In the Spotlight
Back to reality for supporters of drug importation.
Sally C. Pipes, 12-30-04
The Health and Human Services Task Force on Drug Importation, which delivered its report to Congress four days before Christmas, ought to move the debate over importing foreign sourced drugs into the United States from fantasyland back to reality. As the report makes clear, the issue isn’t about free trade or re-importing drugs produced in the United States. It centers on public safety, property rights, price controls, and pharmaceutical progress.
Continue reading . . .
From the Editor:
This issue of Medical Progress Today is devoted to reprising some of the best recent commentary on drug safety that is available on the web. As the withdrawal of Vioxx continues to reverberate throughout the medical community, some of the initial furor is beginning to subside and a more complex picture of drug safety issues is beginning to emerge. The commentary we have collected below is the leading edge of what we hope will be a change in the substance and the tenor of our national debate on drug safety.
Still, even at this stage we can see that the initial chorus of Cox-2/FDA condemnation was short-sighted.
First, for at least some patients, Vioxx offered powerful benefits that outweighed its risks. Weeks after Vioxx was withdrawn, stories started to surface on patients with disabling pain who only reported relief on Vioxx as opposed to older painkillers or even other Cox-2 drugs. For those patients, the trade-off between quality of life and a slightly elevated heart attack risk might be a bargain well worth making.
We also shouldnt forget that Cox-2 drugs were designed to avoid the bleeding and gastrointestinal problems associated with older painkillers, which may cause 16,000 deaths and over 100,000 hospitalizations a year. For patients at high-risk of dangerous gastrointestinal bleeding, and low-risk of heart disease, Cox-2 drugs remain a valuable therapeutic option.
Second, there is no such thing as a me-too drug. Patients can respond very differently to the same drug, or to different drugs with slight, but critical, molecular variances. Critics who argue that one or two drugs per therapeutic class are enough to meet clinical need and that new entrants should face pre-emptive bias against approval are ignoring powerful evidence that individuals metabolize drugs in remarkably different ways. Putting the issue in perspective, Dr. Sally Satel writes that a mutation of even a single nucleotide can cause the gene within which it is embedded to produce an altered protein or enzyme that determines disease or, theoretically, response to treatment.
Translation: tiny genetic differences between patients can make the difference between a powerful response, devastating side effects, or no response at all. Given that reality, having only one or two treatments for doctors and patients to rely on amounts to medical malpractice.
Third, a monitoring system that only focuses on adverse events will miss critical opportunities to expand a drugs indications, and deny millions of patients new treatment options.
Take, for instance, Cox-2 inhibitors like Vioxx, Celebrex, and Bextra. Evidence has been accumulating for years that some cancers, particularly cancers of the breast, colon, esophagus, and prostate, over express the Cox-2 enzyme. The very study that led to Mercks withdrawal of Vioxx was a cancer prevention study, and the preliminary results of that study were finally released last week. The studys lead researcher noted in The New York Times that from preliminary findings it was clear that markedly fewer patients developed precancerous polyps while taking Vioxx and that no other study had shown such pronounced effects in patients like those in this study, who previously had such polyps and were at risk for developing more. [Ed. - emphasis added]
If both results of this study had been published simultaneously heart risk vs. cancer prevention - it is possible that Merck would have weathered the ensuing publicity storm and kept Vioxx on market. Instead, researchers across the country are left scrambling as literally scores of Cox-2 studies on cancer and Alzheimers are cancelled prematurely, at least in part because patients are too scared to keep taking the drugs.
Nonetheless, if evidence continues to mount that Cox-2 drugs are effective in preventing some forms of cancer or dementia, you can bet that patient advocates will demand the resumption of these studies and they may yet be hailed as miracle drugs.
Right now, unless other evidence comes to light, the only sin Merck seems to have committed was that it marketed Vioxx more widely than was necessary i.e. only to patients at high risk of gastrointestinal events, or those who didnt respond to other, less expensive NSAIDS.
This is a mortal sin in the eyes of industry critics, who view any mix between capitalism and medicine as a fatal flaw. On the other hand, profit-seeking gives companies a powerful incentive to sponsor trials seeking new indications for their products and to gain a competitive advantage over their rivals. As John Graham of the Fraser Institute writes, in the huge statin market, companies are investing hundreds of millions of dollars in clinical trials to demonstrate the unique qualities of each of their drugs. This competition improves patient care, drives down drug prices, and spurs new lines of medical research.
Right now, it is fair to say that we know too little about drug safety and too little about how drugs can best be used to optimize patient health. The answer to our ignorance is more science, not more regulation.
Better science can address safety concerns, spur medical innovation, and reassure patients that the drugs they are using are truly safe and effective for them not just on average.
This is a quick outline of the drug safety debate we need, and are beginning to have.
FDA Clears Test of Patient DNA To Screen for Drug Effectiveness
Wall Street Journal, 12-24-04
For the first time, the FDA has cleared a DNA microarray test “for doctors to use in reviewing patients’ genetic information.” The test will hopefully improve doctors ability to match patients with the best medications for cancer, heart disease, and psychiatric disorders. The test analyzes DNA from a patient’s blood for “one of the genes from a group called cytochrome P450 genes, which are active in the liver to break down certain drugs and other compounds.”
Acting FDA commissioner Lester Crawford said that “physicians can use the genetic information from this test to prevent harmful drug interactions and to assure [that] drugs are used optimally, which in some cases will enable patients to avoid less effective or potentially harmful treatment choices.”
Rethinking Over-the-Counter Drugs --- Finding on Aleve Underscores Dearth of Overall Research; Little Incentive for Trials
Wall Street Journal, 12-22-04
Consumers expect that over-the-counter drugs are safer than their new, prescription-only cousins – but that assumption hasn’t ever been rigorously tested. In fact, today’s drugs are only approved after much more rigorous (and longer) clinical trials than those used for decades-old generic drugs. Companies also have a financial incentive to find new uses for patented drugs, meaning that they are often screened repeatedly in different populations. For instance, studies for new drugs like Celebrex and Vioxx have focused on their potential for preventing cancer or Alzheimer’s – and involved thousands of patients who took these medicines for years on end. Trials of that size and duration are much more likely to identify rarer side-effects than those required for initial FDA approval.
This makes newer drugs look more dangerous than older ones – but for patients with chronic conditions who take generic painkillers for years, the opposite could be true. We just don’t know yet.
Because there is so much we don’t know, we need to avoid the instinct to demonize any class of drug, new or otherwise. Instead we should ensure that we are making the best use of all the tools at our disposal to match patients to the best treatments for their particular ailments.
Painkillers Fall Under Sharp Review --- Health Officials to Focus On Side Effects, With Eye Toward Regulatory Action
Wall Street Journal, 12-24-04
The FDA and the NIH have launched a broad initiative to review painkiller side effects of many (at least 18) anti-inflammatory medications, “several of them household names.”
“The list of studies is potentially so broad that neither the [NIH] nor the [FDA], which are heading the initiative, could specify yesterday exactly how many such clinical trials will be intensely reviewed.”
The initiative will include all “NIH sponsored research involving all so-called nonsteroidal anti-inflammatory drugs, commonly called NSAIDS”, including “such familiar products as aspirin and ibuprofen.”
The initiative stems from the concern by some researchers that all NSAIDS (with the exception of aspirin, perhaps the most studied drug in the world) may carry with them some elevated risk of cardiovascular adverse events if used for long enough a time.
Still, consumers shouldn’t be apprehensive. Many of the drugs that we use today, and have used to decades, have well-known risks that are outweighed by their other benefits. The current furor is driven largely by how much better we have become at identifying very small risks in very large population groups. Should that mean that fewer drugs should be approved? No. As one rheumatologist from the University of Chicago noted, “aspirin has enough known dangerous side effects, such as gastrointestinal bleeding, that it probably couldn’t gain FDA approval today.”
And if we didn’t have aspirin, where would the treatment of heart disease be today?
Studies on Painkillers In Jeopardy; Researchers Assess Risk-Benefit Ratio
Washington Post, 12-26-04
The risk of drug treatment always has to be weighed against its benefits – provided you know what they are. But what can we do when hysteria short circuits valuable scientific research?
Before the Vioxx withdrawal, there were literally dozens of studies testing Cox-2 drugs for the prevention of cancer or Alzheimer’s. Now, those studies have all been halted abruptly.
“The spate of bad news about painkillers has dealt a major setback to what had been a highly promising effort to use the drugs to prevent a host of leading killers, including many types of cancer, Alzheimer’s and other forms of dementia.”
One researcher said the current media frenzy has “created a situation of mass hysteria that’s completely unwarranted.... I don’t think we have all the data yet and we may be drawing premature conclusions.”
Hopefully, as more information emerges on the utility of this class of drugs, public fears will recede and the studies can be completed. Until then, patients with a family history of cancer or at high risk of developing dementia will just have to wait patiently until our politicians and trial lawyers have sorted out all the issues in the court of public opinion.
The Right Road To Safe Drugs
Robert Goldberg, Ph.D., New York Post, 12-28-04
Goldberg’s message on drug safety: We can do better.
“The FDA can make drugs safer by embracing cutting edge scientific tools that can reassure each American that his or her medicines are safe and effective.”
The current FDA approval process, “set up when modern molecular biology was in its infancy,” is “good at detecting whether a drug has widespread side effects. It is not so good at discovering whether a small group of people would suffer increased risk of illness or death.” Critics want more of the same status quo – longer, larger clinical trials, that will delay patient access to new medicines for years, if not altogether.
In the long run, molecular science will solve the drug safety problem by creating “a personalized approach [that] identifies which groups of patients might be more likely to get a side effect from a medicine” and optimize drug treatments based on a patient’s genetic makeup.
A World Of Hurt
William Safire, The New York Times, 12-27-04
Safire warns us that “people seeking relief [from pain] have been afflicted by the overreaction to reports that several new pain alleviators, taken in large doses by especially vulnerable patients, may increase the risk of heart problems.”
Leading the charge are trial lawyers trying to sign up tens of thousands of potential clients for lucrative lawsuits, “publicity famished politicians”, and “editorialists [inveighing] against the pharmaceutical industry for putting profits before safety.”
Safire recommends that instead of “terrorizing the FDA into a cover-your-posterior paralysis,” we should “beef up its staff and expand the role of independent review panels to initiate as well as speedily review trials.” Hopefully, we have not gone so far as to be beyond his eminent advice.
Demonizing the drug business
Deroy Murdock, Washington Times, 12-27-04
How many people know that “nine major drug companies donated $2.135 billion in products and services to combat HIV/AIDS, TB, malaria” and other infectious diseases afflicting developing nations?
Not many, I expect. Murdock also notes that pharmaceutical company largesse outstrips the entire budget of the WHO, the U.S. Agency for International Development’s Global Health Budget, and the (by comparison) paltry spending by the European Commission on HIV/AIDS, TB and malaria ($451 million).
Why, then, is it that columnists and activists routinely decry the industry for its “greedy, bloodsucking, murderous behavior all over the globe.” The picture is a caricature, to be sure, but why is it so readily embraced?
Pharmaceutical companies are in the awkward position of actually helping people through their business. If you think that profiting from the sale of cures for deadly diseases is inherently evil, then there is nothing that these companies can do to convince you otherwise.
Murdock reminds us this holiday season that without the charity of the much-maligned pharmaceutical companies “millions of destitute Africans, Asians, and Latin Americans” would have lost their lives.
Attacks on Vioxx don't ad up
Paul Mulshine, The Star-Ledger, 12-23-04
Part of the maelstrom engulfing the pharmaceutical industry is being actively fanned by trial lawyers eager to rake in billion-dollar payoffs similar to earlier victories in tobacco, asbestos, and breast implant litigations – each one of them a stain on the nation’s judicial system.
Far from being killer drugs, Mulshine points out that the Cox-2 drugs were designed to avoid the side effects of other pain medications like aspirin and ibuprofen, which “kill about 16,500 people a year and cause about 103,000 hospitalizations, according to a report earlier this year by the American Gastroenterological Association.”
Aspirin may be dangerous, but it is a generic drug with no deep pockets behind it and a benign reputation. Conversely, the media has focused so relentlessly on the new risks of Cox-2 inhibitors (as opposed to benefits) that drug companies are now sitting ducks for the lawsuit lobby.
Who will invent the next generation of Cox-2 drugs, ones that will avoid both the heart attack risk of first generation drugs like Vioxx, and the bleeding problems associated with older painkillers?
“Certainly not Merck. That firm will be lucky to survive the onslaught of litigation ... And if Merck goes under, it will no longer be able to produce such drugs as the cervical cancer vaccine [it now has] in development – the first ever cancer-vaccine, by the way.”
Do Not Operate Heavy Equipment While Reading This
Holman W. Jenkins Jr., Wall Street Journal, 12-29-04
"Aren't we all feeling a bit silly," Jenkins asks, over "last week's hysterical meltdown over common pain relievers?"
"Controlled trials are wonderful scientific tools making use of the law of large numbers," but those large numbers can still occasionally produce "flaky or misleading results." What we really rely on to establish the clinical value of a drug is its use by doctors and patients, the "larger empiricism that takes place once a drug lands in the market." Seen in this light, Merck's Vioxx withdrawal shows an abysmal "disrespect for doctors and patients", because "plenty of drugs far more dangerous than Vioxx are still available by prescription."
When a clinical trial or other mechanism discloses a manageable risk, the correct reaction is to disclose the risk and inform the market, letting doctors and patients make their own informed decisions. After all, isn't that why we require drug prescriptions to begin with?
Commentary from Past Issues
The Painkiller Panic
Wall Street Journal, 12-23-04
The Journal editorial today is a clarion call for sanity in the midst of what is shaping up to be a very irresponsible debate on drug safety: “One of the most frustrating things about the latest news on painkillers is that almost none of the people reporting it understand the concept of relative risk – i.e. that a doubling of adverse events like heart attacks still doesn’t mean that event is very likely. A doubled risk might well be a chance worth taking, especially if the baseline risk is low to begin with and the drug’s benefits are significant for the patient in question.”
The key phrase is “patient in question.” Regulators (and certainly not industry critics) are in no position to substitute their judgments for that of physicians and their patients, who can best determine for themselves the relative benefits and risks of a given treatment.
Public hysteria over small incremental risks will, in the long run, create a very large threat to public safety if the FDA retrenches and makes it even harder than it already is for industry to create vital new medicines.
The Price of Too Much Caution
Dr. Scott Gottlieb, New York Sun, 12-22-04
This is another winner from Dr. Gottlieb, who reminds us that the current furor over pharmaceutical safety has, ironically, grown out of the real safety gains made by industry in recent decades. Comparing the pharmaceutical industry to the airline sector, Gottlieb notes that both of them are very heavily regulated and have excellent safety records; nonetheless, the better and more successful they are at safety, the worse every individual failure appears in the public eye.
Gottlieb writes that safety is always a trade-off between risks and benefits, and that “today we have the safest [drug] system in the world, but few glaring gaps to easily improve on. When it comes to making new drugs safer, most of the obvious solutions are already accounted for and we have reached the flat part of the curve that measures incremental safety against the additional cost. We can make our drug development system a little safer, but only at a very big cost.”
REVIEW & OUTLOOK (Editorial) Pazdur's Revenge
Wall Street Journal, 12-20-04
The Wall Street Journal notes that recent revelations about Vioxx and Celebrex have created a perfect storm where avaricious trial lawyers “have launched a campaign of unprecedented size and scope that threatens the R&D budgets not just of Merck but of the entire pharmaceutical industry.” Says one trial lawyer: “It’s not as big as asbestos and it’s not as big as tobacco but it’s number three.”
Meanwhile, “Congressional opportunists” and some bureaucrats at the FDA are using the controversy to “make it even harder for innovative therapies to get to market.” One of those bureaucrats is Richard Pazdur, “the FDA’s oncology (cancer) drugs chief,” who wants to slow down the fast-track approval process for new cancer drugs. “The faster approval concept was a response to protests from AIDS activists in the 1980s and was later extended to cover therapies for other terminal diseases.” The Journal says that the “Pazdur interpretation of the rule would effectively kill the accelerated approval process, since there are off-label therapies for just about everything.”
Punishing drugmakers for doing good
Doug Bandow, The San Diego Union-Tribune, 12-16-04
Doug Bandow has written a gem of a business plan for aspiring MBA’s: “Create a company. Spend billions of dollars. Develop life-saving products. Be vilified.”
Sounds good, except for the “be vilified” part. Unfortunately, this is the reality in the pharmaceutical industry right now, where companies are routinely pilloried for not being perfect – rather than lauded for being good.
In no other sector of the market economy are the incentives for enhancing human well-being more closely linked to the profit motive than they are in the pharmaceutical and biotech sectors. Nonetheless, the very same mechanisms that drive medical innovation – profits, patents, and advertising – are the forces that “a gaggle of activists and politicians” denigrate, and then clamor for turning “drugmakers into public utilities” and allowing the government to set price controls for drugs.
Bandow reminds his readers that “medicines lengthen lives, improve the quality of life, and reduce hospitalization and surgery. Americans might prefer to pay less for their medicine. But they will be the biggest losers if they myopically kill the golden pharmaceutical goose.”
In praise of Big Pharma's me-too drugs.
John Gapper, Financial Times, 12-2-04
There is probably no such thing as a me-too drug: even among the class of Cox-2 inhibitors different drugs have different benefit profiles (and risks) for individual patients. This means that doctors or the government can’t take a whole class of drugs and say which one is “best” for everyone, because any given drug may still not work for a substantial minority of patients.
The moral we should take from this lesson is that competition and variety is good for health care, especially for the evolving field of personalized medicine, where physicians will someday be able to offer the right drug, to the right patient, at the right dose, at the right time. Companies will have to adapt to this new reality by identifying high responder groups, and patients at high risk for adverse events throughout the drug discovery and marketing process.
This may mean that few (if any) drugs in the future will be prescribed ad hoc to tens of millions of patients the way some are now, but companies will be able to market treatments to “niche” populations with confidence that their treatments work and are worth every penny paid by consumers and insurers.
Commentary: The Curse of Too Much Caution
Henry Miller, M.S., M.D., Wall Street Journal, 11-26-04
Miller says that the FDA is a favorite target of Congress and the media because, as one former FDA commissioner puts it, the FDA is a “slow-moving target that bleeds profusely when hit.”
The current round of FDA bashing may be a prequel to yet more regulation of the pharmaceutical industry in pursuit of the holy grail of perfect drug safety. Miller takes issue with reflexive calls for greater regulation, wisely pointing out that “greater safety is not synonymous with greater regulation.” In fact, more regulation may lower the “net benefit” to patients and society because regulation is only designed to catch one type of error: the drug that is approved that should have been withheld or withdrawn.
When regulators approve a new drug that later proves unsafe, they will inevitably be excoriated by Congress, consumer groups, and the media. On the other hand, if they fail to approve an otherwise beneficial product, or drag out the approval process interminably, the guardians of public health will utter nary a peep. Says Miller, “the first kind of error is highly visible”, and thus correctible. The second is invisible and largely incorrectable.
In fact, not once in all its history has the FDA been investigated because it failed to approve a new drug. Miller concludes that a drug safety agency that only focused on killing unsafe drugs would make the FDA too risk averse, and keep valuable new drugs from ever reaching market.
Instead, he suggests an independent FDA ombudsman who would have the power to sanction the agency for both types of errors, thus ensuring that FDA has the right incentives to pursue safety and innovation simultaneously.
REVIEW & OUTLOOK (Editorial): The Trials of Merck
Wall Street Journal, 11-18-04
The Journal notes that there are two distinct accusations against Merck, “the first broad and fallacious and the second narrow and possibly true.” The broad charge is that Vioxx and other Cox-2 drugs are virtually identical to older, cheaper drugs like aspirin and ibuprofen, and that “bringing them to market after even a hint that they increase cardiovascular risks is irresponsible.” This is manifestly untrue, since the older drugs, which are taken long term by many arthritis sufferers, cause “16,000 deaths every year from gastrointestinal bleeding.” So much for generic safety. Cox-2s do prevent those gastrointestinal effects, and for a “sizable minority” of patients with disabling pain, Vioxx and other Cox-2 drugs were a valuable addition to the nation's medicine chest.
However, if Merck knew about the heart risks “much earlier than it let on, yet inappropriately marketed the drug too widely as if it was just easy on the stomach aspirin”, then Vioxx crossed the line and should pay the penalty – for “marketing fraud, not for producing an inherently unsafe drug”. Only time will tell if the second, narrower accusation is true or not. All-in-all, the Journal opines that the best course of action would’ve been to leave Vioxx on market with a very stringent label recommending use only in patients without heart disease and with a history of gastrointestinal problems.
No matter what happens to Merck, the most troubling facet of the case is that it will “lead to longer drug approvals and new liability standards that will wreck havoc throughout the whole industry.”
Commentary: Was Withdrawing Vioxx the 'Right Thing to Do'?
Holman W. Jenkins Jr., Wall Street Journal, 11-10-04
Mr. Jenkins thinks that the Vioxx withdrawal was a blunder. On balance, the market and physicians had been aware of risks with the drug since a large clinical trial in 2000 first hinted at the problem. Later, the Wall Street Journal ran “a front-page story on the heart risks of Vioxx and other so-called Cox-2 drugs on August 21, 2001.” And, to top it all off, trial lawyers were coordinating a national litigation effort “by early 2002.”
What changed this year? Good question. Jenkins concludes that “Merck is in hot water now not because Vioxx was excessively risky, but because the wrong people were taking it - a problem for which doctors and the insurance system are also to blame.” In fact, according to one researcher, “the biggest determinant of whether a patient takes a Cox-2 or a cheaper drug is whether an insurance company is paying.” Overall, Jenkins concludes - rightfully, we think - that “the Vioxx debacle is symptomatic of a system that shields consumers from price signals and sometimes actually discourages them from making the right health-care choices.”
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