Pharma’s Cutting Edge

Story from BusinessWeek suggests that limited liability protections are in the cards to encourage development of at least certain types of high-priority vaccines in the U.S. Let’s hope so. It’s overdo. Hell…I predicted it as a key event for 2005; it would suck to count this one as a loss when I do the year-end tally in January. But, seriously, putting a cap on industry’s liability for high-priority vaccines will provide the impetus for manufatcuring capex and R&D investments that some companies are undoubtedly anticipating.

How is it that a sizeable number of CEOs of healthcare technology firms are not skilled in the sciences and technologies that drive healthcare technology innovation? A better question: How is it that investors do not demand as much at a time when R&D productivity is supposedly under a microscope?

Without such skills, CEOs must rely heavily on the abilities of others to understand and communicate innovation opportunities and challenges for them. For firms focused on the successful identification and management of such opportunities and challenges, it is unrealistic and unhealthy to expect the communication chain from the lab to the executive office to remain unbroken. Think about how scientists communicate with each other. We debate vigorously, directly, at times impolitely. We persuade by weighing the strength of evidence supporting alternative hypotheses and convincing others through logic that the evidence supporting one side is undeniably stronger. This form of communication is not directly applicable to the board room. Non-scientists typically find it frustratingly non-committal and confrontational. It is the rare scientist who can effectively translate this usually arcane discourse and debate into an unbiased, convincing strategy for action.

What’s more, it is not the wise CEO who accepts any advice at face value. It is one of the CEO’s most important roles to question, to challenge, to explore alternatives. How can a CEO effectively challenge expert advice without the knowledge required to ask the most relevant questions? Should an analytically oriented CEO rely solely on the analysis of a trusted advisor? Should an intuitively oriented CEO rely on ill-informed intuition to make judgments? Crash courses in science and technology for key decision-makers are not enough. Communication-skills training for scientific managers are not enough. It is well beyond time that boards of directors require CEOs of healthcare technology innovators to have advanced training and practical experience in science and technology.

Pharma’s Cutting Edge
Vol. 3 Number 11 - November 2005

On Lack of Dose Response and Study Information: A Double Whammy Against Investors

Putting aside just how truly horribly this press release is written, I thought it might be worthwhile to discuss one particular morsel amidst this mess. That is: what does it mean when a company reports positive efficacy results from just the low-dose arm of an ascending dose, parallel-group Phase 2 study?

Let’s first consider the obvious causes of a lack of dose-response. Were the treatment groups well-matched at baseline? We can’t tell from the abstract; perhaps more information was presented at the meeting (the American College of Rheumatology). Of course, most investors don’t attend these meetings, nor do most investors have access to well-written, detailed, timely reports of such meetings. This is why all presentations involving investigational therapies under development by public companies should be made available as soon as possible after they have been presented and should be linked directly to press releases. Why the SEC does not demand as much is beyond me.

We do know from the attached press release that background therapy was heterogeneous, meaning that the possibility for important baseline mismatches among treatment groups is relatively high. We don’t know whether an attempt was made to prevent such differences (e.g. by stratifying randomization on 1 or 2 pre-defined factors) or to adjust for them statistically if they occurred (e.g. ANCOVA). This is key information, folks. Without it the results are nearly meaningless.

Another culprit could be the dose range studied. We’re not provided with the pharmacokinetic properties of this drug nor the relationship between pharmacokinetics and pharmacodynamics (e.g. decreases in immunoglobulins) in this press release, so it would be necessary to research such issues elsewhere. But let’s give HGS scientists the benefit of the doubt and assume that they chose a dose range that should, based on well-defined PK/PD relationhips, have covered the “steep part” of the dose-response curve. Could they have been fooled by Phase 1 data? Absolutely. It happens all the time, especially in diseases like RA, where the primary endpoint is subjective, and Phase 1 studies rely mostly on objective PD measures (also called biomarkers) to determine the PK/PD relationships. Clinical scientists make their best estimates of expected dose-response based on all available data–human, animal and in vitro–often using simulations for assistance, but it sometimes just isn’t good enough. So, it’s possible that HGS just got unlucky and ended up at the top of the dose-response at the lowest dose studied. They’re unlucky, because they still have an obligation to demonstrate a no-effect or minimal-effect dose and a submaximal dose to minimize the potential risk of long-term serious complications of therapy. That means either doing another Phase 2 dose-response study at lower doses or carrying at least two, preferably three, active treatment doses into a Phase 3 parallel-group study. The latter can be accomplished at modest excess cost (but longer duration) over a single dose study by allowing for dose-titration for non-responses to lower doses.

What about the possibilty of a strange dose-response curve, like a genuinely flat curve or a shallow, inverted “U”? I have read about such phenomena, but practically speaking, it rarely happens. Dose responses are usually linear. I don’t know why, but it’s a great thesis project. What does seem to occur with some frequency is a Type II error (failure to demonstrate a true dose response, in this case) due to study design, conduct or outcome factors not directly related to the primary endpoint. For instance, suppose that a drug causes a dose-related side effect that leads either to non-compliance with therapy (i.e. missed doses) or early study discontinuation. Subjects who receive lower doses would be less likely to experience the adverse effect and thus more likely to derive benefit from the therapy. The dose-response would be either flat or inverted, depending on factors including the severity of the adverse effect, the robustness of drug benefit, and the slope of the true dose-response curve. The type of analysis chosen is also relevant. We’re not told whether the primary endpoint was analyzed using interpolation for missing data (e.g. last observation carried forward). In Phase 2, study completer data (data only from subjects who completed all visits) are often used for the primary analysis. Use of study completer data would tend to reduce an apparent treatment effect of doses associated with early study discontinuations.

Note that just being told how many subjects contributed to the primary endpoint inference (i.e. the “N” of each group) would have helped us to deduce whether there were tolerability or safety issues associated with dose. It wouldn’t have been all we needed to determine which of the above factors contributed most to the lack of dose-response, but it would have helped. Generally speaking, I believe that investors should seek maximal transparency from such press releases, which means demanding the type of information I’ve discussed briefly here. Public companies should not be allowed to use the power of widely available information to tout the promise of investigational therapies without also providing a readily available means to check their claims.

So, is this the report that finally raises the groundswell that rids the FDA of its patronage jobs, the smoking gun that reveals FDA management’s scandalous willingness to be influenced by outside agencies with agendas far-removed from concern for public health? Nah…it’s just fun reading…just for giggles.

See this article.  Scott Grundy, a cardiologist at the University of Texas Southwestern who helped write the U.S. cholesterol guidelines, argued that overall the results of the study do show that Tricor was a useful addition on top of current treatment….”What we’re seeing in a lot of clinical trials when we’re working with drugs that are what I might call incremental therapy,” says Grundy, “is the studies are not as robust as were the ones with the cholesterol-lowering, aspirin and blood-pressure lowering drugs.”

With due to respect to the venerable Dr. Grundy…duh. I’m sure he meant that the results are not as robust as the early studies of the drug classes he mentions. The studies themselves being run today are just fine, as I’m sure Dr. Grundy would attest (since he helped design and conduct many of them). In any case, it would have been nice had Dr. Grundy chosen to given the press a sound bite that stressed the difficulty of add-on therapies (of any type) improving the odds of having and surviving a heart attack, given the already dramatic improvements that pharmaceutical and medical device industry products have made to cardiovascular event occurrence and survival over the previous two decades. Yes, it would have been nice.

In any event, see my previous comments on the precarious position drug makers developing PPAR-alpha/gamma dual agonists face after the recent Pargluva non-approval. I’ll discuss second-generation PPAR-alpha agonists by Lilly and others in some future issue of Pharma’s Cutting Edge, once more clinical data are available.