Uptake blockers do not improve on statins

It has not been a very good couple of weeks for big pharma in the public eye. They've been taking a pounding in the political arena since the primary season finally got into full swing. Last week, we learned that today's medicines, rather than funding tomorrow's miracles, mostly finance power lunches with your cardiologist. And this week, Merck and Schering-Plough, after much delay, finally announced the results of a major study, called ENHANCE, that did not demonstrate any benefit to using the highly-touted drugs Vytorin and Zetia rather than a generic statin.

Because almost everyone who owns a TV knows that Vytorin blocks both sources of cholesterol, and that "Zetia works differently", the results seem particularly damning. The companies involved did not help this appearance by holding back the results so long, and indeed doing so may have exposed them to lawsuits from shareholders and customers. The study was primarily performed by imaging the carotid artery, and in this regard no statistically significant difference was observed between patients treated with Vytorin (statin + Zetia) and statin alone. Also, there was no statistically significant difference in the number of patients who died from cardiac events or strokes, or suffered non-fatal infarctions in the study. While vytorin lowered cholesterol levels by 56% after 24 months vs. the 41% lowering seen in the statin group, this did not translate into improved outcomes by any measure.

So, is this a case of evil pharmaceutical companies trying to gouge consumers over worthless medications? Not exactly. Like every campaign promoting prescription drugs, commercials for Zetia and Vytorin oversold the benefits and did not sufficiently emphasize the risks of these medications. Their failure to improve outcomes in this study is troubling, but because adverse outcomes were so rare overall, it would be difficult to establish an effect one way or another. Also, this study was not geared towards measuring plaques and clots directly; rather it (indirectly) measured the effect of these drugs on atherosclerosis. The effect of uptake blockers on infarction rates was an incidental measurement.

One important consideration when interpreting these results is that the study group was not constructed to resemble the general population. Rather, the study was performed on individuals who had familial hypercholesteremia, a genetic condition that causes greatly elevated levels of LDL in the bloodstream. Without the data in hand I of course cannot make a solid judgment, but one possibility that immediately suggests itself is that in this population even a significant diminution of LDL levels is not sufficient to improve outcomes. There's just too much cholesterol for these uptake blockers to affect the outcome. In a normal individual with significantly lower levels of LDL Zetia and Vytorin might have a much greater effect.

Moreover, all the individuals in this study were already taking statins—which contributed to the low rate of adverse outcomes. It may be that the marginal improvement from adding an LDL blocker on top of a statin simply isn't that great. However, for individuals who cannot take a statin due to side effects, taking an uptake blocker might be a significant improvement over doing nothing. The study does not, as far as I can tell, speak to this possibility.

There is always the possibility that this study points to completely unsuspected aspects of arterial disease. For instance, these results might indicate that once lesions form they attract cholesterol very strongly, and therefore only extreme reductions in circulating LDL can affect their growth. Alternately, this outcome may indicate that mechanisms unrelated to circulating lipids play a more significant role in determining plaque thickness than previously suspected. In light of the highly unusual population used as study subjects, any grand pronouncements in this regard are premature. If these findings are replicated in upcoming studies of greater duration on more representative samples, however, a substantial re-examination may be in order.

The findings of the ENHANCE study don't really indicate that you should burn your Vytorin prescription and go back to just a generic statin, but it does create doubt as to whether this approach will prove efficacious in the general population. Further study, promptly published, is called for, and it would be wise for Merck and Schering-Plough to pull their advertising campaigns for the time being. Doctors should also be less eager to prescribe Vytorin for patients who are responding well to statins alone, but for patients who are not improving greatly with statins (or cannot take them at all), then a prescription for Vytorin (or Zetia) would still seem to be justified. As always, the best approach is to exercise and eat healthy foods, though that's much easier said than done.

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Pharma's Funding Lie

With medical coverage emerging as a major domestic issue for this election cycle, the cost of drugs is likely to become a hot topic, especially given the array of pills many aging baby boomers must take. The industry line is best articulated by a GlaxoSmithKline campaign implying that high drug prices really fund R&D for future drugs ("Today's medicines finance tomorrow's miracles"). Activists counter that the pharmaceutical companies are actually marketing-focused, a view popularly reinforced by incrementalism and the highly-visible promotional campaigns for conditions that are primarily cosmetic, such as hair loss and erectile dysfunction. A new study in PLoS Medicine by Marc-André Gagnon, and Joel Lexchin (click the link, PLoS is free) suggests that the latter view is closer to reality: they find that companies spend in excess of $57 billion annually on marketing to doctors and consumers. This amounts to nearly twice as much being spent on promotion as on R&D (which receives ~$30 billion). While by no means the final say in the dispute, this paper and distortions of its findings (on both sides) may figure significantly in future debates.

The easiest criticism of this paper, and one that may often be repeated, is that the authors did no primary research. The paper is essentially a synthesis of research performed by two independent firms: IMS (its data is widely cited by industry groups such as PhRMA), and CAM. The article contains a single table, and a quick glance at it will inform the reader that whenever two numbers were available, the authors always took the larger. The authors explain this well in the case of detailing, and I agree with their decision there. I also agree with the principle, though I am not convinced of the magnitude, of the "other" category. When it comes to the cost of free samples, however, I disagree with the choice to use the retail price in the assessment.

The authors' justification on this point is rather feeble, and comes across as almost petulant in tone:

Using the wholesale value for samples, the CAM figure would be appropriate if we were arguing that the money spent on samples should go to another activity such as R&D. However, we have used the retail value of samples because this is consistent with companies' reporting of drugs they donate [19]. As these are both categories of products that are being distributed without a charge to the user, it is inconsistent for donations to be reported in terms of retail value and samples in terms of wholesale value.

It seems to me that there is no point to this assessment unless our ultimate intention is to compare money spent on promotions that could be spent on R&D to the actual money spent on research. Certainly that is the only comparison that actually speaks to the issues the authors raise in the introduction. Including money that could not be spent on research or anything else, because it is fictional money, is nonsense. If the aim is to define the actual costs of the promotion to the drug company then the wholesale price is more appropriate. If the authors have an objection to using the wholesale cost for one kind of handout and retail costs for another, then the correct response would have been to use the proper, intellectually honest number (wholesale cost) in their own analysis and argue that pharmaceutical companies ought to do likewise when reporting charitable contributions. Just because Eli Lilly misrepresents its costs doesn't mean you can, too.

However, there are other factors that make the CAM estimate questionable on this point, especially that any number of samples was reported as one. Most likely the actual cost of samples to the company lies somewhere between the CAM and IMS estimates; promotional costs therefore lie somewhere between $48 and $57 billion, or 160% to 190% of research expenditures.

Another key feature to note from the table is that direct-to-consumer advertising makes up a relatively small fraction of the total expenditure. This reflects a truth that anyone even tangentially related to the healthcare system has known for a long time: most of the actual marketing that pharmaceutical companies do is lobbying your doctor. Although they are pervasive, fundamentally uninformative, and frankly annoying, television and print advertisements for drugs constitute such a small percentage of the actual promotional costs that banning them again would not lead to a noticeable reduction in drug prices.

The findings of this paper should also be put in the context of a transformation underway in the pharmaceutical industry. The so-called "blockbuster" drugs that provided substantial profits over the past decade or so will soon lose (if they have not already lost) their patent protection, and some needed to be withdrawn due to failures of the clinical trial system. In order to adapt, many companies are shedding most or all of their R&D operations. The emerging model in the industry is to allow "small pharma"—tiny companies started by academics or entrepreneurs using venture capital—to do most of the legwork and then buy up or enter marketing partnerships with those companies once they have promising products that have passed phase I or II clinical trials. This model was promising and robust up to about two years ago, because plenty of capital was available. In the present economic climate the availability of capital is far less certain, however. In addition, the same issue that induced big pharma to shed R&D—poor ROI—will eventually act to inhibit the venture capital investments that small pharma requires.

Despite this increasing aura of uncertainty, the fact remains that many pharmaceutical companies appear to be undergoing a transition from being primarily research entities to being primarily production and marketing entities. In that light, the new estimate of the research-to-marketing ratio is hardly surprising, though it will doubtless be embarrassing to PhRMA and feed the rhetoric of populists such as John Edwards. Yet despite the vitriol that will surely be spewed, in reality there is little that can be done. As mentioned, the most visible marketing efforts of pharmaceutical companies constitute only a minor portion of actual promotional costs. While it would be wise and probably beneficial to public health to restrict these advertisements once again, it is unlikely that any reduction in medical costs or increases in R&D budgets would be achieved by such regulations.

Congress, if it desired, could take steps to reverse the current trend and strengthen FDA power to restrict off-label marketing of existing drugs, and of course a new President could make this an enforcement priority at FDA. However, enforcement of any such provision would be extremely difficult and subject to legal challenge on First Amendment grounds. Moreover, the FDA (and not coincidentally the USDA) are in need of a major overhaul and possible restructuring in order to achieve their existing missions; stapling on another major enforcement problem will not serve anyone. Regardless, off-label marketing does not constitute a majority of the promotional budget.

The First Amendment clearly protects on-label marketing, and at any rate promotions of proven drugs actually serve the public interest, up to a point, by making doctors aware of improved approaches for dealing with illness. The truth of this statement, however, is inversely related to the degree of incrementalism in drug discovery. "It's a bigger pill" is generally not a compelling rationale for new prescriptions or enormous marketing outlays. Nonetheless, the presence of a definite public interest in allowing marketing to doctors makes unclear what steps Congress should (or even can) take to regulate or diminish promotional spending.

The only tool readily available for public use against on-label marketing is shame. Either the companies themselves can be pressured to reduce their promotional budgets (unlikely), or activists can put pressure on professional societies and medical boards to implement ethical restrictions on what kinds of promotions their members can engage in (possible). Regulations against accepting expensive lunches and dinners or attending marketing "seminars" in exotic locales may be able to push back some spending. In this regard, the Gagnon and Lexchin study may prove a useful tool; the grandstanding of politicians most likely will not.

Fundamentally, however, this trend cannot be stopped, because marketing will always be a better—or at least more predictable—investment than research. Although this attitude is ultimately self-defeating, the safer course to higher profits in the near term is to aggressively market existing drugs and secure longer periods of exclusivity by lobbying for longer patent protection or incrementally improving medicines and delivery systems. The release of combination drugs such as Caduet reflects this sensibility. Most money spent on research never produces so much as a Phase I trial, and the discovery of a revolutionary medicine, though extremely profitable, is also extremely rare. For that reason, a conservative mind will always prefer promotion and production to research and development. This is the attitude that underlies the ongoing strategic shift in big Pharma's approach, as well as the findings, debatable though they may be, of Gagnon and Lexchin.

Gagnon MA, Lexchin J (2008) The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States. PLoS Med 5(1): e1 doi:10.1371/journal.pmed.0050001

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