department of ethics, trade, human rights and health law, world

Department of Ethics, Trade, Human Rights and Health Law, WorldDepartment of Ethics, Trade, Human Rights and Health Law, World Health OrganizationHealth Organization


Bioethics and Bioethics and Public Policy SeminarPublic Policy Seminar

Yale Interdisciplinary Yale Interdisciplinary Bioethics ProjectBioethics Project

New Haven ConnecticutNew Haven Connecticut13 October 200413 October 2004


PharmacogeneticsPharmacogenetics: : Too Quick a Move from Too Quick a Move from Research to Practice?Research to Practice?

Alexander Morgan CapronAlexander Morgan CapronDirectorDirector

Department of Ethics, Trade, Department of Ethics, Trade, Human Rights and Health LawHuman Rights and Health Law

World Health OrganizationWorld Health Organization


The Starting PointThe Starting Point

"If it were not for the great "If it were not for the great variability among variability among individuals, medicine individuals, medicine might as well be a science might as well be a science and not an art" and not an art"

–– Sir William Sir William OslerOsler, 1892, 1892


The PremiseThe Premise

Much if not most of that "great Much if not most of that "great variability" originates in genetic variability" originates in genetic differencesdifferencesAs those differences are understood As those differences are understood and become detectable, medical and become detectable, medical interventions can be adjustedinterventions can be adjustedMedicine will become a more exact Medicine will become a more exact and scientific fieldand scientific field


A Dramatic ExampleA Dramatic Example

Did you read "The Genome in Black and Did you read "The Genome in Black and White (and Gray)" by Robin White (and Gray)" by Robin MarantzMarantzHenigHenig, NY Times , NY Times MagMag. (10. (10--1010--2004)?2004)?Standard treatments for heart failure Standard treatments for heart failure (beta(beta--blockers, ACE inhibitors) don't blockers, ACE inhibitors) don't work as well for Blacks as Whiteswork as well for Blacks as WhitesA new medication, A new medication, BiDilBiDil, treats the , treats the nitricnitric--oxide deficiency more common oxide deficiency more common in heart failure in Black patientsin heart failure in Black patients



In 1999, FDA declined to approve In 1999, FDA declined to approve BiDilBiDilfor general use since it lacked efficacyfor general use since it lacked efficacyBeginning in 2001, Beginning in 2001, NitroMedNitroMed conducted conducted a RCT in more than 400 black women a RCT in more than 400 black women and 600 black men with heart failureand 600 black men with heart failureIn 2003, study was halted early In 2003, study was halted early because because BiDilBiDil was too effective to be was too effective to be withheld from the control group withheld from the control group



"Thus, a drug that had been "Thus, a drug that had been deemed ineffective in the deemed ineffective in the population at large seemed to population at large seemed to work so well in one racial work so well in one racial subgroup that the scientists subgroup that the scientists thought everyone in that thought everyone in that subgroup should get it."subgroup should get it."

––Robin Robin MarantzMarantz HenigHenig, (NY Times), (NY Times)


Why Connect Drugs with Genes?Why Connect Drugs with Genes?

Even if our genetic code is 99.9% Even if our genetic code is 99.9% the same, the 1/10% covers millions the same, the 1/10% covers millions of nucleotidesof nucleotides––and variations (an A and variations (an A for a T, a C for a G) can effect genesfor a T, a C for a G) can effect genesSingle nucleotide polymorphisms Single nucleotide polymorphisms (SNPs) occur in groups of people & (SNPs) occur in groups of people & grouped themselves (grouped themselves (haplotypeshaplotypes))When they occur in genes, SNPs can When they occur in genes, SNPs can affect drugs in unpredictable waysaffect drugs in unpredictable ways


Why Connect Drugs with Genes?Why Connect Drugs with Genes?

Some people may differ from the Some people may differ from the majority because their cells lack the majority because their cells lack the receptors or do not produce the receptors or do not produce the proteins or enzymes needed for proteins or enzymes needed for drugs to enter the cell or to be drugs to enter the cell or to be metabolized or excreted as expected metabolized or excreted as expected Can result in lack of therapeutic Can result in lack of therapeutic effect or, worse, in toxicity effect or, worse, in toxicity


Examples Accumulating QuicklyExamples Accumulating Quickly

In Sept., Swiss investigators reported that In Sept., Swiss investigators reported that two years after treatment with two years after treatment with temozolomidetemozolomidealong with radiotherapy for along with radiotherapy for glioblastomaglioblastoma (a (a deadly brain deadly brain tumortumor), 46% of patients in one ), 46% of patients in one group were alive, compared to 14% in group were alive, compared to 14% in another (about same as just radiotherapy)another (about same as just radiotherapy)Difference in the groups? Difference in the groups? Whether in the Whether in the tumortumor cells the gene cells the gene for DNA repair was turned on or off for DNA repair was turned on or off


Examples Accumulating QuicklyExamples Accumulating Quickly

Similar results with breast cancer drug Similar results with breast cancer drug HerceptinHerceptin & lung cancer drug & lung cancer drug IressaIressaConsequences:Consequences:•• Avoid putting patients on drugs that are Avoid putting patients on drugs that are

unlikely to help them & may harmunlikely to help them & may harm•• Allow patients to pursue other approaches Allow patients to pursue other approaches

to their illnessto their illness•• Possibly reduce wasted carePossibly reduce wasted care


What Does This Suggest as What Does This Suggest as Benefits of Benefits of PharmacogeneticsPharmacogenetics??1.1. Improve treatment efficacyImprove treatment efficacy2.2. Improve drug safetyImprove drug safety3.3. Minimize adverse reactions to drugsMinimize adverse reactions to drugs4.4. Minimize drug side effectsMinimize drug side effects5.5. Improve patient adherence to Improve patient adherence to

treatmenttreatment6.6. "Rescue" drugs in development "Rescue" drugs in development


But May Enthusiasm Lead to Too But May Enthusiasm Lead to Too Quick a Move to Clinical Practice?Quick a Move to Clinical Practice?

Errors in the science (associations versus Errors in the science (associations versus understanding mechanism)understanding mechanism)""GeneticizationGeneticization" of illness" of illness––overlook other overlook other important differencesimportant differencesFoster "reductionism" (DNA, not people) Foster "reductionism" (DNA, not people) Fractionalization of drug fieldFractionalization of drug fieldBarriers to treatment (gene test)Barriers to treatment (gene test)Exceed capabilities of practitioners Exceed capabilities of practitioners Need for "genetic counselling"Need for "genetic counselling"


Information That May Be Derived Information That May Be Derived from a from a PharmacogeneticPharmacogenetic TestTest

differential diagnosisdifferential diagnosisavailable therapeutic optionsavailable therapeutic optionsprognosis of the diseaseprognosis of the diseaseprobability of other drugs being safe and probability of other drugs being safe and efficaciousefficacious

These are not different in kind from other sorts of These are not different in kind from other sorts of predictive tests medical examinationspredictive tests medical examinationsMajor issues: that practitioners not overlook Major issues: that practitioners not overlook other causes & under stand the genetic testother causes & under stand the genetic test


Information That May Be Derived Information That May Be Derived from a from a PharmacogeneticPharmacogenetic TestTest

risk for the primary relatives to be afflicted by risk for the primary relatives to be afflicted by the diseasethe diseaserisk for the patient of being afflicted by an risk for the patient of being afflicted by an unrelated genetic diseaseunrelated genetic diseaserisk for the primary relatives to be afflicted by an risk for the primary relatives to be afflicted by an unrelated genetic diseaseunrelated genetic disease

Data of this sort is different than that from other Data of this sort is different than that from other kinds of tests kinds of tests Usually has resulted in "genetic counseling," Usually has resulted in "genetic counseling," but that may not be realistic in primary carebut that may not be realistic in primary care


Two Forms of Pharmacogenetic Tests

Differentiating People

Tests which examine an individual's DNA, ultimately gaining information unrelated to the disease being treated.

Differentiating Diseases

Tests which examine the differences in DNA that are directly related to the disease being treated.

"The nature of the information provided by a medical test is the key to considering its implications, not whether the test involves genetic data."

- Nuffield Council on Bioethics


Decisions Prior to the use ofPharmacogenetic Tests

Whether or not to take the test

Must a medicine be made availableafter the test has been taken

Should a medicine be made availablefor a patient who refuses the test


The decision to take the test relies on multiple factors:

~ access to the test

~ access to interpretation of the results

~ cost of the test


The decision to make the medicine available after the

test results have been obtained:

~ no alternative treatment

~ who decides if the potential benefit outweighs the risk


The decision to provide or withhold the medicine if the patient refuses the test:

~ licensing conditions of the medication

~ test refused due to fear

~ voluntary consent v. coerced submission to the test

~ no treatment alternative


Differentiated ConsentDifferentiated ConsentThe process by which physicians will, "explain The process by which physicians will, "explain

to the patients that pharmacogenetics to the patients that pharmacogenetics testing can result in more than just a testing can result in more than just a statement if a drug will be safe or whether statement if a drug will be safe or whether it will work, detailing the types of it will work, detailing the types of information that can in fact results information that can in fact results ……Patients would then have to decide if they Patients would then have to decide if they want to learn all about the secondary want to learn all about the secondary information that might be entailed by the information that might be entailed by the test in questiontest in question……" "

~ ~ Christian Christian NetzerNetzer & Nikola & Nikola BillerBiller--AndornoAndorno (2004)(2004)


Questions of EquityQuestions of Equity

RaceRace--specific medicationsspecific medications

Pharmaceutical investmentsPharmaceutical investments

Ramifications for poorer countriesRamifications for poorer countries


ResearchEffects on basic research

Shrinking the pool of patient-subjects (prematurely?

Will companies sponsor research on current medications? Those where patent has nearly run?

Need for explicit consent on use of samples


The Future•Numerous policy issues remain before clinical practice will be ready for pharmacogenetics–but it may come before practice is ready.•Likewise, many broader issues for society, on licensing, use, and availability of medicines

"The translation of pharmacogenetics research into clinical practice will be intellectually challenging, time-consuming, and expensive. It will usually require explicit clinical evaluation, meaning that translation will lag years behind basic research."

~ David B. Goldstein


Thank YouThank You

Citation:Citation:Christian Christian NetzerNetzer & Nikola & Nikola BillerBiller--

AndornoAndorno, ", "PharmacogeneticPharmacogenetic Testing, Testing, Informed Consent and the Problem Informed Consent and the Problem of Secondary Information"of Secondary Information"

BioethicsBioethics, vol. 18, pp. 344, vol. 18, pp. 344--360 (2004)360 (2004)

department of ethics, trade, human rights and health law, world

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