Critical Path to Establish Performance Test Standards for Diagnostics

Standards will help establish for diagnostics what USP monographs do for drug safety: An interview with Critical Path President/CEO Dr. Raymond Woosley.

In October, the Critical Path Institute (Tucson, Ariz.) received $2.1 million in funding from the Science Foundation Arizona for a project that aims to develop performance standards and a way to evaluate and compare diagnostics for specific cancer therapies.

The project will work initially with diagnostics developed by Ventana Medical Systems, also based in Arizona, but these performance standards could be available for all relevant diagnostics.

Resulting standards could provide FDA with greater assurance of the reliability of new diagnostic tests and could, thus, help the FDA evaluate their clinical utility and advance personalized medicine.

Critical Path CEO and Director, Dr. Raymond Woosley, likens the institute’s potential role in diagnostics standard setting to that of USP, whose monographs establish standards for drug product quality and safety.

Dr. Woosley spoke briefly with managing editor Heidi Parsons on the project and its implications.

PhM – C-Path is working in many different areas, including cardiovascular drug safety and biomarkers, and rare and orphan diseases. Why does the Institute’s focus seem to be on cancer therapies?

RW – I think the main reason is that lung cancer remains a major medical challenge in the nation and the world. In 2002-2003, the FDA joined a consortium with other government agencies, CMS (Medicare) and NCI to focus on oncology and when Dr. John Niederhuber came in as the new director of the NCI, he asked C-Path to help with a project on lung cancer. Also, we have a great working relationship with Ventana Medical Systems, a company based here in Arizona that focuses on cancer, so there was a great deal of serendipity involved. Also, our chief scientist, Dr. Jeffrey Cossman, is a cancer pathologist, and his expertise has really been important. Coincidentally, he trained with Dr. Tom Grogan, founder of Ventana, so again, serendipity came into play. The grant from Science Foundation Arizona is providing funding that will help us pursue our interest in lung cancer.

PhM - Please tell us about the test that is now being evaluated in the initial research program with Ventana.

RW – In this project and as part of the larger consortium with FDA and NCI, we are focusing on diagnostic tests for epidermal growth factor receptor (EGFR), not only with Ventana but other companies that have developed diagnostic tests for EGFR.

PhM – Tell us a bit more about EGFR?

RW - This is the receptor for one of a family of growth factors initially discovered by Dr. Stanley Cohen, who won the Nobel Prize for this work. He had noticed that newborn kittens’ eyes were closed but that the mother cat would lick their eyes. A few days later, their eyes would start to open and he wondered if there was a connection. He extracted from salivary glands a growth factor that causes skin to grow, i.e. epidermal growth factor.

Others started looking at cancers to see whether they grow because of these factors, and some do. They then developed drugs that block the receptors for this factor….that’s the concept behind Genentech’s drug Tarceva and others. They block the receptors and that prevents the growth of blood vessels that feed the tumor, so they die.

Her2nu is another growth factor, from a different family of growth factors, that is the target in Genentech’s breast cancer treatment Herceptin.

PhM –How do you test a test? What are your and Ventana’s respective roles in the overall project?

RW - Any time a test is developed, the developer (in this case, Ventana Medical Systems) tests it internally or has it tested by an outside party, traditionally the laboratory in an academic medical center. In this case, C-Path will provide an independent evaluation of their methods.

Part of the project will involve running tests over and over to determine if one gets the same results each time and perhaps on tissues that have already been well characterized in other tests in in clinical trials.

We would then vary conditions for the test trying to anticipate how it is likely to be used in the field---for example, we might use tissues that had been frozen in one case and not in another, change reagents, alter humidity levels, and see if these changes have any impact on the reliability of the test.

As a result, we’ll be able to say, "If you perform the test in certain ways, it won’t yield dependable results, but if you do it is another way, the test will be reliable." This will, in effect, establish a standard way of performing the test. If new information becomes available, the testing may have to be revised and one can find ways to get better results, and then a new standard will be established.

What has been missing so far is a permanent, independent entity to help these tests evolve to higher performance standards.

PhM – So you’re functioning as a clearinghouse, a sort of Underwriters Laboratory?

RW – Correct, our role would be somewhat analogous to how the United States Pharmacopiea (USP) sets the standards for purity and content for chemicals using monographs that define the standards for product purity and quality of each chemical or reagent. We expect that we will create a monograph for how to reliably test for EGFR….(e.g. when you test a certain tissue or clinical material under specific conditions, it will have acceptable performance parameters.).

PhM – What are NCI’s and FDA’s roles in all this?

RW – The National Cancer Institute (NCI) is completing the planning for a large clinical trial that will make lung cancer biopsy tissue available for use in the assays. FDA is a scientific advisor and partner in the project. They want to know that as the study progresses and the data become available, they will be able to incorporate the information into their regulatory decision making and perhaps in the labeling for drugs and diagnostic tests of value for patients with lung cancer. C-Path will work with the diagnostic companies to obtain information that will assist those planning and interpreting the clinical trial. For example, this will enable the NCI to help understand the performance characteristics of tests that are done on tissues samples.

Once the FDA is confident that the tests are performing reliably, they can use the results of the clinical trial and other trials being performed by the industry in their evaluation of the outcomes of clinical research.

PhM – Is there more basic research out there, such as the work that led to the identification of EGFR, that will furnish more leads for CPATH?

RW - There’s an enormous amount of scientific information that, with this type of process could make its way into new products, new labeling and clinical practice.

PhM - Does the question of manufacturability come up in these and other Critical Path projects?

RW – Yes, it does. Just as we need new methods for testing drugs, we need new methods to manufacture the drugs and, in most cases, we will need new standards for evaluation of the reliability of the manufacturing process. We have to find acceptable ways to change manufacturing processes that encourage companies with be innovative and improve manufacturing methods without having to start from scratch. New technologies will need to be incorporated into the manufacturing process by industry with the prior knowledge that they will be accepted by FDA scientists.

Stay tuned for more on this interview, including the full podcast.

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