Policy Challenges in Personal Genomics Kathy Hudson Genetics Public Policy Center Johns Hopkins University DNApolicy

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3. Personal Genomics Challenges Evidence, evidence, evidence Analytic validity Clinical validity Clinical utility Cost-effectiveness analysis Who wants this information, how will it be used

4. Personal Genomics Personalized medicine is only as good as the test used to inform drug selection and dose. The current regulatory system is ill-equipped to meet this challenge. The right diagnostic is key to determining the right drug and the right dose.

6. Two Types of Tests Laboratory developed tests (so-called homebrews) Test �kits� Level of regulatory oversight oddly disparate Difference not apparent to patients and health care providers.

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9. Problems with �Two Path� System Different standards based on mode of delivery (LDT v. Kit) Absence of public access to information Economic disincentive to FDA route Difference in level of validation opaque to physicians and patient Inadequate oversight of claims Disincentive to develop point-of-care tests with global significance

10. CMS Regulation of Genetic Testing Laboratories No requirement for proficiency testing (no external assessment of analytic validity) No evaluation of clinical validity Little public access to information No authority over claims and labels Buried in an agency with a different mission and expertise

11. FDA Regulation of Tests Test kits Evidence of clinical validity for intended use(s) included in submission Authority over manufacturer or distributor claims Only a few human genetic tests have been approved by FDA as kits Laboratory-developed tests Enforcement discretion IVDMIA confusion Ovasure oddity

15. PGx in the label

16. Variables in PGx Drug Re-labeling Indication Efficacy vs. Toxicity vs. Dosage Analyte Human vs. Microbial Language Required vs. Recommended vs. Info Timing Pre-market vs. post-market on or off patent Diagnostic FDA cleared IVD or CLIA only Alternatives Other drugs available for indication

17. Tale of two drugs, two adverse reactions, and two HLA-B alleles

18. Abacavir (Ziagen�) Glaxo-Smith Kline Inhibits the activity of HIV-1 reverse transcriptase Hypersensitivity to abacavir is characterized by: Fever Rash Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain) Constitutional (including generalized malaise, fatigue, or achiness) Respiratory (including dyspnea, cough, or pharyngitis).

19. Genetic Variant Associated with Adverse Events (Abacavir) Hypersensitivity to abacavir was reported in approximately 8% of 2,670 patients (n = 206) in 9 clinical trials (range: 2% to 9%) with enrollment from November 1999 to February 2002. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir.

20. PREDICT-1 Clinical Trial April 2006-April 2007 (n = 1,650) randomized, double-blind study Evaluated prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction Use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.

21. Black Box Warning WARNING: HYPERSENSITIVITY REACTIONS/LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY � Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN (abacavir sulfate). (5.1) � Hypersensitivity to abacavir is a multi-organ clinical syndrome. (5.1) � Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. (5.1) � Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1) � Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product. (5.1) � Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.2)

22. Carbamazepine (Tegretol�) Novartis Sodium channel blocker Anti-convulsion and mood stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat ADD, ADHD, schizophrenia, Phantom limb syndrome, Paroxysmal extreme pain disorder, and trigeminal neuralgia

23. Genetic Variant Associated with Adverse Events - Carbamazepine Retrospective case-control studies found association between HLA-B*1502 variant and risk of developing Steven Johnson Syndrome and Toxic epidermal necrolysis with carbamazepine treatment. Prevalence of HLA-B*1502 higher in people from China, Taiwan, Thailand, Malaysia, Indonesia, and the Philippines.

24. 2004 Medical genetics: a marker for Stevens-Johnson syndrome. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT. Nature. 2004 Apr 1;428(6982):486. 2007 Investigation into the multidimensional genetic basis of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. Pirmohamed M, Arbuckle JB, Bowman CE, Brunner M, Burns DK, Delrieu O, Dix LP, Twomey JA, Stern RS. Pharmacogenomics. 2007 Dec;8(12):1661-91. Dec 19, 2007, FDA requested change to package insert March 1, 2008, FDA issues updated label FDA moves at the speed of light

25. Black Box Warning: SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have been reported �. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations, But, the risk in some Asian countries is estimated to be about 10 times higher. Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502 and inherited allelic variant of the HLA-B gene. HLA-B*1502 is found almost exclusively in patients with ancestry across broad areas of Asia. PATIENTS WITH ANCESTRY IN GENETICALLY AT RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.

26. Epilepsy Drugs Currently Approved and Marketed Carbamazepine Carbatrol� Clobazam Clonazepam Depakene� Depakote� Depakote ER� Diastat Dilantin� Ethosuximide Felbatol� Luminal Lyrica Mysoline� Neurontin� Oxcarbazepine Phenobarbital Phenytek� Phenytoin Primidone Rufinamide Sabril

27. Abacavir and Carbamazepine Timelines Abacavir Dec 1998 � approved Mar 2002 � genotype id�d Aug 2006 � trial begins Aug 2007 � trial results Feb 2008 � trial published Jul 2008 � black box warning Carbamazepine 1974 � approved Apr 2004 � genotype id�d No prospective trial Dec 2007 � retrospective published Mar 2008 � black box warning

28. FDA fickleness Retrospective studies sufficient sometimes RCTs required sometimes Black box warnings are not warm and fuzzy If alternative is available, physicians may not be willing to test to treat Pharmaceutical companies seeking �genotype neutral� drugs?