Part II: Genetic Tests in Development for Clinical Use (continued)

Results

Scientific literature. Based on the search strategy detailed in Appendix A4, a total of 4492 citations were initially produced for cancer genetic tests in development as they applied to the top 10 cancers by mortality. In an attempt to reduce this total, we limited the database timeframe to period from 2000 to 2005, which resulted in 2519 citations for 3 of the top 10 cancers. Finally, we sampled citations for three of the cancers:

Using a broad definition for genetic tests "in development," we sampled 3 cancers:

1. Esophageal: 45/55 (81 percent) citations were screened in.
2. Pancreas: 77/110 (70 percent) citations were screened in.
3. Liver: 92/123 (75 percent) citations were screened in.

Examples of abstracts screened in include "development of a quantitative three-tiered algorithm and multi-gene RT-PCR to discriminate between Barrett's esophagus and esophageal adenocarcinoma," "chemokine receptor CXCR4 expression in colorectal cancer demonstrated significant associations with recurrence, survival and liver metastasis," and "use of microsatellite marker of loss of heterozygosity and k-ras codon 12 mutation analysis of PCR in accurate diagnosis of pancreaticobiliary malignancy."

Based on the sampling of the abstracts from the MEDLINE search, we found that many of the papers were preclinical reports investigating different genes that may explain biological pathways of tumor development or reports of microarray investigations that are searching for genes of interest. Additionally, these reports of basic science and tumor cells are far from implementation and presentation as commercial projects. As a result, a significant majority of these papers were excluded from our report.

Gray literature

Category I: High utility

LexisNexis and Cambridge Healthtech Institute

We comprehensively searched these databases using the methods described above. These databases had the highest yield in returning tests of interest.

A. LexisNexis: Using the combination of key words "cancer," "test," and "gene," we obtained the following results within the different subheadings of LexisNexis:

1. Medical News (1 year) = 1132 citations.
2. Business News/ Industry News (1 year) = 1241 citations.
3. Business News/ Mergers and Acquisitions (1 year) = 233 citations.
4. Business News/ Business and Finance (1 year) = 251 citations.
5. Business News/ Knight Ridder (1 year) = 94 citations.

Table A provides further detail of our search of LexisNexis. We scanned a total of 2951 titles from the combination of LexisNexis sources and identified 879 articles of interest. From the articles of interest, we extracted 142 tests of interest and ultimately 50 unique genetic tests. Database III provides a listing of the genetic tests that were obtained from the LexisNexis search.

B. Cambridge HealthTech Institute:

Table A also details our search strategy using the CHI Toolbar. Using the combination of "cancer," "test," and "gene," we scanned a total of 494 titles and found 52 articles of interest. From these articles of interest, we identified 24 genetic tests of interest and 10 unique genetic tests.

Database III provides a listing of genetic tests in development for cancer as identified by both LexisNexis and CHI resources. Table 1 demonstrates the distribution of cancer indications for all genetic tests found using LexisNexis and CHI databases. The 10 most deadly cancers in the U.S. account for 80 percent (49 of 61) of the test indications, with breast cancer accounting for 20 percent (12 of 61). The other cancers being investigated include bladder, cervical, GIST, mesothelioma, and tumors of unknown origin. There were 17.6 tests of interest found for every 1000 titles scanned.

Table 2 summarizes the distribution for test purpose among the genetic tests found using LexisNexis and CHI. A significant majority (94 percent) of the investigations identified with LexisNexis and CHI were for disease diagnosis or management. Further information on test specifics was limited since clinical utility has yet to be established for most of these tests.

Category II: Low to moderate utility

EDRN, CLIA, ClinicalTrials.gov, Google and others

Table B lists the category II gray literature resources investigated and summarizes the search strategies and results for each database. Initial literature searches of these databases found over 200,000 titles. However, after re-focusing our methods and discontinuing further exploration of low yield sources, we identified 190 abstracts of interest from 8 gray literature sources (Google, CISTI, CLIA, EDRN, FDA pre-market, ClinicalTrials.gov, and NY Academy of Medicine) and found 39 unique genetic tests which are included in Database III.

The Early Detection Research Network publication identified 75 genetic tests in development; however, almost 80 percent (59 of 75) of these tests are in the pre-clinical exploratory phase of drug development, while only 21 percent (16 of 75) are in at least phase 2 clinical validation studies. Only the latter tests, in at least phase 2 of clinical development studies, were included in Database III. Google News and clinicaltrials.gov also contributed to our category II gray literature database with 5 and 13 tests, respectively. The CLIA database identified one test in development that was of interest to our database while the FDA pre-market approval site identified two tests. The 10 most deadly cancers in the U.S. account for 82 percent 40 of 49) of the total test indications; while ovarian cancer accounts for 22 percent (11 of 49) of these indications (Table 3). The other cancers being investigated include bladder, cervical/endometrial, kidney, and tumors of unknown origin.

Although it appears that almost all of the Category II genetic tests are associated with the diagnosis and management of cancer, it may be too premature to assign a definitive role for any of these tests since most are only in the pre-clinical phase of development and have yet to establish any clinical validity or utility data.

Category III: Not applicable

These resources did not yield any search results because they were either non-operational Web sites or contained information not applicable to this particular report.

Interviews, conferences

A. Interviews:

We conducted interviews with different experts representing commercial laboratories, academic hospitals, and the FDA.

1. Olufunmilayo Olopade, MD, Director of Cancer Risk Clinic, Univ. of Chicago.
2. Steve Gutman, PhD, Director of OIVD, FDA.
3. Richard Bender, MD, Medical Director, Quest Diagnostics.
4. Gerd Moss, MD, Austin Finley, PhD, John Rich, Roche Diagnostics.

During these interviews, we discussed issues concerning current genetic tests available (Part I), as well as tests in clinical development (Part II). Drs. Olopade and Gutman both reviewed draft versions of our current genetic test database from Part 1. Meanwhile, Dr. Bender from Quest Diagnostics suggested looking at the commercial Web sites for information on current genetic tests.

Dr. Olopade is a member of the EDRN Network Consulting Team and she is the Director of the Cancer Risk Clinic at the University of Chicago. During our interview, we discussed a wide range of issues involved with genetic testing. Particular tests discussed were Oncotype Dx, Mammaprint, OvaChek, BRCA1 and 2, and Her2-neu. Additional topics mentioned included: the impact of Myriad's Genetic direct-to-consumer marketing campaign for its BRCA testing for breast cancer screening, direct-to-consumer genetic test companies such as DNA Direct, Genetests.org as a source for genetic tests research, and the future of pre-implantation genetic testing. Finally, Dr. Olopade also mentioned a new pharmacogenomic test in development, involving gene polymorphisms for metabolizing CPT-11 (Camptosar, irinotecan) chemotherapy used in advanced colon cancer.

Dr. Bender is the Medical Director for Hematology/Oncology at Quest Diagnostics. We spoke with Dr. Bender at the ASCO Annual Meeting where we discussed issues involving genetic testing from a commercial laboratory standpoint. In particular, we discussed future pharmacogenomic testing and some of the challenges in validating these new tests. Dr. Bender introduced an upcoming 7-gene pharmacogenomic panel for evaluating response in chemotherapy for colon cancer. More specifically, this pharmacogenomic panel looks for several gene polymorphisms (ERCC1, UGT1A1, TS, XPD, GST-P1, XRCC1, and DPD) in order to evaluate the likelihood of toxicity and/or response to 5FU, oxaliplatin, and irinotecan chemotherapy.

Dr. Gutman is Director of OIVD at the FDA. Due to confidentiality reasons, Dr. Gutman was not allowed to speak about specifics of individual genetic tests available or in development. However, he did discuss pertinent issues such as "home brew" vs. FDA approval, direct-to-consumer genetic test companies such as DNA Direct, the future of genomic testing, and codevelopment of drug and diagnostic test. Dr. Gutman also received a preliminary draft of the genetic test database for review.

We held a conference call with representatives from Roche Diagnostics to discuss current and future genetic tests in cancer. Involved in the call were the head of oncology test development (Moss), director of sales and reimbursement (Rich), and the director of public policy (Finley). Roche Diagnostics is currently testing their AmpliChip technology in large multi-center international clinical trials for leukemia patients. Roche's aim is to develop their Amplichip technology for use in leukemia patients, in clinical trials to help classify leukemia patients and correlate to outcomes. Genetic tests for cancer using Roche's Amplichip technology, as well as other cancer genetic tests in development identified by expert review of this report by Roche, have been included in Database III.

B. Conferences:

1. Pharmacogenomics in Drug Development and Regulatory Decision Making

This meeting was jointly sponsored by the Drug Information Association, FDA, Pharmacogenetic Working Group, PhRMA, and the Biotechnology Industry Organization. The focus of this workshop was on the implementation and integration of pharmacogenomics in the mid to late clinical phases of the development of new drugs, biologics, and associated devices. A draft version of the FDA's "Drug-Diagnostic Co-Development Concept Paper" was provided for discussion.

2. The 2005 American Society of Clinical Oncology (ASCO) Annual Meeting

Numerous opportunities to gather information about genetic testing were available at the ASCO Annual Meeting. With the recent design, development, and clinical evaluation of several new targeted agents in oncology, more specific tests are needed to select the patients most appropriate for these agents and to evaluate their response to these molecularly targeted therapies.

From a scientific standpoint, the ASCO meeting featured many important studies and abstracts in which the integration of diagnostic tests with specific and targeted types of therapies was the focus of the presentation. the tests presented included: BRCA1 and pancreatic cancer risk, circulating tumor cell assay for breast cancer, EGFR expression in colon cancer and response to cetuximab, BCR/abl mutations and imatinib (Gleevec) resistance, and pharmacogenetic studies for 5-FU based chemotherapy regimens. In addition to abstracts, the ASCO meeting also featured several presentations relevant to our project as part of their cancer genetics track. Examples of presentation titles include, "Beyond anatomic staging: is it time to take the leap into the molecular era?" and "Clinical relevance of genetics and genomics in gastrointestinal cancer: current and future biologic paradigms."

The ASCO meeting also provided an excellent opportunity to make contacts with several of the commercial vendors involved in genetic testing for cancer. In particular, the meeting featured over 400 corporate exhibits where attendees could visit booths, speak with representatives from the various pharmaceutical, medical diagnostic, and commercial laboratories, and obtain clinical and commercial literature regarding specific tests. There were numerous companies involved in genetic testing for cancer present at the corporate exhibitor hall, such as Quest Diagnostics, LabCorp, Genomic Health, US Labs, Roche Diagnostics, and Veridex.

Summary

Our initial exploration of the scientific literature led to our realization that MEDLINE searches would be more useful for collecting information of various biomarker and genetic tests in the pre-clinical stage of development. We concluded that for the purposes of this report, a different search strategy would have to be employed in order to more efficiently identify genetic tests in later phases of development that may have clinical impact in the very near future. As a result, we focused our search to the gray literature and were able to identify 104 genetic tests in development. Among these 104 tests, over two-thirds (60 of 104, 68 percent) were identified from the LexisNexis (n=50) and Cambridge Healthtech Institute (n=10) databases. Another 39 tests (38 percent) in development were found among 8 additional gray literature databases. The remaining 5 tests (4 percent) were added through additional alternative resources such as interviews with opinion leaders and attendance at national conferences. Three-quarters of the tests (84 of 104, 76 percent) were being developed for only 5 of the top 10 most common cancers by mortality. Breast, prostate, lung, colorectal, and ovarian accounted for these five most common indications. Finally, although it appears that almost all of these genetic tests in development are associated with the diagnosis and management of cancer, it would be speculative to assign a more definitive role for most of these tests since clinical validity or utility has yet to be established.

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