmaceutical communications and one of its feisty evangelists … me.

Here’s the link:

http://www.bizjournals.com/sanfrancisco/stories/2006/07/10/newscolumn5.html

Article today in the Wall Street Journal on the persistent and quiet revolution going on inside the FDA to implement the Critical Path even as the brickbats from Grassley, Waxman, Hinchey and other media hounds come up with 19th approaches for evaluating 21st century medicines.

WSJ(7/10) FDA May Be Open To `Shifting’ Drug Trials
Jul 10, 2006 (From THE WALL STREET JOURNAL)
By Anna Wilde Mathews

CLINICAL TRIALS of medicines are traditionally performed in a “blinded” fashion so that the findings will remain secret until the studies are completed. But regulators and the pharmaceutical industry are increasingly interested in starting to use a very different model that lets studies change as they go along, based on early results.

Drug companies have begun to perform such adaptive trials for their new medicines, hoping for more efficient tests that could save millions of dollars. The Food and Drug Administration, meanwhile, is sending increasingly encouraging signs that it is open to considering the results of such trials. In a move that could lay the groundwork for greater future use of such studies, Scott Gottlieb, an FDA deputy commissioner, is set to announce today plans to develop regulatory guidelines for adaptive trials. The FDA has also put together an internal team to work with its drug-review divisions on the adaptive designs, which are statistically complex.

It’s clear what adaptive trial designs can help accomplish: As Peter notes, “Adaptive trial designs represent a major advance in drug safety because the best kind of safety is better understanding of how a drug works *
and who it works best for.”

How? Adaptive trial designs allows researchers to tailor the
study of the drug and its dosing to what they learn about the medicine and
the patient in real time. It’s another tool for personalizing medicine
that the 21st Century Task Force endorsed in is report.

As we pointed out in our recent Washington Times op-ed, the best post market safety is good pre-market surveillance through the use of critical path tools. The battle over FDA reform — and the real end game — how to use user fees — will come down to whether to invest in 21st century or 19th century tools. Spending dough on the status quo won’t cut it.


And speaking of NICE, have a look at Heinz Redwood’s new paper, “The Use of Cost-Effectiveness Analysis of Medicines in the British National Health Service: Lessons for the United States.”

Here’s the link:

http://www.phrma.org/files/Nice%20Report.pdf

The lessons learned are important ones and once again the phrase that pays (or, rather, doesn’t) is price controls = choice controls.


What do Madame Curie, Albert Einstein, Jonas Salk, George Hitchings, Joshua Ledeberg, Gertrude Elion and Sir James Black all have in common? They are Nobel Prize winners who have transformed the 20th century for the better through the contributions to science and medicine. And, according to the Wall Street Journal’s Thomas Burton, their research has, uh, “limitations” because they all did consulting or received honoraria from pharmaceutical firms. I guess by extension Louis Pastuer’s findings on pathogenesis are limited or have in Burton’s tart terms, “shading and nuances” because he received funding for the work from French beer and wine producers.

Burton wasn’t talking about Nobel prize winners in his article, of July 6, 2006 in the The Wall Street Journal Europe , “Antismoking drug from Pfizer shows promise in research “

He was writing about Chantix, a new Pfizer drug that helps suppress smoking by smoothing out the production of dopamine (not blocking as Burton states) involved in creating the craving for nicotine. There is less binging or withdrawal as a result. I know a little bit about the drug since I had the chance to talk to the Pfizer pharmacologists who designed the drug to produce the biochemical effect. In any event, the drug uses a different pathway and novel approach so the robust results are not surprising one respect.

What is suprising is that Burton decides to regard the fact that the researchers source of money is somehow a limitation on the drug’s effectiveness equal to that of the study’s exclusion critieria….

“Despite the positive findings, there were several limitations to the research. One is the fact that people with pre-existing conditions such as depression, alcohol or drug abuse, and diabetes requiring insulin were excluded from some of the studies. Another stems from the fact that the majority of authors of the three studies, which were published in the Journal of the American Medical Association, either have done consulting work or received honoraria or research grants from Pfizer and other drug companies, or are Pfizer employees or shareholders.

Such apparent conflicts of interest won’t normally change the major findings of research. But they can affect nuances and shadings of the way they are presented. “All of these papers were rigorously peer-reviewed,” says the University of Wisconsin’s Douglas E. Jorenby, who headed one of the studies. (He has received research funding from Pfizer but not consulting fees or honoraria.) A Pfizer spokeswoman says, “Regarding consultation fees, Pfizer follows standard protocols for consulting agreements and provides adequate disclosure.”

As one of my friends who works for a drug company noted, “Based on the logic presented here every commercially conducted/funded research project has a built-in âlimitationâ. Seems easier just to add some standard warning label - like on cigarettes - to every commercially supported study and be done with it.”

But it’s worse. This approach slimes the good work of every good and great researcher who in any way associates with private companies. It disqualifies and discredits pivotal work and deprives the public of pathbreaking research that cannot be duplicated anywhere else. Let’s be clear: not only is the commercialization of science not bad. Commercialization of science, it’s industrialization is critical to advancing the public health. Those purists who want science to be conflict or profit free want the medicine THEY can control, plain and simple.

That’s a sure-fire recipe for medical Lysenkoism.

Scott Gottlieb’s statement on why the FDA is not going to go down the road of comparing medicines prompted CMPI’s Chairman, Michael Weber, MD — one of the world’s experts on heart failure and hypertension — to submit this post about the trend towards states using cost-effectiveness studies to limit access to certain drugs. Setting aside questions of genetic tests that suggest high response to one drug compared to the one deemed “cost effective” by a bunch of second rate economists engaged in data dredging, Dr. Weber writes about the impact this approach has on the quality of care:


Most patient visits to the doctorâs office result in a prescription being written. Physicians depend heavily on the availability of appropriate drugs, and particularly the flexibility of choice to provide medicines that best fit the needs of individual patients.

For this reason, lists of drugs available to be prescribed - typically called formularies - should include an array of agents that optimize patient care. This selection of drugs can affect local prescribing, as in a typical health plan, or it can have broad-based implications, as in a national or governmental formulary.

Cost-effectiveness as a basis for choosing drugs for a formulary sounds beguiling; it implies a rational process that provides benefits to the patient and value to the healthcare system. But this approach is more complex than it appears.

Consider the two components of cost-effectiveness. Strange as it may seem, cost is hard to figure since it involves not only the price of acquiring drugs, but also â among other things — providing for additional doctor visits, extra tests, and adjustments to other drugs being taken. These all contribute to the overall expense.

Effectiveness is equally hard to define. After all, this is not just a simple measure of drug efficacy, but must also take into account acceptability, tolerability and ease-of-use for patients and doctors. Difficulty in achieving true effectiveness is highlighted by the fact that by 12 months of taking life preserving drugs with proven long-term benefits, only 50% of patients are still refilling their prescriptions.

So, simply put, cost-effectiveness is a term that compounds the inaccuracies of two difficult-to-define variables. When all is said and done, we are dealing with a euphemism that has become popular with government agencies and health insurers. In their jargon, the term cost-effectiveness in essence means that they will usually select drugs for formularies that offer them the best financial deal.

Underlying this selection process is the assumption of so-called class effect: if drugs are similar to each other chemically they should work in similar ways, so why not choose the cheapest? But consider these brief examples of common clinical conditions that argue against this approach.

A class of drugs that is widely used for the common problem of clinical depression is known as the SSRIs. Ever since Prozac, these agents have been widely accepted. Yet there are important differences among the several members of this group in their performance; sometimes clinicians find it necessary to work through three or even four different drugs before finding one that works best for a particular patient. These drugs also differ in their safety profiles, so again it is critical to have a broad selection available.

Commonly used pain killers, NSAIDs like ibuprofen, naproxen, aspirin and celecoxib also - on average - share similar benefits in patients with arthritis or other painful conditions. Even so, individual patients can get different degrees of pain relief from one drug as compared with another. There are also issues of convenience: some drugs can be taken once daily, others need multiple doses. And there are also differences among these agents in safety issues, including their propensity to cause gastrointestinal upsets or ulcers, to raise blood pressure or have other effects that necessitate switching to alternative members of the class. Having choices is imperative.

Consider a broader issue. Suppose, at first sight, there doesnât seem to be much meaningful difference among drugs within a particular class. There is still a compelling argument â old-fashioned competition — for including a variety of these drugs on formularies. Most obviously, manufacturers of rival brands will recognize the need to keep their prices within bounds, thus driving down costs across the class.

But there is an even stronger need to stimulate competition. Look, for instance, at what happened with classes of drugs called ACE inhibitors or angiotensin receptor blockers that are now used for treating hypertension, heart failure and a variety of other life threatening conditions related to the heart, strokes and the kidney. As manufacturers were compelled by competitive needs to demonstrate that their particular products could provide special advantages or differentiation, they undertook a wide variety of innovative clinical trials that created truly major advances in improving the quality and length of lives across a wide spectrum of patients.

Without the breakthroughs fueled by this competition, important new therapeutic indications would have remained undiscovered and we would still be using these drugs in a limited fashion, a tragic loss of opportunity to improve many lives. In fairness, manufacturers could hardly be expected to take the major financial risk of investing in large multi-year clinical trials if they were not able to earn at least some revenues during this prolonged and expensive process.

In the short term, cost-effectiveness as a basis for formulary selection may save money for government agencies and may increase profits for health plans. But for the well-being of many individual patients, as well as for critically needed medical progress, the price of drugs cannot be the only criterion for their availability. We should remember that drugs represent only a small fraction of total health care costs and we should not lose sight of our overall health care objectives when deciding on access to drug products.

Here’s an important global public health story that deserves wide attention (and, one might argue, words of praise from certain members of the United States Congress).

Major kudos are due to Mark McClellan (in his previous life as FDA Commissioner) and current FDA Deputy Commissioner Scott Gottlieb for navigating through the many obstacles to expedited FDA approval.

(I am proud to have played a very small role in helping make this a reality.)

Here’s the rest of the story …

The Food and Drug Administration has approved the first 3-in-1 antiretroviral pill for use by the American-sponsored plan for AIDS treatment. The pill, made by an Indian generic drug company, is for patients in countries helped by the President’s Emergency Plan for AIDS Relief.

Under that plan, the United States is now the largest provider of antiretroviral drugs in the world, paying for treatment for 561,000 patients in Africa, Asia and the Caribbean.

The Global Fund for AIDS, Malaria and Tuberculosis, the second-largest provider, pays for about 541,000 patients. (The United States also pays one-third of the Global Fund’s budget.)

The new pill, made by Aurobindo Pharma of Hyderabad, India, combines three common first-line drugs, AZT, 3TC and NVP, which are also known as zidovudine, lamivudine and nevirapine and sold in the United States as Retrovir, Epivir and Viramune.

Geeta Anand had another sob story about the high price of biotech drugs. This time it was about Revlimid, Celgene’s drug for treating multiple mylema, Myelodysplastic syndrome (MDS) an illness associated with the underproduction of blood cells and possibly ALS if the results with transgenic mice are replicated in human trials. Geeta is upset that Revlimid retails for about $6400 a month. Mind you, that’s for a drug which appears to extend for a year or more the lives of about 6000 people who are facing certain death. The cancer stopped progressing in most patients after seven treatments and they were disease free 9.6 months after followup. People with multiple myeloma can live disease free for years. A true breakthrough. Is that worth $6400 a month. A house in the Hamptons is. So is a month at Harvard for the matter.

Revlimid is also approved to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. That is, it’s a genetically targeted therapy for MDS which itself affects about 10000 people a year.

Both diseases are devastating, either fatal or life crippling. But they are not blockbuster in size. They are orphan diseases. Revlimid is a medicine that will control them with specific regimens and in specific quantities. As it is studied further, funding for which will come from Celgene’s well deserved profits and not any idiotic Cracker Jack prize competition suggested by Jamie Love or Bernie Sanders in lieu of real rewards (let’s divide .5 of our GDP by the contribution of the increase to the quality of life years divided by the number of patients, less the total cost of care, less the NIH investment which equals the reward less the 90 percent tax rate…) and in the wake of patent seizures, we might see even wider and newer uses, including ALS.

And one more thing. What if Celgene is a one hit wonder? Celegene now has a full pipeline of products in development. What if none of them get approved? Revlimid might have a 97 percent gross margin but that goes to pay for all the other research. That’s the company’s venture capital for future biomedical discovery activity. You can’t finance the future of medicine on WSJ criticism or Jamie Love’s Cracker Jack prizes. And by the way, isn’t worth $72k to beat back cancer?


You know how we feel about “evidence-based medicine” — that quotation marks are required since what it really means is “cost-based medicine.” Here at Drugwonks.com we are firm believers in patient-centric medicine with no quotes required because that’s what it means — putting the patient at the center of the health care equation.

We are also apostles of the Critical Path, of personalized medicine, of the Biomedical Century. And so it is with great interest that we recommend an article from The New York Times, “Imperfect, Imprecise But Useful: Your Race,” by Denise Grady. Here’s the link:

http://www.nytimes.com/2006/07/04/health/04opin.html?_r=1&oref=slogin

The article addresses the question, “Is race medically relevant?” According to Dr. James P. Evans, director of adult genetics at the University of North Carolina, “The question remains, does any of the differential distribution of gene forms have potential medical significance. I think the answer is sure. There may be differentially distributed genotypes that put a group, in aggregate, at increased or decreased risk for certain diseases or affect their responses to certain medications.”

Yes indeed. More information is better.

Are we there yet?

Ms. Grady writes, “Ideally, he said, doctors would like to know precisely which genes in each individual explain susceptibility to disease. But for most diseases the science is not there yet.”

No better argument exists for the need to accelerate down the Critical Path.

“In the meantime,” says Dr. Evans, “If we can glean some hint from someone’s ancestry, we should use it if it can help us treat them better.”

Drugwonks Exhibit A: The urgent need to aggressively identify and exploit biomarkers.

Yes — there are Luddites. Consider the statement of one editorialist, “In medicine there is only one race — the human race.” Nice sound-bite but, as the NEJM reports, important racial differences exist in the way people react to various medicines, including drugs used to treat high blood pressure, heart failure, depression, and pain.

How does this relate to patient-centric medicine? Ms. Grady writes, “The differences could affect the dose a person needed, or whether a particular drug should be used at all.”

The battle for using “continent of ancestry” (the PC term used in place of “race”) is similar in tone and temperament to the “evidence-based” versus patient-centric debate. Just as “cost” must not be the only issue in determining the most appropriate treatment for an individual patient, so too must race (pardonnez-moi — continent of ancestry) not be excluded because of political considerations.

Patient-centric, n’est pas?

Ms. Grady writes, “As a patient I would like to know about this kind of thing. More important, I would really like my doctor to know about it. If information linked to race could help somebody even a little, it would seem worth having. But it could be lost if researchers become wary of studying this subject or even talking about it.”

Is there even a debate here? Do we want doctors to use all relevant information so that their recommendations can be as targeted, effective and safe as possible? Or do we want them to close their eyes and write the prescription?


This just in about the dangers of taking high doses of Tylenol, especially if you are knocking a couple back this holiday week. I fully expect the new darling and David Graham of the media, FDA Drug Safety numbers cruncherRosemary Johann-Lang, who complained “How does one justify balancing the risk of fatal liver failure against one day less of ear pain?” about Ketek — the last line of defense for many against community acquired pneumonia — to rise up and leak a memo claim “how does on justify balancing the risk of fatal liver failure against one day less of fever?” which in turn will be interpeted by members of Congress and the media as a call to take Tylenol away from everybody… (More on Rosemary’s obsession with insignificant safety signals in other areas in another post)

High Tylenol doses linked to liver woes

By CARLA K. JOHNSON, Associated Press Writer


Healthy adults taking maximum doses of Tylenol for two weeks had abnormal liver test results in a small study, researchers found, raising concerns that even recommended amounts of the popular painkiller might lead to liver damage


CMPI

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.

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