Hashim Khan Saturday, 2012

25-60% of patients benefit from drugs 2 million ADRs & 100,000 death US alone Drug toxicity- 4th to 6th, causing
leading cause of death in USA Billions of dollars Thousands of hospitalizations

$56 billion on lab diagnostic tests

But 60-70% of the downstream treatment decisions Pregnancy, neonatal testing, predictive testing, gene expression profiling

 DNA from patients

Saliva, buccal swab, blood etc. Buy test and devices from companies ex: Roche, Genelex, Luminex Test other than DNA? Routine diagnostic testing? Protein based assays

Options
Assays shipped? Assays on site? Assays in clinic? Assays in diagnostic center?

Example of such company

PGxl laboratories

 Pharmacokinetics
ADME : absorption, distribution, metabolism, elimination

Pharmacodynamics drug effect on phenotype (ex. downstream signaling pathways, receptors & enzymes)
More important than pharmacokinetics

Chronic/incurable/recurrent Trial and error medication Narrow therapeutic index Life threatening side effects Predictive value and clinical utility of drug is high Protecting/ non adverse drug responders

Functional analysis (mouse models) Replication studies (humans) 58% trials fail in phase III PGx testing in the starting phase of the trial to determine if the drug will likely to fail in phase III trials
Phase 1: Screening for safety Phase 2: Establishing the testing protocol Phase 3: Final testing Phase 4: Post approval studies

Biomarkers would tell if the drug is effective in population or worse Introduction of PGx testing into developing and marketed drugs already under process

 Early 2005 introduction of PGx into the system Guidance for Industry:
Pharmacogenomics data submission (FDA 2004) Promotes submission but doesnt enforce it Voluntary Genomic Data Submission (VGDS)

FDA and EMEA (European Medicines Agency)

handle Development , marketing, clinical applications

 Analytical validity (genotype)

Analytical sensitivity (9/100) Analytical specificity (91/100) Laboratory quality control Inter-assay variability, intra-assay, reproducibility Assay robustness resistant to pre-analytic & analytic variability (DNA extraction / amount of DNA etc)

Clinical Validity (phenotype)

Clinical sensitivity test value positive Clinical specificity test value negative

 Positive predictive value (PPV)

will develop unwanted response

Negative predictive value (NPV)

Will not develop unwanted response

Penetrance : frequency of phenotype of related SNP Modifiers: genetic and environmental

 Clinical Utility:
Evaluating risk and benefit for a PGx when introduced in clinical practice Administration setting (optimal timeline for administration of testbefore or during the first phase of treatment) Availability of counter interventions and effectiveness Comorbidities with concomitant medications Economic Evaluation cost and benefit of testing? Facilities assessing the existing resources Education Monitoring surveillance after PGx test is done, follow up with the benefits of PGx testing

 Ethical, legal and social implication

safeguards

Indian ethical standards? Social integration

 Reagents, Systems & Assays = Medical devices Based on risk

Low risk Class1 (exempt from marketing application to FDA) non-genetic IVDs ASRs (Analyte-Specific Reagents 1997 FDA)
Antibodies , proteins, ligands, nucleic acid in diagnostic application ASR is a building block , but not a test system Still needs clarification between ASRs & test systems

Manufacturing & labeling requirements) Class 2- Many genetic tests drug metabolism 501k submission plan Comparison with predicate device (similar) for analytical validation and comparison If no predicate device de novo 510(k) submission
Clinical trials and literature data submission (Mammaprint from Agendias) Breast cancer recurrence within 5-10 years with stage I or stage II disease status First cleared molecular test from FDA Feb 2007 FDA Review time 30 days overall process 6 months

Class 3 highest risk require premarket approval submission (PMA) Extensive radiation and chemotherapy

 Clinical Laboratory Standards Institute (CLSI)

Test performance standards from FDA http://www.fda.gov/cdrh/index.html Congressed passed CLIA in 1997, administered by CMS (The Centers for Medicare & Medicaid Services) Evaluates quality of performance but not clinical utility

IRBs and informed consent Investigational device exemption (IDEs)

Most IVDs do not need to submit IDEs IDEs used for exempting the devices used in clinical trials

 Most genetic tests are laboratory developed tests that do not required Marketing approval from FDA However, some are In vitro Diagnostic Multivariate Index assay
Complex genetic tests class II & class III 510(k) or PMA approval http://www.fda.gov/cdrh/oivd/1610.pdf

 Drug metabolizing enzyme testing CYP450 was passed based on the literature by FDA Early 2007 - no requirement of PGx testing but recommendation
http://www.fda.gov/cder/genomics/genomic_biomarkers_table.htm Up to date Pharmacogenetics test utilized in drug testing

 2005 University of Arizona & FDA Toxicogenomics (toxicant)

The overall goal of the Critical Path Initiative is to modernize the scientific process through which a potential human drug, biological product, or medical device is tested and developed.

 Warfarin (thromboembolic events)

21 million prescriptions annually CYP2C9*2 & CYP2C*3 & VKORC1 FDA approved 1 month Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test

 Amplichip- Roche (Swiss) CYP450 testing system

CYP2D6 & CYP2D19 genes polymorphisms 600$-1300$ test Couldnt show Clinical utility and cost effectiveness ? (experimental/investigational/unproven) by insurance companies FDA approved based solely on analytical performance & validity information but not clinical utility

 Cross talk between geneticist, statisticians, pharmacologists, molecular biologists, physicians Education Prospective clinical trials Gene-gene interaction and environment study Broad phenotype and unequivocal data Surveillance of ADRs post market Incentives for companies after patent expires

 Using resources online for specific disease is very essential

Ex: The national comprehensive cancer network Keeps update on colorectal cancer & advised to include KRAS PGx testing to administer Erbitux and vectibix

WGAS (whole genome association study)

Statin treated patients identified risk variants in SLCO1B1 gene associated with increased myopathy Related to uptake of hepatic statins

 HHS Secretarys Advisory Committee on Genetics, Health, and Society (SACGHS)

Recommendation on federal regulation on genetic assays Premarket clearance Genetic info on drug

Labels of the drugs:

Abacavir Carbamazepine Erbitux, Vecitibix Only K-RAS wild can get these drugs administered

Cost minimization Cost consequences analysis Cost-benefit analysis Cost effectiveness analysis Cost utility analysis

Incremental cost effectiveness ration (comparison with the

existing)
ICER=(C2 - C1 )/(E2 - E1 ) [c2=new c=cost e=effectiveness]

 NICE = National institute of health and clinical excellence - UK CADTH = Canadian agency for drugs and technologies in health PBAC = pharmaceuticals advisory committee Australia AMCP = Academy of managed care pharmacy
About submitting data on cost effectiveness

 Incremental value of testing ?

Pricing and reimbursement issue

Breast cancer disease recurrence score (RS)

Oncotype Dx (tests 21 gene profile) Such complex test need addition justification for the added value

1. 2. 3.

What is the frequency of the genetic variation? How closely is the variation linked to a consistent phenotypic drug response? Are there other significant influences on drug response such as diet, disease, or drug interactions? 4. What are the sensitivity and specificity of the genomic test? 5. How prevalent is the disease of interest? 6. What are the characteristic outcomes associated with the disease with and without treatment? 7. How does the pharmacogenomic strategy alter these outcomes? 8. What alternative treatment options are available? 9. How effective are current monitoring strategies for preventing severe adverse drug reactions and predicting drug response? 10. Concordance of actual treatment with PGx results
Ex: decrease in selection of chemotherapy by only 2% when PGx is used

Genomic test result in decision making if got importance the % might increase

1. Polymorphism prevalence & high degree of penetrance (phenotype vs. genotype) 2. Genetic test highly sensitive and specific 3. Less costly alternative test not available 4. Without treatment leads to significant mortality and morbidity 5. There is significant impact on the cost/ effectiveness with the PGx testing

Doesnt increase Quali So disease risk and treatment outcome are most important when implementing the PGx test

 Oncotype Dx test increased the QUALY by 0.09 years and decreased the cost by $2000

 Regulatory frame work not yet optimized Pharmacogenomics with pharmaceuticals is difficult due to difference in translational science (biomarker selection, additional costs, incremental value etc) Public policy and stakeholders standings not clear

 Need systematic evaluation of biomarkers and integration of PGx Support for basic research of biomarkers before clinical trials start Unified approach from biotech, pharma and diagnostic industry on PGx for drugs Appropriate regulatory process and initiatives Identification and evaluation of association Evaluation of intervention based on PGx results

Reduce mortality and morbidity Cost saving (side effects or for disease) Greater utilization by afflicted Better compliance (more net benefit to patient)

Broader phenotype definition Selection of marker Choice of study design Large sample size 2-5% minor allele (at least needed) WGAS need not to type all the SNPs Limitation of test by population Limitation of use of test by dosage regulation (commercially undesirable) Still enthusiasm on pharmacogenetics PGx Concerns on restriction on markets mitigated by success of targeted therapies We do not know the Indian market yet

 Genomic medicine offers significant hope for fundamental improvements in the healthcare We have to educate ourselves first, plan, assess risks and involve deeply The only word that best describes us regardless of anything is Committed
Committed to achieve success Committed to save peoples life Committed to expand

We should give more importance to our team compare to ourselves this is what drives happiness and true involvement in what we do.

 Hashim - R & D and Decision Making

Technical details of the tests and the devices of testing (R&D) Approval of market strategy and products approval Final decision making Smooth regulation of start up & team progress Company approval and establishment Market Analysis of available tests Economic Evaluation & cost analysis Forecasting the market & market strategy planning Banking & Finance management Company approval and establishment Review of the forms and data submission process Management of the regulatory framework Quality assurance Company approval & establishment

Mallesh Market analysis

Khalid Regulatory approval process

Every 10 days each person presents once Each will have 10 days to prepare for presentation 3 presentations in total/ 10 days Each person will give monthly plan for all three presentation Ex: the topic of presentation, the date We need to be very responsible Our normal work routine must never disturb our project Topics of presentation for the month will be posted on the calendar schedule, we should have some living to make up our costs We will discuss the upcoming presentation topics before the month starts (last week of previous month after last presentation) We will make recommendation for change in the topics together We will have support for each other at any point of time for any matter related to the business We need to be professional and should have good time management skills. If the presentation cannot be made that day, we will accommodate the presentation some other day of the same week, however the presentation will not be cancelled for that week, except in very rare events.

 Every meeting will have a code starting from M1

Ex: M1, M2, M3. MN

Each presentation topic and points to be covered will be posted in the new page on website Presentation topics before the start of next month
Ex: M20: Process of market approval by Mallesh Topics to be covered: Market strategy Driving forces Economical challenges Planning Wrap up

 Education phase
August December 2012

Planning phase
January May

Preparation & Establishment

June December

Timeline or other business related things will keep changing as required

? Diagnostics