Pharma’s Cutting Edge

It was bound to happen sooner rather than later, and Pfizer or GSK was likely to be the first to do it: create exclusive contracts with investigators I mean.  That would be your best enrolling sites.  Scared?  You should be. 

As reported by ClinPage from the annual DIA meeting last week, Pfizer’s Andy Lee let on that Pfizer has been signing exclusive deals with Pfizer’s best enrolling sites.  Either the sites will contract for studies only with Pfizer or they will not contract with Pfizer for any studies.  It takes chutzpah to make a move like that, but more than chutzpah it takes research volume, lots and lots of money devoted to clinical research.  Without the money to keep a site at capacity, or on the sidelines getting paid to be at less then full capacity, no company can hope to craft such deals.  Only the very largest research companies can afford this, and even the largest CROs will not be able to wrest a site from big pharma’s grip for the benefit of its more modestly sized clients.  Talk about a game changing situation.

As I say, it wasn’t hard to predict this move, I’m only surprised that it’s been going on for a while, and I hadn’t heard about it.  These things tend not to stay secret.  Why am I not surprised?  Because pharma development productivity, particularly in the later stages of clinical development, must improve to compensate for environmental pressures on sales and volume growth.  It must, or the industry’s entire business model is in jeopardy, and I don’t see the industry allowing its model to collapse without a good fight.

Despite some propaganda to the contrary, the workflow inefficiencies constraining overall development productivity are not widely appreciated, and no company has demonstrated that it knows how to improve productivity, however it is (reasonably) defined.  That said, it is likely that local operational inefficiencies, such as those confounding clinical study enrollment, are disrupting local process flows sufficiently to negatively affect cumulative study completion rate.  In other words, know one knows for sure, but it’s likely that decreasing the average time from protocol approval to final subject enrolled will ultimately decrease total development cycle time without diminishing the quality of development (i.e. the learning that accrues from doing studies), thus improving R&D productivity.  It’s also pretty clear that if you can find a way to contract with better performing (in terms of enrollment) sites more frequently, you are more likely to decrease this cycle time.  As Pfizer’s Lee noted in his DIA appearance, and is generally appreciated now, some investigative sites consistently enroll better than others, and it’s believed that they do so without diminishing the quality of research.  If you can lock these high-performing sites up, with exclusive contracts say, you’re more likely to increase enrollment speed than if you must compete for sites and risk losing high-performer to your competitors.

As far as I know, Pfizer is the first to try this all-or-none strategy.  I think other firms will wait to see how it shakes out before following their lead.  Although, as I say, exclusivity is the surest way of locking up the best performing sites, it’s also probably the riskiest.  A company the size of Pfizer doesn’t have to worry about not doing enough studies to keep a site busy–thereby wasting the premium it must pay to maintain exclusivity–but it does have to worry about frightening or angering the doctors that prescribe its drugs.  It’s easy to imagine that an investigator or research institution might wish not to engage in an exclusive relationship with a single sponsor:  Will it create a perception among patients, insurers, regulators, or professional associations that she is in the sponsor’s back pocket?  Maybe such thinking is reasonable, especially for academic sites.  Harmful perceptions aside, I would imagine that many high-performing sites will find such strong-arm negotiating tactics ridiculous.  After all, from the investigator’s perspective, it’s not as though research studies are hard to find.  It’s a supplier’s (investigator’s) market in developed countries by all accounts.  Why not hold out from such a deal, and let competition decide who gets the best sites?  If supply remains regionally and situationally constrained, as it is presumed to be, investigator grant payments will continue to increase.  Exclusive deals, unless very lucrative, will not benefit sites in these regions.  And perhaps no amount of money will satisfy some site’s need to work on the most promising medicines, regardless of who is developing them. 

This enrollment strategy absolutely is worth keeping an eye on.  If any investigators have signed such a deal with Pfizer or another firm, I’d love to hear from you.

I’m interested in expanding coverage of innovative technologies and business models at startup firms, including drugs, biologicals, and enabling technologies.  If you work with or for a startup that you’d like to see get some attention in these pages, please feel free to contact me. 

Last September, I argued in this blog for a data infrastructure, which would be supported by a public-private partnership, capable of capturing real-world, “N of 1″ clinical experiments.  Such experiments collectively represent a huge potential repository of clinical scientific evidence.  Today, experimental evidence coming from routine clinic encounters is underutilized.  Case reports, case series, and retrospective chart reviews, have gained a reputation as weak evidence of causation (typically described as anecdotal evidence) and have thus fallen into disfavor.  Too bad, because such anecdotes have historically frequently been the impetus for exploration of a new use for a drug or a signal of an adverse effect that was previously unseen or unrecognized as therapy-related.  In contrast, with the rise of managed care and the need for drug and device manufacturers to demonstrate a favorable benefit to risk balance for new therapies, studies that make use of databases linking diagnoses, outcomes and therapies are becoming more common.  Such studies are likely to become increasingly important for delivering improved safety surveillance of therapies and would benefit from larger, more demographically diverse patient pools.  They would also benefit from a larger amount of clean contextual metadata (data about data).  For instance, researchers might now be able to tell when a prescription was first filled by searching PBM or insurance records, but it would be more difficult to ascertain the day the prescribed drug was stopped.  However, perhaps the prescribing physician noted in the patient chart (the Electronic Health Record, EHR, in my utopican example) that the drug was stopped 20 days after filling the prescription because of a rash that developed and was restarted after a 30-day off period without reoccurrence of a rash.  Charts may be abstracted for smallish studies, but you can’t manually abstract charts on a million patients.  Plus, today’s abstractions (e.g. CPT coding) are lossy mechanisms for transforming information into a usable form.

So, what’s needed for both the small case studies and the large epidemiological studies is a scalable infrastructure capable of pooling information from disparate sources and storing it in a way that makes it accessible to a variety of information systems, ideally without significant information loss.  I imagined that such a system was far off, but maybe I was being pessimistic.  In the June issue of BIO-IT World, Mike May reports on the Mayo Clinic’s efforts towards making this vision a reality.  They call their system LexGrid, or Lexical Grid.  LexGrid is described by Mayo as “a way to bridge terminologies and ontologies with a common set of tools, formats and update mechanisms.”  Basically, as I understand it, LexGrid takes these variously coded ontologies from all sorts of information systems (pharmacy, EHR, lab, etc) and links them together, representing them by a common model.  So, local data elements become common data elements, local descriptions become common terminologies, local classifications (like CPT) become defined by the common terminology structure.  Pretty cool idea.

Even cooler is that it’s being done in clinical medicine first, and the system’s designer Christopher Chute has some grand visions for how it can be used:  “every [person] on the planet would have every health encounter…stored as a structured representation of that event, so that you’d be able to ask useful questions across nine billion people.”  Now that’s what I’m talkin’ about.  How about pharma getting behind Dr. Chute and his colleagues on this project? 

Vical, yesterday reported that its licensee, AnGes MG, a Japanese gene therapy firm, achieved an important milestone in its development of gene therapy for critical limb ischemia.  The therapy delivers plasmid-containing hepatocyte growth factor gene directly to the affected vessel via catheter and balloon. 

The Phase 3 study reported that over 70% of HGF-treated subjects experienced improvement in symptoms or ulcer size compared with 30% on placebo.  AnGes plans too submit an NDA to Japan’s MHW.  A similarly designed Phase 2 study of the therapy is currently recruiting in the U.S.

If approved, pHGF would be the first gene therapy approved in an ICH territory country for treatment of peripheral arterial disease (PAD).  Genzyme is currently testing an unrelated gene therapy for severe peripheral arterial disease.  This is a disease in need of drastic medical and surgical treatment improvements.  I’ll be watching for additional evidence of gene therapy effectiveness in PAD and will provide updates as warranted.

In my last post, I  discussed what I believed would be the basis for debate and concern among the panelists at Wednesday’s FDA DMEDP Advisory Committee–the benefit to risk balance of the drug in light of modest efficacy and risk of suicidality.  This was indeed the topic of much of the committee’s deliberations.  As you now know, the committee voted unanimously (14-0) against approval of rimonabant due to a perceived unfavorable benefit to risk balance.  They also voted unanimously that Sanofi-Aventis hadn’t sufficiently characterized the safety profile of the drug.

What does this mean?  It means that this FDA division and its outside advisers, and probably much of CDER along with them, is taking the position that they want real, sustained evidence of benefits when risks during chronic use of a drug are small in number but potentially fatal.  Stated differently, risk tolerance is low among this regulatory body, and it wants to see relatively more evidence of benefit to counterweigh a risk of a serious adverse event than in the past (I’m thinking 2 to 3 years ago).  With rimonabant, they looked at a drug intended for chronic use that was associated with modest, reversible benefits on weight and markers of cardiovascular disease; no long-term cardiovascular outcome evidence; tolerance issues that promoted drug discontinuation, and an uncommon but potentially fatal adverse effect.  In the current regulatory climate, rimonabant never stood a chance.

Perhaps DMEDP and its advisers would have thought differently had rimonabant been a drug developed to treat a disease without the social baggage of obesity.  In this country, many people, including many health professionals, still consider obesity a condition caused solely by sloth and overindulgence that should be treated by willpower alone.  But I don’t think so.  Rather, I believe that this division and its advisory committee members are simply willing to be more paternalistic than in recent history, in light of missteps made by prescribers, pharmacists, sponsors and others that have led to a series of recent, high-profile drug recalls and new prescribing warnings for marketed drugs.  In essence they’re saying:  “The American public is either unable or unwilling to responsibly manage its use of new drugs.  Until that situation changes, we must intervene by taking away the tough decisions…by limiting the choices that are available to it.”

I haven’t seen FDA place a lot of the blame on itself for the inability or unwillingness of prescribers and users of new drugs to manage their use responsibly, but most senior folks at FDA must know that through their inability to demand creation and dissemination of effective prescribing information, and through their inability to demand creation of and to enforce effective new-drug risk management plans, and through their unwillingness to require the types of large trials needed to define risk before marketing that they shoulder part, perhaps most, of the blame.  None of this has to do with the needed resources for postmarketing surveillance being requested in the new PDUFA negotiations; I’m only speaking of what needs to happen before a drug reaches the market.  For that, FDA has said it has the resources it needs to do the job well.  So, why hasn’t it?

Sponsors, for their part, also shoulder significant blame for the rise of paternalism at FDA.  Perhaps they just missed seeing the writing that has been on FDA’s wall for the past few years, but I think they saw it quite clearly and chose in some cases to ignore it, hoping it would go away, and in others to address it weakly, with a wink to their investors.  Now they must overcome this guilty-until-proven-innocent mentality to market new drugs for chronic disease states, not to mention the formulary and insurance coverage hurdles awaiting new drugs once approved for marketing.  The regulatory landscape won’t change for quite a while.  If anything, we haven’t seen the top of this wave.

Sponsors, if you hadn’t heeded prior warnings, you’ve now been clearly warned:  It’s up to you and you alone to demonstrate that your new chronic-use drugs work as intended, using highly relevant and generally accepted measures of effectiveness; that they can be used safely, where safely means that the risk of use is very clearly outweighed by the benefit, even if that means you must find ways to limit risk by restricting the user base and creating redundant methods of safeguarding their proper use.  New chronic-use drugs must also be priced so as to be fiscally viable to large purchasers, and their value must not be a matter of faith but rather of overwhelming evidence.  Which other companies are in late stages of development with CB1 antagonists?  That would be Pfizer, Merck, and Solvay/BMS.  We’ll see soon if they have been paying attention.

Sanofi-Aventis made many of the right moves with rimonabant.  They misstepped by not gathering safety information in a way that could be used to create a sound risk-management strategy. There is time for them to make amends, in part, by gathering more evidence of both efficacy and safety.  Should S-A be able to generate evidence from the CRESCENDO outcomes study already in progress that very obese users (i.e. BMI >40) experience a meaningful reduction in their risk of cardiovascular events while using rimonabant, they will go a long way towards tipping the scales in favor of benefits.  In the meantime, S-A must collect more evidence from Europe that shows the drug can be used safely in the “real world”.  This, combined with some way of predicting suicidality through the use of simple baseline measures, other than or in addition to weight and history of depression, should suffice to create a viable risk management strategy.  Whether S-A would want to launch in the U.S. with a restrictive prescribing strategy and its attendant black-box warnings is another question.