How current assay approval policies are leading to unintended imprecision medicine

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Published: 29 Oct 2020
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Dr Roberto Salgado - Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium

Dr Roberto Salgado speaks to ecancer about the current assay approval policies and how they are leading to unintended imprecision medicine at the IBCD 2020 meeting held virtually this year.

Initially Dr Salgado talks about the problem of the PD-1 testing kit and how the presence of different testing kits for the same bio-marker are impacting bio-marker driven research.

Dr Salgado explains the reasons behind the current different thresholds in defining a positive marker and how they affect the world of cancer research and treatment.

He raises an important point saying that low and middle income countries are the most affected by this lack of unity in cancer testing kits and the global community needs to take heed of this issue and try to resolve it.

He further speaks of the challenges currently being faced by patients and oncologists and points out how the industry and the academic world can work together to standardise assays globally.

He winds it up by talking about the future of biomarker driven research and the important areas researchers and oncologists alike should be looking into.


The PD-L1 experience is an experience that we need to use to learn, that we need to use to identify the weak points of the current framework. The big problem with PD-L1 assays, and this is one of the many issues surrounding or that have been identified with the PD-L1 assay, is that the development of immune checkpoint inhibition combined with an assay to identify those patients has been a very exclusive association between the drug company that develops the drug and the assay company that develops the assay.

So the main challenge that we learned by just looking at how it works today is that in real life you have drug company A that has a drug and it has an assay and you have drug company B that has another drug and another assay but you do have the same patients. One of the hurdles, and there are many hurdles in this framework, is that company A doesn’t talk to company B. So company A uses an assay which is different, with a different compound, with a different antibody, than company B. We all know this after the trials have been published, once all of them have been approved by the regulatory authorities, leaving the situation for patients, for people like me, pathologists, in doubt. Because if I get tomorrow a patient with breast cancer and the clinician wants to use drug A, conceptually, in the current framework, I would need to use assay A. If the clinician wants to use drug B, I would need to use the assay B, meaning I would need to use, for the same breast cancer, two different assays.

What is missing today is that these drug companies have not been talking to each other. So the development of these assays have been done completely separate. Nowadays we have 15-16 different indications for PD-L1. We have up to six non-equivalent PD-L1 assays available. This is not workable at a single pathology lab worldwide.

We tend to criticise a lot the PD-L1 assay and I do think that we need not to criticize it, as such, but we need to learn from it. I invite you all to read a comment that has been published last week in the Lancet Oncology. That’s a comment that has been developed by representatives of the College of Medical Pathologists, the European Society of Pathology, the Latin American Society of Pathology, the European Working Group of Breast Screening Pathology, the International Biomarker Working Group, which I co-chair with a few others, endorsed by Ian Cree who is the Chair of Pathology of IARC WHO. We have written it such, we have written in a very constructive manner, I think, what the issues are with the current assay approval policy and we have proposed also a list of solutions. Because criticising is easy but proposing solutions is difficult.

So we came together and we discussed solutions and we proposed these solutions which are ridiculously simple to the community to start changing the paradigm of companion diagnostics. We are not saying get rid of companion diagnostics, we are just saying change the paradigm for the good of the patients.

How can different assay options impact patients and treatment and clinical trials?

Imagine, we have different regulatory frameworks across the globe. In some countries you have to use the companion diagnostic assay if you want to get a drug reimbursed. In other countries this is not obligatory, like in the European Union. In Japan it’s obligatory; in other countries in Asia it’s not obligatory. So for patient care the risk is not only that if you would get breast cancer one day and your tumour will be tested in the US, it might receive a different result than if your tumour will be tested here in Europe. So you might be given a different treatment based on the assay that was used for the simple reason that you have this regulatory framework which does not allow labs to use the assay they think is the best assay available.

So in the real world, we as academics can do plenty of concordance analysis showing that some assays are good and some assays are less good but the regulatory framework obliges pathologists in certain settings to use assays which they deem not to be the best one available for that particular purpose. I do think this will hamper the best selection of patients which I do think personally is not acceptable anymore.

If we want to treat patients and give the patients the best opportunities, there should not be a difference in the selection of those patients across continents. This difference is there because the framework surrounding it is what it is.

What steps need to be taken by the industry and academia to standardise assays globally?

One of the most difficult things is that drug companies focus on giving the drug to the patients. Everybody wants to give the drug to the best patients who might respond the best. So we, as a community, we should not be giving drugs to patients who are not likely to respond so that’s why we need biomarkers.

I would encourage the drug industry to partner with the academic community and with the assay industry to try to change the paradigm that is the exclusivity of linking a drug with a biomarker driven assay, to change that paradigm.

What does that mean in real life? In an ideal world, and this is based on the recommendation that we have developed, in an ideal world this would mean that these companies start to share information about the assay. They need to start to share confidential information which nowadays is not shared for commercial reasons.

We only start to know the specifics of the assay once the trial has ended, not before. So now in real life we start to do all these analytical validity studies after the trial. So what we should do, together with the industry, and mostly the drug industry and also the assay industry and also the regulatory, and involving patients as we need to do all these harmonisation studies or equivalence studies between all the different assays, before the trial so that the assay that is being used in the trial is the best one available so that the biomarker gets validated. Once the trial gets positive we do know that the biomarker is validated and then it’s up to the community and, again, this involves industry again, regulatory, the assay industry. We need to develop the framework that the assays are the best ones available to find that patient which is not necessarily always the assay that has been used in the trial.

Because in real life, and as the experience that we have with the Working Group that I co-chair with a few others, is that there are many different realities worldwide using companion diagnostic assays and using assays. You will not have this uniformisation that the whole world for a specific drug will use just one assay. The reality is that there are plenty of assays used and we need to try to challenge this topic.

This would mean that industry would need to stop grasping the exclusivity of saying, ‘If you want my drug you need to use my assay,’ which I do think is conceptually not sustainable anymore.

What does the future look like for biomarker driven research?

That’s a difficult one. I think that there are two main answers to that. One is we are always following innovative technologies and regulatory should sustain innovation, which it does not with the current framework, by the way. Because if you have this exclusivity that the drug is linked to a biomarker you hamper innovation by other groups because they say if the drug is reimbursed by the reimbursement agencies, all because it’s FDA approved, why should we do research on that biomarker to find the same patients?

Nowadays the EMA has developed a new policy in which laboratory developed tests can be used to identify those same patients if those labs prove the clinical validity of that assay to identify the same patients. But to be able to do that they need the tissues, and who owns the tissues? The sponsors of the trials, which is mostly industry. As long as industry doesn’t want to share those tissues to be compared with other assays and stay and be open to formally claim these are the biomarkers, it’s as good as a companion diagnostic, because they need to care to give the right drug to the patient. If that doesn’t happen then nothing will change and we will continue to use assays that are suboptimal, in my view.

Is there anything you would like to add?

The only item that I would like to suggest is what I am saying is, in theory, very simple, in practice very complicated and difficult. This may sound a bit naïve and it is a bit naïve, we need to always focus on the end user. Whatever policy we develop we need the end users are the most important people. And the end users, in my view, are the pathologists who need to select… have the moral and sometimes also legal obligation to select the best assay available to find that patient to be given the best drug by the clinicians and that’s why we need the trials. That’s why we need to change the paradigm that every new biomarker that has the potential to change clinical practice should be developed very early on in the process, together with industry, so they need to release their exclusivity thinking, academia, patients and regulatory, very early on in the process. So that, at the end of the cycle, that the biomarker that is used in daily practice is endorsed by industry, patients, regulatory and the academics. By academics I mean people like me, I don’t work in an academic hospital. People who do the surgical practices, surgical pathological practice, every day to find those patients.

The other message I would like to share with all of you is the importance to realise that in big parts of the world pathology labs, or countries in general, don’t have the means to use these very expensive innovative technologies like machine learning, artificial intelligence etc. So we need to find paradigms and biomarkers that allow also in those settings to find those patients who may benefit the best from the best drugs available. Also in those settings people get cancer and also in those settings we need to get the best drugs available. As in the so-called developed world, also there, and that’s important. The reality is the current companion diagnostic paradigm, as we know it today, is just too expensive for them. That’s very important to realise.