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FIGURE 3-2 The development of the diagnostic for ALK alterations also proceeded rapidly from a Phase I laboratory-developed test to PMA approval.

NOTE: ASCO, American Society of Clinical Oncology; EML4-ALK, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase; FDA, U.S. Food and Drug Administration; FISH, fluorescence in situ hybridization; IDE, investigational device exemption; IUO, investigational use only; LDT, laboratory developed test; MGH CTA, Massachusetts General Hospital clinical trial assay; NDA, new drug application; NEJM, New England Journal of Medicine; PMA, premarket approval.

SOURCE: Ho, workshop presentation, March 21, 2012. Copyright © 2012 Pfizer Inc. All rights reserved.

detected by the original diagnostic, new clinical trials would be required. Nevertheless, patients will likely be treated with crizotinib based on results from other than the approved diagnostic test, certainly in other parts of the world. But there will be no formal data supporting those uses. “It raises a lot of interesting questions as far as further development of diagnostic tests.”

Ho mentioned the issue of biologic heterogeneity within a patient and within a population. The success of targeted therapy will depend on the source of this heterogeneity. In NSCLC, the population exhibits heterogeneity, which allows population subgroups to be identified. But there is also significant heterogeneity within a tumor, even if one driver mutation within the tumor as a whole is playing a critical role in the cancer. The same situation may apply in other diseases, though this question remains largely unanswered.

The underlying biology of human malignancy is very different from that of other therapeutic indications, Ho said, which has implications for



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