Pharma’s Cutting Edge

It’s funny.  I write these posts usually twice or more per week not knowing who, if anyone, is reading them besides blog reporters (e.g. FDA News, which has generously featured my posts in its daily drug newsletter on numerous occassions), blog aggregators (e.g. Seeking Alpha…ditto), the PR firms that service big pharma (e.g. Edelman; looks like Pfizer’s an important client) and, of course, the search-engine spiders.  So I probably shouldn’t care about not posting for a week or two, especially when it’s due to competing activities that involve me receiving compensation for my thoughts, but I do.  I’ve missed the ritualistic dispersal of my ego to the ether and have even felt a chill of guilt reading through other editorialists’ musings the past couple of weeks.  This makes me think the act of writing the posts provides some catharsis for me, one that was particularly important when I left my last job at big pharma to start my own businesses.  Who knew?  I thought I was providing a service for others, not for myself.

Anyway, I’m no longer on my own, as I’ve become an employee with an established business called Fast Track Systems.  If you’ve been in the biz for a while, you might remember them as Data Edge, the company that supplies most of the pharmaceutical industry with clinical trial/CRO contracts data that are a must-have for benchmarking trial and related outsourcing costs (for planning, negotiation, and audit purposes).  They’ve re-branded, but they still supply the industry with these data, now provided under the collective name TrialSpace (the PICAS clinical “grants” data are now in TrialSpace Grants Manager and the CRO data are in TrialSpace CROCAS).  These data products and related services remain Fast Track’s core business, but in the last few years they’ve hired a young, visionary CEO to build new business in the eClinical space.  I joined them because of their vision but also because they’re delivering on it…now.

Peruse my back collection of posts and you’ll find numerous references to the urgent need for pharma R&D to come up to speed process-wise with other research-based industries.  Clinical research, in particular, has badly lagged not only other industries but also the rest of pharma’s research enterprise in its adoption of time- and cost-efficient operations.  There’s no direct evidence to explain this lag, but I believe it’s largely because of inertial forces in the form of past industry successes (i.e. the really good years), whereby clinical research costs are relatively unconstrained in the face of high returns on R&D investment.  It’s also likely related to the general inertia to process change that pervades medical practice.  Doctors still write office notes and prescriptions on paper for God sakes.  As medical practice comes out of the paper age, so too will the industries that serve it.

Which leads me to the eClinical (can someone please invent a better word) paradigm shift (can someone please invent a better phrase) now occurring in the life science industries.  The move away from paper-based information flow and its associated processes towards electron-based information flow and its associated processes is absolutely necessary to restrain growth in clinical research expenses.  It will do so by improving productivity (the amount of work output for any unit of resource input), reducing cycle time (the time needed to complete a task), and potentially (no, it’s not yet been proven) by increasing technical success rates of therapies that reach the clinic.

I’ll have much more to say about the eClinical revolution in the months ahead.  For now, though, I’ll simply say that I’m genuinely excited to be part of a visionary enterprise that is working hard to make this shift occur quickly and as painlessly as possible.  The technology is here, and it’s ready to be used now.  Are you ready for it?

“[T]he agency is establishing new rules for approving drugs to treat some conditions for which other therapies exist, and you can bet drug companies are frantically re-examining their current R&D efforts.”

So writes Dr. Scott Gottlieb, a recent short-term Deputy Commissioner of FDA, to open his commentary “Drug Danger” published in yesterday’s WSJ. 

As the late, great Sam Kinison playing Prof. Turgeson in “Back to School” once asked:  “Well…Is he right?!?”

In short, no, he’s not right.  Not at face value.  For one thing, nothing happened at the recent Arcoxia advisory committee hearing that shocked anyone who follows the industry or the COX-2 story closely, and it hasn’t left any competent drug companies scrambling to re-examine their R&D efforts.  As Dr. Gottlieb I’m sure knows from his own experience at FDA, industry follows FDA policy-making closely, and when change is afoot, you can bet that drug company execs know it and are either adapting to it if they like it or arguing behind the scenes against it if not. 

For another thing, FDA isn’t establishing new rules.  Hell, FDA hasn’t even made a ruling on Arcoxia yet.  And, even when they eventually rule against marketing approval for Arcoxia, as I’m almost sure they will, FDA dooesn’t set rules by precedent.  FDA must consider each new drug application separately, on its own merits.  Sure, precedence is considered in NDA reviews, but not in the way it’s considered by courts when interpreting the law.  In other words, you can’t view the Arcoxia decision in a vacuum, nor can you assume it portends a policy shift.

But Dr. Gottlieb presumably knows all that.  He also presumably knows that FDA has always had latitude to determine what represents an appropriate balance of risk and benefit to the proposed population for treatment.  The “default condition” provided by law for investigational drugs filed appropriately with the Agency is approval to market.  In order to deny marketing approval, FDA must determine that a drug sponsor has failed to provide adequate evidence that a drug can be used safely as intended.  And only FDA (via powers it receives from the Secretary of HHS) determines what is adequate evidence.  I’m simplifying a bit, but that’s the gist.

The question of interest that Gottlieb raises with his alarmist opening comment is whether FDA testimony given at the Arcoxia commitee hearings reflects a deliberate and pervasive change in attitude among FDA policy-makers that has influenced (allowed?) its scientific reviewers to be more cautious in their calculations of the benefit:risk equation, so cautious, in fact, that they now violate the rule of law, requiring not only that sponsors demonstrate investigational drugs to be safe for use as intended but also measurably better than drugs that have preceded them.  Writes Gottlieb:   “In voting 20-1 to reject Arcoxia, FDA’s advisers said that for certain ailments, we have enough medicines. This will ultimately deny patients needed choices and it reflects a dangerous way of looking at drug development, safety, and, more importantly, the practice of medicine.”

Again, that says nothing about the FDA.  Advisers are free to say whatever they want and FDA has no obligation to heed their advice.  But, for sake of argument, let’s say that Dr. Gottlieb had instead used comments from FDA reviewers to make his point–that FDA believes we have enough medicines for certain ailments and is seeking to restrict approval of new medicines based on some calculation of their relative worth.  And that would be a bad thing. 

Well…Is he right?!?

Yes, I think he is.  I’ve argued as much in these pages and elsewhere several times (funny…no one from WSJ asked me to write an editorial).  Patients DO need medication choices, many choices, in fact to provide opportunities for any given INDIVIDUAL patient to find a treatment that she can use safely as intended and to provide market competition that constrains cost.  But damn if Dr. Gottlieb didn’t pick a bad opportunity to espouse this view; leave out the Arcoxia bit and the WSJ forum becomes a great opportunity to beat back the likes of Marcia Angell and others who would require demonstrations of “superiority” to older drugs before FDA approval of NMEs.

If Arcoxia is rejected by FDA it won’t be because it’s a “me-too” drug that has not been proven superior to older NSAIDs, it will be rejected because it’s a solidly tested follow-on product that really didn’t look so good when used as the sponsor intended in large Phase 3 trials.  Arcoxia might benefit some patients much better than most, and it’s likely that if there were a way to select such patients, the expert advisors would have felt much better about giving Arcoxia the thumbs up.  But Merck did not provide evidence that doctors or patients could use to predict with confidence which patients likely would benefit or suffer disproportionately from using the drug.

By criticizing the committee’s decision, Dr. Gottlieb implies that individual-response prediction tests are best left to post-hoc subgroup analyses of pivotal studies and post-approval explorations.  Sometimes, like when a debilitating condition is poorly served by existing medicines or when an investigational drug provides a clear margin of benefits compared with risks, it is acceptable to allow post-marketing experimentation to determine who benefits and who doesn’t.  And, again, each case must be determined individually.  The advisory committee in this case determined that the availability of Arcoxia outside of research use was not advisable based on the totality of evidence they had before them.  Their decision was not irrational, induced by fear or revenge, and it certainly was not illegal; it’s also not necessarily a harbinger of ultra-conservative decision-making on the rise at FDA, although, admittedly, Dr. Gottlieb’s insider knowledge of FDA has to make one wonder whether he’s on to something.  The pendulum of conservatism is always swinging at FDA, so what’s important to the industry is not where it is today but whether it’s stuck in position–at the wrong end.

When Merck submitted the Arcoxia NDA, it knew it was taking a gamble by relying on a demonstration that Arcoxia was no riskier than an older NSAID, diclofenac, as the key determinant of Arcoxia’s benefit:risk balance.  Diclofenac itself has been implicated as risky, leading FDA epidemiologist David Graham to call for its removal from the US market.  Merck also had an opportunity in its large Phase 3 program to try to identify sub-populations in its trials that could benefit preferentially (or be exposed to less risk) from Arcoxia, such that the benefit:risk balance would be convincingly favorable.  Did they try and fail? 

The onus should always, appropriately, be on sponsors to provide compelling evidence before marketing that allows prescribers to have confidence that a new drug can be used safely as intended.  It’s unnecessary, inappropriate and (I agree with Gottlieb) even dangerous, to allow regulators to create a higher hurdle than this one.

As you might have read in papers like the International Herald Tribune, Exubera, the first marketed inhaled protein therapeutic–recombinant human insulin–isn’t exactly flying off pharmacy shelves. 

Now that sales are flagging, analysts of all stripes are writing that they long ago knew this was going to happen.  This Monday-morning quarterbacking is known in behavioral circles as hindsight bias, or, as I like to call it, bullshit.  What nearly every stock analyst and pundit wrote while Exubera was in Phase 3 testing was that Exubera was going to be a big success.  Nearly every clinical opinion leader I heard from (there were many) said the same thing. 

What happened once Exubera was launched, its lackluster sales, isn’t nearly as interesting as how Pfizer and industry observers reacted to what was happening in the two years prior to launch.  Within industry, there are lessons here for market research, scientific communications, investor relations and executive management of all functions.   Chief among these lessons is this:  If you care about predicting customer responses to new products, and I’m sure you do, you cannot rely on inferences drawn from surveys, interviews, direct observations, product analogs, etc from a single point in time.  You must follow trends in attitudes and actions as information becomes available, and you must do so continuously during development and after launch.  A corollary is that you must carefully plan how you seek and disclose attitude-influencing information. 

Which leads me to my second lesson:  Keeping emerging product information secretive can be important for competitive reasons, but secrets are antithetical to the tasks of predicting market responses to products and to setting financial market expectations; a balance is therefore required.  With a product like Exubera, there were opportunities for disclosing to interested parties, namely key opinion leaders, selected patients, and investors, certain competitive information earlier and more fully than was done.  Here, I’m thinking specifically about the emerging product profile (i.e. safety, tolerability, efficacy, convenience, and usage) and Pfizer’s data and arguments supporting the cost-effectiveness of the product, which I’ve reviewed here previously.  If you’re a Pfizer employee, it’s now time to review whether your internal and external information disclosures were sufficient and timely to meet your market research, commercialization preparation, and financial market goals.  Be brutally honest with yourselves and take corrective policy action if deficiencies are found.  You may need different policies for different classes of products (e.g. a pioneering product vs. a fast follower).

For observers, and investors particularly, my suggested take away is this:  Recognize in yourself your reluctance to change your opinion as evidence mounts to the contrary; the strength of your unwillingness to change your mind is proportional to the strength of your held opinion.  This is hardly a novel insight, as published evidence supporting it dates to at least the 1950’s.  In behavioral circles, it’s known as attitude strength, or as I like to call it, stubborness.  You might not be able to overcome your stubborness, but you might be more willing to hedge your bets if you can admit to it.

You’ve by now read that Dendreon shares surged Friday following a Thursday meeting of a CBER advisory committee that indirectly endorsed FDA marketing approval for Dendreon’s first therapy, Sipuleucel-T (aka Provenge), an active immunotherapy for men with advanced hormone-refractory prostate cancer (HRPC).  If approved, Sipuleucel-T would be the first active cellular immunotherapy for cancer ever marketed. 

The method for producing Sipuleucel-T and its proposed mechanism of action is depicted in this slide adapted from a Dendreon presentation.  Each patient receives a treatment made from his or her own (i.e. autologous) antigen-presenting cells (APCs).  A treatment cycle will generally include three infusions of autologous APCs, at a cost estimated by one Dendreon consultant to be around $20,000 per infusion.

The advisory committee’s endorsement of Sipuleucel-T was based on its relatively benign safety profile (aside from a modestly increased risk of cerebrovascular accidents, the therapy was safe and tolerable) and the demonstration of a median survival advantage relative to placebo of about 4 months in one trial, allowing half the recipients of active therapy to live just over two years.  A second trial was associated with a trend towards improved survival. 

There are very few treatments for HRPC.  Probably the most frequently prescribed regimen in the U.S. is a combination of prednisone and docetaxel (Taxotere, Sanofi-Aventis).  This chemo regimen appears to be less well tolerated than Sipuleucel-T (although Dendreon made no direct comparison) and is associated with toxicities such as edema, liver damage, and neutropenia that have earned it a black box warning from FDA.  In exchange for its troubles, Taxotere added only 2.5 months median survival advantage to men with HRPC in its pivotal trial.  It’s not surprising then, that patients and doctors lament the lack of treatment choices for HRPC and are asking FDA to expedite approval of promising new therapies, Sipuleucel-T in particular.

I think FDA will use common sense and approve Dendreon’s therapy prior to completion of the ongoing 500-patient Phase 3b trial, which is now roughly 80% enrolled and is expected to report in 2010.  As one commenter noted, the drug seems safe and is reasonably well-tolerated.  If there’s a decent chance based on the results of one trial and an integrated analysis of efficacy that it will prolong survival why not approve it.  Sipuleucel-T promises no miracles, but when lifespan is measured in months, patients deserve a chance to add on a few.   

Okay, so all of the above is the good news.  The less good news is that treatment with Sipuleucel-T won’t cure men with HRPC, prevent their tumors from growing or their pain from returning, or return them to the workforce.  It’s also going to cost a pretty penny.  So, economically-speaking, treatment with Sipuleucel-T will be a perceptible, albeit relatively small, burden on U.S. federal healthcare outlays and perhaps on individuals who fall within coverage cracks or doughnut holes.   On the not-so-obvious front, should Sipuleucel-T become widely adopted and viewed as a standard-of-care that cannot be denied to patients with HRPC, it will make it more difficult for other drugs aimed at HRPC to be tested and approved.  Sponsors will likely have to recruit patients with more advanced disease, after they’ve failed Sipuleucel-T.  Remember, Sipuleucel-T is an active immunotherapy and probably cannot be used in conjunction with cytotoxic drugs that suppress T cell numbers or activity.

Dendreon may be on the cusp of bringing the first active immunotherapy for cancer to market after decades of basic research, 11 years of clinical testing and numerous failures by sponsors of other, similar therapies to do likewise.  It’s a momentous achievement.