May 2012 Archives

An interesting op-ed published by Trevor Butterworth in The Daily does a great job explaining how a new federal agency could effectively bias the U.S. health care system against more innovative and effective treatments under the guise of comparative effectiveness research. The "Agency for Healthcare Research and Quality (AHRQ)," is tasked with conducting comparative effectiveness research on a variety of medicines and treatments, but isn't subject to any oversight on how it communicates the findings of that research - not even from the FDA, which strictly regulates what pharmaceutical and medical device companies can say about their products to physicians.

But is the agency likely to be a neutral arbiter of "what works?" Butterworth thinks this is unlikely:

"Imagine that all the pharmaceutical companies united to create an institute for quality research, and gave it $1 billion to study "comparative effectiveness" -- whether drugs still under patent worked better for people than cheaper generics. Imagine that the pharma companies dug farther into their pockets and came up with another $11 million to train physicians, pharmacists and nurses to be ambassadors for this institute, and that these ambassadors would travel the country offering $4 million worth of further education credits to any doctors or nurses who would agree to listen to their spiel.

If you're thinking that this is, in fact, what Big Pharma already does, remember, this is still a hypothetical exercise. In reality, such a plan would never get by the Food and Drug Administration, which is to drug marketing what the Spanish Inquisition was to heresy. But if, somehow, such a project were ever to happen, you'd seriously doubt whether it would be unbiased, wouldn't you? It strains credibility to think that the pharmaceutical industry would go to such expense to say that the cheaper drugs were just as good as the expensive ones."

For instance, out of the $1 billion the agency has been granted to conduct and disseminate its research, it plans to spend $11.6 million to recruit health care professionals to explain the results of its research to large medical practices and health care providers across the country. Another $26 million will be spent on a PR campaign to increase public awareness of the program and its work (which, btw, is already available for free on its website).

Butterworth points out two major problems with this approach. The first is that in without FDA oversight of communications, the AHRQ won't have any external check on its recommendations, which will likely be drawn from meta-analysis of many published studies - blended results which are likely to be very sensitive to small changes in methodology or background assumptions, or downplay the effect of its recommendations on subpopulations.

As a government agency, AHRQ may also be tempted to favor generic drugs and cheap treatments that lower costs in the short term, but may lead to higher costs (and worse outcomes) in the long term.

It may also underestimate the market effects of incremental innovations that will spur greater innovation (and lower costs) in the future. As Butterworth points out, "there's always a trade-off between care and cost," and while one cannot fault the government for attempting to promote cheap treatments where they can (appropriately) substitute for more expensive treatments, markets and individuals are much better at balancing these trade-offs than centralized decision makers (no matter how well intentioned).

Butterworth also points out the stark double-standard with respect to how the government regulates medical research. No pharmaceutical company could make these kinds of communications to physicians or hospitals. Efficacy claims (comparative or otherwise) that companies can make on a drug's FDA approved label are typically the result of one or more double-blind, placebo controlled trials published in peer reviewed journals. They certainly wouldn't be allowed to attack their market rivals using the type of meta-analysis of multiple studies that AHRQ will be using to drive its comparative effectiveness agenda.

America's health care system certainly needs more information to help patients and physicians make patient-centered medical decisions, and there are some studies that only the government may be big enough to fund (like cancer trials testing multiple therapies). There is also certainly a lot more evidence needed on what kinds of payment systems drive better health care outcomes. But data dredging in support of generic medicines (which already account for about 80% of all U.S. prescriptions) is both unneeded and unlikely to do any real good.

Though we often think of "personalized medicine" as cutting-edge, technologically advanced medicine tailored to an individual's particular biochemistry, an article in today's Wall Street Journal about the blood-thinning drug Plavix offers an instructive example of how a more expansive conception of personalized medicine is essential to improving patient outcomes.

As the article notes, Plavix tends to be a very effective treatment for the blood clotting that often leads to heart attacks, but it doesn't work for everybody. Roughly 30% of people have a gene variation that limits their body's responsiveness to the drug, hindering its effectiveness. As a result, some people end up taking Plavix without enjoying its salutary benefits. As genetic testing becomes more common and less expensive, it will become easier to identify who these people are and to move them to more effective treatments (or adopt different dosing strategies to overcome the genetic resistance).

But the article also offers a simpler explanation for why patients on Plavix don't always benefit from the drug: they simply forget to take it. Research into patient compliance suggests that "50% of heart patients stop taking important medications within a year of their initial prescription."

Both of these factors--the presence of drug-inhibiting genes and the tendency of patients to stray from their prescribed drug regimens for chronic diseases--can profoundly affect patient outcomes. And though high-tech genetic research has the potential to expand our knowledge of drug effectiveness tremendously, we should not forget that any tool - from a telephone call from a nurse practitioner to an email, or an app on your iPhone - used to improve a particular individual's health constitutes a kind of "personalized medicine."

Simple solutions like reminding patients to take their medicine could ultimately prove just as helpful in saving lives as advanced technology that delves into the complex relationship between genes and drug effectiveness.

Fostering the development of "personalized medicine" therefore does not just mean investing in R&D. It also means creating financial incentives for insurance companies and health care providers to look after their patients' health in more personal ways that are designed to maintain health rather than just to treat illness. The technologically adept among us can also make use of iPhone apps such as "RxmindMe," a free service that alerts individuals when they need to take their prescriptions.

Low-tech forms of personalized medicine are just as crucial as their high-tech counterparts. A full embrace of personalized medicine demands that we appreciate the potential that lies in both.

Medical Progress Today contributor Avik Roy recently published an article well worth reading in Forbes defending one of the most often criticized features of Medicare's prescription drug program--the so-called "donut hole." The "donut hole" refers to a gap in the program's drug reimbursement scheme, which forces seniors to bear the full cost of their drug expenditures up to a certain point, after which "catastrophic coverage" kicks in and Medicare bears almost all of the costs.

Medicare Part D requires seniors to pay for 25% of their drug costs up to a certain threshold ($2,830 in 2010), after which they pay 100% of their drug expenses for all expenditures between $2,830 and $6,440. Once the upper limit of $6,440 is reached, however, seniors only pay for 5% of their remaining drug costs. The "hole" in the so-called "donut" is the middle spending region in which seniors are expected to pay the full cost of their drug purchases.

The apparent irrationality of this gap in coverage, as well as the financial burden that it imposes on senior citizens, have long been criticized by politicians and pundits along both sides of the partisan divide. Roy's article, however, offers a compelling explanation for why this coverage gap is an essential cost-saving mechanism:

"The thresholds were designed by the actuaries who mined actual drug usage statistics to identify the optimal price points. The idea was to help seniors pay for basic drug coverage--like pills for high blood pressure and heart disease--while giving them the incentive to use generic drugs, which account for 80 percent of all U.S. prescriptions. Those seniors with truly serious and costly conditions would benefit from the backstop of catastrophic coverage.

This cost-sharing system has worked astonishingly well. Medicare Part D has spent 30 percent less money than the Congressional Budget Office originally projected it would. Last year, it became the first federal health program in memory in which spending actually decreased from year-to-year."

The "donut hole" is a crucial cost-saving device because it incentivizes seniors to be judicious in their drug purchases. Without it, seniors would have little reason to prefer cheap generic drugs over more expensive branded alternatives. Unfortunately, the Patient Protection and Affordable Care Act effectively closed the donut hole, which will make the sustainability challenges facing Medicare all the more intractable.

Medical Progress Today managing editor Paul Howard has an article in the Washington Examiner today about how outdated FDA regulation has inhibited American innovation in the pharmaceutical industry. The good news is that Congress is acting to revamp some aspects of the FDA's drug-approval process, streamlining regulations and facilitating U.S.-based medical innovation:

"Thankfully, Congress is close to passing bipartisan reform legislation that should give patients faster access to new medicines and medical devices and perhaps streamline the process for bringing life-saving and life-enhancing products to market. It won't transform the FDA overnight, but it would be a major step forward. The new legislation is based on several user-fee agreements (user fees allow the FDA to hire additional staff to review product applications) negotiated by the FDA and the drug and medical device industries. The bill's overarching theme is that better communication between companies and regulators will lead to better outcomes for patients.

For instance, the user-fee agreements mandate additional meetings between companies and regulators to ensure new drug reviews are as seamless as possible; require that the agency develop a benefit-risk assessment model for new medical products; and require ongoing FDA staff training on how to review applications that incorporate biomarkers, which can help companies develop safer and more effective medicines targeted at patient subpopulations based on genetic or other diagnostic criteria. Congress has also added provisions that would improve and make permanent incentives for pediatric drug research; extended incentives for companies researching new antibiotics and antifungals for drug-resistant pathogens; clarified standards for the FDA's 'fast-track' and 'accelerated-approval' programs for serious and life-threatening diseases; and create a 'breakthrough-therapies' designation for expediting development of the most promising medicines.

Overall, the legislation will improve the FDA's ability to bring safe and effective new products to the public in a timely manner. Without these improvements, life sciences investment will increasingly move abroad, and American patients will wait longer for more innovative therapies."

You can read the full article here.

Today the Senate is voting to reauthorize the Prescription Drug User Fee Act of 1992. A number of amendments have been added to and rejected from the reauthorized version of the law, but the one we've been watching most closely is amendment #2107 proposed by Sen. John McCain (R-Az). The amendment, which was recently rejected by the Senate, would have allowed American citizens to import cheap prescription drugs from Canada, under certain conditions. While this proposal might sound like good policy at first glance, it would in fact have dire consequences for pharmaceutical innovation if implemented.

Prescription drugs are cheaper in Canada only because of price controls imposed by the Canadian government, which effectively prohibit pharmaceutical companies from selling their drugs to Canadian citizens at market value prices. Faced with a choice between selling their drugs in Canada at a reduced price or not selling them at all, pharmaceutical companies reluctantly choose the former. Since the U.S. government does not force drug companies into collective purchasing agreements (insurers and PBMs bargain directly with drug companies over prices), American citizens generally pay somewhat higher prices for their patented drugs than do Canadians.

Although Americans may resent that other developed countries pay lower drug prices, it is absolutely crucial that pharmaceutical companies be free to set their own prices in at least some wealthy markets if we want pharmaceutical innovation to continue. By purchasing drugs at market prices, rather than at prices set by a government cartel, American citizens effectively subsidize global pharmaceutical innovation for everyone.

Profits that pharmaceutical companies reap from their sales to American citizens help those companies recover the extraordinary investments they make in drug research and development, and even more importantly, these profits are used to fund the next generation of pharmaceutical advances.

The failure of the McCain amendment is thus a victory for global medical innovation, insofar as it protects pharmaceutical companies' ability to charge sufficiently high prices to develop future innovations.

More importantly, is it a victory for the millions of patients who will live longer, healthier lives tomorrow because we didn't embrace price controls today.

A great article published yesterday in Forbes by Grace-Marie Turner offers an insightful analysis of how outdated, uncompetitive American tax and regulatory policies threatens America's current status as the global leader in health care innovation. Turner convincingly argues that though the U.S. currently leads the world in medical innovation, the onerous burdens imposed on the pharmaceutical and medical device industries by high corporate tax rates and a complex, costly domestic regulatory environment may cause leading companies within these industries to scale back their American enterprises and to relocate offshore. She writes:

"Our edge is not gone yet, but U.S. legislators must quickly act to stop the drain...The cost of developing a new drug now exceeds $1.3 billion and takes an average of 12 years, and only a small percentage of new molecular entities ever reach the market. Instead of mitigating the risks that go along with these huge investments, the U.S. government has been erecting ever higher hurdles.

High American corporate taxes, in particular, deter investment. The top corporate income tax rate in the U.S. is 38 percent compared to an average of 15 percent in other countries.

In addition, many countries have instituted strong and permanent incentives for research and development, but the United States has kept its R&D tax credit "temporary" for decades. America now ranks 17th out of 21 countries in the Organization for Economic Cooperation and Development in the effective rate of its R&D tax credit.

The new health law also has created major new hurdles for investment in the biomedical sciences. Consider ZOLL Medical Corporation, a medical device company that now finds itself in the bull's eye of Obamacare. The law imposes a 2.3 percent tax rate on the revenue that medical device manufacturers collect -- revenue, not profits! This will increase ZOLL's tax rate to more than 50 percent, completely wiping out its R&D budget..."

If the U.S. continues to cling to its unrivaled 38% federal corporate tax (not to even mention state-level corporate taxes) and continues to impose exorbitantly costly and byzantine regulations on medical innovators, there can be no doubt that these pioneers of health care innovation will, over time, relocate to other countries with more business-friendly policies.

It's no secret that the Obama administration has long had difficulty selling the Patient Protection and Affordable Care Act (i.e. Obamacare) to the public. Public opinion never favored the law, and shortly after it passed through Congress the limited popularity that the law had cratered. With a majority of Americans opposing the law, and with nearly half of all Americans saying that they "strongly favor" its repeal, the Obama campaign has been trying desperately to engineer a change in public opinion by touting the law's many supposed benefits.

And in this endeavor, it turns out that the Obama campaign's greatest ally may be the law itself, not because its virtues are so easy to sell, but because the law contains a provision requiring that $20 million be spent this year advertising the law's "preventative benefits" to the public. Peter Suderman of Reason Magazine picked up on this provision in the law from a report in PR Week, which confirmed that the marketing firm Porter Novelli has won a $20 million grant to, in the words of an HHS official, "inform the American people about the many preventative benefits now available to those with Medicare, Medicaid, and private health insurance as a result of the Affordable Care Act."

Of course, the Obama campaign will claim that there's nothing wrong with this picture. After all, the law literally demands that $20 million be spent advertising its supposed benefits, so the Obama administration has to award a $20 million advertising grant to someone just to avoid breaking its own law.

But I expect that the vast majority of people will reject this defense as a cheap political ploy. A $20 million public advertising campaign selling the virtues of Obamacare cannot be interpreted as anything other than a $20 million public advertising campaign advocating for the president's reelection.

Yesterday's Wall Street Journal featured an article citing new studies that challenge the longstanding perception that hormone-replacement therapy (HRT) is an exceedingly risky treatment for women suffering from menopausal symptoms. This perception itself became widespread and entrenched roughly ten years ago following a government study conducted by the Women's Health Initiative that abruptly ended when data showed that women using HRT had higher rates of heart disease, stroke, and breast cancer than other menopausal women taking a placebo. However, new studies featured in the journal of the International Menopause society, Climacteric, indicate that some women using HRT can in fact benefit greatly from it; these women using HRT generally enjoy a relief from menopause symptoms as well as other significant health benefits, most notably a reduced rate of heart disease.

What separates these studies, and what led them to reach such widely divergent conclusions, is that they tested the effectiveness of HRT for women in marginally different age groups. The study published by the Women's Health Initiative primarily examined the effects of HRT on women who had long been in menopause--according to The Wall Street Journal, the average woman who participated in the Women's Health Initiative study had already been in menopause for 12 years. However, the Climacteric studies seem to corroborate the "window-of-opportunity" theory, which predicts that women who begin using HRT treatment before 60 or within ten years of menopause are more likely to experience health benefits than those who use HRT later in life.

The lesson to be taken from these studies is that medical research is done best when personalized and tailored to individual patients. The sweeping conclusions reached by the Women's Health Initiative a decade ago concerning the purported dangers of HRT for menopausal women only actually hold for a particular subset of menopausal women, and the health benefits of HRT for women who don't fall in that subset can be tremendous.

This case thus illustrates a serious danger latent in the "comparative effectiveness research" approach taken by the Patient Protection and Affordable Care Act: mass studies of how different treatments affect large swaths of people are not likely to pick up the subtleties and nuances in treatment effectiveness that can vary from person to person based on a whole range factors that determine each individual's unique biochemistry. These diverging studies further illustrate that the most significant advances in medical research, and by extension in medicine itself, are likely to be patient-oriented, but these advances may not be realized if we continue to support overbroad, one-size-fits-all "comparative effectiveness research" as our method for evaluating medical treatments.

Of course, this is a homage to Josh Bloom's recent MPT Spotlight article that touches on innovation in HIV medicines, and dismantles the concept that only the first or second drug in a class is actually innovative.

But the great-grand daddy of all me-too drugs by this account is insulin. Before the advent of insulin, if you had the bad luck to develop diabetes your quality of life was terrible and your life expectancy quite short. (The disease could only be barely managed by draconian diets that sometimes led to death by starvation.)

In 1922, a team of Canadian researchers led by Frederick Banting began trying to isolate insulin from the pancreas of dogs, and eventually succeeded in purifying enough of the insulin (from another animal source, cattle) to begin human treatments. The effect was immediate and near miraculous: injecting insulin just a few times a day brought diabetics back from death's door and granted them an almost normal life.

In 1923, Banting and his colleague Dr. John Macleod won the Nobel Prize for medicine for their pioneering work in insulin research. The invention of insulin saved millions of lives, but also came with a rare and potentially serious problem: insulin derived from cattle pancreases could cause allergic reaction in some diabetics (insulin that was later derived from pigs was found to be less allergenic).

The next major insulin innovation came in 1978 when Genentech used recombinant DNA technolgy to insert the gene for human insulin into bacteria, which then produced human insulin, which is the overwhelming source of insulin used by diabetics today.

According to the American Diabetes Assocation, there are more than 20 types of insulin available in the U.S. today, which differ in "how they are made, how they work in the body, and how much they cost."

Finding which type of insulin regime works best for an individual diabetic is a trial and error process - but at least there are lots of choices available.

So does this mean that insulin innovation is a dead end? Not at all.

One thing that everyone seems to agree on is that sticking yourself with a needle several times a day is really no fun at all. In fact, the Holy Grail of insulin research is a pill for diabetes.

Well, you might ask, how hard could that be? Awfully darn hard, it turns out, according to this fascinating article that explores Novo Nordisk's epic struggle to turn a nearly 100 year old drug into a pill:

When swallowed, insulin embarks on a journey that takes it through the stomach and the intestines, where it faces the assault of acids and enzymes. It must then cross the gut wall, usually accessible only to smaller particles known as amino- acids, to reach the bloodstream and travel to the liver.

"The gut should make sure you don't get toxic material into your body," says Thomsen, sketching the product's travel route on the board of a conference room at Novo's headquarters in Bagsvaerd, Denmark. "You have to cheat Mother Nature."


The challenges aren't over once the insulin crosses the gut wall. Researchers must extend the hormone's ability to stay in the bloodstream and boost its capacity to be absorbed by the body, a concept known as bio-availability, according to Thomsen. Novo has already found a way to give insulin more staying power and it's searching for ways to further increase bio- availability, he said.

Finally, scientists must avert absorption swings caused by the vagaries of human digestion. On days when the patient suffers a bout of diarrhea for example, the pill's passage through the bowels may be too quick to allow proper insulin absorption. Novo says the once-daily tablet should give patients enough of an insulin buffer to guard against hypoglycemia, a state of dangerously low blood-sugar levels.

Still, if Nordisk's scientists succeed, the pill is expected to be enormously popular among diabetics - a blockbuster that could reach "peak sales of from $5 billion to $10 billion", according to one analyst cited in the Bloomberg article.

Nordisk may take its insulin pill into mid-stage trials sometime in the next year or two. And not everyone thinks that they will be successful. Others have tried and failed.

Regardless, there will still be a huge need for better diabetes treatments. The disease afflicts hundreds of millions worldwide, and kills one diabetic every seven seconds.

So a pill that made treatments a little bit less painful and more tolerable could improve diabetes compliance, prevent the ravages of uncontrolled blood sugar, and save millions of lives.

But it will most certainly will be a "me-too" product - a tweak on a century-old drug that will still require an enormous amount of scientific innovation and financial risk.

Later this week -- possibly as early as tomorrow -- a bipartisan majority in the United States Senate is expected to vote in favor of S. 3187, the Food and Drug Administration Safety and Innovation Act, which among other things, reauthorizes the Prescription Drug User Fee Act of 1992. MPT readers will, of course, be familiar with PDUFA and what it does. But in an article published in yesterday's Washington Times, I called it "arguably the most important piece of health care legislation [most people have] never heard of."

Before PDUFA, FDA typically took two years or more to evaluate new drugs -- that's after they already had been through some 10 or so years of clinical testing. The net effect was that American patients were often the last to benefit from important medical breakthroughs. Since 1992, the PDUFA user fees have enabled FDA to hire new medical reviewers and improve its scientific capacity. More important, the average drug-approval period was cut in half, to just more than a year.

As I wrote in the Times:

"Ideally, individual firms should not have to pay user fees to fund regulatory oversight that is ostensibly for the public's benefit. But in an era of tighter federal budgets, Congress has given the FDA more and more responsibilities but not the additional revenue to fund them. Without PDUFA, the FDA's budget shortfall would mean fewer new medicines reaching the patients who need them. Reauthorizing the user fees is a second-best choice, but in the face of a slow economy and pressure to reduce the federal budget deficit, it seems to be the best available option."

As a libertarian, I generally oppose efforts to give the government more money. But let's face it: given all the responsibilities Congress has given the FDA, if we starve that federal agency of resources, we'd only be shooting ourselves in the foot. I'd prefer that FDA have far less power and fewer regulatory authorities. But until that day comes, we are better off with an agency that has sufficient resources to review medical products in a timely fashion.

The Food and Drug Administration Safety and Innovation Act (FDASIA -- let's pronounce it Fudd-Asia) not only reauthorizes the user fees for prescription drugs, but it also reauthorizes the medical device user fees first introduced in 2002, and it establishes new user fees to fund FDA review activities for generic drugs and biosimilars. But what is especially noteworthy about this year's reauthorization, known to insiders as PDUFA V, is that it incorporates very few additional "Christmas Tree" amendments - measures unrelated to the primary purpose of a bill that are added to "must pass" legislation.

Prior PDUFA reauthorizations, typified by 1997's Food and Drug Administration Modernization Act (FDAMA) and 2007's Food and Drug Administration Amendments Act (FDAAA), included dozens of amendments to the statutes regulating drugs, medical devices, and even foods. FDAAA, for example, introduced new advisory committee conflicts of interest rules, gave the FDA new post-approval recall authority, established a public database of clinical trials, and even changed the way the agency regulates the safety of pet food.

This year, congressional leaders succeeded in getting relatively clean bills reported out of the House Energy and Commerce Committee and Senate Health, Education, Labor & Pension Committee. It's not that the bills don't incorporate a few non-user fee related items. They do. But for the most part, this handful of additional items will help to streamline the drug and device approval processes by expanding eligibility for the Accelerated Approval pathway, permitting FDA to expedite the testing and review of "breakthrough therapies," and requiring the agency to solicit the views of actual patients when assessing the safety and benefits of medical products.

Other provisions provide incentives for the development of new antibiotics and orphan drugs.The bills also permanently reauthorize the Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA), which give FDA the authority to require pediatric testing of already approved drugs (which I oppose) and give companies that do pediatric testing an additional six months of market exclusivity (which I support).

One provision would also instruct FDA to issue a long-awaited guidance document clarifying the rights of drug and device manufacturers when promoting their products on the Internet (an issue I wrote about here). And the bills even soften the harshest effects of the FDAAA conflict of interest rules.

Arguably, the worst aspect of the House and Senate bills are one provision requiring the FDA to consider stronger warning labels on sunlamps and tanning beds and another intended to address the drug shortage problem that MPT contributors have written about here, here, and here. It's not that I think the drug shortage problem needs to be addressed, though. I just happen to think that the drug shortage provisions of the FDASIA will do extraordinarily little to solve the underlying problem.

All in all, this bill may be about as good as we could expect. So, it'll be a good day when the Senate and House pass the legislation, and when President Obama signs it into law.

The New York Times had a great article yesterday on the genius of providing expanded access to primary care physicians in return for a low monthly fee ($54). The physicians in these groups don't accept insurance, so the fee is really a monthly membership - like a gym membership - but in return patients get expanded access to physicians via same day appointments, email, and phone calls.

From the Times:

Call it concierge medicine for the masses. The idea is that routine, mundane primary care should not require expensive insurance and can be cheaper without it. Direct primary care practices charge $50 to $60 a month for adults, with lower fees for children. Depending on the practice, the monthly fee also may cover certain lab tests, basic X-rays and stitches for cuts.

But the fee does not cover anything beyond primary care. Typically employers combine direct primary care with high-deductible insurance plans, needed to cover hospitalizations and visits to specialists.

"Health insurance is supposed to protect you against risk, like car insurance does," said Dr. Bliss. "We don't insure our cars for tire changes and tune-ups."

Allow me to pat myself on the back here. Back in 2008, I suggested in a City Journal article that concierge practices could be adapted for many Americans, and that combining them with high deductible insurance plans would be a great way to provide protection from catastrophic health expenses without paying thousands of dollars annually (or if you live in New York, monthly) for first-dollar health insurance coverage.

Here's what I wrote then:

Last October, one West Virginia doctor made national news when the Wall Street Journal chronicled his prepaid primary-care plan. Vic Wood offers the 100 or so patients in his plan unlimited primary and urgent care, basic diagnostic tests, and many generic drugs for a monthly fee ranging from $83 for an individual to $125 for a family.

One patient is a private music teacher who, before joining Wood's plan, had gone without health insurance for four years because his wife's health insurance would have cost him $400 a month. Wood diagnosed him with high cholesterol and is treating him, with excellent results. A local business started offering Wood's clinic as a benefit, switched to a major medical plan with a high deductible, and saw its monthly premiums drop by $4,000. The firm's health insurer lowered its rates the following year, noting that workers "required less time in the hospital and used Dr. Wood's clinic for nearly all of their primary care," reported the Journal.

Why doesn't the entire system work this way? Because of our tax system, which encourages employers to offer expensive, pre-tax first dollar coverage, even though most patients could easily pay out of pocket for routine care - and even though the tax subsidy and red tape that comes with third party insurance drives up the cost of routine care.

Shifting to a direct primary care system could offer patients better outcomes at lower prices, give doctors more job satisfaction and more time to focus on disease prevention, and refocus insurers on doing what they do best, i.e. putting together pools to hedge against catastrophic risks.

(Getting insurance back to its core purpose, hedging against catastrophic risks, is the subject of an excellent blog post by my colleague Avik Roy.)

But the basic point here, which is hugely unapprreciated, is that our tax system drives up the cost of health care by encouraging insurers to bundle cheap services with very expensive services. This "tying" creates incredible perverse incentvies through out our health care system.

Unbundling primary care from insurance would make routine health care access much more affordable, and encourage physicians to compete in the marketplace by offering services focused on disease prevention and chronic disease managment - instead of waiting for someone to get sick to pay attention to them.

A standard tax deduction or tax credit (for low income Americans), along with reforms to Health Savings Accounts (like allowing people to pay for direct primary care services from HSAs) would encourage providers and insurers to look for new synergies in health care delivery. Together with insurance market reforms (like longer term contracts that were guaranteed renewable), hybrid insurance-direct care plans could provide critical financial protection for consumers while also transitioning us to the kind of market based health care system conservatives pine for, while assuring liberals a robust safety net for the poor.

There's another different question, of course: what should we do about the 5 or 10 percent of Americans who have high cost, chronic health conditions that are very expensive and likely to remain that way - for instance, people with severe mental health or substance abuse problems, multiple co-morbidities, etc.

I think this system of direct primary care could be adapted for them as well, with the right mix of risk-adjustment mechanisms and targeted subsidies to encourage insurers and physicians to to keep this population in the best health possible.

But it should be far easier to address this challenge rather than trying to shoe-horn hundreds of millions of Americans into an insurance system that doesn't make sense for them and that is bankrupting the federal government and employers alike.

To its credit, the Affordable Care Act does contain a provision that allows direct primary care plans to offer plans on state insurance exchanges beginning in 2014. Still, the ACA's enormous cost sharing and premium subsidies are focused on first dollar care, and HHS seems determined to restrict HSAs through punitive regulations, both of which bode ill for the abilty of direct care practices to flourish on state exchanges.

If the ACA is overturned in June, Congress' first order of business should be replacing it with a universal tax credit or tax deduction (or blend of the two) that would encourage Americans to migrate into catastrophic insurance plans and HSAs and seek out direct primary care practices for routine care.

Everyone would benefit from this system - except the health care bureaucracies in Washington, who spend enormous amounts of time and money trying to manage our current bloated system.

Recently I've written about the FDA's needing to balance safety and innovation. A new opportunity is on the horizon that will put the Agency to the ultimate test. For the first time in over a decade, the FDA is considering the approval of a new diet pill... and more than one company has a promising product for the FDA to review. With the epidemic of obesity being one of our nation's biggest health concerns, it seems only logical that a weight loss pill that demonstrates some clear benefits should be given the utmost consideration. But history (Fen-Phen) and the potential for severe negative side effects has made the decision less than automatic. Determining the best approach requires a careful analysis of the level of risk that is acceptable when dealing with a crisis like obesity.

The drug combination fenfluramine/phentermine (commonly called Fen-Phen) was an anti-obesity treatment. Fenfluramine was created in the 70s and proved to only temporarily reduce weight. But when the drug was combined with phentermine in the 90s, its popularity soared and it was hailed as a miracle weight loss drug. That was, until 1996 when the New England Journal of Medicine published a paper reporting 24 cases of heart-related problems linked to Fen-Phen. Ultimately, the product was recalled in 1997 (one-third of the people taking it experienced heart valve damage), but the damage incurred before the recall was costly... approaching upwards of $13 billion dollars, to say nothing about the lives that were impacted negatively.

Unfortunately, the FDA did not fully do its homework on Fen-Phen. In 1994, the Agency became aware that fenfluramine was potentially linked to pulmonary hypertension, but refused to incorporate this into labeling (even though European agencies had already done so). This mistake has resonated throughout the years, and since then, the FDA has been reluctant to approve diet pills.

But almost 15 years later, the Agency has seemingly changed its stance. Today, obesity stands as one of our nation's most pressing challenges. Over two-thirds of the country is considered to be overweight or obese. And this is more than just a mere image problem. With obesity comes the rising cost of healthcare. The extra weight has been linked to chronic diseases such as Type 2 Diabetes and hypertension, and the cost of treating complications has been astronomical. The crisis has placed a disproportionately heavy burden (pun intended) on our nation's healthcare system.

In come Vivus and Arena Pharmaceuticals with their respective weight loss drugs Qnexa and Lorqess. In the last few months, both drugs have seen resounding approval by FDA panels. While these panels' votes don't necessarily mean that the drugs will be approved by the FDA, they have to be considered influential in the final decision. And this could be promising in the fight against obesity.

Arena's Lorqess showed an average weight loss of over three percent over a year, and over one-third of patients losing at least five percent of their weight. Qnexa demonstrated an even greater impact. Average weight loss was 11 percent, with 83 percent losing five percent of their weight or more. Both drugs demonstrated weight loss success that meets FDA standards for "significant" weight loss.

But it's not enough that these drugs may help treat the epidemic. They must prove to be safe as well. Research on Lorqess and Qnexa includes data that indicate some potential safety hazards. Lorqess may be linked to an increasing risk of high blood pressure in diabetics, or possibly damaged heart valves (much like Fen-Phen), and even a small chance of tumors (in rats). Research on Qnexa showed a potential rise in heart rate and heart palpitations, as well as the possibility of birth defects (such as cleft palates).

The FDA - although faced with the pressure of fostering innovation in the fight against obesity - can't afford to take these potential adverse events lightly. And to date, there is no sign the Agency intends to do so. Both manufacturers were tasked with additional studies and providing information to rule out these side effects, or to at least demonstrate they were not prevalent (prior to a final decision). In fact, the FDA will likely delay the final decision a few additional months to give Arena and Vivus ample time to properly collect data. Additionally, it appears as if post approval cardiovascular studies will be required (should either or both drugs be approved) to ensure that history doesn't repeat itself.

Obesity is clearly a huge problem for Americans. If there really is a pill out there that can assist in the weight loss process (in addition to changing lifestyle habits), the FDA has a duty to make every effort to get it to market. But it should not sacrifice safety to do so. The FDA must consider whether the benefits outweigh the risks... and even then, the Agency must still provide the entire story. Information needs to be effectively communicated to the public in the form of properly worded labels - and if brought to market, ensure appropriate post-market surveillance. And it seems that this is exactly what the FDA is on track to do.

After a recent blog post where I noted Peter Pitts' op-ed on Group Purchasing Organizations (GPOs) in the Washington Examiner, financial journalist Phil Zweig wrote to me to gently correct one of Peter's assertions:

In his article, Peter Pitts rightly attributes the drug shortages to the anticompetitive, exclusionary contracting practices and other abuses of hospital group purchasing organizations (GPOs). Those of us who have been trying to draw congressional and public attention to the GPOs' pernicious role in this crisis certainly welcome his support. Unfortunately, however, he is mistaken in stating that GPOs "keep costs low." In fact, overwhelming anecdotal and empirical evidence demonstrates that they grossly inflate healthcare costs. The reason is that GPOs are paid by vendors, including generic drug makers, in the form of "administrative" and other fees, which are calculated as a percentage of sales volume. So the higher the price of a product, the more money a GPO makes.

This perverse incentive was created by a misguided 1987 statute called the Medicare anti-kickback "safe harbor" provision, which exempted GPOs from criminal penalties for accepting vendor kickbacks. Overnight, GPOs became the marketing agents for suppliers, not the servants of hospitals. Under the original business model, which had worked well for nearly 80 years, GPOs operated like co-ops, covering their expenses out of the savings they achieved for members hospitals through volume discounts. The new kickback-based business model gave rise to a pay-to-play scheme in which GPOs awarded exclusive contracts to vendors in return for huge fees. But higher costs for providers, insurers and taxpayers are just part of the problem. Worse still, these abuses have denied patients and healthcare workers access to the best, safest, and most cost effective supplies, devices, and drugs.

This has been documented in four Senate Antitrust Subcommittee hearings held from 2002 to 2006, federal and state investigations, independent studies, media exposes, and numerous antitrust lawsuits against GPOs and/or their dominant supplier partners. A 2002 Government Accountability Office pilot study found that hospitals often got lower prices on their own. As Sen. Herb Kohl (D-WI) and former Sen. Mike DeWine (R-OH), then ranking member and chairman, respectively, of the Senate panel, pointed out in a joint 2003 letter to then Secretary of Defense Donald Rumsfeld (DOD was then considering using GPOs to procure health supplies), "the savings figures that GPOs frequently use as benchmarks to demonstrate savings are based on a manufacturer's list price that hospitals rarely, if ever, pay."

A September 2010 study initiated by Sen. Charles Grassley (R-IA), then ranking member of the Senate Finance Committee, concluded that empirical data was "lacking to support claims of savings with group purchasing organizations." More recently, a study in the current issue of the Journal of Contemporary Health Law and Policy found that in 2010 hospitals were able to save an average of 15% compared with GPO contract prices in competitive "aftermarket" bidding for capital equipment. In contrast, the GPOs have presented no independent data to support their specious claims of cost savings---only "surveys" of hospital materials managers conducted by academics hired by the powerful GPO lobby. As history has shown time and again, cartels drive up prices, competition lowers them.

Accordingly, to end the drug shortage, Congress must restore integrity and free market competition to the healthcare supplies industry. And that can only be achieved by repealing the Medicare antikickback "safe harbor" exemption.

A recent GAO report notes a general dearth of enforcement actions by relevant federal agencies who have jurisdiction over GPOs, at least since 2004, but also notes that in an earlier 2010 report GAO was unable to "identify any published peer-reviewed studies that included an empirical analysis of pricing data that indicated whether or not GPO customers obtain lower prices from vendors."

Senator Bernie Sanders (I-Vt.) floated a creative proposal to make AIDS drugs cheaper in the United States. He would eliminate patents for some AIDS drugs but give a prize to the companies that discover and develop them. These drugs would then enter the generic market, where their prices would be closer to their manufacturing costs, meaning they would be much cheaper than they are today. In other words, taxpayers would largely pay the drug companies, not patients, insurers, or AIDS Drug Assistance Programs. Sanders' plan would largely shift AIDS drugs from being "private goods" to being "public goods."

It is in our interest to give drug companies a sufficient incentive to invest in new AIDS drugs. To do so under the current patent system, drug companies must be able to price their AIDS drugs well above production costs to a large segment of customers to cover the expense of research and development. Pharmaceutical companies charge American patients a high price for AIDS drugs while charging African patients a low price. Why? Price discrimination. Americans are generally rich and Africans are generally poor; most Africans couldn't afford a high price.

I'm not aware of Senator Sanders using this language, but he is essentially saying that AIDS drugs are, or should be, public goods. Public goods are things like parks and national defense that are generally provided by government (i.e., taxpayers) and made freely available to everyone, regardless of their ability to pay. These new generic AIDS drugs wouldn't be completely free, but they would be close to it.

Every few years, when the FDA's user fee agreements come up for reauthorization (and this year is no exception), the usual suspects line up in Congress to try and pass legislation that would allow for the importation of drugs from price controlled countries like Canada.

This is bad economics, bad public health policy, and bad for medical innovation.

Allowing the importation of price-controlled medicines into the U.S. market undercuts protections for intellectual property rights and dampens incentive for medical innovation. It also opens the U.S. prescription drug market to penetration by counterfeit drug manufacturers run by criminal (or potentially even terrorist) enterprises, since it is impossible to completely certify the provenance of drugs imported from even close trading partners in Europe or Canada.

But the foolishness of the approach is also underscored by an article in the New York Times on a related topic - the expiration of patent protection for the blockbuster drug Plavix.

Notes the Times:

For more than a decade, cardiologists treating patients who have had a heart attack have routinely scribbled one drug onto their prescription pads: clopidogrel bisulfate, better known as Plavix. But now, in a farewell that has been years in the making, the story of Plavix is coming to an end. The drug is set to lose its patent protection on Thursday. ...

Bristol-Myers is hardly the only company to face the loss of a best-selling drug: at least 19 are set to lose patent protection this year, which is expected to cost the pharmaceutical industry about $38.5 billion in lost sales, according to an analysis by Barclay's. About 80 percent of the prescriptions written in the United States are now filled with generic drugs.

Pause and consider that for a moment: 8 out of 10 prescriptions written in the U.S. are for cheap, highly effective generic medicines. The industry has been losing patent protection for many blockbusters in recent years, and will continue to lose billions of dollars in sales from patent expirations over the next several years.

(Cue the cheers from public and private insurers.)

But wait! Each of these drugs was once an expensive branded medicine, and the profits of those drugs paid for the next generation of marketed drugs. So without the branded medicines that preceded Plavix, there would be no cheap generic Plavix now.

There is no other health care good or service like prescription medicines in this respect: MRI machines don't suddenly plummet in price after 10 years. Newer, better machines come along, to be sure, but they are also more expensive. Doctors who graduated from medical school ten years ago aren't any cheaper than their colleagues who graduated last year.

Prescription drugs are unique in that after patents expire and prices fall to pennies on the dollar they will continue to be widely used for decades and continue to generate enormous health benefits for consumers.

But you cannot get the benefits of cheap generics without paying a premium price for branded medicines. The U.S. - which generally lacks price controls for prescription drugs - pays somewhat higher prices for new medicines, but also has much lower prices than almost every other developed nation for generics, because of fierce competition among generic manufacturers after a drug loses patent protection.

This is a win-win for American consumers, who benefit both from rapid innovation and a widening array of cheap generics.

But it also means that the U.S. underwrites the lion's share of global medical innovation, allowing our wealthy trading partners to "free ride" on our investment (just as Europe underinvests in defense spending because the U.S. provides Europe with a security guarantee).

No one has better illustrated the economics than my colleague Peter Huber, who wrote in Forbes several years ago that:

Almost all the cost of a drug is in the development and the complex hardware required to concoct the chemicals that become the medicine. These costs are fixed, and they are sunk. Like the jet's fuselage, you pay for them once, up front, regardless. Once a drug is in production, churning out one more little pill costs next to nothing. You can almost give it away to the desperately poor in sub-Saharan Africa. Provided, of course, that somewhere else [someone] pay billions.

Drug-buying collectives and cartels have an unconditionally negative impact on economic welfare. As they coalesce, they transform drug manufacturers into price-regulated utilities. Sure, you can go ahead and invest a billion to develop a new vaccine or AIDS drug. But just like your electric power company, you can sell your product only at a price acceptable to Canada's minister of health. Or maybe Kenya's. Yes, Merck or Pfizer has honestly earned the government-issue, fixed-term monopoly that we call a patent. But when it tries to cash in at the store, it meets a government-established buyers' cartel on the other side of the counter.

Patent a miracle drug, choreograph the pricing just right and you recover your sunk costs efficiently, earn a good profit and move on to your next miracle. You can survive the arrival of me-too generic competitors: They put an end to your sunk-cost recovery only after the patent expires. Collectivized buying, however, imposes generic pricing from the get-go. ...

When rich people form buying cartels to put a price squeeze on properly patented drugs, the few win in the short term and everyone loses down the line.

The U.S. already subsidizes prescription drug coverage for the elderly and poor, through Medicare and Medicaid. Wal-Mart and other large buyers offer dozens of generics drugs for $4 for a 30 day supply to everyone, including the uninsured. Pharmaceutical companies offer their own prescription drug assistance programs offering free or low cost medicines for those without insurance or who cannot afford their insurance co-pays.

All this is by way of saying that the near term policy justification for any legalized importation scheme is thin to non-existent, while the long term repercussions are dire. Expanding de facto generic pricing - whether through direct importation, government drug price "negotiations" for Medicare Part D, or through expanding Medicaid's mandatory discounts - is another powerful signal to drug companies and their investors that they're investing in the wrong business.

We may cheer when many of the drugs we use are cheap generics. We'll rue the day when they all are.

(For another great article by Peter Huber on drug pricing and innovation, see this.)

Sometimes it's good to recognize your limitations.

For example, I could describe how DNA works, or how to make crystal meth, poison your neighbor or blow stuff up. I won't, but I could. And I'd know what I was talking about.

Perhaps I could also write something about teapots from the Ming Dynasty if I read about it on Wikipedia, but in reality I wouldn't know one if it fell off the Chrysler Building onto my head.

Nicholas Kristof is a columnist for The New York Times. As such, he has written about a wide range of topics such as politics, human rights, poverty, foreign affairs, and economics. He does this extremely well, as demonstrated by his multiple awards, including two Pulitzer Prizes. He also appears to be nothing short of brilliant, and an all-around good guy as well.

But sometime prior to May 2nd, when his last column, "How Chemicals Affect Us" was published, he may have been walking a little too close to the Chrysler Building.

Kristof's formal training is in law and foreign languages. Notably absent are: chemistry, toxicology, pharmacology and reproductive biology. Which is a shame, because that is what his entire piece was about.

And it showed. Kristof rattled off a bunch of mostly unrelated claims, that, to a non-scientist would appear very scary. These involved the usual suspects, such as increasing cancer rates, low sperm counts and a host of others. But once you scratch beneath the surface, a very different story arises.

The column makes generous use of the nonsensical term "endocrine disruptor," something that is supposed to interfere with our endocrine system--the incredibly complex series of glands that produce hormones. "Disruptor" is a nice scary sounding word, but scientifically meaningless. What exactly do endocrine disrupters disrupt? And how?

In your body, hormones, whether synthetic or natural, interact with receptors on particular cells and elicit a response. Two common natural hormones are estrogen and testosterone, both critical to sexual development. Drugs frequently interact with hormone receptors and either amplify or diminish a physiological process. The breast cancer drug Tamoxifen blocks the estrogen receptors in breast tissue, suppressing the growth of cancer cells that are dependent on estrogen to replicate.

Once in a while something will go very wrong.

A particularly awful example of this was diethylstilbesterol (DES), a drug that until 1971 was sometimes given to pregnant women since it was thought to prevent miscarriages and premature deliveries. But its use was discontinued after it was discovered that it caused a rare cancer and reproductive abnormalities in the daughters of mothers that took the drug. Sons had different and less serious conditions, but by any measure, this was a drug disaster.

Thalidomide, used for morning sickness more than 50 years ago was found to be a potent teratogen-- a chemical that can cause severe developmental problems. Children of mothers that took this drug often were born with undeveloped arms or legs, or sometimes none at all.

Even today, teratogenic drugs exist, but they are treated quite differently. Accutane, used for severe acne, is a powerful teratogen. However Roche, its maker, is so careful that it doesn't get near a pregnant woman that a pregnancy test is required every month before it can be purchased and the women needs to sign a form swearing she's using at least two methods of birth control.

It is very rare, but still possible for these unforeseen side effects to occur; however, modern preclinical assays make this much less likely for drugs.

But can you take a serious teratogen like DES or thalidomide, which were given in therapeutic quantities to pregnant women, and claim any relevance to trace chemicals found in everyday life?

At this point it becomes clear that Kristof is entering the Ming Dynasty. He equates DES with a chemical called bisphenol-A (BPA), a component of many plastics that has been in use for more than 50 years. Very small amounts of BPA leach out from the plastic, which has caused it to be tested a bazillion times, with no evidence of human harm. Sometimes, if you shovel enough into a rat, bad things can happen, but you better have a big shovel. Even the FDA has said, on several occasion and despite withering activist pressure, that it is safe as used, a decision called "cowardly" by environmental groups that wanted it banned.

But what does giving mega-doses of BPA (or anything else, really) to a mouse or rat have to do with the real world where we take in (and rapidly excrete) tiny quantities of it?

Since BPA plastics are used to seal food cans, among other things, virtually all of us have some measurable amount of it in our bodies, albeit in miniscule amounts. Just like we have thousands of other chemicals, both synthetic and natural, floating around in there.

This fact has led groups and individuals to try to pull the wool over the eyes of those lacking a science background--that is, they imply or just assert that the presence of a chemical is necessarily related to any health consequences from it. This contradicts one of the tenets of toxicology--the dose makes the poison. It may sound trite, but it's just as true as ever.

If this were not the case, one would expect to be seeing massive health consequences for the estimated 80 thousand chemicals used in modern life today. So where are they?

I have no idea. In fact, the incidence of almost all cancers in the U.S. has been slowly drifting downward over the last thirty-five years according to the American Cancer Society. And the myth of declining sperm counts was thoroughly debunked in a Columbia University paper in 2008 and several other large epidemiological studies. The research alleging declining sperm counts used to reach this "conclusion" was flawed.

All of this brings up some practical matters. How is testing 80 thousand chemicals going to work? Should we ban all 80 thousand until they are first tested? What will it cost? Who is going to do it, and how will they measure whatever property they are looking for? At what dose? In what animal? And please believe that even if this monumental task were ever completed, there would be no shortage of borderline or ambiguous data with no clear answer. And it will still be animal data, which may or may not have any relevance to human health. Then what? How can anything useful ever come out of this?

Kristof "takes a cue from [his] experts," but I have to wonder about his choices. One of them, Dr. John Peterson Meyers, the chief scientist at Environmental Health Sciences is so afraid of BPA that he and his family stopped buying any canned food and refuses to touch receipts (many of which have traces of BPA) from gas stations or ATMs. Kinda makes me wonder if you could screw with his head by giving him a whole bunch of really bad birthday gifts and include the gift receipts, knowing he couldn't return any of them.

In the end, this is all silly. People are not dropping dead from ATM receipts or canned soup. Cancer is still cancer, but rather than the "cancer epidemic" we hear so much about, there is actually less of it than there used to be, despite the aging of our population. And if you should be in the mood to count your sperm, they will be fine too.

Health doesn't come from eliminating everything that might conceivably be unsafe from the environment. It comes from not smoking, getting vaccines, wearing seatbelts, staying in shape -- and a whole lot of luck.

Tea time.

An FDA advisory committee voted that Gilead's Truvada is a safe and effective way to prevent HIV infections in high-risk individuals. The FDA will weigh the advisory committee's vote and is expected to make a final decision by June 15. If approved, Truvada will be the first drug to protect healthy people from acquiring HIV infections through sexual activity in what is called pre-exposure prophylaxis (PrEP). For instance, if one sexual partner has HIV but the other doesn't, the healthy partner can take Truvada every day to avoid becoming infected with the AIDS virus.

What is interesting is how many people argued against using Truvada for PrEP. For the most part, the logic of the critics was flawed. Consider the following analogy:

Many people eat hamburgers for lunch. Health advocates say these people should really be eating steamed vegetables. A new, healthier hamburger comes along (perhaps one that is made of lower fat beef or maybe half beef and half grains). Will these health advocates embrace this healthier hamburger? Probably not; they still want people to eat steamed vegetables for lunch.

What logical mistake are they committing? As David Henderson and I point out in our book, Making Great Decisions in Business and Life, they shouldn't compare reality with fantasy because fantasy is impossible. The only choice we have is between imperfect but feasible alternatives.

I think it's arguable that the FDA doesn't need explicit authority from Congress to develop more flexible regulations for the most promising therapies early in drug development. The FDA has at least some regulatory flexibility already, under the 1997 Food and Drug Modernization Act.

But let's get to that thought in a moment.

MSNBC reports that the FDA is explicitly endorsing a provision in both the House and Senate versions of pending legislation that reauthorizes FDA user fee programs for drugs, devices, generic drugs, and biosimilars. (And kudos to Senators Bennet, Burr, and Hatch, who introduced the legislation back in late March.)

Experimental drugs that show a big effect early in development for treating serious or life-threatening diseases would get a faster and cheaper path to U.S. approval, under a proposal likely to become law this year.

U.S. drug regulators would be able to label such treatments "breakthrough" therapies, and work with companies to speed up clinical trials, for example by testing the drugs for a shorter time or enrolling fewer patients.

The U.S. Food and Drug Administration has said it supports the proposal, which is included in both versions of an FDA "must-pass" funding bill currently working its way through Congress and set to be passed by the end of the summer. ...

Dr. Janet Woodcock, head of the FDA's drugs center, has said the FDA needs more flexibility to bypass "business as usual" when it sees unexpected effects, or when a new medicine can greatly help patients.

"What happens when you have a breakthrough drug that shows an effect that's never been seen before?" she told reporters in March, discussing the proposal.

"If we'd done business as usual during the AIDS epidemic, we would have never controlled that epidemic," Woodcock said.

This is all to the good, as I noted in another blog post.

On the other hand, it also reinforces an underappreciated reality: the FDA looks over its shoulder at Congress when it reviews and approves new medicines, and develops new drug approval mechanisms.

This is only natural. The FDA is in the news only when there is drug safety problem, at which point it will get savaged by Congressional committees for not predicting and preventing every potential safety problem in advance.

Sadly, the FDA isn't going to be called up to the Hill to be congratulated on new drug approvals, or for streamlining the drug development process in general. So the pressure on the FDA tends to go only in one direction - towards requiring more data, more clinical trials, and more tests. This, in turn, drives up the costs of drug development and leads to delays in patient access to new medicines.

(To be fair, FDA aside, public and private payers in the U.S. and Europe are also demanding more data from companies to justify premium pricing in markets that are increasingly crowded with cheap, relatively safe, and effective generic drugs. The public is also increasingly wary about side effects from medicines for chronic illnesses that patients may take for years or decades. So the agency is only one factor in the development equation, albeit one of the most decisive ones.)

In short, the environment on the Hill often isn't very hospitable to regulatory innovation.

Still, the FDA is empowered to set standards for "adequate and well controlled trials", and Congress has explicitly given the agency the authority (under the 1997 FDA Modernization Act) to approve drugs based on single arm trials, but it still almost always requires two placebo controlled trials for drug approval.

In other words, the FDA has plenty of discretion. What it needs from Congress - and from the public - is permission to exercise that discretion and to do so with confidence that policymakers will not excoriate them when something goes awry. (And something will always go awry eventually, because neither medical science nor human beings are perfect.)

On that front, there's a lot to like in the current FDA user fee reauthorization. On both the House and Senate side, Congress has broadened the accelerated approval pathway and directs the FDA to embrace new technologies like biomarkers.

To be sure, FDA leadership hasn't embraced every proposal for updating its drug development toolkit - it expressly opposed the first version of Senator Hagan's TREAT bill - but its recent support for the breakthrough therapies designation is a very welcome sign that agency leadership knows that it needs Congress' permission to stop doing "business as usual" and help drive a more flexible mindset among its own reviewer staff.

AIDS was a very visible crisis. The challenges we face today are more subtle and longer term - unsustainable health care costs, an aging population that will become increasingly vulnerable to chronic diseases like Alzheimer's and cancer, and a drug development pipeline that is floundering. But they also demand a rethinking of the entire drug development and approval process - starting with the FDA and it's stakeholders.

Since FDA is a regulatory body, Congress must take the lead role in defining the policies that frame and provide effective oversight for the FDA's regulatory functions. The House and Senate should be applauded for for crafting user-fee legislation that can facilitate and acclerate access to more innovative treatments for millions of American patients.

Now, it is up to the FDA to show that it can embrace and create real change.

The Food and Drug Administration's approval last week of Elelyso (taliglucerase alfa), a new treatment for Type 1 (non-neuropathic) Gaucher disease, is remarkable for a number of reasons. Not the least of these is the fact that it provides a competitor and alternative to Cerezyme (imiglucerase), one of the primary alternative treatments for Type 1 Gaucher, and which unfortunately has recently been one of the raft of important drugs in short supply due to a contamination problem in the production facility.

Arguably more noteworthy is the fact that, because the incidence of Gaucher is quite small even for an orphan disease (only about 6,000 patients in the US suffer from Type 1 Gaucher), FDA was willing to approve the product on the basis of two Phase III clinical trials that enrolled a total of 56 patients. That's truly remarkable, given that a single, typical Phase III trial will often examine 1,000 to 3,000 patients. And many Phase III trials enroll thousands more.

One of the trials was a "parallel-dose" study, seldom permitted in Phase III, in which 31 patients were double-blinded and randomized into one of two arms. In one arm, patients received 30 units of the drug per kilogram of body weight, and in the other they received 60 units. No placebo or active alternative control. In the other study, 25 patients already taking Cerezyme were switched to Elelyso and monitored for nine months.

The director of FDA's Office of Drug Evaluation III, Julie Beitz, says that the agency's flexibility on trial enrollment and methodology "demonstrates FDA's commitment to developing treatments for rare diseases." And though I am often quite critical of the FDA's rigidness and risk aversion, I have to applaud the agency for its decision in this case.

But, what I personally find most remarkable about Elelyso is that this is the first ever FDA-approved human drug produced in genetically engineered plants -- in this case, carrots, developed by the Israeli biotechnology company Protalix Biotherapeutics -- a phenomenon that lets me indulge my interest in medical AND agricultural applications of biotechnology at the same time.

Scientists first figured out how to genetically engineer plants in 1983, and we've been growing them commercially since 1994. Yet, even though scores of medical drugs and countless industrial chemicals have been produced in non-genetically engineered plants for over 100 years, there has been a bit of a taboo against growing medically or industrially useful proteins in genetically engineered plants.

Elelyso is not the first commercial medical product to be produced in genetically engineered plants. In 2006, the US Department of Agriculture approved a poultry vaccine against Newcastle disease produced in genetically engineered tobacco plant cell cultures grown in a laboratory environment. Since the late 1990s, Ventria Biosciences has been growing a protein called avidin, which is used in a number of approved diagnostic tests, in whole, genetically engineered corn plants. And there are a number of other not yet approved plant-grown therapeutic proteins in the development pipeline. All of which is really, really cool.

Aside from being scientifically fascinating (in fan-boy geek sort of way), producing medically useful proteins in genetically engineered plants has a number of advantages over the more conventional way of producing biotech drugs in engineered bacteria, yeasts, or mammalian tissue cultures. Those other methods are very good in many ways. But bacteria and yeasts are too genetically and biologically simple to produce some of the more complex proteins, which require post-translational modifications that single-celled organisms cannot manage. And while animal tissue cultures often work best at producing these complex proteins, they are very expensive to maintain.

Plants, on the other hand, are biologically advanced enough to produce many large, complex proteins. And their maintenance is far simpler -- and therefore cheaper -- than animal cell cultures. It's also much easier to scale up production rapidly from proof of concept to commercial manufacturing with plants than with cell cultures. And the costs associated with doubling, tripling, or quadrupling output are tiny compared to doing so with animal cells.

That cost advantage is already important, but it will become increasingly obvious as we move into a future in which more personalized medicine means that treatment options are targeted to smaller and smaller patient populations. Unfortunately, while FDA may be willing to become more flexible with its own approval requirements for drugs that treat rare diseases, the regulatory requirements for genetically engineered plants imposed by the USDA are growing, not becoming more streamlined. So, this may mean that a big chunk of the plant-based "bio-pharming" cost advantage gets eroded by unnecessarily strict regulatory hurdles.

Still, as investment analyst Ritu Baral told the journal Nature, the Elelyso approval is "a huge proof of concept for the entire platform." It shows that human therapeutic proteins can be produced in genetically engineered plants and that those products can be approved for commercialization. That adds one more weapon to the medical treatment arsenal - and an potentially very useful one at that.

At RealClearMarkets, AEI scholar and physician Scott Gottlieb makes an interesting point about the effect of the Affordable Care Act on middle class families who make too much to qualify for federal subsidies on health insurance exchanges beginning in 2014:

A family of four with an aggregate income of more than $88,000 annually or an individual earning around $44,000 could find themselves badly strained by healthcare costs under the Obama plan.

Many of these folks currently get their health coverage from work. They benefit from an implicit subsidy built into that workplace coverage that lets them spend pre-tax dollars through their employer to purchase health insurance. Depending on their tax rate, that subsidy helps offset some of the premium costs.

Under the Obama plan, many of these families could instead find themselves buying their health insurance on the new state-based exchanges that get started in January 2014. For a family of four, premiums on even one of the lower priced "silver" options could still cost more than $15,000 annually on the exchanges.

How would this work? The penalties for employers dropping coverage are modest to begin ($2,000) and many employers could wind up saving significant amounts of money by ending employer-based coverage and sending employees to the exchanges.

Gottlieb points out that the coverage on the exchanges is "broad, but not deep" requiring significant co-pays and deductibles that can add up fast:

A family of four earning $90,000 annually takes home about $60,000 after local, state, and federal taxes. If they lose workplace coverage, and move onto the exchanges, they could find themselves spending as much as 25 percent of the family's take home pay for an average policy ($15,000 for the "silver" plan).

That's just on premiums. If they get sick, they could be stuck with another $11,500 more in deductibles and cost sharing, and this doesn't include co-pays on drugs. .... While full coverage for a lot of routine care is mandated under these plans - raising the cost of the insurance policies - the overall co-pays on other stuff can still be steep.

All of this turns on how many of these middle class families end up in the exchanges. It's widely accepted that the individual and small group insurance markets will quickly move onto the exchanges. In short order there will be two principal places left that Americans buy coverage: On the new exchanges, or through large employers that continue to self-insure and offer group coverage at the workplace.

There's now an emerging consensus that many large employers will choose to drop workplace coverage, and instead pay the $2,000 per-employee penalty that the Obama plan levies on them. It will simply be a lot cheaper for large employers to put their workers into the health exchanges and pay the penalty.

The exact labor market dynamics are apt to be relatively complex; some employers may decide that keeping coverage for middle and high-income earners is a competititve advantage. Others will undoubtedly "do the math" and send people to the exchanges.

But even if just a fraction of employers send people to the exchanges - say 15% or 20% - millions of middle class families could lose employer-based insurance and find that they can't find afforable insurance coverage on the exchanges. (Especially since the Obama HHS isn't proving to be very friendly to lower cost plans like Health Savings Accounts.)

Since it is also widely acknowledged that the cost controls in Obamacare are relatively weak, costs for these middle class families (and for tax-payer funded coverage on the exchanges) will rise quickly.

Obamacare will expand the "safety net" for some of the uninsured (about 50% of whom will be covered through Medicaid, which raises more problems) - but it will also pull the rug out from under the middle class.

Vertex's drug for cystic fibrosis, Kalydeco, was hailed for its groundbreaking science when it received FDA approval last year. And it is a tremendous achievement: the first medicine to actually affect the underlying mechanism that causes cystic fibrosis, a fatal genetic lung disorder that often kills patients by middle age.

Still, the drug is only effective in a small sliver of CF patients (about 4%) who have a rare genetic mutation. Now, however, Vertex is testing a new drug that may make Kalydeco effective in the "vast majority" of CF patients (about 30,000 in the U.S.), according to Luke Timmerman in Xconomy:

The Cambridge, MA-based company (NASDAQ: VRTX) is announcing today that a combination of its ivacaftor (Kalydeco) therapy and an experimental drug called VX-809 was able to provide a significant improvement in lung function for adult patients with the most common genetic mutation in CF, known as F508del. ...

The data is based on an early peek at an ongoing study, and only includes 48 patients out of 108 expected to enroll, so it's far from the final answer researchers are looking for. But it's enough of an encouraging sign that Vertex plans to advance the combo regimen into the third and final phase of clinical trials normally required for FDA approval, after it analyzes the final data this summer.

Depending on how the clinical testing progresses, and how the drug combination affects patients with one or two copies of the most common defective gene, nearly 90 percent of CF patients could benefit from the treatment.

It's a development that - literally - will help CF patients breathe a little easier.

According to a recent report in the Pharma Times:

The US government is the world's leading funder of global health research and development, investing more than US$12.7 billion over the past 10 years in new vaccines, drugs, diagnostics and other products for neglected diseases of the developing world, a new report has found.

The health and economic benefits of this support, both domestically and internationally, provide "clear reasons" for the US to maintain - and, where possible, increase - this support, says the Washington-based Global Health Technologies Coalition (GHTC), which released the report along with independent research group Policy Cures.

The article also notes that:

The US government was involved in developing more than half (24/53%) of the 45 global health products introduced between 2000 and 2010, while US federal agencies are working with other stakeholders on 200 (55%) of the 365 global health products currently in the R&D pipeline, including what is likely to be the first ever vaccine against malaria, three HIV vaccine candidates and a new generation of improved TB drugs, the report points out.

That's a more than a public health record to be proud of. Improving health in developing countries can pay dividends down the line by producing wealthier, more stable countries that represent future trading partners for American companies, future producers for American consumers, and - hopefully - produces more stable, democratic regimes.

The report also calls for the U.S. to do more to accelerate translational research, noting that government funding has been concentrated on early stage research, as opposed to clinical research, which is much more expensive, uncertain, and difficult.

Improving translational research - especially in ways that make drug development more predictable and less expensive - would pay dividends across many different therapeutic areas, including neglected diseases.

We should also note that U.S. funded research (primarily by private industry) on chronic diseases (like diabetes and heart disease) also benefits populations in developing countries - who, as they become wealthier, develop many of the same illnesses prevalent in affluent Western nations.

A vote on pharmaceutical and medical device user fees (PDUFA and MDUFA) is fast approaching. Recently, the House released a proposed version of the laws that aims to build upon previous user fee acts. If the user fee acts are approved, the FDA would receive more money - potentially to build a significantly more efficient process that enables safe and effective products to come to market more quickly than they do today. As Paul Howard noted in a recent post, this legislation is generally viewed as a good thing for all parties involved, and has even seen bipartisan agreement... something that seems like a miracle these days.

By reauthorizing the user fee programs for pharmaceuticals and medical devices (and extending a program to biosimilars), Congress wants to ensure that the FDA can continue to add resources and reduce the time it takes to approve a product. These are appropriate goals that should promote innovation and enable the FDA to focus on its core mandate of "protecting the public health by assuring safety, efficacy and security" in drugs, devices and biologics.

The problem is that the House tacked on a clause to their version of the user fee acts that - according to some insiders - would add to the FDA's mandate by also making the FDA somehow responsible for "promoting economic growth, innovation, competitiveness, and job creation among the [pharmaceutical and medical device] industries."

At least on the surface, FDA leaders would be rightfully up-in-arms over this apparent legislative add-on, if, in fact, their new mandate was explicitly to create jobs and ensure innovation. Clearly, Congress would be remiss in giving the FDA an inappropriate role and placing unnecessary burdens on the Agency that would interfere with its primary directive - getting safe products into the market at an accelerated pace. But while there is reason for some concern - the clause does create some ambiguity as to the FDA's direct responsibility in job creation - this appears to be an issue of semantics.

Direct responsibility for job creation doesn't appear to be what the House actually intended. The choice of words may be unfortunate - imagine they used "thus promoting" instead of "while promoting", and the clause takes on an entirely new meaning. The nuance of what they wrote, however, acknowledges that the FDA has an impact on jobs. And that acknowledgment is long overdue. Ultimately, the FDA must understand that it does play a significant role in job creation and innovation... and it has been doing so for years.

As gatekeeper, the FDA holds the keys to the success of the pharmaceutical and medical device industries. And given recent history, the evidence suggests that the Agency is not doing its part to ensure that these industries continue to flourish in the U.S. While PDUFA and MDUFA have provided the FDA with additional resources to speed up the review process, it's no secret that difficulties still remain in getting the review process done in a timely way. This inefficiency has motivated companies to take product launches outside the U.S., negatively impacting innovation in this country... and shifting jobs overseas.

The FDA's role in job loss in this country is increasingly being recognized, so the intent of the legislation is to acknowledge the critical role that Agency efficiency or inefficiency plays in our economy, and in the overall health care of our population. The flaws in the FDA review process have undermined innovation in industries that have been the crown jewels of our economy. It is understandable that Congress wants to make sure that we reclaim our place at the forefront of medical and technological advances... and ultimately keep jobs in the U.S.

But job creation only happens if innovation is possible. To ensure innovation, there needs to be a renewed focus on improving the FDA's approval and post-market review process... and making products safer and available at a faster pace. Job creation will follow if the FDA performs its core mandate properly, and this is the true subtext of the "job creation" clause in the House's version of the user fee acts.

So the real subject of discussion is how well the FDA is set up to perform its core mandate (thus promoting job growth), and the level at which it is held accountable to do this.

As Paul Howard described in the post mentioned above, the user fee acts have given the Agency a ton of additional resources to focus on their job as-is, but the FDA has not clearly demonstrated that this money has gone to good use. The solution isn't to throw more money at the problem. It's about redefining the process and measuring outcomes. With the PATIENTS Act, Congress is essentially stepping in as the "Board of Directors" to make sure that the FDA is providing adequate return on investment (user fees) to its shareholders (industry and taxpayers).

Dr. Howard is correct in his assertion that the FDA needs more accountability and guidance in its performance of current responsibilities before being given new ones. The FDA certainly has a lot on its plate, and adding additional language to their mandate - especially ambiguous language - will only impede innovation, and negatively impact jobs... the very thing the House hopes to promote! The FDA mandate needs to be realized, and it's certainly worth recognizing that job creation (or loss) is an outcome of the FDA's ability (or inability) to get safe products to market in a timely manner. By holding the FDA accountable for its core responsibilities (via the PATIENTS Act), Congress can ensure that user fees foster exactly what the House intended in their proposed bill... innovation, competition and economic growth.

A few years ago, the idea that the immune system could be ramped up to help the body fight off metastatic cancer didn't seem to be panning out. That changed last year, with the FDA approval of the first treatment to extend survival in patients with metastatic melanoma, Yervoy.

Yervoy appears to work by blocking a molecule that modulates immune system response. Once the molecule is blocked, the immune system kicks into overdrive, attacking the cancer.

A new initiative, at the Moffit Cancer Center, goes once step further and tries to rebuild a patients' immune system using genetically modified cells chosen for their propensity to fight cancer. From Fierce Vaccines:

Designer lymph nodes are built with specialized gene-modified cells that are injected into patients and produce a pre-planned immunologic response for cancer patients locally and then throughout their bodies. The researchers are examining a cancer vaccine "boosting" effect of the manufactured lymph nodes in patients with advanced melanoma. ...

"We used Moffitt's Total Cancer Care™ tissue biorepository, genomic database and longitudinal clinical database to identify the novel genes for creating designer lymph nodes," said James Mulé, Ph.D., executive vice president and associate center director for Translational Research at Moffitt. "The gene signature is also associated with better patient prognosis and survival, and will also be used to pre-select patients for immunotherapy interventions."

The work, funded by a five-year, $2 million National Cancer Institute grant (RO1CA148995) as well as by the Adelson Medical Research and V Foundations, is in collaboration with researchers at Scripps Florida in Jupiter, Fla. Researchers at Scripps are using high-throughput screening technologies to rapidly identify biologic functions of the candidate genes.

These are the kinds of technologies that have the potential to completely transform cancer care - and we need to ensure that we are developing,validating, and approving these products as quickly as possible.

For patients living and dying with diseases like metastatic melanoma today, progress can't come fast enough. But can it be faster? I think industry, academia, and the FDA would all admit that we can do better.

Greg Conko recently explained how some elements of the PATIENT'S FDA bill, sponsored by Senators Burr and Coburn, could be a game changer in this respect.

I've been meaning to write about a recent letter - really a full blown article - published in Nature Biotechnology that examines the quality of the evidence - or rather dearth of it - in articles published in major medical journals that detail the supposed ills of industry engagement with physicians and academic medical centers and call for more stringent conflict of interest regulation at public and private institutions.

In their letter, Lesko, Scott, and Stossel point out that while extensive interaction between academic medical centers, physicians, and pharmaceutical and medical device companies has undoubtedly accelerated innovation and provided enormous benefits to patients, this has not prevented growing concerns about and criticism of such interactions. The ostensible concern is that:

...such relationships may degrade the performance and reporting of biomedical research and also induce physicians to behave in a manner inconsistent with cost-effective or ethical patient care--which are loosely defined under the operational term 'financial conflicts of interest' (COIs).

This is a legitimate concern, at least on its face. But it should be a testable hypothesis. So where is the evidence that such interactions result in actual harm - as opposed to theoretical harm?

The authors survey four major medical journals to assess "whether the positive and negative aspects of industry academic relationships were equally represented in top-tier medical journals but also to assess the weight of evidence in the COI literature that patient outcomes or public attitudes are indeed negatively affected by corporate interactions with academics and physicians."

This is certainly a fair question for medical journals that tout their professionalism and adherence to objective science. Still, Lesko et al found that out of 108 articles selected for analysis, nearly 90% "unambiguously emphasized" the risks of industry relationships (often in their titles: "Just how tainted has medicine become?") while presenting little quantitative evidence of such risks and downplaying potential benefits while calling for increased regulation of industry.

Here's the nut graph: is clear that the preponderance of articles published in the four highest-impact medical journals that publish primary research focused on problems concerning COI relationships. These articles differed qualitatively from benefit-emphasizing academic-industry relationship papers. Most risk-emphasizing articles presented no evidence and many of the ones that did present evidence extrapolated that it had a bearing on patient outcomes or public attitudes.

The problem is that only presenting one side of an argument, often with little supporting evidence and without giving equal weight to opposing viewpoints, leads to a "conformity cascade" that shapes public policies that restrict industry interaction with the medical community to the point that innovation - and therefore patient health - may be affected.

In other words, it's like presenting a drug label that has 98 words about risk in bold print, and two words about benefits in small print. In that case, the patient is likely to avoid any treatment at all.

Ironically, the caricaturing of industry is likely to lead to the very jaundiced view of medical professionals and medicine that COI proponents say they want to prevent - since everyone has some conflict of interest (whether for tenure, publication, or in competition for grants or hawking their latest industry-bashing book), then no one can be trusted at all.

For a longer discussion of the growing thicket of COI regulations, and some practical solutions for managing conflicts that doesn't throw out the baby with the bathwater, see this Project FDA Report How Conflict-of-Interest Rules Endanger Medical Progress and Cures by Richard Epstein.

Reuters reported yesterday on what appears to be an alarming problem: "the studies doctor groups rely on when it comes to setting guidelines about the best evidence for preventing and treating a given disease" are "small and of inconsistent quality." Nearly two-thirds of those studies included 100 or fewer patients, and many failed to randomize patients into double-blinded test and control arms.

So much for evidence-based medicine, eh? Well ... not so fast.

It turns out that the study on which these conclusions were based, and published yesterday in the Journal of the American Medical Association, didn't actually investigate whether medical practice guidelines rely on the "small and inconsistent" clinical trials the authors examined. So, if the authors set out to prove what they're now claiming, they looked at the wrong data.

The JAMA study, "Characteristics of Clinical Trials Registered in, 2007-2010," looked at 96,346 clinical trials registered in the database but focused on the roughly 40,000 that tested treatment interventions in three medical specialties: cardiology, oncology, and mental health. They then examined various characteristics of those trials and drew several conclusions.

For example:
• 62 percent of the trials registered between 2007 and 2010 enrolled 100 or fewer participants.
• 66 percent were conducted at a single research site.
• 47 percent were funded by organizations other than industry or the National Institutes of Health.
• Randomization and blinding were less commonly used in earlier-phase [i.e. not phase III] trials, oncology trials, and device trials.

What the study did not examine, however, was which of these trials were actually used by medical professional societies and other expert bodies to develop practice guidelines, and what weight any particular study may have been given. But that didn't stop the authors from drawing sweeping conclusions about the quality of practice guidelines.

Lead author, Dr. Robert Califf of the Duke Translational Medicine Institute, told Reuters that "Those are the studies doctor groups rely on when it comes to setting guidelines about the best evidence for preventing and treating a given disease." To which Reuters reporter Genevra Pittman added, "But if the evidence comes from small groups of patients in trials with less-than-reliable methods, doctors are left without a lot to work with when developing recommendations and making decisions in everyday care.

"What's at stake for the public is, you would want your doctor to know what he or she is doing as opposed to just guessing or having an opinion," Califf said.

Many of us would indeed like to know whether a doctor's treatment recommendation is based on the results of a large or small, double blinded trial, on a large or small pool of observational data, or on intuitive guesswork. But what we don't know from this study is how common any of those things are in the day to day practice of medicine. All we can conclude is that the trials registered in one particular government database don't all meet the same level of methodological rigor.

Of course, we could have guessed that even without this new study. After all, it is very well known among physicians, medical researchers, and those of us who study the medical products industry that phase I trials test an experimental treatment option in a small population, generally in the range of 20 to 80 healthy people, essentially none of whom are randomized into a control arm. Phase II trials include a somewhat larger group of patients -- somewhere in the range of 100 to 300 -- and that these too often do not include a control arm. We also know that many more early phase than phase III trials are conducted, because half or more products never make it to phase III. Consequently, any large database of clinical trials that includes phase I and II studies will inevitably include a large number of trials with a small number of unrandomized patients.

Studies testing medical devices also often do not include a randomized control arm because in most cases, there's no such thing as a placebo device, and it is often difficult to enroll patients in trials with a "no intervention" control arm. It's also effectively impossible to double blind such a study, since the treating physicians would be able to tell whether or not they're using the experimental device. The FDA generally recommends using another active intervention (i.e. a different device or an alternative non-device treatment) or "sham/placebo" devices for controls where possible. But the agency's guidance for conducting device trials explicitly addresses how the placebo effect should be addressed when analyzing device trial results because medical researchers understand that controls are difficult.

We do know, of course, that lots of medical interventions commonly used in day to day practice are either unsupported or only weakly supported by large and rigorous clinical trials. Indeed, we even know that many well-designed trials (and other types of scientific experiments, for that matter) can not be reproduced. So, I certainly do not want to disregard the importance of good research into the evidence behind evidence-based medicine. Indeed, other researchers have conducted studies that investigate this question well, and have done a world of good for medical science. But this new JAMA study doesn't fit the bill.

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