An editorial in Cell asks “How Much Longer Will We Put Up With $100,000 Cancer Drugs?” I’m of two minds on questions like that. OK, three minds. The immediate impulse, not an honorable one, is to respond with pure snark, which is always tempting, in the vein of “If you can keep your company going while pricing these things so much lower, come on down and do it”. But that’s not doing anyone any good, and besides, the second impulse is to agree with them. Some of these drugs are almost certainly priced off what they should or could be, given their widely varying clinical impact. The market for pharmaceuticals is not exactly an open, transparent, price-discovering one. Just to pick out one complication, complaints about drug pricing often are based on list price, even when hardly anyone or anything actually pays it. But figuring out what price is actually being paid is difficult to impossible. And the third response is a more pragmatic one – the worry that whether these prices are appropriate or not, they end up looking like a tempting political target, especially in the current environment (more on that in a later post today).
This new article is more focused on trying to lower the cost of drug development, which I think is a worthy goal, of course. Here’s one factor:
One element that contributes significantly to the high cost of cancer drugs is the inefficiency of the overall commercial enterprise. As one recent example, there are currently 803 clinical trials testing checkpoint immune-therapeutics (at least 12 antibodies from a dozen different pharma companies), which together plan to enroll over 166,000 patients (Brawley, 2016). There is enormous redundancy in these studies, as many pharmaceutical companies perform similar trials with comparable drugs, but fail to share the data generated. This herd mentality is caused in part by the notion that immune checkpoint therapies can indeed lead to long-lasting remissions (potentially even to cures) and that significant numbers of patients in each clinical indication benefit from these treatments. While it is in the short-term good that so many patients get access to potentially lifesaving drugs, in the longer term, patients will have to pay the price for this inefficiency and duplication.
This is a mixed bag of statements, since later on in the article there’s a mention of inefficiencies from not trying out combination therapies. But many of those clinical trials listed *are* combination therapy trials. One problem is that we don’t even know if (as said above) that the various drugs are comparable or not. Where I think some of the biggest market-driven inefficiencies lie is in not having, say, some big head-to-head trials of Opdivo and Keytruda. Merck and BMS use different antibody assays in their clinical work, and it’s hard to make direct comparisons. I would also note that the point above about inefficiency will be magnified, severely, under a “right to try” regulatory regime, or many of the other proposals that have been floated to loosen the FDA’s efficacy requirement. As Biocentury notes, the former is getting a big push now, since Vice President Pence signed such legislation while governor of Indiana. We could simultaneously end up with a lot more people taking investigational drugs while getting a lot less useful data out of it, which seems like a worst-of-both-worlds situation when you’re talking about the efficiency and cost of the whole process.
The Cell article goes on to cite the “frequent absence of a rigorous biomarker program” as another factor hurting efficiency in clinical trials. That seems quite odd, given that the industry has poured vast amounts of money and effort into identifying biomarkers for just that reason. Neither has academia covered itself in glory during this quest. And that brings up something else that applies to the whole article – nowhere in it (at least to my eyes) do you get a sense that drug companies themselves are interested in making drug development more efficient, when just the opposite is the case. The current system is in danger of killing us; we need all the help we can get to raise our success rates.
After concluding that large drug companies are inefficient because they’re large, and small drug companies are inefficient because they’re small (no, really, that’s pretty much how the article goes), the authors then propose to do drug discovery and development without drug companies at all. No, really, that’s, uh, pretty much how the article goes. “Many of the fundamental discoveries that formed the basis for new categories of cancer drugs were made by academia”, it says, which is certainly true, but leaves out that basically all of the work that transformed these discoveries into human therapies was done by industry. When people say that a drug was “developed” by an academic team, what’s often meant is that, at best, the molecule itself was found in academia, and most of the time it’s not even that. Toxicology, pharmacokinetics, formulation, the design and running of the clinical trials themselves – these things are not trivial, to say the least of it, and they are rarely done in an academic setting. The authors are aware of this, though:
There are three main reasons why academic drug development typically stalls at the stage of clinical testing. First, the stringent quality control over the large-scale manufacturing of clinical grade drugs and their formulation is not a routine skill of academic groups. Second, the funds to support the high cost of performing non-clinical regulatory toxicology studies and clinical trials are hard to raise by non-profit organizations. Third, even when these first two steps could be executed, academic drug discovery and development units are not equipped to handle marketing and sales of approved drugs. Yet, it is at the level of commercialization that the interests of large pharma to maximize return on investment are diagonally disparate from the typically idealistic motivation that drives most academics to spend countless hours at modest compensation to solve important problems in oncology. Nevertheless, academics are driven into the arms of big pharma after initial proof of concept clinical trials for the reasons listed above. While it is gratifying for most academic investigators to see their discoveries reach the clinic, it leaves them unable to influence the pricing of “their” drugs when they reach the market.
Ah, but after everyone else has done all that work, put in all that time, and spent all that money, it’s not the original discoverer’s drug any more, to be blunt about it. When they discovered it, it wasn’t a drug yet, just a promising candidate, and there are plenty of those. The paper calls for “concerted multidisciplinary team efforts that are adequately financed and staffed with scientists having all the required expertise to enable drug discovery”, and yeah, that’s what you’re going to need, for sure. Here’s more:
A key advantage of academic drug discovery is the freedom and indeed incentivization to tackle major challenges that would be viewed as too risky by big pharma and even by many biotech companies. Currently only a fraction of the cancer genes listed in the Cancer Gene Census have drugs or chemical leads that act on the cognate protein. This means that there are very large numbers of cancer genes that remain to be drugged. For example, we have no drugs that work directly on mutant KRAS, mutant p53 or MYC. Hence there is a huge amount of work to be done to complete the job of drugging of the cancer genome.
That first part has some truth in it, although I have to note that all three of those targets listed have had substantial resources spent on them for many years by the drug industry already. It’s not that these great ideas have been sitting there because companies won’t work on them, believe me. We have worked on them, and failed. I should also note that when progress does get made on one, what happens is that the work becomes the basis for a new company and/or a partnership with a large one.
The authors suggest that this latter process needs to be broken up, and they suggest that academic partnering with generic firms might be a route to that, since “generic drug makers are used to working with lower profit margins”. The idea is that the candidates coming from the academic consortia will be “de-risked” to the point that it’ll be similar to developing generics, apparently, but I don’t see how that can possibly be true. Especially not a couple of paragraphs down from where you were talking about drugging KRAS and cMyc. You can’t have it both ways. Innovative drugs are never “de-risked” when they’re going into the clinic.
Two elements will be mission critical for this model to succeed. First, academic organizations will need to abide by their societal responsibility and resist the temptation to sell their drug candidate to the highest bidder. Second, it will be imperative that agreements on price caps are part of the negotiations with potential investors or with companies that take forward drugs arising from academic drug development. Ideally, this approach would also be accompanied by pricing strategy leading to affordable drug cost in middle- and low-income countries, thereby reducing inequality in global cancer therapy. Given the substantial de-risking achieved prior to commercialization, our model should be attractive to these parties and their investors. The academic drug discovery and development units could be sustained in this model by receiving royalties on sales of the drugs they originated.
Asking research universities to pass up an opportunity for profit has traditionally been a low-percentage move – apparently, to date, they have not been abiding by their societal responsibility. It’s also not clear how the pitch to investors will go, as long as these are investors under the usual dictionary definition of the term. These elements, which are correctly described as critical, come down to “and then everyone will act differently than they have so far”, which is a tough thing to have on the flow chart. For all the rest of the paper’s discussion of the technical aspects of drug discovery, it all hinges on (as Adam Smith would have put it) expecting dinner via “the benevolence of the butcher, the brewer, or the baker”. And of course, he explicitly warned that this was not the case.
This isn’t a conclusion that I necessarily find comforting. If (and there are a lot of ifs) such academic consortia could produce drugs for lower cost, that would be a relatively benign way of bringing those prices down. I just have trouble picturing it actually happening. There are other mechanisms by which drug prices can be brought down, and some of them aren’t all that benign. Those, I can picture.