Cancer drugs can be expensive. Some are so expensive patients forgo potentially life-saving treatment, or don't follow dosing schedules recommended by their doctors due to the expense. For many patients in lower-income countries, expensive anticancer drugs are not even an option due to their high costs.
One approach to changing this reality is investigating alternative, less-expensive treatment approaches with "near-equivalence" when it comes to efficacy and patient outcomes.
Ian Tannock, MD, PhD, Emeritus Professor of Medicine and Medical Biophysics at Princess Margaret Cancer Centre, and other oncologists recently cowrote a Comments and Controversies article in the Journal of Clinical Oncology about near-equivalence, and how to ensure alternate treatment approaches deliver the same benefits to patients (2021; doi: 10.1200/JCO.20.02768). In an interview with Oncology Times, Tannock spoke about these strategies.
1 This article is about near-equivalence. How would you define what near-equivalence is?
"This paper looks at a number of strategies, essentially, to show that a less-intensive or less-expensive option could give nearly the equivalent outcome of what might be the FDA or NCCN standard. And there are a number of strategies for doing that.
"Those include giving lower doses of drugs and giving drugs less often-particularly targeted agents where they're often used well above the doses that are needed to inhibit the target ultimately and where Phase I trials haven't really optimized the data to show the minimum amount needed.
"Another strategy is to look at alternative drugs-drugs that might do the same thing, for example, class action drugs. If you think of common drugs like NSAIDs, we can use any of those. But it simply isn't done with anticancer drugs. You've got two anti-PD1 anticancer therapy drugs at the moment-pembrolizumab and nivolumab-approved and others in development. If somebody came along and showed in a relatively small trial that one of those other drugs in the same class could offer similar benefit and was much cheaper, that would be another strategy.
"What's currently wrong with non-inferiority trials is that to get statistical certainty that an alternative drug is not inferior within a margin that's often set at about 20 percent of the benefit of the drug that's currently used, you need a very large trial-ultimately about 2,000 patients. There's not a lot of incentive for pharmaceutical companies to sponsor those trials, so very seldom are those trials done.
"So in trying to look at near-equivalence, we say we should accept the results of smaller trials. And in a non-inferiority trial, we should be looking at not just making sure the benefit is almost the same as the new drug, but take into account things like price and toxicity.
"There's also the concept of 'pharmacoeconomics,' which is very related to near equivalence. It's looking at pharmacologic properties of drugs to ask how one can get near equivalent outcomes (the same outcomes with less statistical certainty) by using substitute drugs or giving drugs with food rather than fasting.
"So, it's a matter of having knowledge of the pharmacology pharmacokinetic drug concentration in blood and tissue and pharmacodynamics-and when considering that knowledge, asking: Could one use lower doses? Could one use less-frequent administration? Or could one use an alternative drug? Or could one use the drug given with food to increase bioavailability? Or could one use another drug that stimulates bioavailability of the drug? So, there are a number of strategies for trying to show near-equivalence."
2 So, does near-equivalence mean the alternative drug isn't as good as the other one?
"Not exactly-it means the evidence would suggest the alternative is as good as the standard treatment, though the statistical certainty of that may be weaker. I don't think we'd be looking at things that we knew were not as good. We are looking really at alternative treatments where within a degree of statistical certainty they are equivalent.
"One example is a small 75-patient trial using proximal endpoints to show that abiraterone at a quarter of the dose after a meal (for patients with prostate cancer) was just as effective as the full dose (four pills) on a fasting stomach. And there's also pharmacokinetic data showing that. The trial was randomized. The endpoint was time to PSA progression (not overall survival), but the data showed that with wide statistical limits it was just as good, and in fact slightly better, than the regular dose.
"We made an application to the NCCN to recognize this alternative treatment strategy to the full dose, which they accepted."
3 So what's the bottom line you'd like oncologists and the cancer care community to take away from this paper?
"Ultimately we'd like to see the FDA and the EMA take this type of analysis into account. And for practicing oncologists, we do have a problem. The cost of new cancer drugs is obscene. The message is that we need to be aware of cost and the effect that cost has on access to effective cancer treatment.
"We've developed some pretty good drugs over the last few years, but they need to be accessible to everyone-including people in countries that at the moment sometimes can't afford them. We need to recognize that there are strategies to make treatments cheaper and thereby more accessible to patients."