I don't think I have ever seen or read a more misleading, deceptive and outright false description of the drug development process. The gist of the article is that surrogate endpoints are not only useless, they are false markers of effectiveness that drug companies use to get worthless but profitable meds approved. Not suprisingly, a lot of so-called health care reporters have lauded MSJ piece as extraordinary journalism. Which just goes to show you that facts need not get in the way of a good story.
But for those who still care about facts, here they are:
Just this weekend at an educational forum about lymphoma, a well- respected hematologist-oncologist from a major medical center – not a drug company – supported the new FDA Breakthrough designation to approve drugs with significant data after phase 2 clinical trials. He says drugs approved on PH 2 data are now helping people with lymphoma. Conversely he notes that despite powerful PH 2 data for Gleevec, the FDA required an additional three years for Ph 3 data. He says, "A significant number of patients died during that period."
Let me put it this way: In short, the article is based on a fundamental misunderstanding of the clinical trial process, confuses overall survival with the impact on life expectancy and concludes that what we need is to expose more people with incurable diseases to interminable waits that are a prolonged death sentence.
1. We are using surrogate endpoints to expedite Ebola treatments. We used them for HIV, Hepatitis C, heart disease, dozens of orphan drugs. The results: faster access, more lives saved. Would the authors oppose using surrogate endpoints — measures of disease progression used to estimate treatment response — for dying Ebola patients. Surrogate is not code word for fake or ineffective. Quite the contrary.
2. They imply that cancer trials take shortcuts. In fact, cancer drugs take longer to approve than many other types of medicines. And only 7 percent of cancer drugs get approved. If companies were controlling the drug development process you would think they would have better success!
3. The authors should have asked why haven’t we made even more progress? They blame surrogate endpoints when in fact they are looking relying upon randomized clinical trials that ignore subgroups of patients, surrogate endpoints that establish linkages between genotype and phenotype and genetic variations. They ignore the rapid growth in targeted therapies and the significant gains in quality of life and life expectancy they yield
4. As a result, The authors claim the solution is more randomized controlled trials (RCTs) and (we assume) the number of people enrolled in each trial. Setting aside the obvious result: an increase in the cost and time required to develop and use new products, this approach is based on wishful thinking and a willful ignorance of the genetic, molecular and clinical diversity that, when ignored, turn RCTs into an tool that harms patients.
Specifically, RCTs are totally inadequate in evaluating treatments in cancer therapy where genomic analysis is uncovering the tremendous heterogeneity of what was previously considered one disease, eg, colon cancer. Genomic analysis of individual patient’s cancers is disclosing the large number of mutations, and thus targets, within one person. Developing RCTs for targeted therapies would likely be impossible and heartless for those waiting for effective treatments.
For example, Bruce Chabner gives the example of PLX4032 for the treatment of metastatic melanoma. That compound had an 81 percent response rate in patients with BRAF mutations in a phase 1 trial. Yet in a phase III study, patients were randomized to PLX4032 or dacarbazine, which has a 15% response rate. Dr. Chabner and others ask whether it is ethical to randomize patients to a drug that everyone knows won’t work if you know in advance which treatment will work for whom.
"If patients with incurable disease who have the right biomarker for response are informed of these impressive early results they will want and perhaps deserve access to the new drug and may not accept random assignment to a modestly effective and toxic standard agent." (N Engl J Med. 2011 Mar 24;364(12):1087-9. doi: 10.1056/NEJMp1100548. Early accelerated approval for highly targeted cancer drugs.
Actual clinical RCTs are often statistically underpowered leading to inconclusive or incorrect results precisely because such studies are biased against prior knowledge. This is due in part to the effect of diminishing returns, because larger sample sizes are needed to achieve sufficient power capable of detecting the necessarily smaller positive effect sizes available as fitness improves.
5. Do potent cancer drugs carry risks? Of course. People also die surging surgery. We see the advertisements on TV - certain drugs for arthritis carry a risk of leukemia. But patients still want and need these potent drugs that change their quality of life! Drug approval is not always about survival, and it’s never risk free.