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Five Years of Cancer Drug Approvals: Most Cost Too Much and Give Us Too Little

Posted 17 December 2015 | By Vinay Prasad, MD, MPH 

This is the guest post rebuttal (to this post from Mark Shapiro, VP of Clinipace) by Dr. Vinay Prasad, Assistant Professor of Medicine in the Division of Hematology Oncology in the Knight Cancer Institute. Prasad also holds appointments in the Department of Public Health and Preventive Medicine, and as Senior Scholar in the Center for Health Care Ethics at Oregon Health & Science University.

Mr. Shapiro comments on some of the arguments made in our investigation of five years of cancer drug approvals.  For this reason, I have been asked to respond. Let me address these comments, but first let us agree on the sobering truth about cancer drugs.

The Hard Reality

Mr. Shapiro calls the last few years in cancer drug development “exceptionally busy” and he is right, but not in the way you might think.  While, of course, we have had some great cancer drugs over the last 10-20 years:  traztuzumab, rituximab and imatinib to name a few, the majority of novel cancer drugs approved in the last two decades are marginal, mediocre, better than nothing, but certainly not great.  If you find and replace the word ‘groundbreaking’ in his piece with ‘marginal’ you would be closer to the truth.

For example, an analysis of 10 years of solid tumor drug approvals shows that the median improvement in survival is 2.1 months, and median improvement in the surrogate endpoint of progression free survival is 2.3 months among all approved drugs [1].  These gains are simply not good enough for our patients.  A diagnosis of metastatic colorectal or lung cancer or pancreas cancer in 2015 is still a dismal prognosis, and that remains a tragedy that we must work to overcome through vigorous basic science research and a rational clinical trials agenda.  Hailing marginal drugs as “groundbreaking” is a common mistake [2].

Moreover, these marginal gains have occurred among the carefully selected patients in pivotal clinical trials. In the real world, where patients are older [3] and have more comorbidities, the gains from these toxic cancer drugs—with narrow therapeutic windows—are likely far less than in pivotal trials. 

At the same time, the amount of money made from marginal drugs is staggering.  Pharmaceutical companies routinely report double-digit profits, and a cancer diagnosis is a leading cause of personal bankruptcy.  Yes, there are great drugs in the pipeline, but even the impressive anti-pd-1 antibody drugs only work in a fraction of patients with certain tumor types.  In short, cancer drugs are too expensive, and, on average, not good enough.

Cost Per Year of Treatment Course

Mr. Shapiro may be correct that some novel drugs are taken for far less than a year.  He doesn’t comment on the fact that this is a testament to just how marginal they are.  I encourage him and others to use the median duration of treatment to see if drug prices correlate with efficacy, novelty or any other rational metric.  We have analyzed our data in several ways, and are confident that no analysis will be able to show that any rational factor predict price—which was the sole conclusion of our paper. Had median duration of treatment been better reported in pivotal trials, we would have used that.  Unfortunately incomplete trial reporting and lack of data sharing still plagues the majority of industry sponsored cancer trials.

But to his point, others have performed formal cost-effectiveness analyses of new cancer drugs that are based on treatment durations and not annual costs.  Here are two well-done examples of what they find: Pertuzumab based on the CLEOPATRA trial—a widely celebrated drug-- costs ~$700,000 for a quality adjusted life year [4], and regorafenib costs $900,000 [5].  We now see dollars per QALY that approach a million dollars in cancer medicine—unsustainable by any nation.

Mr. Shapiro writes, “for drugs used in patients for whom treatment will likely be short, one would expect higher prices, or else the drug wouldn’t be commercially viable. “ But, sit back and think just how absurd this is.  The worse a drug, the more it should cost, as otherwise it will not be commercially viable?  A drug that improves survival 1 day should cost 80,000 for a pill.  Unfortunately, there is no way for payers to refuse such a medication, as lobbying efforts have prevented Medicare from negotiating price, or from opposing anything listed on one of several drug compendia.

The extreme example that I provide of a drug that improves survival 1 day is not far from the actual example of erlotinib, which was approved based on improving survival 10 days in pancreatic cancer.  What other marketplace could charge so much for such a terrible product?  A car that runs for a year would cost more than one that runs for a decade?  I find this observation, which may be apt, to be simply more evidence that our pricing system is broken.

Finally, we have to acknowledge that spending absurd amount of money for cancer drugs comes at the loss of other services in health care.  As just one small example, women in the US stay rarely receive home support after delivering a child, while home visits are the norm in France [6]. In short, money spent on trivial drugs invariably means fewer services for other health matters.  We must acknowledge that even though it doesn’t feel like we are choosing, we are making these choices daily.

Next In Class Versus Novel Drugs

Mr. Shapiro notes that in some cases next in class drugs work in patients who have developed resistance to the parent compound.  A good example is nilotinib in imatinib-refractory CML.  He states that “we shouldn’t downplay the value of having multiple drugs in a class.”  I agree, but his take misses the key issue. 

It is fine to have several next in class drugs, but should each new drug cost more than the parent compound?  One cannot evoke the oft-made argument that drug development:  costs are high because finding a new drug is hard; akin to exploring an uncharted ocean.  In contrast, finding a next in class drug is more straightforward; akin to exploring a city without a map—there is far more guidance at the outset. 

Second, it is naïve to think that nilotinib and dasatinib were developed solely for imatinib failure/ resistance (as they really ought to be used).  Instead the sponsors of both drugs have promoted them for first line use based on data that they improve some surrogate endpoints, but without any conclusive evidence they improve outcomes that matter to patients.  In response, Novartis has raised the price of imatinib, so that it remains on par with these second generation Bcr-Abl inhibitors.  For these reasons, next in class drugs do not bring down prices, and are much more likely to seek market share in the front line rather than remain reserved for true intolerance/ resistance.

Mr. Shapiro’s example of the many TKIs in kidney cancer—is a poor choice, I think. As a simple matter of fact, no one has shown that switching to another drug at tumor progression in RCC is better than remaining on the same drug, and there are reasons to suspect it may not be.  Elegant analysis of tumor growth rate hints that these drugs slow growth rate, and discontinuation at progression may be hasty [7].  I would like to see a trial testing a strategy of continuing sunitinib versus the standard of care of switching upon progression.

In short, yes, I want to have several options for cancer drugs, and I use and like next in class drugs.  But I also want competition to lower prices (it does not appear to), and I want the use of novel more costly next generation agents to be rational (it currently is not).

Crossover

Mr. Shapiro alludes to the fact that some decent cancer drugs showed OS benefit despite crossover (meaning they are good), and others may have lost those benefits because of crossover. However, the conventional narrative about crossover should be revisited—it is not clear that the presence of crossover always masks a survival benefit-- and I have written on this extensively.  I encourage interested readers to learn more from these links:

http://www.vinayakkprasad.com/s/2013-May-JNCCN-Double-Crossed-Why-Crossover-is-Distoring-Medical-Science.pdf

http://www.ncbi.nlm.nih.gov/pubmed/24365533

http://www.mayoclinicproceedings.org/article/S0025-6196(15)00380-8/fulltext

Conflict of Interest

Finally, I worry about the elephant in the room here-- conflict of interest.  Mr Shapiro cites the study, “Comparative healthcare costs in patients with metastatic melanoma in the USA.” Melanoma Res. August 2015. Vol 25(4):312-320 which argues that traditional cytotoxic chemotherapy—not just the BRAF inhibitors—are quite costly in metastatic melanoma.  However, the study is an observational study with many caveats and potential biases, and is funded by Roche-Genentech. Incidentally, Roche markets venmurafenib.   I think the numbers provided for the cost of decarbazine are inflated.  It is well known that industry funded cost analyses favor the novel, lucrative commercial products [8].  As such, it is hard to trust this analysis.   Quite frankly it is unclear why the sponsor don’t just use the costs from BRIM-3 trial of venmurafenib versus decarbazine—to get a sense of decarbazine’s price.

The review article on TKIs cited has two authors with several financial conflicts, and Mr Shapiro works for a contract research organization, which benefits from an industry that amasses heavy profits.  In contrast, I have no financial conflicts of interest, and am giving my perspective as a practicing hematologist oncologist and policy researcher.

The reason I look at conflict is that I find it hard to believe that any objective person could examine this topic and conclude that the cancer drugs we have are not on average 1. marginal and 2. far overpriced.  How to fix this problem is the most important issue moving forward, not debating whether there is a problem.

Conclusions

Most cancer drugs cost too much and give us too little, and Medicare does not have the ability to say no or negotiate price.  Mr. Shapiro refers to some marginal drugs “groundbreaking” and in doing so is in good company.  But we do a disservice to patients when we hail a marginal drug as a great leap forward.  We have to make sure language is proportionate to the reality of cancer drug development [2].

I remain convinced of the conclusions of our paper.  The cost of cancer drugs is not explained by rational factors.

[1] http://www.ncbi.nlm.nih.gov/pubmed/25068501
[2] http://oncology.jamanetwork.com/article.aspx?articleid=2464965
[3] http://jco.ascopubs.org/content/22/22/4626.full.pdf
[4} http://jco.ascopubs.org/content/early/2015/09/03/JCO.2015.62.9105.full
[5] http://jco.ascopubs.org/content/early/2015/08/21/JCO.2015.61.9569.short
[6] http://www.npr.org/templates/story/story.php?storyId=92116914
[7]http://www.ncbi.nlm.nih.gov/pubmed/23395639 and http://www.ncbi.nlm.nih.gov/pubmed/18827177
[8] http://www.ncbi.nlm.nih.gov/pubmed/26320099


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