Pharma’s Cutting Edge

Just a quick update on NICE’s technology appraisal of Exubera, Pfizer’s inhaled insulin.  In May, I reported on the draft NICE tech appraisal in an in-depth review.  NICE issued their Final Appraisal Determination on October 12th, and the period for appeal ends tomorrow.  If Pfizer does not appeal the FAD, it will be used as the basis for a NICE guideline.

This appraisal provides good insight into stringent requirements for cost-effectiveness demonstrations, particularly regarding evidence standards.  Whatever you might think of it, this is where evidence-based medicine lives today.  If you’re not already familiar with it and you work in the industry, this appraisal is a good opportunity to gain familiarity.

Amylin was good enough to provide a PDF of supporting materials from its R&D day yesterday (see Amylin - Investor Relations - Event Details).  I wish more companies were so kind to the interested public. 

As expected, though, juicy details of Exenatide LAR–this company’s best chance of making the big time soon–were hidden from view.  Nevertheless the single data slide on LAR suggests that proof-of-concept in humans has been demonstrated.  Now, it’s a matter of awaiting Phase 2 to complete, making enough of the stuff to do Phase 3 and sell it.  Amylin hints at their time line for this by stating that they expect to finalize the commercial manufacturing process by 2H08.  Typically, a company won’t ship Phase 3 drug supplies until the commercial process is established or nearly so.  Expect a minimum of 18 months before filing for approval after Phase 3 starts, pushing a filing to 1H10 by my reckoning.  I don’t know what Amylin has previously told investors about this.

The only other reason I mention this research day is that I like Amylin’s approach to research.  They’re sticking with what they know best–neurohormonal regulation of metabolism–instead of diversifying into all sorts of therapeutic areas (their foray into CHF with GLP-1 the single exception).

It’s an axiom by now that diversity in the pipeline of an emerging company is a good thing, and it likely is, to the extent that technology diversity does not unduly impinge on a small-firm’s experience (aka incumbent) effects.  Such effects are essentially learning opportunities that come only through experience. Experience effects contribute greatly to productivity, in this case R&D productivity.

So there’s a tradeoff a small firm must make between diversity of the pipeline, which increases the chances of A product succesfully entering the market by diminishing the risk that ANY ONE technology will fail in development, and gaining experience that allows it to compete with larger firms, without requiring extraordinary sacrifice by investors or risking insolvency.  It’s a difficult tradeoff to get your brain around, given the multiplicity of factors that interact nonlinearly, which is why system modeling of the type I’ve discussed previously is advisable. 

Try to get a hold of the article by Eichacker et al in today’s NEJM  (sub. req.) entitled: ”Surviving Sepsis: Practice Guidelines, Marketing Campaigns, and Eli Lilly”.  They give the most detailed published account that I can recall that attempts to show how industry influences clinical practice guidelines.  They do so by temporally aligning communications made at scientific events with guideline development progress, revelations of clinical trial data and pharmaceutical sales (see the supplemental bibliography to the published editorial) for their sources of information).  In this effort, the authors are assisted by Lilly’s own PR firm for Xigris (rhAPC, Lilly’s drug to treat sepsis), Belsito & Company, which published a brief account of its “surviving sepsis” campaign on the Council of PR Firms website (I’m guessing this account will be removed from the site soon, so read it while you can).

Influencing practice guidelines is part of what the industry does.  It is fiduciarily obligated to its investors do so, to the extent it is allowed, because in the age of evidence-based medicine, disease management and quality-based compensation of physicians, practice guidelines increasingly influence prescribing, and you can’t sell drugs without prescriptions.  That said, it is also in industry’s interests to behave ethically, honestly and to the benefit of its customers (both doctors and patients) as it does so.  The two goals are not mutually exclusive!  There are at least two sides to every scientific story.  To the extent that an industry member argues its side aggressively, it can hardly be blamed.  To the extent that it lies or obscures the truth when doing so, it can be.

In the case of Eli Lilly and guidlelines for the management of sepsis, Eichacker et al suggest that the whole truth was not revealed by practice guidelines.  They don’t go so far as to state that Lilly was responsible for the guideline omissions, but they imply as much.  I hope that Lilly feels the need to respond directly to this implication, as it should every similar implication, because a questioning of the integrity of a pharmaceutical company in a visible public forum such as the NEJM is always serious enough to warrant a direct response.  If Lilly did something wrong in this case, they should own up to it and make amends.  If not, they should show where Eichacker et al over-reached when drawing their conclusions or making their implications.

The practice of influencing clinical guidelines is certainly not new.  Perhaps the best-known example is also probably one of the first: when Merck influenced and then widely promulgated NCEP cholesterol guidelines to boost sales of Mevacor (Mevacor was approved in September 1987; the first NCEP guideline was published in January 1988).  See this U of Michigan case study for a very brief account.  With Mevacor, Merck showed the industry the way, and the industry has become more adept at managing guideline and thought-leader development ever since.

Eichacker et al have used the Lilly example as a reason (excuse?) to raise alarms about industry influence over medical practice guidelines generally, albeit some 15 years late.  There’s no denying that they raise some valid concerns.  However, they offer little in the way of practical suggestions for addressing them.

It’s easy to say “Ban industry funding of practice-guideline development efforts and its financial support of the individuals involved in such efforts.”  But, even if such a ban were agreed to by likely industry-fund recipients, those organizations and individuals determined to take industry money for their efforts would find a way, including through other non-banned funding mechansims (e.g. of research projects) to do so.  And this “solution” provides no alternative funding sources for such efforts that are without their own conflicts, some potentially much more worrisome than those discussed by Eichacker et al (think managed-care funding for one).

Medical science, medical education and medical practice in most of the world is inextricably linked and dependent upon pharmaceutical industry funding and will likely remain so for the forseeable future.  It is unreasonable to expect that the industry will spend money on research without some control over how that money is spent, and it is also unreasonable to expect industry to fall short on its obligations to its investors when it comes to influencing medical practice, thereby maximizing the commercial value of its products. 

Understanding this reality, responsibility falls first upon the medical community to find practical solutions to keep industry money from unduly swaying legitimate scientific debates in industry’s favor.  Avoiding taking industry money for one effort (e.g. IDSA’s refusal of industry support for its practice guidelines) and accepting it for another is merely the appearance of avoiding undue industry influence.  To minimize the potential impact of financial conflicts, it makes more sense for physician organizations to require objective guideline-development criteria that don’t favor industry-funded studies over non-industry funded studies and guideline-development procedures that involve broader swaths of the medical community working in an open environment (e.g. online).

For its part, responsibility falls on the industry to help dissuade its member companies from abusing their influence over key medical decision-makers, even when non-offenders may not be directly affected by the unethical behavior.  I have not read any suggestions from industry members how to do this.  Here’s one:  appoint a board of ethical review officers within the major trade organizations (in the U.S., PhRMA and BIO) whose responsibilities include writing industry standards of ethical behavior and policing medical practice guidelines.  If evidence of unethical behavior is found in a guideline, an inquiry is launched, and, if a member company is found to have violated ethical standards, it would face sanctions such as revocation of trade-group listing and public “outing”.  It might not be viewed as a serious solution to those who would prefer to see Pharma divorced from medical practice and policed by public governments, but to the industry it would be a huge concession to academic medicine and a huge step forward.

You’ve probably read that Januvia, Merck’s DPP-IV inhibitor for type 2 diabetes was approved today as monotherapy and as add-on therapy to either of two other types of oral diabetes medications, metformin or thiazolidinediones (TZDs), to improve blood glucose control in patients with type 2 diabetes when diet and exercise is not enough. 

I’ll have a look at the label and FDA reviews for Januvia as soon as I can, focusing on the evidence Merck presented to assure FDA that Januvia is safe in a broad diabetic population.  I’m already convinced that it is effective in relatively early diabetes and has the exciting potential to slow the progressive beta cell failure that is a hallmark of the disease. 

As far as safety, you’ll recall that DPP-IV is a coactivator of T cells and is involved in metabolism of a number of peptides, so there is a theoretical safety issue with inhibiting it with a drug like Januvia.  Given that FDA’s DMEDP didn’t ask for advice from its advisory committee, I’m assuming that there were no safety signals to speak of.  If the safety evidence in the reviews and label is compelling, I see no reason other than cost (~$5/day) not to try Januvia as first-line therapy.  Cost will likely keep Januvia off many Tier 1 (low co-pay) formularies for monotherapy, where both generic and branded forms of metformin are cheaper.  That said, there’s a very large potential patient base for this product in monotherapy and combination therapy, and I expect its uptake to be robust, better than the uptake of Avandia when it was first launched.

Congratulations are due to Merck.  Well done.

Dennis Nowak reports on the rampant dissatisfaction with working conditions among German doctors in the Oct 12th issue of the (”Doctors on Strike — The Crisis in German Health Care Delivery).  If you care about the future of healthcare delivery, and you’re not already familiar with the German healthcare system, read this brief and compelling account. 

In it you’ll read how most of Germany’s physician’s have recently walked out of work to protest an increasing workload and relatively low wages (the purchasing power of a German physician’s wages is now about 20% that of a U.S. physician).  It wasn’t always this way, when healthcare costs were lower as a percentage of GDP, German physicians worked relatively less and earned relatively more.  But Germany has relied on sacrifices among its healthcare workers to help constrain growth in government healthcare costs.

As result of this policy, the loss of purchasing power for physicians in Germany has been paralleled by relatively small increases in Germany’s per capita public healthcare expenditures.  According to a 2005 NBER report from Christian Hagist and Laurence Kotlikoff that compared healthcare costs in ten OECD countries,  Germany’s per capita healthcare expenditures increased at an annualized rate of 3.6% between 1970 and 2002, the lowest annualized rate among major economies.  Compare this rate with Norway’s, the highest, of 5.3%.

Despite the controlled growth in per capita healthcare expenditures, Germany’s per capita healthcare expenditures as a percentage of GDP have spiralled upwards, becoming the highest among the 10 leading economies (8.6%).  This is because of Germany’s anemic GDP growth over this period, just 1.5% annualized, again the lowest among major economies.  As a result, Germany’s per capita healthcare expenditures as a percent of per capita GDP has increased, to become the highest among the 10 major economies in 2002 (8.6%).  Compare Germany’s level of spending with the U.S. 2002 level of 6.6%, which puts the U.S. in the middle of the pack [note that I’m speaking of per capita spending in 2002; aggregate spending on healthcare as % of GDP is higher in the U.S. than in Germany: ~16% vs. ~11%].

You can quickly see how a healthcare delivery crisis can arise when the general economy weakens and a dominant proportion (80% in Germany in 2000; compare with 45% of healthcare spending from public sources in the U.S. in 2004) of healthcare expenditures are made by the government: governments restrain healthcare costs by putting downward pressure on healthcare-worker wage growth, as GDP growth stalls, but real-wage growth lags healthcare delivery needs (owing to population aging) resulting in overworked, underpaid healthcare workers who then look to other countries for better conditions, leaving less highly qualified workers, who work more, so quality suffers, etc.

Is Germany’s crisis a foreshadowing of healthcare crises everywhere?  Just wondering.