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How Did We Get Here From There?

Date: June 5, 2024

We have discussed fludarabine many times on this website. We have also bemoaned the lack of well-conducted phase-3 clinical trials that do an honest apples-to-apples comparison of drug combinations. I am convinced that single arm phase-2 trials are very prone to systemic bias (“cherry picking” of candidates), and single-institution studies are even more prone to false positives.

Think about it – imagine you are a bright newly minted researcher looking to make a name for yourself in a top-rated cancer institution. You have this really neat idea of that you think would work well in a particular group of patients. You are going all out, working your tail off, putting your career and credibility on the line, doing a phase-2 single arm clinical trial. It is very human to select those among your patients who are most likely to benefit from the therapy in question. Beauty is in the eye of the beholder. You are also more likely to give weight to the positive results and downplay the pesky negative ones. You massage the data every which way, slicing and dicing until the statistics give you the answers you are looking for. Someone said there are lies, damn lies and statistics.

The editorial below in the latest edition of Blood refers to fludarabine as part of a combination therapy in poor prognosis AML patients. It underlines what we have been saying all along: there is way too much bias in the reporting of phase-2 trials. Without properly done phase-3 trials with control groups, the results are not worth talking about! What makes this editorial all the more striking is that it is authored by someone at M. D. Anderson, the strongest institutional supporter of fludarabine based therapy. Heck, they pretty much invented fludarabine.

How did we get here from there? How are patients supposed to make smart therapy decisions in this era of exploding options, when most of the claims of early stage clinical trials are just not dependable? One thing is for sure: no therapy can claim the title of “gold standard” in my book, not unless it has been subjected to a fully randomized Phase-3 clinical trial conducted at multiple institutions. I am even less thrilled by glowing testimonials from a few patients. Ladies and gentlemen, it stands to reason that only the happy patients are healthy enough and dedicated enough to write about their results! Dead men tell no tales, and the really sick ones are busy being sick 24/7, and you will hear about them only if and when the lawsuits start to fly.

I am not complaining about our capitalist system or the fact that agendas exist for researchers, drug companies and physicians. I am very well aware personal gain and money (as well as real dedication and desire to heal) are what make the world go round. But as you sift through the minefield of agendas, just be sure that your agenda gets a hearing as well.

My agenda? Simple. Keep my CLL husband as healthy as I can, for as long as I can. And in the process see if I can help a few other patients along. Do I get some pleasure debunking myths, pointing out the emperor is not wearing the latest fashion clothes, in fact that he is often buck naked? You bet! I would not be human if I did not get some pleasure from pounding away on my laptop — harder than I have ever worked when I got paid to do it. One patient at a time, we would like to think we make you a little bit more competent in dealing with our complex healthcare systems. That gives me a lot of pleasure.

Be well,

Chaya
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Abstracts

Blood, 15 June 2024, Vol. 107, No. 12, pp. 4577.

How did we get here from there?

Elihu Estey

UNIVERSITY OF TEXAS M.D. ANDERSON CANCER CENTER

In this issue of Blood, Milligan and colleagues report that survival was shorter (P = .05) in high-risk patients randomized to receive, generally as salvage therapy, the widely used combination of fludarabine and cytarabine (FLA) rather than standard cytosine arabinoside, daunorubicin, and etoposide (ADE). The relative effects of FLA and ADE were the same when used alone or when combined, in separate randomizations, with granulocyte colony-stimulating factor or all-trans retinoic acid.

Fludarabine and cytarabine (FLA) or FLA with granulocyte colony-stimulating factor (FLAG) may prove more effective in patients who have better prognoses. Nonetheless, a fundamental question is how enthusiasm for FLA/FLAG in high-risk patients has been sustained when Milligan and colleagues suggest that the enthusiasm was unjustified. Alternatively, why was the published literature on FLA, in retrospect, misleading? To understand how we got here from there, it may be useful to note that none of the studies of FLA or FLAG in acute myeloid leukemia (AML)/high-risk myelodysplastic syndrome (MDS) cited by Milligan et al made reference to a control group (ie, patients given other therapies). Although typical of published phase 2 studies and consistent with the accepted view that such studies are intended to determine efficacy with efforts at comparison reserved for phase 3, the lack of a control group seems inconsistent with accepted scientific practice. Together with the natural, laudatory desire of investigators to report "positive" results, the absence of controls, and the seeming failure to consider the prior probability of positive results, may result in published results that are falsely positive. The lack of controls in phase 2 trials is also medically problematic. Specifically, patients are not as interested in knowing whether a given therapy is active as they are in knowing, as soon as possible, whether it is better than another, a question that implies a control group.

One approach to this issue are randomized "selection" designs intended to select for possible future investigation, the best among several therapies (which could include a standard) regardless of its degree of superiority. This goal requires fewer patients (eg, 20 per treatment arm) than standard designs, so more treatments can be studied. Using a selection design, the probability of correctly selecting a truly superior agent among four is typically 60%. Although seemingly underpowered compared with standard phase 3 designs, the 80% to 90% power associated with the latter is in fact nominal. This is because these designs ignore the often-informal process leading to selection of typically a single new therapy, which is then compared to a standard. History suggests that without data from a trial, it is often impossible to know which of several new therapies should be selected. Consequently, selection of one therapy and rejection of 3 others may itself be associated with a false negative rate as high as 75% even before the phase 3 trial begins. Simply put, the worst false negative may result from an arbitrary decision not to study a treatment at all, a possibility reduced by use of selection designs. Finally, in order to further speed evaluation of the relative efficacy of new agents, phase 2 to 3 designs have been proposed and shown to be more efficient than distinct phase 2 and phase 3 studies.

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PLoS Article (Full-text PDF)

PLoS Med. 2024 Aug;2(8):e124.

Why most published research findings are false.

Ioannidis JP.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

PMID: 16060722
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