Much Ado About … Some Things

Given that the ‘festive season’ is approaching, maybe we should try to find something joyous to say about cancer. It’s not difficult. Over the last 60 years (1950-2013) the 5-year Relative Survival Rates for white Americans for breast and prostate cancers have gone from about 50% to over 90% (99.6% in fact for prostate). A number of other types (e.g., testicular cancer) are now largely curable, if treated early enough. Similar trends have occurred in most developed countries – all this through advances in surgery and radiotherapy but, most of all, because of new drugs.

Big Pharma

It’s big business. According to the Financial Times, annual spending on cancer drugs hit $100 billion worldwide in 2014 and is projected to exceed $150 billion by 2020. As you would hope, this expenditure on drug development and production has resulted in a gradual rise in available cancer drugs, represented below by the number of new cancer drugs approved each year by the American Food and Drug Administration (FDA).

Number of new cancer drugs approved each year by the American Food and Drug Administration from 1949 to 2016 (from Hope Cristol, The American Cancer Society, 2016).

Data compiled from drugs@fda.gov, National Cancer Institute, FDA Orange Book, FDA.gov, and centerwatch.com. Reporting and analysis by Sabrina Singleton, ACS research historian.

We should note that the FDA equivalent on this side of the Atlantic is the European Medicines Agency (EMA) and they tend to follow similar licensing patterns. Thus in 2016 a total of 74 new drug approvals were granted by the FDA and the EMA — 19 by the EMA only, 19 by only the FDA, with 36 approved by both. Of the drugs approved by the EMA in 2016, 17 had received prior FDA approval (i.e. in 2015 or earlier). However, only six drugs registered in the US in 2016 had prior EMA approval, indicating that drug companies tend to apply for approval in the US first before registering their products in the EU.

So rejoice and be merry — and drink to the triumph of science!!

It’s not unbounded joy, of course, because global cancer incidence continues to rise and a number of cancers (e.g., lung, liver and pancreas) remain refractive to all approaches thus far with survival rates stuck below 20%.

A Winter’s Tale

But what’s this? A further, wintry blast of reality from The British Medical Journal no less. It comes from Courtney Davis and her friends at King’s College London and the London School of Economics and Political Science (LSE) who looked at the track record of cancer drugs approved by the EMA between 2009 and 2013. Over this period the EMA approved the use of 48 new cancer drugs.

Charge your glass

It might be a good idea to sit down with a stiff drink at this point and remind ourselves that there are only two aims for cancer drugs: they must either extend the life of the patient or improve their quality of life.

What Dr. D & chums found was — and here, to be absolutely clear, we should quote exactly what they said — “… that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.”

To be precise, it was 57% (39 of the 68 drugs) that entered the market with no evidence that they improved survival or quality of life.

Cripes!

What does this mean – and how can it be?

Well, first up, clearly a lot of money has been spent by drug companies and health services for absolutely no benefit to patients. Unsurprisingly the authors of the study called on the EMA to “increase the evidence bar for the market authorisation of new cancer drugs.” Which I take to mean ‘get some meaningful data before you stick stuff out there.’ But here’s where things get tricky. If your aim is to extend life, how can you prove a drug works other than by giving it to a significant number of patients and waiting a long time to see what happens?

The way round this has been for clinical trials to use indirect or “surrogate” measures of drug efficacy. The idea is that these endpoints show whether a drug has biological activity and thus might be of clinical use. However, they are not reliable measures of improved quality of life or survival.

So this report leaves us with a long-standing problem. On the one hand there is the understandable drive to get new drugs to patients asap but, on the other, there is the fact that only human beings can model how well a drug works in us. However good your in vitro systems may be and however closely mice may resemble men, they’re not the real thing.

One thing we could do that the report suggests, is to integrate the development and commercialization of cancer drugs at least across the two biggest markets of America and Europe so that the FDA and the EMA don’t appear to be operating in parallel worlds.

All told then, perhaps we should supplant our earlier merriment with the chilling thought that, even after so many years of perspiration and inspiration, cancers still present an immense challenge.

References

Davis, C. et al. (2017). Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ 2017;359:j4530 doi: 10.1136/bmj.j4530 (Published 2017 October 03).

SEER Cancer Statistics Review (CSR) 1975-2014, updated June 28, 2017.

Cristol, H. (2016). Evolution and Future of Cancer Treatments, The American Cancer Society.

 

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