1. The Rise of Personalized Medicine: Implications for the IVD Industry Linda D. Bentley, Esq. MassMEDIC Diagnostics Industry Update March 31, 2009

2. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Personalized Medicine The use of patient-specific information to tailor products and therapies that will increase the likelihood of a favorable outcome for that patient. Involves the use of biomarkers which may be associated with genes, proteins or metabolic pathways. Potential benefits include: Earlier detection of disease Information about likelihood to develop disease Identification of therapies Prediction of response to treatment –Effectiveness –Appropriate dose –Adverse events

3. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Stephen Smith. (2009, March 3). MGH to use genetics to personalize cancer care. Boston Globe, p. A.1.

4. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC In Vitro Diagnostics Offered by clinical laboratories as testing service –CLIA (Clinical Laboratory Improvement Amendments of 1988) certified laboratory –Customers are physicians and other laboratories –Most not currently subject to FDA clearance or approval Sold as test kits –Customers are other laboratories –Regulated by FDA as medical devices requiring 510(k) clearance, PMA approval or De Novo Classification Device means an instrument, apparatus, in vitro reagent or other similar or related article intended for use in the diagnosis of disease or other condition or the cure, mitigation, treatment or prevention of disease and does not achieve primary purposes through chemical action within or on body and not metabolized.

5. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC FDA Regulatory Pathways Established –510(k) Premarket notification Show that product is substantially equivalent to predicate device Could require nonclinical and clinical studies Some diagnostic tests used in conjunction with drug follow 510(k) route while others will require PMA –510(k) - UGT1A1 gene assay (Camptosar) but PMA for HER2/neu (Herceptin) –Premarket Approval Application (PMA) Generally required of IVDs with higher risk Safe and effective for intended use, i.e., clinical study May involve advisory committee review –De Novo Classification No predicate device so automatic Class III/PMA Permits low/moderate risk device to by-pass PMA, e.g., MammaPrint

6. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Laboratory Developed Tests Formerly known as “home brews” FDA asserted authority, but historically exercised enforcement discretion and didn’t regulate “New” FDA interest in some of these tests –Warning letters Who developed and validated test? –Proposed draft guidance In Vitro Diagnostic Multivariate Index Assay (IVDMIA) –Utilizes algorithm, involves multiple markers or requires explanation of test result CLIA –Applies to all clinical laboratories that perform diagnostic tests –Analytical validity versus clinical validity

7. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Potential for Change FDA FDA’s newly appointed Senior Genomics Advisor in Office of Chief Scientist –Dr. Elizabeth Mansfield has worked in FDA’s OIVD and in industry Critical Path Initiative - new tools for product evaluation –Biomarker assessments to correlate the presence of genes or proteins and likely response to medication –Guidance for the pharmaceutical industry on co-development of drugs and diagnostic tests. Collaboration with NIH and other research institutions in applied research efforts to study the genetic basis of drug- related toxicities. Medco partnership (PBM)

8. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Potential for Change (cont.) External efforts to change FDA regulatory process Proposals in Congress to subject all IVDs to FDA review or approval Citizen petition –Genentech (12/5/08) asked that all IVDs be actively regulated by FDA –AdvaMed (3/27/09) submitted proposal on “Risk-Based Regulation of Diagnostics”

9. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Potential for Change (cont.) Others - Governmental and Private Secretary’s Advisory Committee on Genetics, Health and Society (SAGCHS) –Chartered in 2002 to provide advice to Secretary of HHS –Issued report May 2008 on potential of pharmacogenomics http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS_PGx_rep ort.pdf http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS_PGx_rep ort.pdf The Personalized Medicine Coalition –A broad spectrum of academic, industry, patient, provider and payer communities seeking to advance the understanding and adoption of personalized medicine. www.personalizedmedicinecoalition.org www.personalizedmedicinecoalition.org Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group

10. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Challenges Early Stage –Few products on market - tests not widely adopted, e.g., FDA- cleared test for 2 gene variants and warfarin –Need to access accuracy and predictive value FDA has incorporated pharmacogenetic information in some drug labeling, but clinical usefulness of most tests still unknown Reimbursement uncertain Current coding not conducive to innovative test development Payers not convinced of usefulness May not support cost of developing tests Needs robust health information technology

11. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Challenges (cont.) Economic Incentives for co-development –Decreased market for certain drugs –Faster drug approvals FDA Guidance on genomics and drug development –More post-marketing surveillance Education and training Ethical, social and legal issues

12. M INTZ L EVIN C OHN F ERRIS G LOVSKY AND P OPEO PC Linda D. Bentley, Esq. Member Mintz Levin Cohn Ferris Glovsky and Popeo, P.C. One Financial Center Boston, MA 02111 ph: (617) 348-1784 LDBentley@mintz.com www.mintz.com