Greg Conko Archives

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.

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 ClinicalTrials.gov, 2007-2010," looked at 96,346 clinical trials registered in the ClinicalTrials.gov 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.

Last week, the FDA held a public hearing on "Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice." That's important because FDA's clinical trial regulations have not been substantially updated in over two decades. And though additional hurdles have been added to the clinical trial process over the past few years -- in order to more fully explore things like cardiovascular risk and hepatotoxicity issues, for example -- not much has changed in the way of basic clinical trial design.

Increasingly, though, new computational tools and other technological advances are enabling the use of innovative methods that could improve clinical trial quality. Better use of adaptive trial design and biomarkers, for example, should help trial sponsors collect better, more robust data from fewer patients and in a shorter amount of time. But FDA is only now beginning to test the waters with these new methods.

On the other hand, over the past two decades, FDA has increasingly been demanding more of the same -- more data from more individual tests within trials with more patients. The average number of patients supporting each NDA rose by 19 percent from 1995 to 2001. This trend, on average, appears to have leveled off in recent years, according to PAREXEL's Bio/Pharma R&D Statistical Sourcebook 2010/2011. But the number of patients in trials for many conditions continues to rise. And difficulty in recruiting a sufficient number of participants now often leads to termination of clinical trials before usable data can be generated. The escalating cost of recruiting, retaining, and testing so many participants caused the editors of the journal Nature Biotechnology to recommended that the FDA "put[] an upper limit on the number of people who could be included in a trial."

In addition, the length and complexity of trials continues to increase, according to the Tufts Center for the Study of Drug Development. The length of trials grew by 70 percent from 1999 to 2005, and the median number of tests conducted per patient (such as routine exams, blood tests, and x-rays) rose by 49 percent from 2000 to 2007. These new hurdles have also made it more difficult to enroll patients in trials and to keep them in the trials until completion. And the problem is most acute for drugs that treat chronic conditions such as diabetes and cardiovascular disease, where many thousands of patients must be enrolled in especially lengthy trials to satisfy FDA's innate risk aversion.

All of this has had a predictable effect on drug research and development. As Avik Roy concluded in his recent Manhattan Institute paper, "The enormous cost and risk of Phase III trials create incentives for researchers and investors to avoid work on medications for the chronic conditions and illnesses that pose the greatest threat to Americans, in terms of health spending and in terms of the number of people affected."

It appears at least that FDA has begun to take this seriously. But as one might expect, the agency is moving only very cautiously to embrace the innovative clinical trial approaches that might help to alleviate the problem. The agency has, for example, been receptive to adaptive trial design proposals, but it insists that adaptive trials be designed more carefully than conventional ones in order to prevent biases from being introduced into the statistical analysis. If the rules for adaptive trials are too rigid, it could prevent firms from reaping the full benefits of the innovative methodologies. Many firms have therefore been reluctant to experiment with these innovations until more is known about how the agency will evaluate them after the fact.

The agency has to do more and faster because, as science journalist Malorye Allison explained in a January Nature Biotechnology article, "The expanding timelines, size, failure rate and cost of trials have finally reached a point where, like the towering US debt, nobody can pretend it is viable." As I wrote a few months ago, "there is no doubt that [a] radical reinvention of the standard, 20th Century clinical trial design will be necessary if the research-intensive pharmaceutical industry is going to remain sustainable in the 21st Century."

At last week's hearing, representatives from the Association of Clinical Research Organizations (ACRO) argued that FDA "should not be yoked to any political agenda, like 'saving' the current U.S. research enterprises," according to the Pharma Times. Instead, "its goal should be to facilitate a new model that can generate more medical products in less time at less cost." I couldn't agree more. But since we're talking about an extraordinarily conservative regulatory agency that abhors risk -- not just patient risk, but political risk to itself -- implementing the kind of radical re-thinking that will be necessary is easier said than done.

Last week, Sens. Tom Coburn (R, Okla.) and Richard Burr (R, N.C.) introduced their proposed Promoting Accountability, Transparency, Innovation, Efficiency, and Timeliness at FDA Act (or PATIENTS' FDA Act). On these pages, Paul Howard described the basic theme underlying the bill as "What gets measured gets done." To a great extent, I'd say Paul hits the nail on the head with that description.

The legislation provides for a lot of measurement of FDA's activities, with regular reporting to the public and to congressional oversight committees. It would require FDA to lay out a plan to improve its performance and to identify outcomes-based metrics for Congress to assess the agency's progress in meeting them. In short, the idea is to promote improved FDA performance by "ensuring greater transparency and accountability," according to Sens. Coburn and Burr.

Paul's discussion captures that spirit nicely. Still, I think there are two especially important features of the legislation that Paul did not address -- ones that would not only improve transparency, but also subtly change at a more fundamental level the way FDA goes about its work.

Section 105 of the bill, for example, would require FDA to report the "scientific and regulatory rationale for any significant decision," such as the rejection of New Drug Application, Biological License Application, or a medical device Pre-Market Approval application or 510(k) notice. According to Coburn and Burr, drug and device manufacturers "have noted that some FDA reviewers request reams of additional information about a drug or device that is beyond the scope of data needed to meet the FDA's approval standard." In such cases, sponsors would have the right to request a scientific justification for such decisions, forcing the agency to provide a rational, scientifically-grounded explanation for its request. The hope is that, just by requiring the agency to explain its scientific rationale for its decisions, the provision will actually work to streamline and rationalize decision-making.

The provision does not, in any way, change the FDA's standards for judging safety or efficacy. It merely would provide an opportunity for sponsors, patient groups, and congressional overseers to judge whether or not the FDA is meeting those standards. "Such documentation will provide important transparency into the FDA's regulatory decision-making. Documentation will also help to address concerns about evolving goalposts, and increase regulatory predictability, consistency, and accountability," say the Senators.

While Section 105's "scientific rationale" provision would not change existing standards in any way, Sections 201 and 202, on the other hand, are intended to "recalibrate" the FDA approval process "to better ensure patients have the opportunity themselves to weigh possible risks against the probable benefit of a particular drug or device."

Coburn and Burr note that "many patients accept the risks of a product because of the potential benefit it may afford them. However, too often well-intended decisions at the FDA may result in review decisions that prevent innovative products from being available to certain patients willing to accept greater risks than others." That seems like radical stuff -- an express recognition that patients differ in their tolerance for risk and a belief that patients should have the right to choose for themselves. Unfortunately, the actual statutory language offered up in Sections 201 and 202 is not nearly as revolutionary as the Senators' description. Still, these provisions, while quite modest in scope, represent a far bigger breakthrough in FDA transparency than perhaps any other proposal being offered this year.

For all intents and purposes, the FDA currently has sole authority to decide whether the potential benefits of a new drug or device outweigh its potential risks, and thus be offered on the market to patients and physicians. Patients and physicians who believe that the risks remain too great can choose not to use or prescribe particular products. But those who believe that FDA has been too risk averse have no corresponding choice. If the FDA says "no," the product cannot be used.

Providing greater room for individual patient choice would therefore be laudable. All Section 202 would do, though, is require FDA to "implement a structured benefit-risk assessment framework in the new drug approval process to facilitate the balanced consideration of benefits and risks, a consistent and systematic approach to the discussion and regulatory decisionmaking," something the agency has already agreed to do.

But, while this provision is not particularly revolutionary, the move toward a more formal assessment of benefits and risks in FDA decision-making should nevertheless be good for patients. Like the "scientific rationale" provision mentioned above, benefit/risk analysis is a valuable transparency and accountability tool because it forces the agency to reveal the values they place on each variable and "to state their assumptions clearly, exposing possible biases to criticism and correction." In addition, when combined with the increased use of patient-reported outcome data (to which FDA has also already agreed), the exercise would force FDA to think more systematically about its decisions and raise the saliency of patients' values in the approval process.

So, Section 202, while important, is far from radical. Section 201 on the other hand, which addresses medical device approvals, represents a somewhat more fundamental change. It would require FDA to "assess the safety and effectiveness of a device ... from the perspective of a reasonable patient in the intended use population who would assign the most value to the effect the device purports to have or is represented to have ... and who would be willing to accept the probable risks that may be associated with the use of the device as prescribed ..." Here too, FDA retains sole approval authority. But under the terms of Section 201, the agency is required to approve a medical device whenever a "reasonable patient" would judge the device's "purport[ed]" benefits to outweigh its "probable risks."

In statutory construction, the term "reasonable person" has a well established meaning, so this provision would not lower FDA's approval standard by matching approval decisions to the preferences of especially risk-tolerant patients. The provision would merely operationalize the standard most people think FDA is already using -- i.e. decisions that match the preferences of, for lack of a better term, the "median" patient. Nor should we expect FDA to faithfully operationalize the intended effect of the "purported benefits" clause. As long as FDA gets to judge, you can be sure it will demand some pretty strong empirical evidence of any claimed benefit. Still, this provision would codify the view that patient values matter, not only the paternalistic judgments of experts who don't have to suffer with the diseases or disabilities treated by the particular products in question. That, to me, is a major plus.

As Paul noted last week, the PATIENTS' FDA Act is "an attempt to remedy the not-so-benign neglect that Congress has inflicted on the agency and to begin to generate the data necessary to improve its performance in a thoughtful way." All that's left is to enact the legislation and then ensure that Congress begins to take its oversight authority seriously. Neither of those two things will be easy to accomplish.

An editorial in the new edition of Nature Biotechnology (behind a pay wall, unfortunately) takes a jaundiced view of the proposed TREAT and FAST Act legislation that MPT contributors have addressed previously here and here. These bills would expand the FDA's existing Accelerated Approval process to include drugs that treat conditions other than HIV/AIDS, cancer, and a handful of orphan diseases. That's not to say that the Nature Biotechnology editors oppose the effort. They don't. But they do point out some serious shortcomings with the proposals that make them look "more like an evolution than a revolution in drug approval."

To recap, FDA approval generally rests on a demonstration in two or more Phase III clinical trials that a drug or biologic reduces mortality or alleviates a clinically relevant symptom. Accelerated Approval helps expedite the R&D process by basing approval on a demonstrated improvement in a surrogate endpoint -- such as tumor shrinkage or lower T-cell count -- that is reliably associated with the hoped for clinical improvement.

The underlying premise is that critically ill patients in desperate need of a life-saving treatment shouldn't have to wait around for years while a drug is tested for efficacy when there is some evidence now that the drug could help. Currently, Accelerated Approval is primarily targeted at AIDS and cancer treatments, while patients with most other conditions have to wait at the back of the line for products to navigate the customary testing and approval process. TREAT and FAST would "codify the precept that any medicine targeted to a condition with no effective treatment should qualify for 'accelerated approval'."

That's a laudable goal. But as Nature Biotech points out, Accelerated Approval has been helpful for AIDS and cancer patients, but hardly a panacea. "[T]he pathway hasn't exactly been a mother lode of new approvals. In 2011, only 3 of 30 new molecular entities went through accelerated approval." And in the two decades since Accelerated Approval was first implemented by FDA, "only four drugs a year have emerged from this pathway. It is this underwhelming output that the new legislation seeks to address."

What's more, a study published in the Journal of Clinical Oncology in 2009 and funded by the National Cancer Institute concluded that oncology drugs that go through the Accelerated Approval track were not actually getting to market more quickly than other drugs. Median development times for the 19 Accelerated Approval drugs examined in the study was 7.3 years, compared to a median of just 7.2 years for the 32 regular-approval oncology drugs.

At least part of the problem is that, "[i]n recent years, FDA has been ratcheting up the requirements" to qualify for Accelerated Approval, because the agency has never been particularly comfortable with the concept in the first place. And the entire process has been under attack since its inception by critics in the public health community who believe the process is little more than a mechanism for letting unproven and possibly unsafe products on the market (critics who are not themselves afflicted with life threatening diseases, I would hasten to add). This has led some observers to conclude that Accelerated Approval amounts to very little advantage for new products.

"Much of the controversy has surrounded Richard Pazdur, the director of the Center for Drug Evaluation and Research (CDER)'s Office of Hematology Oncology Products, who has expressed skepticism about the use of single-arm, 'quick' trials. The oncology experience doesn't augur well for indications less traveled." [See here for some choice words about Pazdur.]

Perhaps the biggest issue that will need to be addressed, however, is whether or not clinically relevant surrogate endpoints can be defined for conditions other than AIDS and cancer?

"[I]n many cases these endpoints simply don't exist. ... It usually takes years to generate scientific consensus around a qualified marker--something that would be particularly difficult in rare diseases where few researchers are working. Paradoxically, rare diseases in which disease progression is slow and definitive proof of efficacy requires prolonged monitoring of patients are just the indications that stand to benefit most from biomarker research. ... But these cases are a drop in the ocean when one considers how few published biomarker studies are adequately powered and well documented, avoid sampling bias and accurately estimate error."

On the plus side, there has been a lot of attention paid in recent years to the identification of biomarkers, whose improvement could serve as meaningful surrogate endpoints. And it's worth noting that, in the late 1980s and early 1990s, many of the same reservations were expressed regarding Accelerated Approval has worked for AIDS and oncology. So, "[i]f TREAT and FAST spur FDA to further clarify regulatory requirements for this pathway, the quality of phase 2 trial design will likely be improved and attrition will likely decrease. They may even allow some companies to reach the market and generate revenue earlier while spending less on R&D."

If that happens, it would be good news all around -- good news with a lot of qualifications, but good news nonetheless.

I finally had a chance to read the Supreme Court's recent decision in the Mayo v. Prometheus Labs case, which invalided two patents claiming methods for analyzing blood test results to determine correct drug doses. The decision is likely to have substantial impacts on the drug, diagnostic, and biotech industries because it calls into question the validity of a huge amount of intellectual property that those industries rely upon.

My take is that the Court got this one right as a matter of patent law - though it's a closer call than many intellectual property skeptics have claimed. Here, I should note that some colleagues and I contributed to an amicus curiae brief to the Court urging the justices to find the patents invalid. Even so, the decision raises several new questions about scientific innovation. And it may be worth reconsidering the structure of our patent laws or finding another way to incentivize the very important research work that could become less common in the absence of market exclusivity for these kinds of discoveries.

So, what's the case all about?

I couldn't agree more with something Paul Howard wrote yesterday in his post on the Bennet, Hatch, and Burr "Advancing Breakthrough Therapies for Patients Act" proposal. "It's time -- long past time -- to update and expand [Accelerated Approval] for the millions of patients who could benefit from science-based reforms," says Paul.

Like the Faster Access to Specialized Treatments Act (FAST) and Transforming the Regulatory Environment to Accelerate Access to Treatments (TREAT) bills recently introduced in the House and Senate respectively, the Breakthrough Act (apparently no cute acronym available) would make a "seemingly" major shakeup in the way FDA reviews and approves promising new treatments. One that, as Paul suggests, is long overdue.

According to Pharmalot, "If a drugmaker or a biotech believes its med would qualify [as a "drug intended for a serious or life-threatening disease or condition where preliminary clinical evidence indicates they may demonstrate substantial improvement over existing therapies"], the FDA could be asked to designate the med as a breakthrough. From (sic) the agency would meet with the sponsor through the development process, provide advice as development progresses, minimize the number of patients in clinical trials and shorten the duration of the trials, among other things."

In theory, those are all wonderful things that can streamline the testing process by giving developers a sense as to what endpoints the FDA believes are most important and how best to measure them, thereby helping developers better structure trial methodology to get the necessary data in the shortest time. The bill text would require the Secretary of HHS (i.e. the FDA Commissioner's boss) to take "steps to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients enrolled in the trial and the duration of the trial and considering alternatives to the traditional multi-phase, sequential development approach, designed to abbreviate, consolidate, and condense clinical trials and studies."

The bill would essentially instruct FDA to be helpful and not a hindrance to new drug development. That is, it would require the agency to provide real assistance to drug firms that try to bring beneficial new treatment options to market but have difficulty knowing how to satisfy the FDA's demand for evidence of safety and efficacy. To some observers, that would seem to be a radical improvement.

One of the most frequent complaints about the FDA drug and device review process is that it is highly unpredictable, even when manufacturers meet with the agency prior to designing clinical studies. The process of developing safe and effective new medical products is difficult and uncertain in the best of circumstances. But time and time again, we hear stories about how FDA promised a developer one thing before a clinical trial but changed its mind after the results were in. A few years ago, after learning that FDA had rejected approval for one its drugs even though the expert advisory panel voted unanimously in favor of approval, Schering-Plough CEO Fred Hassan told The Wall Street Journal, "What will it take to get new drugs approved? The point is, we don't know."

So, at least in theory, the Breakthrough Act would seem to represent a huge improvement in the way things are done at the FDA -- and surely could not make things worse. For those reasons alone, I would argue that the reform proposals it includes are worth supporting. Still, I think that something far more radical is needed to shake up the agency.

In addition to the Breakthrough Act, I'd like to see the FAST or TREAT proposals or something similar be implemented as well. I'd like to see the FDA embrace adaptive trial design more fully and more swiftly. And I'd like to see the agency adopt a robust benefit/risk assessment model and formally incorporate patient-reported outcomes into the new product approval process, as the FDA has proposed in its recommendations for the current round of PDUFA reauthorization.

Fortunately, achieving all those things is not only conceivable, it's possible to do them this year. Two of the proposals are already on the table for this round of PDUFA reauthorization. The FAST/TREAT proposal is merely an extension of an existing law. And though the Breakthrough Therapies Act may seem radical to some, it really represents a fairly modest change -- only improving the way FDA goes about performing its duties, not actually changing those duties. So, by all means, let's adopt the Breakthrough Therapies proposal. But let us not stop there. There is plenty more to be done.

We at MPT have written extensively about how the FDA's and other groups' conflict of interest rules, which have the effect of discounting or ignoring information connected in any way to the drug and device industry, are not only short-sighted, but counterproductive (see here, here, and here for just a few of the more recent examples). Now, via Richard Epstein, we learn that some of the biggest critics of these rules are patients themselves:

"In addition to the endless regulatory hoops mandated by the FDA for marketing approvals, a significant, and wholly unnecessary, part of this protracted slow-down [in new drug development] stems from sharp limits on conflict of interest waivers for the agency's vital advisory committees that help the FDA review new medicines, which Congress imposed on the agency, with excessive zeal, in 2007. Rather than coming from industry, complaints about onerous conflict-of-interest rules have come primarily from patients groups representing the users and consumers of pharmaceutical products, for whom new drugs and devices often spell the difference between life and death. ...

"Quite simply, the current FDA conflict of interest rules regard doctors and scientists with any financial connections with drug and device manufacturers as corrupt shills, who should be banished from its sacred precincts. Yet it takes an all-too-tolerant position to such 'pure' advisors like Sidney Wolfe, from Public Citizen, who has served on the FDA's Drug Safety and Risk Management Advisory Committee since 2008, despite being an avowed enemy of the industry and a close ally to plaintiff's lawyers who launch multibillion dollar class action suits against drug companies - and who contribute generously to Public Citizen's coffers."

Now, it's not completely true that FDA has never ruled out someone for a so-called "intellectual conflict". Indeed, Sidney Wolfe himself was once prevented from voting on the disposition of a class of birth control pills containing the hormone drospirenone because a Public Citizen publication had warned against using those products. And a prominent cardiologist had once been invited and then "disinvited" from participating in an advisory committee hearing on the blood thinner prasugrel because the doctor had made disparaging comments about the drug.

Still, in the latter case, FDA later acknowledged that it should not have excluded the cardiologist for having a possible "intellectual bias". And though Wolfe was only permitted to sit on the advisory committee panel considering drospirenone as a non-voting member, he continues to vote on numerous other products despite having campaigned for more than 30 years against the evils of the pharmaceutical industry.

The point remains, conflict of interest allegations almost invariably run in one direction: against drug and device manufacturers and not their critics. The only time it seems the critics are willing to overlook a drug industry conflict is when the otherwise conflicted party is joining in on the criticism of another manufacturer's product.

Consider one particularly ironic case that I wrote about previously: U.S. Sen. Charles Grassley (R-Ia.) has been a frequent critic of FDA for not being harsh enough on industry conflicts of interest. But, at the same time, Grassley has frequently relied upon Cleveland Clinic cardiologist Steven Nissen to pursue their joint campaign against the diabetes drug Avandia. But it turns out that Nissen just happens to be one of the investigators on a study purporting to show that Avandia's closest competitor, Takeda Pharmaceutical's drug Actos, is superior to Avandia because it doesn't increase cardiac risk. And, as it turns out, Takeda provided $25,000 in funding to Nissen's Cleveland Clinic team to conduct the Actos study.

If the tables were turned, and it was Takeda's product that Grassley wanted banned, would he have relied so easily on Nissen's judgement that Actos was safe? Steven Nissen is a highly regarded scientist, and I am aware of no credible evidence that his views on Avandia or Actos have been biased by the funding from Takeda. But you could bet your bottom dollar that, in such a case, Nissen's views would not only be discounted, they'd probably be ridiculed as nothing more than "bought and paid for science".

Ultimately, conflicts of interest can never be eliminated, though they can and should be managed. But it seems clear that the way Congress and the FDA are trying to manage them has been a dismal failure.

Yet another major pharmaceutical company is now being persecuted prosecuted for off-label promotion. This time it's Johnson & Johnson, being pursued over allegations that the company illegally promoted its antipsychotic drug Risperdal for unapproved uses. As The Wall Street Journal reports, though, settlement negotiations have hit a snag.

Federal prosecutors in Philadelphia reached a tentative agreement under which J&J would pay a whopping $1 billion in fines. But Justice Department officials in Washington rejected the deal and are now seeking an even higher payment. According to the Journal:

"The Justice Department prosecutors are seeking a settlement of around $1.4 billion, the sum that Eli Lilly & Co. agreed to in 2009 to resolve allegations it had improperly promoted its antipsychotic drug Zyprexa, according to one of the people familiar with the matter. Yet J&J officials have resisted paying that amount.

"An outright rejection of a deal is unusual, according to Shelley Slade, a former Justice Department health-care fraud lawyer who now represents whistleblowers suing drug makers. Ordinarily, prosecutors in a U.S. Attorney's Office work with counterparts in Washington, D.C., to find mutually agreeable terms, Ms. Slade said."

As with many of these off-label promotion cases, the allegations are broad ranging and appear to include a mix of ethical and unethical behavior - ranging from the promotion of Risperdal to treat pediatric patients with attention-deficit disorder prior to 2006 when the drug was approved for that use to the payment of kickbacks to pharmacies to push Risperdal over alternative drugs. And the company is being pursued not only by the feds, but also by several state attorneys general.

But, while J&J thought its position in the state lawsuits was strong enough to fight in court, the federal government has a tool at its disposal that makes an out of court settlement almost guaranteed: the potential exclusion of any of the company's products from Medicare and other federal health programs. Federal anti-fraud laws permit government programs to exclude, suspend, or "debar" corporations that have merely been accused in an indictment of fraudulent behavior from doing business with the federal government. No guilty verdict is necessary.

As you can imagine, with the federal government picking up the tab for more than a quarter of all US health spending, exclusion from federal health programs would be tantamount to a corporate death sentence. "It is thus not surprising," notes Ropes & Gray attorney Joan McPhee, "that virtually all rational corporations ... conclude, as a business matter, that they cannot incur the risks associated with taking an indictment and going to trial, even when, in the corporation's assessment and that of its seasoned counsel, the threatened case is without factual or legal merit."

Because I have argued in both the popular and scholarly press that much (though not all) off-label promotion is protected by the First Amendment, I have been asked repeatedly why few defendants have challenged the off-label promotion ban in court. In part, it is because the high profile cases brought against drug firms often include allegations other than constitutionally defensible speech - such as the kickback allegations in this case. The flip-side of that is that the Food and Drug Administration and Department of Justice have been very good at selecting the cases they pursue, so as not to set up clean constitutional questions. And, when backed into a corner, the FDA and DOJ have been able to dispense with problematic cases before a clear ruling that the off-label promotion ban is unconstitutional (see my descriptions of the WLF and Allergan cases in this paper, for examples).

But arguably the most important reason why more of these cases don't make it to court is the fact that an indictment, what McPhee calls the "admission ticket" to the courtroom, all by itself spells potential doom for a drug firm. "[W]hile there are strong legal and constitutional defenses to the government's attempted criminalization of truthful, nonmisleading off-label dissemination, there is no available avenue for targeted corporations to gain access to a judge or jury without risking corporate death."

So, J&J may believe that the Justice Department's demand for a $1.4 billion settlement is wholly unwarranted. But I'd be willing to bet they eventually take that deal.

Last summer, Pfizer announced that it would begin experimenting with a new, "virtual" clinical trial design in which patients would "participate remotely without having to visit trial sites." The Research on Electronic Monitoring of OAB Treatment Experience (REMOTE) trial was designed to use smart phone and other Internet tools that would enable enrollees and their doctors submit data on the safety and efficacy of Pfizer's Detrol LA (tolterodine tartrate), an already approved treatment for overactive bladder problems.

Pfizer touted the virtual design as having "the potential to widen the available trial population, speed up clinical development while cutting costs (which weigh heavily in patient recruitment and retention), improve patient compliance, reduce withdrawal rates and deliver better-quality, more reliable 'real-time' data."

Unfortunately, the company had to admit recently that enrollment didn't live up to expectations, leading some to question whether the concept is realistically feasible. The good news is that Pfizer's senior director of clinical sciences, Miguel Orri, believes the company has learned enough from the early setbacks to salvage the idea. And the company is planning to launch a re-designed REMOTE 2 trial with tweaks that it believes will address the enrollment problems.

Whether the re-designed trial will succeed remains to be seen, of course. But there is no doubt that this kind of radical reinvention of the standard, 20th Century clinical trial design will be necessary if the research-intensive pharmaceutical industry is going to remain sustainable in the 21st Century. As science journalist Malorye Allison explained in a January Nature Biotechnology article (subscription required), "The expanding timelines, size, failure rate and cost of trials have finally reached a point where, like the towering US debt, nobody can pretend it is viable."

As we become more alert to such concerns as cardiac- and hepato-toxicity, and as scientific advances reveal more and more about the individualized effects of various drugs in smaller and smaller patient sub-populations, regulators are demanding additional testing and more data. This is forcing drug firms to design trials with larger enrollment and increasingly more interventions per patient. In turn, it is taking sponsors longer to enroll trials and longer to run them, with costs skyrocketing as a consequence. And, as we move into a world of more personalized medicine, where each new drug can treat a smaller and smaller population of patients, the conventional, randomized, placebo-controlled trial will have to become a thing of the past. Innovative trial designs may be the only way to ensure a steady stream of new and beneficial treatment options into the future.

Fortunately, the entire drug and biotech industry, along with academic and public sector researchers, are now fully aware that trial methodology cannot continue on as before. Pfizer may be a pioneer in this space, but it is not alone. There are over two dozen companies participating in the Critical Path Institute's Electronic Reported Outcome Consortium, which among other things, is working to develop innovative electronic data collection technologies for clinical trials. And even patient groups have begun experimenting (to a limited extent) with virtual clinical trial designs without drug firm participation.

Eventually, I expect to see much more interest in so-called adaptive trial designs as well. Standard trial methodologies enroll a few thousand patients all at once and administer the identical treatment protocol or placebo. But if, half way through, the administered dose isn't working for some patients, or others experience unacceptable side effects, researchers must go back to the drawing board and re-design the methodology to account for the new information. Adaptive trials, on the other hand, use smaller cohorts of patients in a way that lets researchers adjust the methodology from cohort to cohort to respond more quickly to what they learn along the way.

To date, the Food and Drug Administration has been receptive to adaptive trial proposals, though the agency insists that these trials must be designed more carefully than conventional trials in order to prevent biases from being introduced into the statistical analysis. If the rules for adaptive trials are too rigid, it could prevent firms from reaping the full benefits of the innovative methodologies. Many firms have therefore been reluctant to experiment with these innovations until more is known about how the agency will evaluate them after the fact.

The important thing is that innovative clinical trial approaches are now being given serious attention. Without them, the drug and biotech industries will find it difficult to turn cutting edge science into approved, real world products. As Raymond Woosley, president and CEO of Critical Path Institute, notes, "Randomized controlled trials are out of date, and it's time to use the tools of the future."

There's been a lot of press coverage over the past several weeks of the problem with prescription drug shortages. And, as you might expect, members of Congress are eager to be seen as doing something -- anything really -- to help alleviate the crisis. A bi-partisan group of House members led by Rep. John Carney (D-Del.) introduced a bill at the end of January. That came on the heels of another House bill introduce by Reps. Diana DeGette (D-Col.) and Tom Rooney (R-Fl.) in June. And Sens. Amy Klobuchar (D-Minn.) and Robert Casey (D-Penn.) recently moved to attach their drug shortage bill, first introduced last year, to a piece of transportation legislation moving through the Senate.

Unfortunately, most of the proposed action will have little to no affect on the fundamental underlying problems associated with drug shortages. And one of the bills very well may make the shortages worse.

Last week, our very own Paul Howard wrote an article for the Washington Examiner explaining how "a combination of market forces and government price controls have reduced incentives for companies to either enter the market for critical drugs or make manufacturing investments to keep their plants up to date - and running safely." Former Obama administration health policy advisor Ezekiel Emanuel delved more deeply into the price control issue in this New York Times op-ed.

The gist of the problem is that the profit margins for the generic drugs that comprise the vast majority of drugs in short supply are so small that there often are just two or three manufacturers (and occasionally just one) for a particular critical drug. And Medicare price controls contribute substantially to these profitability issues.

Health care scholar John Goodman summarized some of these and other points nicely in a post on his blog last summer. As Goodman pointed out, another contributing factor is the FDA's increasingly strict regulation of drug manufacturing facilities, which he calls a "zero tolerance regime" that is "forcing manufacturers to abide by rules that are rigid, inflexible and unforgiving." This is exacerbated by the fact that FDA not only approves drugs as safe and effective, but also regulates the production facilities themselves, including the quantities produced and the timing of production schedules. So, when one manufacturer's plant is closed, competitors need to get FDA approval before they can ramp up their own production to meet the shortfall.

Waiting for FDA to get through the approvals takes time, and that contributes to some of the drug shortages we've seen. The Carney bill would instruct FDA to expedite these reviews -- both to bring shuttered facilities back on-line more quickly and to let competitors increase production. And all three of the bills would also require drug makers to warn the FDA in advance if they decide to discontinue manufacturing a "critical" drug or if they anticipate an "interruption" in production. To some extent, these measures may help, but the FDA has taken some modest steps on its own to address some of the most problematic shortages. And nothing in the legislation is likely to change the fundamental nature of how the agency operates. Nor would any of the bills address the fundamental underlying economic considerations that are the primary cause of the shortages.

Worse still, The Carney bill would, to some degree, actually intensify the problem. It would try to stabilize prices by banning so-called "stockpiling" and "price gouging". But it's Economics 101 that, when the supply of something falls below demand, the price will rise. What every politician who complains about price gouging forgets, ignores, or just doesn't realize, is that rising prices are a signal (a) for consumers to conserve the supply of a scarce product, and (b) for manufacturers to produce more of it. That's exactly what stockpiling is, an effort to conserve a drug that's in short supply.

When prices of these drugs rise, doctors and hospitals start asking themselves, "Do we really need to use this drug in this situation, or is there a reasonable substitute?" That in turn means that the patients who most need the drugs are more likely to get them, and that patients who could make do with a lower dose or an alternative use less of the product that is scarce. No consumer likes sharply rising prices, particularly when they're seen as an effort by some sellers to profit unfairly. That's why politicians always propose these kinds of measures. But the problem with preventing so-called price gouging is that it means no signal gets sent to consumers indicating that conservation is necessary, and no signal gets sent to manufacturers that it's worth ramping up production. In short, anti-stockpiling and anti-price gouging policies almost inevitably make a shortage worse, not better.

In short, drug shortages are a real problem. But the way to alleviate them is not to eliminate the market signals that incentivize adequate production. In the end, we would be better off if Congress did nothing at all than if they enacted these bills. Better still, though, would be for Congress to lift the rules that have contributed to the shortages in the first place.

In a surprise move, the Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee on Wednesday voted 20 to 2 in favor of recommending approval of the obesity drug Qnexa. If the agency accepts that recommendation and ultimately approves Qnexa, it would become the first new obesity treatment in over a decade. Just a year and a half ago, however, the same committee (though with a slightly different composition) voted 10 to 6 against approving the same drug.

What changed their minds? A couple of things, including a labeling change recommending that lower doses be used in most cases and a proposed distribution program that will make it more difficult for pregnant women to be prescribed the drug. But, according to The New York Times, arguably the biggest change was the realization by Advisory Committee members "that obesity itself causes health problems and that there is a pressing need for treatments."

They've just now realized that obesity causes health problems? Where have these people been for the last twenty years? Apparently, they haven't been paying attention to the almost daily warnings in major and minor newspapers, on television news programs, in announcements from the Surgeon General, the Centers for Disease Control, and the First Lady that America is in the midst of an obesity epidemic that prematurely kills hundreds of thousands of us every year. Is it really too much to ask that the people we put in charge of recommending new medicines for approval or rejection would take seriously the negative consequences of the conditions those products are intended to treat?

To be sure, that's more than a little hyperbolic on my part. The Advisory Committee that recommended against approving Qnexa in 2010 did, in fact, acknowledge that obesity itself poses significant health risks. "We know that obesity is a major health problem, and all efforts to address this issue should be lauded," said the acting chairman of that committee, Dr. Kenneth Burman of the Washington Hospital Center here in DC.

Still, it seems curious, to say the least, that relatively minor proposed labeling and distribution changes for Qnexa would have such a dramatic impact on the Advisory Committee's vote -- from strong opposition to overwhelming support. This time, it does seem as though the committee took the risks of obesity far more seriously. Or was it just that new members of the Advisory Committee brought with them an entirely different perspective? Perhaps it's something else entirely. The point is, we really don't know what caused this dramatic change of heart or what weight the committee assigned to the drug's known risks or those of the underlying condition. Nor, perhaps more importantly, do we know what weight FDA will assign them when the agency makes its decision.

Today's Wall Street Journal has a refreshing interview with Dr. Susan Desmond-Hellmann, who is chancellor of the University of California, San Francisco, and a former drug industry research scientist. The piece begins with an introduction that says, "Many universities are wringing their hands over the increasing coziness of medical schools and their corporate partners. Susan Desmond-Hellmann ... has no such qualms."

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.

On the same day last week that Paul Howard was discussing the Biosimilars User Fee Act, the FDA issued the first two in a series of long awaited guidance documents that will lay the groundwork for implementing the Biologics Price Competition and Innovation Act. Folks in the biotech and generic drugs industries have been anticipating the documents since at least last summer, when CDER head Janet Woodcock announced that the documents had been completed. But FDA kept putting off their release in order to fine tune its approach intended to navigate a course between the very strict process advocated by innovator biotech companies on the one hand and the comparatively less strict process advocated by generic manufacturers on the other.

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.

An interesting article in today's Wall Street Journal explores the proliferation of websites that make it easier for users to search through the FDA's "often impenetrable database" of Adverse Event Reports (AERs). The CEO of one of the sites "likens these efforts to the advent of J.D. Power and Associates safety ratings for cars. 'Suddenly, manufacturers started competing on quality,' she says. 'The best way to drive quality improvements is to make things crystal clear and transparent as possible.' "

That's true, as far as it goes. But it doesn't go very far. The Journal article discusses a number of shortcomings with the data available from AERs. "Most reports come through drug and device manufacturers, but patients, physicians, family members--even lawyers--can send reports to the FDA, and they often contain errors and inconsistencies," for example. And, although drug manufacturers are required to report any adverse events they discover, or that are brought to their attention, most incidents are never reported at all by doctors or patients.

Other problems include the fact that "there is no way to determine whether a side effect is due to a drug or a coincidence. (Device malfunctions are even trickier, since operator error or surgical skill can affect how they perform.) For another, the reporting doesn't necessarily mirror the true incidence of problems. New drugs tend to generate more reports than older ones, and a negative news story about a drug or device can prompt a sudden spike in reported problems. ... What's more, the FDA files don't indicate how widely a drug or device is being used, so there is no perspective."

Still, defenders argue that more information is better than less. " 'If your doctor tells you to take a drug and it's three times more likely to give you a heart attack than another drug, not having that information seems foolish'," says the president and co-founder of one of the sites. Ordinarily, I would agree that more information is better than less. Unfortunately, what might, at first glance, appear to be more useful information, may actually just be out of context data. And it's important to recognize that "data" and "information" are not the same.

Let's assume, for the sake of argument, that the database of AERs was sufficiently complete to provide an indication that one drug is three times more likely to give you a heart attack than another. That doesn't give you the information you need to determine whether the drug is worth taking. The most important missing factor is how effective the drug is at treating the underlying medical condition. When it comes to choosing among treatment options, patients very frequently are willing to trade somewhat higher risks for greater rewards -- particularly when the risks associated with the underlying medical condition are great. But also relevant is how prevalent the background rate of the specific adverse event is and by how much the risk of that adverse event is raised. And how does this whole mix of risks and benefits of one drug compare to those of the other drug?

I don't want to be entirely critical here. And I do certainly want to be on record as tentatively supporting the move to make FDA data easily accessible in a user-friendly way. But without taking into consideration all the relevant factors, merely reporting a certain sub-set of data is problematic to say the least -- possibly even dangerous. What if I find that my blood pressure medication or diabetes drug has a higher incidence of reported AERs than an alternative and I stop taking it before I have a chance to consult my doctor? Since we know that patient compliance with prescribed drug regimens is a genuine problem, that scenario doesn't seem so far-fetched. In such a case, the availability of data, rather than information, might actually cause me to choose a less safe course of action.

I am decidedly not endorsing the standard FDA line that " 'the best source is to read the product label and talk to your doctor or pharmacist'," as FDA director of surveillance and epidemiology Gerald Dal Pan told the Journal. FDA doesn't always have the best information. And I would, indeed, like to see better efforts by the private sector to deliver information to consumers. I'd just like to see it done better than this. It is clear that the Internet will be able to help deliver a broad range of useful information to patients. And it is already making the collection and dissemination of both risk and benefit information easier (see here for a wonderful example).

Clarimed founder and CEO Nora Illuri is right to suggest that "The best way to drive quality improvements is to make things crystal clear and transparent as possible." But when it comes to drugs and medical devices, "quality" is complex, multi-variate trait. And overall medical product quality isn't likely to improve if we focus on only one of those variables.

Who should be liable when a patient is injured by a generic drug? That's an interesting question, since by law, a generic drug must be bioequivalent to and carry the identical labeling as the original brand name drug. So, if the injury arose from the drug's original design or labeling, how can you hold the generic manufacturer accountable?

[Last summer]About a year and a half ago, the U.S. Supreme Court held in a case called Pliva v. Mensing that negligent failure to warn tort actions against generic drug manufacturers were preempted by the Food, Drug and Cosmetic Act. Because generic manufacturers are obligated to use labeling identical to the FDA-approved labeling for the innovator, or branded, product, they can't be sued for failing to include warnings about certain risks if those warnings do not appear on the innovator's label.

It would seem to be common sense that you shouldn't be able to sue someone for not doing something they were legally forbidden from doing. But litigation-happy tort lawyers have been trying to find a way do it anyway. Even more troubling is the fact that four Justices of the Supreme Court seem to agree with that view. After all, their reasoning went, [Update: the generic manufacturers could have ask the FDA to initiate a labeling change in the expectation that FDA would pressure the innovator to agree to the change. "If the FDA agreed that a label change was required, it could have asked, and indeed pressured, the brand-name manufacturer to change its label." Justice Sotomayor's dissent, joined by three other Justices, argued the law should "require the Manufacturers to show that the FDA would not have approved a proposed label change."] [Update: An earlier decision from the U.S. Eighth Circuit Court of Appeals went so far as to argue that,] if the generics manufacturers don't want to be sued, they can just stop making generic drugs. In the view of those four dissenters [judges], if a patient is injured, then by golly there should always be somebody to sue. Well, based on the outcome of a handful of cases now making their way through the courts, it appears that there is -- at least in a handful of jurisdictions.

In a case called Conte v. Wyeth, a California Intermediate Appellate Court in San Francisco held that, since plaintiffs can't sue a generic manufacturer for negligent failure to warn, then they should be able to sue the innovator manufacturer who had some control over the contested labeling -- even if the patient didn't take the innovator's product, and even if the innovator is no longer manufacturing the off-patent drug and therefore no longer keeping its labeling up to date.

The California Supreme Court refused to review the case, which means it hasn't been implemented state-wide but is good law (that is, "good" in the sense of "valid," not "good" in the sense of "good") in the First Judicial District of California. [Update: There is apparently some dispute regarding the extent to which California trial courts are bound by California intermediate appellate court decisions. I'm no expert in California procedure, so I'll concede it's possible that not all courts in the First Judicial District would have to treat this decision as binding precedent.] Not long after Conte was decided, the U.S. District Court for the District of Vermont became the first federal court to agree with the Conte decision, in a case called Kellogg v. Wyeth. Following the rationale of Conte, the federal court held that it was "reasonably foreseeable" that physicians would continue relying on a brand manufacturer's approved labeling even after the innovator ceased making the drug. Thus, innovators have a duty of care to ensure up-to-date labeling for ... well, pretty much forever.

Unless this tort theory is struck down, and soon, it could very well metastasize throughout the country's state and federal courts, giving manufacturers and investors yet another reason to give up on innovation in the medical products space. Fortunately, both the U.S. District Court for the Middle District of Florida and the U.S. Sixth Circuit Court of Appeals have since rejected the Conte/Kellogg foreseeability theory, which presages an eventual Circuit Court split that would have to be resolved by the Supreme Court. And, at a more localized level, Jim Beck at the Drug and Device Law blog may have stumbled onto a way to rein in Conte based on an old California Supreme Court decision [from January 2011].

Yet, while it may indeed be possible to keep what Beck calls this "omniforeseeability" theory from spreading, these cases nevertheless raise a very important question: Who exactly should be responsible for ensuring that a drug's label is maintained in a post-patent, multiple-producer environment? In many cases, such as the one presented in Conte and Kellogg, the innovator manufacturer isn't producing the drug any longer. But none of the generic manufacturers has the legal power to change the label. That poses a real problem that merits a real solution. And its one of things that I'll be thinking through over the coming months and years.

A new study conducted by the research organization Patient View confirms something many of us already knew: the pharmaceutical industry's corporate reputation is pretty dismal -- even among the patients and patient advocates who rely on innovative new medicines. Top scoring individual firms are, as you might expect, touting their positive reputations, defined as "meeting expectations of patients and patient groups." But, that should be cold comfort even to the winners since -- unlike say new car buyers -- pharmaceutical consumers don't generally shop for medicines on the basis of what they think of various manufacturers.

Reputation in the drug industry matters much more in the political sphere than in the retail sphere because, as Ed Silverman at Pharmalot points out, "patient groups are not only growing in number, but increasingly trying to influence regulatory and payer decisions through assertive lobbying." And regulation isn't imposed at the firm level, but at the industry level. A drug firm with a sterling reputation will suffer from regulation motivated by the public's attitudes regarding the entire industry. So, even top scoring firms need to be worried about these results -- and they need to think more strategically about how the entire industry can begin to burnish its reputation.

The study is available only to Patient View subscribers, selected news media, and other readers willing to cough of £750. But via Pharmalot and the Pharma Times, we learn that the survey included 500 patient groups from 61 countries, and respondents were asked about their views regarding the drug, biotech, and generic industries generally, and of the 30 largest companies specifically (The full list of companies can be viewed here.). The study used six indicators to measure company performance: "Whether the company has an effective patient-centred strategy," "The quality of the information that the company provides to patients," "The company's record on patient safety," "The usefulness to patients of the company's products," "The company's record of transparency with external stakeholders," and "Whether the company acts with integrity."

So, what did they find? Just 42 percent of respondents said "they believe the multinational pharma industry has a 'good' or 'excellent' corporate reputation, while for biotech and the generics sector the equivalent figures are 44% and 41%, respectively." And fewer than 30 percent believe pharma's reputation has improved over the past five years. In addition, "while 66% of the respondents believe that pharmaceutical companies are 'good' or 'excellent' at being innovative, only 13% consider them to be 'good' or 'excellent' at adopting fair pricing strategies which ensure that they do not make 'unseemly' profits. Just 31% consider that companies act with integrity, with only one-third believing that drugmakers run ethical marketing practices and 23% considering them to be transparent in their corporate activities."

Leading the pack of individual drug firms was Novartis, coming in first overall as well as in four of the six individual indicators: having an effective patient-centred strategy, the quality of information for patients, its record on patient safety, and the usefulness of its products. Pfizer and Lundbeck came in second and third respectively. For a full list of the results you'd have to read the full report, to which I don't have access.

One caveat worth pointing out is that "patient groups" are not the same thing as individual patients. It's entirely possible for patients, even in the aggregate, to have a higher or lower opinion of individual firms or the entire industry -- largely because patients will have more individualized experience with some companies and little or no experience with others. And, though I think patient groups generally do a good job representing the interests of their members, the professional representatives will tend to be much more attuned to questions related to a company's willingness to share information and work with the organizations.

Perhaps more importantly, as I noted above, the organized patient groups will be more active -- and more effective -- at influencing the development of laws and regulations. And, because even the most respected companies can't escape regulations implemented to rein in or punish the entire industry, the views of the organized patient lobby matter tremendously. So, while a company like Johnson & Johnson might be ranked in the top 20 of the "World's Most Admired Companies," that reputation won't necessarily help it fend off predatory or debilitating regulation if the view of the entire industry remains low -- particularly among the most active advocates.

Since over 80 percent of the respondents in this survey faulted the industry for its pricing practices, one of the first things the industry must do is debunk the belief that it is reaping huge profits on the backs of suffering patients. With soaring drug prices at the top of every pharma industry critics list of complaints, it does appear unseemly for drug firms to consistently return double-digit profitability. But, as the Congressional Budget Office has pointed out, "those figures misrepresent the industry's actual profits." Standard accounting measures overstate profitability for R&D intensive industries by treating most research spending as an expense rather than as a capitalized investment that increases the company's value. "Not accounting for that value overstates a firm's true return on its assets."

Ultimately, the high retail prices of pharmaceuticals reflect the vast expense of developing those products and getting them approved for sale. Without correspondingly high prices to enable the recoupment of those costs, few investors would willingly take the risks inherent in supplying capital to the pharmaceutical industry. The result would be fewer and fewer lifesaving medicines. We scholars may keep pointing that out. But if the drug industry itself doesn't figure out how to do a better job convincing patients and organized patient advocates of that fact, its reputation isn't likely to recover any time soon.

The FDA has come under fire yet again over allegations that a drug advisory panel decision was tainted by financial conflicts of interest.

Some recent research has suggested that women taking birth-control pills containing the active ingredient drospirenone -- such as the Bayer AG products Yaz, Yasmin, Beyaz, and Safyral, as well as several generic versions of the drug -- had roughly double the risk of non-fatal blood clots as those taking other oral contraceptives (see here and here). Last spring, Bayer issued a statement contesting the validity of the study methodology, and claiming that other research -- presumably more valid in Bayer's opinion -- found no heightened risk.

Who's right and who's wrong is a difficult question to answer. But at a December 9, 2011 joint meeting of the agency's Reproductive Health Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee panelists sided with Bayer by a 15 to 11 vote that drugs containing drospirenone should remain on the market.

What's particularly noteworthy about the vote, however, is that an investigation by The Washington Monthly and the British Medical Journal has revealed that at least four of the committee members "have either done work for the drugs' manufacturers or licensees or received research funding from them." What's more troubling, though, is that the FDA did not itself make public any of these financial ties, and it took a couple of reporters to reveal the information.

By itself, the presence on FDA advisory panels of researchers who have done work funded by the drug industry is not problematic per se. After all, the purpose of the advisory panels is to provide the best possible expert advice, so the agency can better evaluate the benefits and risks of medicines. As Harvard Medical School researcher Thomas Stossel has explained over and over to anyone who'll listen, the manufacturers of drugs are going to seek out the best researchers with the most knowledge about a particular disease or condition to provide insights on their research and development programs. So, if you bar anyone with any financial ties to the industry from serving on regulatory advisory committees, that necessarily means settling for people who are not the best. Moreover, despite all the sturm and drang about financial conflicts of interest, and a growing literature examining the effects of these conflicts, "Evidence that relationships compromise scientific integrity is weak or false," and "there is no evidence at all about the effect of physician-industry relations on patient outcomes."

Nor am I especially concerned about the narrowness of the vote in this particular case. The Washington Monthly/BMJ report tries to make an issue of the fact that, without the four conflicted panel members, the result would have been an 11 to 11 tie. That still leaves us essentially where we were previously -- that is, with conflicting evidence and an essentially evenly split panel vote elucidating the fact that, with many drugs, it's difficult to tote up the benefits and risks and make a well-reasoned decision.

More importantly, though, those decisions are left to the FDA, not the advisory committees. By all accounts, the FDA was in fact aware of the financial conflicts. And the agency itself is fully capable of evaluating the full weight of scientific evidence and discounting the advisory committee's decision if deems those financial ties to have affected the votes of various members. The agency often does side with advisory committees in its approval or disapproval decisions. But there are far too many cases in which the agency rejected an advisory committee recommendation (almost always in the direction of rejecting approval for a drug that an advisory committee recommended approving) to think that the committee votes are anything more than what they purport to be: advisory in nature.

What I do find troubling about the whole affair, however, is the fact that the financial relationships were not previously disclosed by the FDA. There is nothing especially pernicious about these financial arrangements. But full information disclosure by federal agencies serves an important function: It lets the public evaluate the performance of our regulatory overseers. Sometimes information disclosure can be used more to intimidate and demagogue public and private actors -- and that is a tendency to be feared. But when it comes to government decision making, we ordinarily should prefer more information to less. In the end, disclosing not just potential financial conflicts of interest, but also other conflicts (such as intellectual ones) is a far better approach than excluding experts from fully participating in the regulatory process. And in that regard, The Washington Monthly and BMJ should be congratulated for their work.

The approvals this past August of Pfizer's lung cancer drug Xalkori and the joint Roche-Plexxicon melanoma drug Zelboraf were seen as a hallmark of the coming era of companion diagnostics, in which drugs that treat specific patient sub-populations are approved at the same time as the tests that help doctors determine which patients will benefit from the medicines. But now that the concept has been validated, some drug firms and patient advocates worry that the FDA may be setting too high a bar for important new drugs to be approved. As discussed in a New York Times article last week, the FDA is now beginning to reject drugs that work in some patients but not others when an approved companion diagnostic test isn't available to identify who may benefit and who won't.

Because many drugs are not fully effective for all patients, the practice of medicine can often be a hit or miss affair in which doctors cycle through various drugs in a particular chemical class until their patients respond appropriately. Individual cholesterol-lowering statins, for example, tend on average to work well in just 30 to 70 percent of patients. And individual blood pressure-lowering ACE inhibitors tend to work in just 10 to 30 percent of patients. But more often than not, if the first prescribed drug doesn't do the job -- or does it with unacceptable side effects -- another drug in the class will work quite well. In other cases, though, as we saw with the breast cancer drug Avastin, some patients will respond to the sole drug in a class extremely well, while others aren't helped at all.

The identification of relevant biomarkers that can predict individual patients' likely response to particular drugs, has been a huge medical breakthrough. Zelboraf works in roughly half of melanoma patients, and they can be identified by the presence of a particular genetic mutation. Xalkori works in about 5 percent of patients whose tumors have a particular chromosomal abnormality. And those drugs were approved along with diagnostic tests that identify the relevant biomarkers. The availability of a companion diagnostic test means that those patients who have little chance of benefiting from a particular treatment don't have to waste valuable time experimenting with a drug that could do more harm than good.

But here's where the story gets complicated. Dozens of other helpful biomarkers have been identified, and are now used in diagnosing patients and determining which medications should be prescribed. But, most of the drugs used in conjunction with known biomarkers were approved without needing to wait for approval of a companion diagnostic. According to the Times, "Before August, the only other dual approval was of Genentech's breast cancer drug Herceptin and Dako's test for the related HER2 protein in 1998. There are more than 70 other tests that guide drug use in some way, according to the Personalized Medicine Coalition, but they are rarely required and often developed well after the drug reaches the market."

Unfortunately, very often scientists have not identified a biomarker to tell the lucky few from the unlucky many. As the Times article notes, "Often, scientists simply do not know what to test for to predict a drug's effectiveness, or they don't find out until near the end of the drug's clinical trials." And even when a biomarker can be identified, "coordinating development and approval of a drug and a test -- by two separate companies reviewed by two F.D.A. divisions -- can raise the cost of drug development if not done well." It can also keep important treatment options out of the hands of patients for many years.

In 2010, in what should have been a hugely controversial decision, the FDA rejected the ChemGenex Pharmaceuticals drug Omapro (omacetaxine mepesuccinate), even though a valid biomarker HAD been discovered, because there was no FDA approved or "approvable" companion diagnostic test available to select patients with the Bcr-Abl T315I gene mutation that identifies them as likely to benefit from the drug. According to Richard Pazdur, Director of the FDA's Office of Oncology Drug Products, "The lack of having a uniform in vitro diagnostic test creates uncertainty about patient selection both in this trial and, more importantly, in a post-approval setting. ... If a patient does not harbor the T315I mutation but is falsely identified as having such a mutation by these un-reviewed assay methods, the patient may not receive more effective, less toxic therapy, such as dasatinib or nilotinib. Conversely, patients with a false-negative test result would receive an ineffective therapy."

In effect, the promise of biomarkers and companion diagnostics to help doctors provide the right treatment for the right patient at the right time can be held up if a drug company isn't able to enter the diagnostics business or convince a company already in the diagnostics business to seek approval for a companion medical test.

While I fully appreciate the possibility that a faulty diagnostic test can have severe negative consequences for patients, the FDA's decision in this case is absurd. I agree with Dr. Ellin Berman, a physician at Memorial Sloan-Kettering Cancer Center and the only member of the FDA's Oncology Drugs Advisory Committee to vote in favor of approving Omapro without the companion diagnostic. She told the Oncology Times, "I think the drug should be approved based on what we heard today. The likelihood of having a standardized test for T315I is, I believe, years in coming." She noted that patients with the T315I mutation and who do not respond to the first line treatment have few other options. "Patients are going to be harmed by this [vote]," she said.

The FDA's failure to provide a lifeline for an identifiable sub-population of patients with a deadly disease and who have already failed to respond to the first line treatment is inexcusable. The development of companion diagnostics will be a tremendous boon for patient health, but we cannot let the absence of an approved diagnostic test stand in the way of promising treatment options.

Way back in September 2009, the Food and Drug Administration announced that it would begin using the social media site Twitter to share news and other information about drug safety and regulation. "Messages on Twitter provide consumers, healthcare professionals, the pharmaceutical industry, and others with timely information on new drug approvals, safety alerts, compliance actions, and consumer information," the announcement said. It was nice for FDA to mention the pharmaceutical industry. But, unfortunately, the drug and device industries have been feeling their way around the Internet and other new media, including Twitter, for several years without substantive guidance from the FDA on what is and is not permitted.

As Ed Silverman at Pharmalot explains in an op-ed posted today, the agency has been promising for years that it would develop of a formal policy on the matter. As early as 1996, the FDA held a public meeting (see reference here) to discuss issues related to the advertising and promotion of medical products on the Internet. Then, in November 2009, the agency held another public meeting, with the promise that it would soon thereafter develop guidance or other policies that addressed Internet promotion and social media. But, as Silverman notes, "the guidelines didn't appear in the wake of the meeting. And they didn't appear by the end of 2010, despite an unofficial FDA deadline to push something out by New Year's Day. And then the agency missed another deadline, this one on March 31. By mid-year, FDA officials said they would stop setting deadlines."

Unfortunately, this is not a case of benign neglect. On April 2, 2009, FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) issued 14 Notices of Violation to drug manufacturers for their use of sponsored links on web search engines that included the name of a drug and a brief statement about the disease it treats, while directing users to a separate website that contained complete benefit and risk information. Under existing FDA rules, if an ad contains the name of a drug or device and any affirmative statement about the product or the disease it treats, then all of the mandatory risk information must also appear in the ad. According to DDMAC, that means that a sponsored link or other web ad may not read something like, "Learn How Spiriva May Help You Manage Your COPD" or "Online Resource for Women with Breast Cancer. www.Femara.com," unless the full risk disclosure also appears in the sponsored link. Having the risk disclosure "one click" away via the hyperlink is not enough.

Since sponsored links resulting from key word searches are generally limited to a total of 70 individual characters, this policy effectively precludes the use of sponsored link drug ads. But the policy has far broader implications for other Internet and social media fora. Is it legal for a drug manufacturer to host a Facebook page or web discussion group in which patients and doctors discuss medicines they're taking or prescribing if every single page does not also include the complete risk disclosure? What about user generated tweets aggregated in a Twitter stream that's embedded on a company-sponsored website? No one really knows for sure how the FDA would treat those issues. And that's a problem.

Again, Silverman points out that, "With the advent of patient-centered 'participatory medicine' poised to become one of the century's great trends in health care, it's more vital than ever that consumers have access [to] well-vetted health information, available via where they live, online. The biopharma industry has recognized this, which is why so many companies have opted to take the risk to push ahead despite the lack of guidance."

As attorney Arnold Friede and I discussed in a short paper two years ago, "The FDA's approach to hyperlinked disclosures is particularly frustrating in light of the Federal Trade Commission's (FTC) more nuanced approach for advertising in other industries. The FTC does not categorically reject hyperlinked disclosures in determining whether an advertisement is misleading or not. Instead, when considering the adequacy of a required information disclosure, it examines the conspicuousness of the hyperlink, whether it signals the availability of risk information, and other contextual factors. Rather than ticking off arbitrary boxes, the FTC looks at an entire presentation and considers the 'net impression' that a 'reasonable man' would form when viewing the information aggregated on linked web pages."

Until April 2009, the pharmaceutical industry had assumed FDA would adopt this so-called "one click" rule for its own purposes. After all, the purpose of a sponsored link is to drive traffic to the web page where the reader can learn more information. But the agency seems to have rejected that common sense approach -- at least so far. Once the agency does settle on a formal policy for Internet and social media advertising, however, adopting the one click rule or some other policy that recognizes the unique limitations and added functionality of the Internet would not be unprecedented. After all, the FDA did something similar with television advertising.

In its "major statement" guidance for risk disclosures in television advertising, FDA acknowledges the inability of TV to carry contemporaneous and instantaneous disclosure of all risk information. Because TV ads are limited to just 30 or 60 seconds, the agency permits drug manufacturers to include just a brief description of the product's "most important risk information," while providing the full risk disclosure through alternative means, such as a toll-free telephone number, in print advertisements that appear concurrently in publications reaching the same audience likely to see the TV ad, or on the Internet.

What's that again? It's an important point, so let me repeat it: FDA's television advertising policy allows viewers of a TV ad to be directed to a drug or device's full risk disclosure on a website not intrinsically connected to the commercial. Under its current interpretation of the statute, however, drug and device manufacturers cannot direct readers of an Internet ad to another, hyperlinked, web page to see the full risk disclosure. It would be ironic -- not to mention downright absurd -- if the agency failed to establish an Internet and social media policy that recognizes the ease with which Internet users can navigate from one web page to another, and to access information linked directly from the one they're currently reading.