Jan 072008
Blogging on Peer-Reviewed ResearchWith 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

 Posted by at 4:26 PM
Oct 042007
The past decade, and in particular the past five years, has seen a steadily increasing drumbeat of concern over the possibility of another influenza pandemic. Avian flu has been a topic of special concern, but the American health system’s inability to deal effectively with even normal flu variants has led to significant efforts to upgrade capacity to manufacture the flu vaccine, as well as improve the supply and distribution of the neuraminidase inhibitor oseltamivir phosphate, better known as tamiflu. Because there are so few effective antiviral drugs, tamiflu is an essential line of defense in case vaccination fails. Unfortunately, it appears that the influenza virus can develop resistance to tamiflu treatment, which would be a serious blow to efforts to control the disease in an emergency. The wise course is to use tamiflu sparingly and at a high enough dosage that the infection does not have time to adapt. But will this be enough?

Tamiflu has the interesting property that the drug in the tablet is ineffective against the influenza virus. Tamiflu gains function inside the body due to chemical processing in the liver that reveals a reactive moiety. If you have an influenza infection, some proportion of the oseltamivir molecules will end up binding to neuraminidase, but the remainder will be excreted without further modification. This means that every time you are dosing a person with tamiflu you are also dosing the environment with it. That could be trouble, because some strains of influenza incubate in the wild, among ducks, for instance, who are likely to be swimming on the rivers or ponds where excreted tamiflu might be expected to end up. If these animals are constantly exposed to very low doses of tamiflu, it is quite conceivable that the viruses within them could evolve resistance to it without losing neuraminidase activity.

The question then becomes whether anything in the environment might degrade tamiflu before it reaches the ducks. We have one advantage in this regard: we generally treat our sewage before we let it go. In an experiment I do not envy one little bit, a Swedish team led by Jerker Fick tested actual sewage to see if oseltamivir carboxylate (the active form of the molecule) would break down in it (the article is open source on PLoS ONE). They took raw sewage, as well as samples of sewage at various stages of treatment, added oseltamivir, and incubated them with a similar temperature and duration to what they might experience in the treatment plant. The results were not encouraging: the amount of tamiflu they were able to recover from these samples was as much as or more than what they could recover from plain tap water incubated under the same conditions. Moreover, they found that the UV/visible light absorbance spectrum of tamiflu would not be conducive to photolysis in the environment. The conclusion from this is that we cannot expect any help from our water-treatment facilities in eliminating oseltamivir from water supplies that might eventually reach host organisms for influenza.

This puts us in a bit of a bind. It is impossible to use tamiflu without releasing it to the environment, even if it is used in accordance with rigorous guidelines designed to prevent resistance from arising in people. Yet, the more tamiflu that reaches the environment, the more likely it is that continued exposure among waterfowl will lead to the development of resistance. Although this is bad news for the future of tamiflu, it doesn’t necessarily herald the inevitable onset of some kind of superflu. For one thing, some of the mutations that confer tamiflu resistance also diminish the ability of the influenza virus to infect hosts. Moreover, there’s no guarantee that tamiflu in the environment will end up dosing avians — it might break down in their stomachs, even if it doesn’t in the sewage plant.

Also, some mutations that confer this kind of resistance leave neuraminidase vulnerable to other inhibitors such as zanamivir (Relenza). Granted, Relenza does not appear to be as effective as Tamiflu, but the fact that resistance is not necessarily shared is an encouraging sign that it will be possible to continue developing improved inhibitors even if the worst happens.

However, the results of this paper and the fact that tamiflu-resistant strains can be transmitted to people who have never used tamiflu indicate that we should be making a greater effort to prepare ourselves for the appearance of resistance. Much has been made about efforts to stockpile tamiflu in case of a pandemic, and while there is nothing wrong with that idea per se, it is foolish to assume that tamiflu is some kind of panacea. If a pandemic does occur, with the attendant explosion of evolutionary possibilities for the influenza virus, the chances of a rapid development of resistance in humans may be quite high. At that point it will be too late to start developing alternatives. In the near term, we should do as has been suggested — use tamiflu sparingly and aggressively to minimize the chances of developing resistance in humans. But we should also provide incentives or a mandate to develop a back-up plan in case tamiflu fails.

Oct 042007
If you wanted to keep someone from driving off in their car, how would you do it? There are some obvious answers: you could put some kind of blockage in front of and behind it, or you could slash the tires, or you could damage the engine, or you could empty out the gas tank. All of these approaches directly interfere with the mechanisms that allow the car to move. Alternately, you could take a more indirect approach: you could break the doors so they don’t open, or remove the steering wheel, or take out the brake and accelerator pedals, or remove the stickshift. None of these latter approaches make it impossible for the car to move — the engine and wheels still function — but by removing the means that allow human beings to control the car these approaches still manage to ensure that the vehicle cannot be driven.

The traditional approach in structure-based drug design is to attempt to block the active site of a protein or important interacting sites, analogous to the “direct” approaches I outlined above. By adding a lump of stuff that obstructs enzymatic activity, ion transport, or (more recently) binding interactions these drugs attempt to interfere directly with the biochemistry of the target protein. This approach has been pretty successful, and certainly no reasonable person would want to depart from it, but there are some weaknesses here. For one thing, many diseases don’t originate from enzymes or ion channels, and developing drugs that obstruct binding interactions can be pretty tricky.

Imagine your disease arises in the following system. You have some kind of receptor (R in my little cartoon over to the side there) that can bind a ligand (L). Binding of L activates R in some way so that it can bind to a partner (P) and this causes some gene to be activated. This cartoon roughly represents the way in which hormone receptors (like for estrogen or testosterone) function. Now, suppose something has occurred to derange this system: perhaps too much of L is being made, or R and P have been aberrantly expressed in some tissue where the gene they activate is toxic or causes inappropriate cell proliferation.

If we come at this by the conventional approach of targeting the L-binding pocket, we have a problem, because any drug that has an affinity for R high enough to displace the natural ligand is likely to produce the same or similar conformational changes that cause P to bind. We could, of course, try to develop a drug that interferes with P’s binding directly, but this approach has its own problems. For one thing, these binding surfaces are often quite large and highly structured, features that are often difficult to replicate with a small molecule. You can create a drug that inserts itself into the site somehow and gets in the way of P binding, but it’s not always possible to design such an agent that specifically hits only your protein. A peptide mimic of R might work, but these are also difficult to deliver.

But there’s another strategy that might work, too. Rather than try to block R from binding L or P directly, what if we could cause some other change in R that prevents P binding whether or not L is around? Just like removing the accelerator or stickshift from the car of my example, this doesn’t directly block either function of the molecule. R can still bind L, and the binding surface P interacts with is still present. However, our drug (D) has caused a new change in R’s conformation that prevents the binding of P. A simplified cartoon is at left.

This is precisely what seems to have happened in a study on the androgen receptor (AR) appearing the October 9 issue of PNAS and reported by Eva Estébanez-Perpiña and coworkers from UCSF and St. Jude’s. Interestingly, this group of researchers was initially seeking to produce a direct inhibitor — in this case, a drug that would bind to the part of AR that interacts with its coregulators. This interaction is therapeutically interesting because aberrant AR activity plays a role in prostate cancer, among other things. Several promising compounds were found that produced substantial inhibition of AR activity at relatively low concentrations. The surprise was that only some of these preferred to bind the targeted site (AF-2). Instead, a number of them were found to locate preferentially to a previously unsuspected site at the top of the molecule, now called binding-function 3 (BF-3), which you can see in the figure I shamelessly stole on the right here.

The reason that this appears to work is that binding to BF-3 changes the structure of AF-2, via an allosteric interaction. Rather than directly getting in the way of the essential reaction, the drug acts at a distance to disrupt the binding surface. Although much still needs to be done to refine these lead compounds into usable drugs, this is a significant demonstration that such an approach has therapeutic potential. In this case, the discovery of allosteric inhibitors was made by accident, but as our understanding of protein structure and allostery improves, expect to see more efforts to approach drug design in this way.

 Posted by at 12:30 AM
Sep 212007
Bad news today from the fight against AIDS: the Merck STEP trial has been discontinued due to evidence that the vaccine neither prevents nor attenuates HIV infection. This is a serious setback, as the trial was utilizing a new strategy and had sufficiently promising results two years ago that it was actually expanded. While this doesn’t mark the death-knell of the CTL approach by any means, it is certainly a major disappointment and will probably send a number of approaches in development back to the drawing board.

The classic approaches to vaccination in humans have failed for HIV for a variety of reasons. Part of the difficulty is that HIV has such a high degree of variation. There’s no guarantee that any single vaccine could protect against every strain for any length of time. Moreover, vaccination using the virus itself is incredibly risky — even a virus that is missing the essential Nef protein from its RNA can damage the immune system. Experiments in SIV show that a damaged or attenuated virus only confers protection if it reproduces at low levels in the host, but at the same time this gives it a greater opportunity to revert to pathogenic status. For this reason, chemical inactivation, which truly kills the virus, doesn’t produce a viable vaccine because the virus does not stimulate sufficient antibodies to protect the patient.

The Merck vaccine used a different approach entirely, based on the idea of activating cytotoxic T lymphocytes. Rather than using inactivated HIV, the Merck team transplanted three HIV genes into an adenovirus (one of the viruses that produces the common cold). The idea was that these genes would get expressed into protein and displayed on the cell surface in the major histocompatibility complex. This would train T cells to attack any cell that the HIV virus had infected. Thus, the approach would not be to immobilize the virus with anitbodies, but rather to destroy any infected hosts cells before virus production really swung into gear. Even if it failed to prevent infection per se, it was hoped that this approach would arrest the development of an HIV infection into AIDS.

Unfortunately, this clever tack seems to have failed, at least in this application. It may take some time to understand why things did not work out, and maybe there was just an unfortunate choice of which HIV proteins were used or some other idiosyncratic issue with Merck’s particular formulation of the approach. Until a detailed post-mortem is complete, however, CTL-stimulation approaches will have to be evaluated in a harsher light, with a little less hope.

NOTE: IAVI probably won’t have the study status updated until Monday.

 Posted by at 8:36 PM  Tagged with: