Sell Side Bias and Scientific Stockholm Syndrome: A Report from the Annual Meeting of the American Thoracic Society

What secrets lie inside?

Analysts working on Wall Street are sometimes categorized as working on either the "buy side" or the "sell side" depending on whether their firm is placing orders for stocks (buy side, such as institutional investors for mutual funds) or filling orders for stocks (sell side, which makes commissions on stock trades).  Sell side bias refers to any tendency for the sell side to "push" stocks via overly optimistic ratings and analyses.

Well, I'm at the American Thoracic Society (ATS) meeting in San Diego right now, and it certainly does feel like people - everyone - is trying to sell me something.  From the giant industry sponsored banners, to the emblazoned tote bags, to the bags of propaganda left at my hotel room door every morning, to the exhibitor hall filled with every manner of new and fancy gadgets (but closed to cameras), to the investigators themselves, everybody is trying to convince me to buy (or prescribe) something.  Especially ideas.  Investigators have a promotional interest in their ideas.  And they want you and me to buy into their ideas.  I have become convinced that investigators without industry ties (that dying breed) are just about as susceptible to sell side bias as those with industry ties.  Indeed, I have also noted that the potential consumer of many of the ideas himself seems biased - he wants things to work, too, and he has a ready explanation for why some ideas didn't pan out in the data (see below).  It's like an epidemic of scientific Stockholm Syndrome.

The first session I attended was a synopsis of the SAILS trial by the ARDSnet investigators, testing whether use of a statin, rosuvastatin, in patients with sepsis-incited lung injury would influence 60 day mortality.  The basis of this trial was formed by observational associations that patients on statins had better outcomes in this, that, and the other thing, including sepsis.  If you are not already aware of the results, guess whether rosuvastatin was beneficial in this study.

Cost: The neglected adverse event / side effect in trials of for-profit pharmaceuticals and devices

Amid press releases and conference calls today pertaining to the release of data on two trials of the investigational drug pirfenidone, one analyst's comments struck me as subtly profound. She was saying that in spite of conflicting data on and uncertainty about the efficacy of the drug (in the Capacity 1 and Capacity 2 trials - percent change in FVC [forced vital CAPACITY] at 72 weeks was the primary endpoint of the study) IPF is a deadly and desperate disease for which no effective treatments exist (save for lung transplantations if you're willing to consider that an effective treatment) and therefore any treatment with any positive effect however small and however uncertain should be given ample consideration, especially given the relative absense of side effects of pirfenidone in the Capacity trials.

And I thought to myself - "absense of side effects?" Here we have a drug that, over the course of about 1.5 years reduces the decline in FVC by about 60ccs (maybe - it did so in Capacity 2 but not in Capacity 1) but does not prolong survival or dyspnea scores or any other outcome that a patient may notice. So, I'm picturing an IPF patient traipsing off to the drugstore to purchase pirfenidone, a branded drug, and I'm imagining that the cash outlay might be perceived by such a patient as an adverse event, a side effect of sorts of using this questionably effective drug to prevent an intangible decline in FVC. The analyst's argument distilled to: "why not, there's no drawback to using it and there are no alternatives", but this utterly neglected the financial hardships that many patients endure when taking expensive branded drugs and ignored alternative ways that patients with IPF may spend their income to benefit their health or general well-being.

This perspective is even more poignant when we consider the cases of "me-too" drugs that add marginally to the benefits or side effect profiles of existing drugs, and which are often approved on the basis of a trial comparing them to placebo rather than existing generic alternatives. One of the last posts on this blog detailed the case of Aliskiren, and I am reminded of the trial of Tiotropium published in the NEJM in October, among many other entire classes of drugs such as the proton pump inhibitors, antidepressants, antihistamines, inhaled corticosteroids, antihypertensives, ACE-inhibitors for congestive heart failure, and the list goes on.

Given todays economy, soaring healthcare costs, and increasing financial burdens and co-pays shouldered by patients especially those of limited economic means or those hit hardest by economic downturns, we can no longer afford (pun intended) to ignore the financial costs of "me too" medications as adverse events of the use of these drugs when cheaper alternatives exist.

In terms of trial design, we should demand that new agents be compared to existing alternatives when those exist, and we need to develop a system for evaluating the results of a trial that does not neglect the full range of adverse effects experienced by patients as a result of using expensive branded drugs. Marginally "better" is not better at all if it costs ridiculously more, and the uncertainty relating to the efficacy of a drug must be accounted for in terms of its value to patients, especially when costly.