For preservative-free methotrexate, a critical cancer drug for pediatric acute lymphoblastic leukemia (ALL) and bone cancer, the FDA has asked other pharmaceutical companies to step in to fill demand after a major supplier, Ben Venue, shut down a plant making the drug for "maintenance and requalification of equipment."
The FDA reports that it has prevented nearly 200 shortages in 2011 thanks to advance notice from manufacturers, but 280 drugs remain in short supply. Short term fixes are welcome. Long term fixes are harder to come by.
The U.S. market strongly encourages substitution of branded drugs by generics immediately after a drug loses patent protection. For very profitable drugs (like statins) generic companies will rush in to fill the vacuum, slashing prices and saving consumers and insurers billions in annual drug costs. For high demand, high profit generics (and branded drugs), shortages will be few and far between.
But for other medicines, like sterile injectable drugs, which have high manufacturing costs and narrow profit margins, fierce price competition may eventually drive all but one or two manufacturers from the market. And when there are only one or two suppliers, it creates the opportunity for drug shortages when unexpected manufacturing problems at a single plant can place thousands of lives in jeopardy.
One solution, offered by the FDA's Sandra Kweder in an interview yesterday, is for "a shift in the industry to assuring good manufacturing practices to prevent finding themselves in a critical juncture where they have no choice but to shut down."
This, however, puts all the blame in the wrong place. By all means, companies should comply with the current Good Manufacturing Practices required by the FDA, and find ways to share information to help prevent or alleviate the effect of drug shortages.
But perverse Medicare price controls, just-in-time inventory supply practices at hospitals, reverse auctions by Group Purchasing Organizations for filling generic drug contracts, tougher FDA manufacturing and inspection standards for domestic companies (which can raise costs), and increased global competition from low-cost suppliers in India and China has created something of a "race to the bottom" in the generic drug market.
In this environment, quality (but higher cost) manufacturers may (rationally) exit the market to focus on higher margin products. And the few low cost suppliers that remain for complex drugs like sterile injectables may not be able to ensure the integrity of their manufacturing and supply chain over time at a rock-bottom price.
In other words, if private and public purchasers insist on driving prices below a sustainable level, drug shortages may become an endemic feature of the U.S. generic drug marketplace - as they have over the last several years.
You can find good articles on the problem (and potential solutions) here, here, and here (by yours truly).
Funding constraints, hopefully addressed by the new generic drug user fee agreement, have limited the FDA's ability to conduct timely inspection of foreign plants, posing a potential safety risk for patients. It also creates an imbalanced playing field for U.S.-based companies that are inspected more frequently and adhere to higher, more expensive safety and quality standards. In this environment, quality American manufactuers can't compete on price.
Until China and other developing countries raise their manufacturing standards to match those of the U.S., a market-based solution that would supplement the FDA's efforts would be for industry to work with regulators to create a voluntary third-party certification system for manufacturing standards and supply chain integrity for contractors based in developing countries where regulatory standards don't meet those of the FDA or EMA. This approach would mimic independent non-profit organizations like the Joint Commission, which certifies hospital quality, for the global pharmaceutical manufacturing and supply chain. Something like this may already be in the works at Rx360.
Under a certification system, companies that submitted to regular third party inspections and other quality measures would receive a "seal of integrity" that they met or exceeded established regulatory standards.
Generic drug purchasers could still opt to buy from the lowest bidder, but they would do so at their own (and their patients') risk. Third party certification of supply chain integrity would help counteract the "race to the bottom" in generic drug pricing without intrusive government regulation by sending better market signals about manufacturers' commitment providing a dependable supply of the highest quality medicines - not just the cheapest.
]]>John LaMattina expressed disappoint in von Eschenbach's position via a Forbes article, laying out a few criticisms. I will address just one here. LaMattina stated that physicians, patients, and payers must be convinced, beforehand, that the risk of taking a new medicine is worth the potential benefit. I agree. He went on to say that if von Eschenbach gets his way, "[t]he doctor might just as well prescribe a placebo," implying that so little efficacy data would be available that new products would be indistinguishable from placebos. I disagree.
Von Eschenbach is not pushing placebos and is not against efficacy data in general; he simply wants to move most of the expensive and lengthy process of proving efficacy from before the product is approved until after. There will still be some proof of efficacy before launch--at least from the proof of concept and safety testing--but the decision on how much more proof of efficacy would be needed before launch would be the responsibility of the pharmaceutical companies, not a government agency.
Question: How do drug companies make internal go/no development decisions? Answer: With data on safety and efficacy. I guarantee that a new drug being developed for pain, will, at an early stage, have some data showing pain relief.
The amusingly-named CLASS Act was supposed to create a voluntary program wherein monthly premiums would be used to finance benefits of at least $50 a day for those needing long-term care. The money would go for services at home or to help with nursing home bills. Last fall, HHS Secretary Kathleen Sebelius finally admitted that it would not be possible to certify the program's financial solvency, so it would not be implemented.
And as another piece of the fiscal gimmickry associated with ObamaCare is exposed, it's possible to overlook the bigger issue. Why should the federal government need to create this program? If there is a real need for a product or service, and someone can provide it and make the case for it, then it will be successful -- because the market has mandated it.
A quote from Senator Tom Harkin (D., Iowa) to the National Journal has been making the rounds on the blogosphere as well -- "the problem with CLASS is that it's voluntary." This summarizes the threat -- that a future Congress could amend the act, forcing another unsustainable entitlement program on all of us. So long as it remains on the books, CLASS is another example of the menacing hand of government threatening our liberty.
In this case, the solution is clear. But as I pointed out earlier this week, the bureaucratic mindset behind programs like CLASS is unlikely to result in better health outcomes at lower cost.
]]>Over the years, Congress has repeatedly expanded the FDA's responsibilities, and today the agency monitors products that account for 25 cents of every dollar in U.S. consumer spending--including tobacco, the food supply, cosmetics and drugs ranging from aspirin to the latest biotech medicines for patients and pets. It has not ensured that the agency is keeping pace with the enormous scientific advances made since the human genome was decoded in 2000. Congress and the Obama administration need to make that a priority.
The stakes couldn't be higher for our health. The U.S. biomedical industry is one of the crown jewels of the American economy. It employs 1.2 million people directly and over five million throughout its supply chain, with a total output of $519 billion in 2009, according to a 2011 Milken Institute report, "The Global Biomedical Industry: Preserving U.S. Leadership." Many of the firms are among the world's most innovative: From 2001-2010, the report shows, U.S.-based companies produced nearly 60% of the world's new medicines, up from 42% the previous decade.
But U.S. firms won't continue to lead unless the FDA retains its role as the world's "gold standard" for evaluating new medical products. Thankfully, the opportunity to remake--not merely tweak--the agency is here today, if policy makers can seize it. Congress is currently considering legislation to reauthorize the agency to collect the fees companies pay for the review of every new drug and medical device application submitted to the FDA. This presents a rare opportunity to examine the FDA's overall needs and performance.
Dr. von Eschenbach's vision for the FDA is of an agency that is as scientifically sophisticated as the companies and products it regulates, while also creating innovative regulatory pathways for the most innovative products:
Breakthrough technologies deserve a breakthrough in the way the FDA evaluates them. Take regenerative medicine. If a company can grow cells that repair the retina in a lab, patients who've been blinded by macular degeneration shouldn't have to wait years while the FDA asks the company to complete laborious clinical trials proving efficacy. Instead, after proof of concept and safety testing, the product could be approved for marketing with every eligible patient entered in a registry so the company and the FDA can establish efficacy through post-market studies.
By empowering the FDA to create new paradigms for evaluating the most promising innovations, Congress can ensure that the FDA serves as a bridge--not a barrier--to cutting-edge technologies.
We'll be working hard in the coming months to turn his vision for FDA reform into reality.
As the introduction notes, "potential conflicts of interest are a growing concern at many schools." That's a problem. What matters are not "potential" conflicts of interest but actual conflicts that result in a researcher or clinician putting his or her own self interest over the interests of the patients whose well-being they manage.
Unfortunately, the fear of being branded with a scarlet letter "I" -- for industry ties -- has led far too many universities, scientists, and clinicians to pass up opportunities to collaborate with the drug and medical device industries in ways that might have redounded to the benefit of patients. Fortunately, while it is clear from the interview that Dr. Desmond-Hellmann takes genuine conflicts of interest seriously, she has rejected the narrow-minded attitude that paints all industry ties as inherently corrupting:
"WSJ: What do you tell professors who won't work with drug or biotech companies?
"Ms. Desmond-Hellmann: I think that's a huge mistake. If you're a professor now, and you want to get your discovery to society, you either need to start a company or work with a company to commercialize a product. When professors have told me they won't work with companies anymore because they feel they'll have this scarlet letter, I think: 'Wouldn't that be sad if all the best scientists and clinicians won't work with companies because the public has said they're evil?'"
Unfortunately, the published interview is rather short, so Dr. Desmond-Hellmann is never asked to discuss her views on what exactly makes for a conflict of interest. We know, for example, that not all conflicts of interest involve money. The literature is full of examples in which such motivations as raw ambition, the desire to achieve research successes or to be the first to discover some phenomenon, or simply a basic fear of failure created conflicts that contributed to fraudulent research and/or harm to an otherwise innocent third party.
As medical ethicist Sigrid Fry-Revere puts it, a conflict of interest is any "clash of competing interests in which a socially sanctioned goal could potentially be compromised by a more personal goal. Conflicts of interest exist in every form of human interaction. Therefore, the question should be not whether conflicts exist, but whether relevant individuals will succumb to the temptation to satisfy more immediate personal desires at the expense of long-term personal benefit and long-term social goals."
In short, conflicts can never be eliminated, though they can and should be managed. And Susan Desmond-Hellmann should be congratulated for approaching the issue of conflicts with an open mind, for expressing an understanding that industry-academy relationships need to be monitored, and for realizing that the benefits of partnering with industry generally far outweigh the risks that might arise from conflicts of interest.
]]>The result, however, is a little underwhelming, as the draft guidance docs still leave many details of the process undefined. As this article on the Nature blog explains:
"Ultimately, the FDA provided few concrete details about what would be required, preferring to judge on a case-by-case basis. That offers flexibility, but companies may be deterred by the lack of specificity, cautions D'vorah Graeser, a patent agent at Graeser Associates International, a law firm based in Chicago and Israel. 'I don't think [the FDA] gave much guidance,' she says, noting that the first few companies to jump in are still taking on a big risk. 'They may be rejected and have to go back to the drawing board several times,' she says."
Or, as Jim Czaban at the law firm Wiley Rein explains, "the Guidances are very small baby steps that leave many important questions unanswered."
Essentially, the guidance on Scientific Considerations in Demonstrating Biosimilarity to a Reference Product tells us that "FDA intends to consider the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity, and recommends that sponsors use a stepwise approach in their development of biosimilar products." This stepwise approach "can include a comparison of the proposed product and the reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness." And, at each step, manufacturers should examine "the extent to which there is residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty."
Un-huh! We had to wait nearly two years for this?
On the one hand, the supreme amount of flexibility the FDA approach allows is a plus. We know, for example, that even the simplest biologics are orders of magnitude more complicated than small molecule drugs, and that there will be a huge amount of variation in manufacturers' ability to replicate approved biological products with anything approaching perfect fidelity. So, tying the process down to a simple, detailed flowchart in which all the possible variations are accounted for would be difficult, if not impossible.
Still, the European Medicines Agency (which, admittedly had a few years' head start on the FDA) has issued a larger and more comprehensive set of rather more detailed guidance that makes it easier for manufacturers to know what they need to do to secure approval. FDA may well be able to follow in EMEA's footsteps and eventually issue its own more detailed proposals. But why did it take so long to get a set of documents from FDA that tell us essentially nothing we did not already know?
After all, FDA has been slowly but surely approving a very small number of biosimilar products since 1998. [No, that's not a typo. The correct date is 1998.] Through a quirk of FDA history that I described in this paper, a small number of follow-on biological products (primarily hormones) have been eligible for approval through an abbreviated regulatory pathway created in 1984 along with the "true generic" pathway. Examples of products approved this way include GlucaGen in 1998, Follistim in 2002, Hylenex and Fortical in 2005, and Omnitrope in 2006.
The abbreviated 505(b)(2) process (named for the section of the Food, Drug, and Cosmetic Act in which it is described) involves a great deal of analytical data from laboratory and animal testing, supported by somewhat less clinical testing than is required for innovator products. Section 505(b)(2) wasn't designed with follow-on biological products in mind, but its approach is essentially the process envisioned under the Biologics Price Competition and Innovation Act. The problem with these new guidance documents is that they convey practically no useful information about the process that could not have been learned merely from observing how the approval of those other biosimilar products had been managed.
Don't get me wrong, it IS nice to see these documents finally in print. But if the agency is serious about creating a reasonable, transparent, and predictable pathway for approving biosimilar products, it's going to have to do better than this.
]]>One defining characteristic of the bureaucratic mindset is an extraordinary level of obsessive compulsiveness. In this world view, the solution to a complex problem is to anticipate every possible contingency and write down what the response should be in each and every case. Of course, this approach is hopeless and self-defeating, and even worse, sets the stage for the regulated to eschew responsibility for compliance, and for abuse by agents of the bureaucracy itself.
It's a hopeless approach because you can't possibly anticipate all the contingencies, and it's self-defeating because to the extent that you even try, you create an impenetrable wall of regulation that defies mastery by any individual. That's why, for example, we have a whole industry that's evolved to help citizens with their taxes. The tax code - all 70,000-plus pages of it, is another exemplar of what the bureaucratic mindset produces.
Although it's virtually impossible to anticipate every possible contingency and prescribe the appropriate response, the attempt to do so, and the presumption that it's been done virtually eliminates the opportunity for individual judgment, and in doing so, eliminates any sense of personal responsibility. The truth is, very complex problems defy simplistic prescriptions. That's not to say that complex issues can't be regulated.
The FDA creates guidelines for an extraordinary range of complex issues involved in regulating and enforcing the Pure Food and Drug Act and its extensions. The agency has no shortage of detractors, but review of its regulatory output suggests that it attempts to avoid the bureaucratic mindset by offering guidelines, not prescriptions for managing the issues for which it is responsible.
For an example of the alternative, consider HIPAA - the Health Insurance Portability and Accountability Act of 1996. Intended to protect patients' rights to privacy of their health information, HIPAA's byzantine prescriptions and penalties have inspired an industry of healthcare providers largely clueless about the letter and the spirit of the law, who take no accountability for its accurate implementation, or responsibility for the inconvenience they create.
Finally, products of the bureaucratic mindset set the stage for abuse by the bureaucracy itself. To the extent that there is oversight, legislation like PPACA invites arbitrary and politicized action, because the requirements are so complicated and contradictory that ultimately they can be used to justify any decision. The tax code has been the "take-down" tool of last resort by law enforcement for many years. PPACA is only 2700 pages, but that's more than enough to serve the same purpose - and all the rules aren't out yet!
Implicit in the bureaucratic mindset are the following underlying assumptions:
1. people's judgments cannot be trusted.
2. bureaucrats who write regulations are sufficiently omnipotent to anticipate all contingencies and prescribe optimal responses to all of them.
3. people who genuinely want to do a good job will be satisfied following rules that others have laid out.
In short, the bureaucratic mindset is the outgrowth of a kind of terminal hubris that imagines those who create and enforce the rules as the only stakeholders worthy of any respect. We've had enough of that already. I, for one, would like to see more judgment and fewer rules. We'd all be better off for it. We might even get better health outcomes at lower cost ...
We are headed for big trouble in two areas of our health care. I don't know which is worse.
First, in the absence of a sudden congressional agreement on a pending bill, the Medicare reimbursement for doctors will automatically drop by 27% by at the end of this month. It will be a very bad time to be 65.
A 2011 survey conducted by the Medical Group Management Association polled over 93,000 doctors about how they handle Medicare patients-- now and if the cut goes through. Right now, over 95% of the respondents accept Medicare patients. But if Congress does nothing (something they excel at), the numbers change in a big way.
In that event, 31 percent of the respondents said that they would stop accepting new Medicare patients, and another 45 percent said they were uncertain. Let's say that the undecideds split evenly when it is time to decide. This will mean that more than half of the doctors in the US will stop seeing people, simply because they happened to turn 65.
Thirty-five percent of the respondents said that would reduce the number of appointments for existing patients, while 51 percent said they would do so for new patients. Nine percent said they would stop treating existing patients entirely.
This ain't good. And it's already happening. A number of recent stories have looked at what seniors face even before the end of the month. One story in particular was particularly awful. A senior woman in Connecticut spent the better part of a day just trying to find a doctor that would see her. The first four offices she called said they were no longer accepting Medicare patients, and the rate cut hasn't even taken place. Pretty horrifying.
Another big mess is the continuing, or maybe growing number of essential, generic drugs that are unavailable because of shortages. Last August I wrote an op-ed in The New York Post about people suffering and dying because their doctors or hospitals were unable to get staples such as epinephrine, morphine, antibiotics, cancer drugs and general anesthetics. There are about 250 drugs in short supply, and that number has been growing every year.
The only "remedy" announced since then was an executive order from President Obama. He directed the FDA to: 1) collect information about impending shortages and work with manufacturers to at least be aware of the shortages; 2) speed up inspections of manufacturing facilities (pretty much impossible, since they are drastically short staffed) and 3) work with the Justice Department to identify instances of collusion and price gouging. The FDA has no power to force any company to make anything, and all the inspections and criminal prosecution in the world won't change this.
So, rather than do anything useful, the administration seemed to be more interested in punishing price gougers, who were raising prices on drugs in short supply by absurd amounts, since desperate hospitals had no choice but to buy them. Hardly an ethical business practice, but perhaps we should worry about the shortages first and market abuses later. And one could argue that the required advance notification of impending shortages will make the problem worse by tipping off unscrupulous buyers to hoard drugs that will soon become unavailable.
The answer to this problem is not at all obvious. Many very smart people have been discussing this and there is no simple solution. Although a good place to start might be to lift the price controls on generics that started the problem. The shortages consist mostly of simple generics where there is little or no profit to be made given price constraints. Seems pretty simple, no? But that would involve doing something to help drug companies-- a political no-no if ever there were one.
Pay attention to this. It will only get worse. The hatred for the pharmaceutical industry is so strong that it is now impossible to get even necessary things done, should there be any hint that a profit will be made. Perhaps some of our political leaders will learn the hard way about how the perpetual demonization of an industry will come back to haunt them. Maybe when people with heart attacks start showing up in the ER only to find that they are short on epinephrine, saline and morphine will they belatedly realize that government policies, made in the name of affordable medicine or simply for political expedience, weren't such a great idea after all.
]]>Ignore for a moment the religious implications of this mandate and instead focus on the logic used by President Obama and three U.S. senators--Shaheen, Boxer, and Murray--in its defense. They argue that insurers "should" provide birth control for free because contraception actually reduces overall costs for insurers by preventing expensive pregnancies. They quote a statistic that it costs about 15% more for employers to exclude birth-control coverage.
These politicians are saying that profit-seeking organizations have missed an area to reduce costs and therefore increase profits. And so the government should force these insurers to take such cost-saving steps. This logic assumes:
(1) These politicians know more about the insurance business than the insurance companies themselves.
(2) The insurance companies are either stupid or biased against birth control to the extent that they are willing to forgo additional profits.
(3) Force, through government mandates, is a good method to enlighten the insurance companies and to achieve the optimal outcome.
I can't imagine how point #1 would be true. Regarding point #2, I make my business consulting with companies and, yes, there are some companies and individuals that make conceptual mistakes. However, marketplace pressures eventually steer companies toward good decisions. If not, these companies eventually lose to better managed companies. Point #3 could justify a whole shelf of books just by itself. Suffice it to say that government mandates bring with them a slew of unpleasant baggage that needs to be factored into the equation.
The problem with this, as we all know, is the placebo effect. The patient's perceived net benefit is equal to the real benefit plus the placebo effect. There could be a real effect like reduced blood pressure or increased CD4 cell counts--or there could be none at all. The placebo effect could convince the patient that there's a real benefit even when there is none.
The FDA's approach to get around this problem is to separate the real effect from the placebo effect via clinical trials with large numbers of patients to determine whether the medicine is really working or not. Sometimes this divide-and-conquer solution isn't possible, or even necessary, when the entire patient experience is holistic and subjective.
Consider pain. In clinical trials, the visual analog scale is used frequently to assess a patient's perceived pain level. This is merely an objective measurement of nothing other than a subjective assessment. A patient's assessment of pain is highly individualized and situationally dependent.
]]> "Already, neuroscientists know that how people perceive pain is highly individual, involving heredity, stress, anxiety, fear, depression, previous experience and general health. Motivation also plays a huge role--and helps explain why a gravely wounded soldier can ignore his own pain to save his buddies while someone who is depressed may feel incapacitated by a minor sprain." (Rewiring the Brain to Ease Pain, Wall Street Journal, 15-Nov-11).The FDA's approach is as follows: (1) See if a drug is "really" efficacious. (2) If so, approve it. (3) Once approved, let patients and physicians experiment with what works the best for them.
For medicines with an entirely subjective response, say, for pain, we could just as easily skip steps 1 and 2 and go right to 3. We could use the huge and efficient laboratory known as the American medical system to let patients and physicians experiment to find what works for them. Doing so would be easier, cheaper, and intellectually honest.
]]>The study, A prospective cohort study challenging the effectiveness of population-based medical intervention for smoking cessation, conducted by the Harvard School of Public Health and the University of Massachusetts, examined a sample of 787 adult smokers who had recently quit smoking. The study's objective was to "examine the effectiveness of NRT... to better inform healthcare coverage decisions."
Participants were surveyed over three time periods: 2001-2002, 2003-2004, and 2005-2006. In the initial interview, they were asked whether they had used a nicotine replacement therapy in the form of the nicotine patch, nicotine gum, nicotine inhaler, or nasal spray to help them quit. They also were asked if they had joined a quit-smoking program or received help from a doctor, counselor, or other professional. During the subsequent interviews, they were asked if they had started smoking again.
One of the most significant conclusions, and the source of much of the controversy surrounding the report was the relapse rates between the first, second and third interviews reported by the participants were no different between individuals who used NRT and those who did not. The lead author of the study, Hillel Alpert, was quoted in the Harvard Gazette as saying "This study shows that using NRT is no more effective in helping people stop smoking cigarettes in the long term than trying to quit on one's own."
Since the study only examined relapse rates, this claim is not supported by the evidence put forth in the study. Effectiveness is measured in more than one dimension -- relapse rates are only one piece. As numerous, larger studies around the globe have indicated (according to a review from the Cochrane Collaboration of 123 different controlled studies), NRT is effective among smokers who are motivated to quit, regardless of setting. The quit rate among smokers who use NRT is 1.5 to 2 times higher than smokers who quit cold turkey.
So, if we were to compare two equal sized populations of smokers trying to quit smoking -- one that used NRT and one that did not -- the population of people who successfully quit using NRT will be larger than the population of people who successfully quit without it. Even if both populations relapse at equal rates in the years to come, nearly twice as many people will have successfully quit smoking for good using NRT.
Furthermore, even if the ex-smokers relapse, there are health benefits to quitting for even a short time period. According to the US Surgeon General's Report, 3 months after quitting, circulation and lung function improve, after 9 months, coughing and shortness of breath decrease, and after 1 year, the risk of coronary artery disease is cut in half (not to mention the social benefits of not constantly being engulfed in a cloud of smoke!).
So, reimbursing NRT may still be cost effective, even if some smokers relapse. Another study in the UK actually examined the cost effectiveness of NRT and found that NRT was a low-cost treatment when measured per life-year saved. And this study examined the cost of nicotine patches 15 years ago; since then, the patent on nicotine patches has expired, so they are available at an even lower cost today.
Alpert, according to the Harvard Gazette's coverage, argues that even though clinical trials have found NRT to be effective, the new findings demonstrate the importance of empirical studies regarding effectiveness when used in the general population. But since the study only includes participants who have already quit smoking, it doesn't provide sufficient evidence to conclude the value of NRT is questionable. There are confounding variables that the study does not take into account -- for example, the number of people who would have failed to quit in the first place had they not used NRT.
To really understand the effectiveness of NRT in a real-world setting, researchers would have to start with a population of smokers who are trying to quit, not a population of smokers who have already quit, and follow them over several years. And since so few people who want to quit smoking are successful, the population studied would have to be very large. Only then can the study measure NRT effectiveness in a real-world setting.
So what does all of this mean for insurers? Not much. The Harvard study examined such a narrow indicator that the value of NRT can't really be argued one way or another based on the evidence provided. Because the study only looked at relapse rates, it does not sufficiently undermine the numerous other studies that have indicated that NRT does improve quit rates and can improve health outcomes.
For consumers, the water is even murkier. The study underscores the point that NRT is not a long-term treatment; it's meant to be taken for 6-12 weeks to help with initial symptoms of withdrawal. It doesn't make the urge to smoke go away forever. Still, based on other studies -- like those included in the Cochrane Collaboration's review -- it can be a valuable tool for people who are trying to quit.
Alpert's point about the importance of real-world evidence in evaluating different treatment options is a good one, though, and as long-term, observational studies become more prevalent, there are clear implications for the FDA. Medical device and pharmaceutical manufacturers will increasingly look to real-world, post-market evidence to find new information about existing products, including information to support new indications for existing products. These studies will be increasingly complex, as they examine many dimensions of similar products and protocols. The FDA will need to learn to process this information quickly, and should re-examine its approach to ensuring product safety.
Currently, the FDA usually makes demands for clinical evidence based on large-scale clinical trials to gain product approval. But if it were to adapt a more flexible approach, looking at more diverse kinds of studies, it could revolutionize the medical products industry as we know it.
Manufacturers could design clinical studies that rely on data reflecting a real-world evidence approach and modeling, rather than merely relying on the current "gold standard" -- traditional, large-scale, randomized, placebo-controlled clinical trials (RCTs) with their associated inclusion/exclusion issues. Instead of waiting years for an actual clinical outcome from RCTs, manufacturers could use a "surrogate endpoint" (like quit rates, in the case of NRT) to establish an event that can reasonably predict improved clinical outcomes. Additional confirmatory studies would provide longitudinal evidence that the treatment either does or does not provide clinical benefits for specific sets of patients, allowing the FDA to react accordingly.
New products would reach the market faster and enable many patients the opportunity to try a new treatment sooner rather than later. This approach, in turn, could reduce development costs, and medical products companies could focus their attention on innovating new life-saving therapies.
To reach this goal, the FDA will need to shift its focus from an almost exclusive emphasis on pre-market gatekeeping to post-approval oversight. There are clearly inefficiencies in the agency's ability to bring new products to market, and it does need to do a superior job in its post-approval oversight role. What's really needed is an overhaul of both the agency's regulatory process and its focus.
Members of the biotechnology industry have questioned the constitutionality of the FDA review process. Genentech, one of the leading biotech manufacturers, suggested that agency reviewers cannot perform the rigorous scientific comparative assessment necessary to reach legitimate conclusions about the "similarity" or "sameness" of two products without first examining secret trade data concerning the manufacturing processes of the innovator, which is prohibited by law.vii Moreover, such unauthorized reliance would violate not only section 505(b)(2) of the Food, Drug and Cosmetic Act (FDCA), but also the Trade Secrets Act and the United States Constitution.
Beyond legal issues, the scientific community has raised concerns over biosimilars and patient safety. This is, without question, the primary topic discussed throughout FDA meetings.viii For decades, the FDA had taken the position that each biologic is unique and inexorably linked to the manufacturing processes used in its creation. Complex operational details of the manufacturing processes are central to and define the identity and unique molecular safety and effectiveness attributes of each biologic. A follow-on biologic manufacturer that uses different starting materials and a different process will produce a product that is different from the innovative product. The effects of the differences between a "follow-on" and its respective innovator product can only be determined by subjecting the follow-on biologic to substantial clinical testing in patients to prove that it is safe and effective.
This concern is legitimate. Even innovative companies have run into serious manufacturing problems when they've made small changes to products they otherwise know and understand intimately. As I wrote in 2007:
In 1998, Johnson & Johnson added a new stabilizer to the European manufacturing process for its drug Eprex, an erythropoietin molecule grown in cloned Chinese hamster ovary cells and used by cancer and kidney-failure patients to help stimulate production of red blood cells.
Later, J&J noticed that some Eprex patients developed a dangerous blood disorder: antibody-mediated pure red cell aplasia, where bone marrow stops producing new red blood cells. It took J&J four years of painstaking research to learn the PRCA cases were caused by an interaction between its new stabilizer and uncoated rubber stoppers used in some syringes.
The moral is that even Eprex's original manufacturer...was caught off guard by an adverse event after a seemingly harmless manufacturing switch.
As a result, while some simple biosimilars will require relatively little clinical testing for safety and efficacy, more complex ones will have to go through a process that is much closer to that of a new biologic.
Still, assuming technology has progressed to the point that clinical testing can be pared back at least somewhat, analysts expect biosimilar prices to be 20-30% less compared to the original biologic. And when you're talking about drugs that can cost $100,000 or more a year, that's nothing to sneeze at.
One final note; While biologics have 12 years of marketing exclusivity under the Patient Protection and Affordable Care Act, the Obama Administration has signaled that it wants to cut that exclusivity down to 7 years as part of its deficit reduction plan. While this might be a boon for payers, who could access cheaper biosimilar drugs five years earlier, it would sharply dampen incentives for innovation - leaving patients worse off in the long run.
]]>Mobile medical applications are becoming increasingly popular as many Americans want to engage actively and control their own health care. Estimates indicate that the number of smartphone consumers using medical apps will grow to 500 million by 2015. This demand for mobile medical applications underscores a market-driven explosion in the use of health-information technology in ways that engage consumers, health care providers and technology vendors to enhance health care outcomes and lower health costs.
All of this innovation and growth in mobile medical applications could come to a screeching halt if the Food and Drug Administration (FDA) moves forward with its proposed regulation of mobile medical applications. The FDA continues to explore options to regulate mobile medical applications as medical devices under the Food, Drug and Cosmetic Act, particularly around adverse-event and patient-safety reporting. At this formative stage of emerging mobile medical applications, complicated and expensive new regulatory structures through the FDA would dampen prospects for future lifesaving innovations. ...
The average time to approve a medical device is about three years and can cost upward of $75 million. In the software market, that is a lifetime. Additionally, if mobile apps are regulated as medical devices, they will be subject to the health care reform law's 2.3 percent medical-device tax, raising prices as taxes are passed on to consumers. Free apps may no longer be free.
The FDA, in its defense, believes that regulation would only be required for a small subset of apps that would directly impact the operation of currently regulated medical devices, as it notes here.
]]>It turns out that a French medical device company sold "tens of thousands" of breast implants filled with industrial grade silicon, in an effort to cut costs and boost profits. Replacing all of the implants, Gelinas reports, could cost hundreds of millions of dollars.
Hence the question: Who pays? Suing the manufacturer is one possibility, although it seems to have shut down. Eventually, Gelinas believes the bill will be paid, in whole or in part, by taxpayers:
Britain's National Health Service has said that it will pay to remove implants that women got after breast-cancer surgery. That sounds reasonable enough. But the French government has already said that it will pay to remove all victims' implants, putting pressure on Britain to do the same. ...
The NHS may pay for another reason: its medical experts could determine that doing so would avoid higher government costs later, as women suffer the ill effects of silicone seepage and come in for government-paid care. The NHS knows that it's likely to do a better job treating these women than would a clinic whose managers view them as people they will never see again. Indeed, national health officials have said that the government might pay for implant removal if women show a "clinical need," a standard they didn't define.
Clinical need is becoming an increasingly fuzzy concept in every health care system. If you're sixty years old, and want to keep jogging, should taxpayers pay for your new bionic knee? If it turns out that green tea prevents cancer, will insurance have to cover Lipton (or maybe Tazo)? How about gym memberships and yoga (regular excercise decreases stress, which is a risk factor for a number of bad health outcomes)?
The line between what's needed and what's wanted is fundamentally blurred by the third party schemes that we use to finance health care, either through taxes (as in much of Europe) or through combination of taxes and private funding (in the U.S.).
When other people pay for your health care, it creates a powerful incentive for small groups of highly motivated providers and special interest groups to demand that insurance cover everything from birth control pills to chiroprators' services. Insurance mandates lower cost for the people who use those products or services, but raises costs for everyone else (and as health insurance costs rise, more people become uninsured!).
Gelinas - and I agree with her - suggests that "government require all but the destitute to pay for their day-to-day healthcare", and that insurance (public or private) should return to its classic role paying for catastrophic costs.
This scheme wouldn't end all of our health care arguments. There'd still be plenty of debate about what constitutes catastrophic care. But that situation would be much preferable to our current system where the federal government is mandating Catholic Hospitals to pay for birth control pills - which sell for $4 for a $30 supply at Wal-Mart, to say nothing of the hundreds of additional mandates imposed on health insurance at the state level.
When insurance covers routine care it distorts how we use the the health care system (through overuse), drives up health care costs (subsidies raise prices), and shifts spending away from other public and private priorities (like education and defence).
The best defense of a catastrophic based insurance system is that it actually reflects demographic reality. Insuring the vast majority of healthy Americans against catastrophic costs would be far less expensive than the first dollar coverage for all medical expenses insurance offers today - as Chris Conover at AEI illustrates here.
The savings could then be funneled into subsidied coverage for the relatively small number of Americans with persistently high medical costs - through risk-adjusted vouchers, or high risk pools.
This would be a direct, simple, and sensible alternative to the Byzantine structure of the Affordable Care Act, which basically extends high cost insurance to the uninsured through massive government subsidies. If the Supreme Court strikes down the ACA, or if a fiscal crisis forces Congress to revisit the issue, universal catastrophic coverage should be the first market-based alternative on the table.
]]>Now I know that in some circles regulation is viewed as a roadblock to innovation and economic growth. But in actuality, when done right, regulation isn't a roadblock; it's the actual pathway to achieving real and lasting innovation. Smart, science-based regulation instills consumer confidence in products and treatments. It levels the playing field for businesses. It decreases the threat of litigation. It prevents recalls that threaten industry reputation and consumer trust, not to mention levying huge preventable costs on individual companies and entire industries. And it spurs industry to excellence.
The tragedy of thalidomide led to changes that strengthened both the regulatory and scientific environment for medical product development and review.
In response to the public uproar, in 1962 Congress enacted the Kefauver-Harris amendments to the Federal Food, Drug and Cosmetic Act. Thanks to these new amendments, manufacturers had to prove that a drug was not only safe, but also effective. Approvals had to be based on sound science. Companies had to monitor safety reports that emerged postmarket and adhere to good manufacturing practices that would lead to consistently safe products.
I agree with Commissioner Hamburg that government regulations should set the basic "rules of the game" in markets. When they do that, they actually do lead to the kind of competition, quality improvements, and innovation that Commissioner Hamburg lauds. But regulations can also become a tool for restricting competition (a barrier to entry) and American history is replete with regulatory policies that hamstrung innovation for decades (like the AT&T monopoly in telecommunications). So the question is not whether regulation is good or bad per se, but what type of regulations are applied to a given technology, and how regulatory agencies like the FDA apply the powers at its disposal (predictably or unpredictably, etc).
In this respect, I think the FDA's overall performance - at least since 1962 - is much more nuanced than Commissioner Hamburg suggests. Safe - and effective - drugs certainly predate the Kefauver Amendments. Many drugs that we take for granted today, including corticosteroids, antihistamines, vaccines and antibiotics (like penicillin and streptomycin) were developed decades before the FDA's current regulatory structure evolved. The efficacy requirements also - whatever you think of them - undoubtedly raised the costs of innovation, as economists Daniel Klein and Alex Tabarrok point out:
The task of proving efficacy is much more difficult, expensive, and time-consuming than the task of proving safety. To a great extent, efficacy, which is sensitive to individual conditions and mediated by market process, had in the past always been judged jointly by doctors and consumers. A drug's efficacy ought to be judged relative to the alternative therapies and is therefore constantly changing, being discovered, and being proven by medical-market experience, with the use of postmarket surveillance and research. Safety, naturally, always calls for strong prior assurance. But the search for improved efficacy had proceeded, to some extent, by people serving as each other's guinea pigs, and the result had been rapid progress. In 1962, however, the FDA began to act on the premise that it could establish authoritative knowledge of efficacy prior to experience and experimentation in actual market processes.
The time spent waiting for FDA approval and the expense and duration of the bureaucratically determined testing procedures combined to cause tremendous delays in drug development and production. Drug development declined significantly after 1962, and the wait for new life-saving drugs increased to more than a decade by the end of the 1970s.
(For a left of center critique of the FDA, see Michael Mandel's review of the FDA's Melafind decision.)
Aside from the efficacy requirement, the FDA arguably learned the wrong lessons from the thalidomide tragedy: namely, that its primary job was to keep bad things from happening, rather than accelerate market access for truly innovative medicines.
By the 1990s, more medicines were approved first in Europe than in the U.S. - in some cases several years longer. After the AIDS crisis hit the U.S. in the 1980s, AIDs activists demanded that the FDA accelerate access to experimental therapies, and the FDA responded - under intense pressure - in creating several new regulatory pathways including compassionate access, treatment IND, and (eventually) accelerated approval. But, again, the agency was responding to a crisis, rather than being proactive in its approach to innovation.
After Congress passed the Prescription Drug User Fee Act in 1992, FDA reviews of new drug applications sharply accelerated, and the U.S. based pharmaceutical industry came to dominate the global scene, albeit for complex reasons that have as much to do with the U.S. ecosystem for life sciences research and the importance of the U.S. prescription drug market, than the FDA per se. In the wake of the Vioxx tragedy in 2004, the FDA seems to have again ratcheted up its safety requirements, demanding more data, more tests, and longer clinical trials from companies to rule out the risk of rare side effects.
The FDA faces steep challenges: drug safety problems are highly visible, while lost innovations are, by definition, invisible. Congress alternates between excoriating the agency and saddling it with new responsibilities - often without the funds to actually implement them. The agency struggles to keep up with the latest scientific developments, and adapt its regulations to changing scientific realities. When it does adapt, it's accused of collusion with the industry it is supposed to regulate.
Recent FDA Commissioners, including Commissioner Hamburg (and before her Dr. Andrew von Eschenbach and Dr. Mark McClellan) have struggled to modernize the agency, and recognize that it is trying to regulate the "21st century products with 20th century regulatory tools" but they face a steep uphill climb because of the culture of the agency, its strained relationship with Congress, limited budget, and restictions on its ability to tap outside expertise. Douglas Holtz-Eakin and I discuss several recommendations for FDA reform here.
But the most important innovation would be for the FDA to find more ways measure safety and efficacy without the use of large, expensive, and time consuming clinical trials - and without coming to all or nothing decisions on drug approvals. Thalidomide, as Commissioner Hamburg notes, returned to market decades later as a drug for leprosy (really a cover for off-label AIDS use) and later for cancer.
The right lesson to draw from the thalidomide scandal is that no drug is safe for all patients, in all circumstances - and that patients and physicians need to be empowered with the information to use new treatments most effectively. That lesson is only beginning to be absorbed now, fifty years after the thalidomide tragedy.
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