Methodology certification and accreditations to perform assays
Dr Stanley Hamilton - MD Anderson Cancer Centre, Houston, USA
The issues around personalised precision cancer therapy are very complex and because the science is so entrancing these days we have a tendency to not remember some of the other aspects that come to affect how these kinds of studies can be done. In particular is the regulatory environment in the United States. If you saw Dr Kurzrock’s presentation yesterday about the WINTHER trial, that trial was opened in Europe very quickly, took a little bit longer in Canada and we haven’t gotten it open yet in the United States. This is predominantly related to the regulatory environment in the US.
What is unique about the regulatory environment in the United States?
In the 1970s and ‘80s there was a scandal in the United States involving clinical laboratories for women’s Pap smears. There were commercial laboratories that were charging patients for Pap smear reading and basically not doing them effectively. A number of women developed carcinoma of the cervix after having had what were alleged to be negative Pap smears at a couple of laboratories. Investigators then went back and looked at this situation and it turned out that the laboratory practices in those laboratories were very poor, without adequate controls and without adequate training of the personnel. As a result of that, the United States’ federal government stepped in to the situation and in 1988 passed what you will hear about over and over again at the meeting as CLIA. CLIA stands for the Clinical Laboratory Improvement Amendments of 1988.
Can you elaborate on the CLIA [Clinical Laboratory Improvement Amendments] law and what it stipulates?
What that law does, and this is a federal law, is that any testing that is used in any way to affect a patient has to be done in a laboratory that is certified and accredited by a number of different organisations to show that they are able to be competent and effectively do the testing. So that one law has now led to organisations that do inspections for the Centers for Medicare & Medicaid Services which have responsibility to go through and basically go to laboratories and have an on-site inspection, look at the record keeping, be sure that the personnel are competency tested and to meet all of the necessary regulatory requirements to get licensure under CLIA. Most other countries around the world don’t have this and so as a consequence it takes us quite a bit longer to go through the process to get biomarkers into clinical trials than is the case in the European countries and other areas of the world.
What have been some of the issues around getting the WINTHER trial running in the United States?
The problem was largely related to getting the accreditation of the methodology that had been proposed in the trial. So when the protocol came out, the methodology in the trial was already established. So as a consequence when our laboratory looked at that methodology this was a technique we were not using so we basically had to start from scratch to train personnel, write the standard operating procedures and meet all the necessary requirements to be able to process those specimens for the trial. This is, again, a constant feature with any of the kinds of clinical trials that we’re doing these days which often involve new assays that are not routine in a laboratory so that we have to go and set up those procedures to be able to have the laboratory participate in the trial.
How might this issue be avoided in the future?
The key to this is having the personnel who are involved with setting up the clinical trials more interactive with the laboratories. As these kinds of trials are being developed the best process forward for the United States where this requirement is not going to go away and if anything the regulations are probably going to become more stringent because the United States Food and Drug Administration has now announced that it’s going to regulate laboratory developed tests over and above what’s already done under CLIA. So as a consequence of that we need the people who are in the situation of developing clinical trials to include people from the laboratory from the outset so that we know what the plan is in terms of the specimen acquisition and processing that’s going to be done for the patients and to be able to start to work on the standard operating procedures, the documentation, developing the assays, the laboratory utilisation of it from the standpoint of the analytic characteristics that are required with sensitivity, specificity, limits of detection, precision, accuracy, to establish all these things in advance so that we don’t have a protocol show up where the clinical people are ready to start enrolling patients and none of this background work has been done on it.
How can standards be harmonised across countries in international trials?
There are two ways in the clinical trial arena that these things are handled. One is to basically use a centralised approach where there is one laboratory that’s doing the testing for all of the sites. The second is to have laboratories working with each other to be concordant with each other and get the same results on the same specimens with methods development. The way that that gets done is dictated by a number of different features and particularly with international trials like in WIN where there are institutions from the Middle East to the West Coast of North America, basically spanning the globe, it becomes very difficult to use a centralised laboratory because of shipping between countries and customs requirements, particularly with human specimens and this sort of thing. So, again, it becomes a matter of getting the people who are knowledgeable on the laboratory aspects involved with the clinical trial protocol development to be sure that what’s being proposed on the clinical side is feasible and that we on the laboratory side are, in fact, able to support those trials.
What’s the take-home message?
I think the key for us in the United States is, and I suspect it’s not going to be limited to us, that this will begin to spread as time goes on and the increasing recognition of the variability of these assays and the risk that some of them pose to patients in a number of situations. It’s now been shown that using drugs in patients who do not have the target for that drug in the case of targeted agents actually is not just a matter of not resulting in benefit but it can actually decrease the survival, probably is actually harming patients who have inappropriately gotten those drugs. So this may be an expanding process over time. The difficulty for us in the laboratory is the large number of organisations with varying types of background that are involved in this area. Everybody realised now as these assays have come on board that this is a real issue with the quality of the testing and the characterisation of the specimens that are used and how the results are produced and how those results are interpreted, leading to treatment for a patient, is a very complicated system. So as a consequence of that we need to do a better job of making sure that the quality is there. So professional organisations, regulatory agencies that have enforcement powers, various branches of the government are all highly cognisant of this issue and have started to develop protocol requirements and this sort of thing that come into play. The problem for us in the laboratory is we end up with too many masters so that we have the regulatory agencies that have enforcement powers that basically can close a laboratory if it doesn’t perform appropriately through more volunteer type relationships, where there’s not really enforcement to it but an attempt to improve the quality and most of us in laboratories, very frankly, want to improve the quality, to groups that are providing recommendations based on their understanding of how the testing is done.
