Hashim Khan

Saturday, 2012

• 25-60% of patients – benefit from drugs

• 2 million ADR’s & 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 doesn’t 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 test-

before 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

• Couldn’t 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 Secretary’s 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. What is the frequency of the genetic variation?

2. How closely is the variation linked to a consistent phenotypic drug response?

3. 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

Doesn’t 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

• Mallesh – Market analysis • Market Analysis of available tests

• Economic Evaluation & cost analysis

• Forecasting the market & market strategy planning

• Banking & Finance management

• Company approval and establishment

• Khalid – Regulatory approval process • Review of the forms and data submission process

• Management of the regulatory framework

• Quality assurance

• Company approval & establishment

• 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