THE PERSONALIZED MEDICINE REPORT
THEPERSONALIZEDMEDICINEREPORT2017 · Opportunity, Challenges, and the Future
The Personalized Medicine Coalition gratefullyacknowledges graduate students at ManchesterUniversity in North Manchester, Indiana, and at theUniversity of Florida, who updated the appendixof this report under the guidance of David Kisor,Pharm.D., Director, Pharmacogenomics Education,Manchester University, and Stephan Schmidt,Ph.D., Associate Director, Pharmaceutics, Universityof Florida. The Coalition also acknowledges thecontributions of its many members who offeredinsights and suggestions for the content in the report.
CONTENTSINTRODUCTION5THE OPPORTUNITY7Benefits9Scientific Advancement17THE CHALLENGES27Regulatory Policy29Coverage and Payment Policy35Clinical Adoption39Health Information Technology45THE FUTURE49Conclusion51REFERENCES53APPENDIX57Selected Personalized Medicine Drugs and Relevant Biomarkers57
HISTORICAL PRECEDENTFor more than two millennia, medicinehas maintained its aspiration of beingpersonalized. In ancient times, Hippocratescombined an assessment of the fourhumors — blood, phlegm, yellow bile, andblack bile — to determine the best courseof treatment for each patient. Today, thesequence of the four chemical buildingblocks that comprise DNA, coupled withtelltale proteins in the blood, enable moreaccurate medical predictions.
The Personalized Medicine ReportINTRODUCTIONWhen it comes to medicine, one size does not fit all. Treatments that help some patientsare ineffective for others (Figure 1),1 and the same medicine may cause side effects inonly certain patients.Yet, bound by the constructs of traditionalcare delivery models, many of today’s doctors stillprescribe therapies based on population averages.As a result, health care systems around the worldcontinue to deliver inefficient care that fails tohelp significant portions of the patient population.Enter personalized medicine. Personalizedmedicine, also called precision or individualizedmedicine, is an evolving field in which physiciansuse diagnostic tests to identify specific biologicalmarkers, often genetic, that help determine whichmedical treatments and procedures will work bestfor each patient. By combining this informationwith an individual’s medical records, circumstances,and values, personalized medicine allows doctorsand patients to develop targeted treatmentand prevention plans. Personalized health care hasthe capacity to detect the onset of diseaseat its earliest stages, pre-empt the progression ofdisease, and, at the same time, increase theefficiency of the health care system by improvingquality, accessibility, and affordability.Health care is in the midst of a transformationaway from one-size-fits-all, trial-and-errormedicine and toward this new, targeted approachthat utilizes patients’ molecular information toinform health care decisions. Completing thattransformation, however, will require a collaborative effort in the U.S. and abroad to keep up withthe pace of progress in science and technology.A myriad of nuanced regulatory and reimbursement challenges as well as complexities regardingthe clinical adoption of new medical norms andstandards, in particular, continue to make itdifficult for health care systems around the worldto capitalize on innovative science and a growingbody of knowledge pointing to a new era in thehistory of medicine.5
6IntroductionFIGURE 1: ONE SIZE DOES NOT FIT ALLPercentage of the patient population for which a particular drug in a class isineffective, on average.ANTI-DEPRESSANTS38%ASTHMA DRUGS40%DIABETES DRUGS43%ARTHRITIS DRUGS50%ALZHEIMER’S DRUGS70%CANCER DRUGS75%SSRIsReproduced with permission from: Spear, BB, Heath-Chiozzi, M, Huff, J. Clinical applicationof pharmacogenetics. Trends in Molecular Medicine. 2001;7(5): 201-204.
The Personalized Medicine Report7THE OPPORTUNITY
8The Opportunity“The power in tailored therapeutics isfor us to say more clearly to payers,providers, and patients: ‘this drug is notfor everyone, but it is for you.’ That isexceedingly powerful.” — John C. Lechleiter, Ph.D.former Chairman, President, and CEO, Eli Lillyand Company
The Personalized Medicine ReportBENEFITSPersonalized medicine benefits patients and thehealth system by: Shifting the emphasis in medicine from reactionto prevention Directing targeted therapy and reducing trialand-error prescribing Reducing adverse drug reactions Revealing additional targeted uses for medicinesand drug candidates Increasing patient adherence to treatment Reducing high-risk invasive testing procedures Helping to control the overall cost of health careShifting the Emphasis in Medicine fromReaction to PreventionPersonalized medicine introduces the ability touncover molecular markers that signal disease riskor presence before clinical signs and symptomsappear, offering an opportunity to focus onprevention and early intervention rather than onreaction at advanced stages of disease.In some areas, early genetic testing can savelives. For example, women with certain BRCA1or BRCA2 gene variations have up to an 85percent lifetime chance of developing breastcancer, compared to a 13 percent chance amongthe general female population.2, 3, 4 Women withharmful BRCA1 and BRCA2 mutations also haveup to a 39 and 17 percent chance, respectively,of developing ovarian cancer, compared with a1.3 percent chance among the general femalepopulation.2 The BRCA1 and BRCA2 genetictests can guide preventive measures, such asprophylactic surgery, chemoprevention, andmore frequent mammography.Personalized medicine also opens the doorto early intervention for patients with familialhypercholesterolemia, which is characterizedby a mutation in the LDL receptor gene. Thesepatients can take drugs that block the PCSK9gene (known as PCSK9 inhibitors) to reducetheir cholesterol levels and potentially decreasetheir risk of developing coronary artery disease.9
10The OpportunityDirecting Targeted Therapy and ReducingTrial-and-Error PrescribingIn many disease areas, diagnostic tests enablephysicians to identify the most effective treatment for a patient immediately by testingfor specific molecular characteristics, thusavoiding the frustrating and costly practice oftrial-and-error medicine. Medicines that targetthose molecular characteristics often improveoutcomes and reduce side effects. One of themost common applications of this practice hasbeen for women with breast cancer. About30 percent of breast cancer cases are characterized by over-expression of a cell-surface proteincalled human epidermal growth factor receptor 2(HER2). For breast cancer patients who expressthis molecule, adding an antibody drug liketrastuzumab (Herceptin ) to their chemotherapyregimen can reduce their recurrence risk by52 percent.5, 6 Molecular diagnostic tests for HER2are used to identify the patients who will benefitfrom receiving Herceptin and other drugs thattarget HER2, such as lapatinib (Tykerb ).Treatments targeting genetic variants involved inthe molecular pathway of disease, such as BRAFin melanoma and ALK and EGFR in non-smallcell lung cancer, represent a remarkable improvement over trial-and-error medicine, and we aremoving toward an era in which we treat all cancercases with a targeted course of treatment(Figure 2).7Other personalized medicine tests measureprognostic markers that help indicate howa disease may develop in an individual when adisorder is already diagnosed. Two complex tests,Oncotype DX and MammaPrint , for example,use prognostic markers to help physicians targetthe best course of treatment for breast cancerpatients. Oncotype DX can determine whetherwomen with certain types of breast cancerare likely to benefit from chemotherapy.8, 9, 10MammaPrint can detect which early-stage breastcancer patients are at risk of distant recurrencefollowing surgery.11 Both tests place patients intorisk categories that inform physicians and patientsof whether the cancer may be treated successfully with hormone therapy alone, as opposedto some combination of hormone therapy andchemotherapy, which is associated with an additional financial burden and toxic effects. Similarprognostic tests for prostate and colon cancerpatients have also been developed.12, 13, 14Reducing Adverse Drug ReactionsAnother category of personalized medicine tests,called pharmacogenomic tests, help predict whatmedications at what doses will be safest for individuals based on their genetic makeup. Doing so isimportant. According to several studies, about 5.3percent of all hospital admissions are associatedwith adverse drug reactions (ADRs).15 Many ADRsare attributed to variations in genes that code for
The Personalized Medicine ReportFIGURE 2: F ORGING A PATH TO PERSONALIZED CANCER CARETACKLING TUMORS: Percentage of patients whose tumors are driven by certaingenetic mutations that could be targets for specific drugs, by types of trialLung41%Pancreatic41%32%Breast31%Other gynecological29%Genitourinary25%Other gastrointestinalOvarian21%Head and neck21%Reproduced with permission from: Winslow, R. Major shift in war on cancer. Wall Street Journal.June 5, 2011. Accessed September 13, 2016 at 304576367802580935000.11
12The Opportunitydrug-metabolizing enzymes, such as cytochromeP450 (CYP450).16, 17 These variants cause drugsto be metabolized either faster or slower thannormal. As a result, some individuals have troubleinactivating a drug and eliminating it from theirbodies, leading to systemic overexposure to thedrug, while others eliminate the drug too rapidlybefore it has had a chance to work. Thus, thesegenetic variations should be considered whendetermining dose.Pharmacogenomic testing can help guidethe safe application of medicines in many healthareas, including heart disease, hematologicdisorders, HIV and other infectious diseases,cancer adjunct therapy, anesthesiology, dermatology, gastroenterology, neurology, psychiatry,and rheumatology. One of the first applicationsof pharmacogenomics was for patients thathad been prescribed the drug warfarin, usedto prevent blood clots. Genetic variations ina drug-metabolizing enzyme (CYP2C9) andan enzyme that activates vitamin K (VKORC1)complicate the safe use of warfarin.18, 19 Dosingis typically adjusted for the individual patientthrough multiple rounds of trial-and-error, duringwhich the patient may be at risk for excessivebleeding or further blood clots. FDA now recommends genotyping for all patients before warfarintreatment, which allows for more precise dosing.Although the data are still evolving, early evidencesuggests that genetic testing in advance ofprescribing warfarin helps patients avoid seriousand possibly fatal adverse effects.20, 21The use of genetic markers to facilitate saferand more effective drug dosing and selectiontakes on added significance at the populationlevel. For example, adverse reactions to the HIVdrug efavirenz (Stocrin /Sustiva ) can occur atstandard dosing due to the presence of a geneticmutation (the CYP2B6*6 allele) in an enzyme thatmetabolizes the medicine. This results in slowermetabolism of the drug and is found significantlymore often in patients of African heritage thanthose of European heritage.22 Lowering thedrug dose in individuals with this allele can helpreduce adverse effects and increase treatmentcompliance. Similarly, the HLA-B*5701 mutation isassociated with severe and life-threatening hypersensitivity to the HIV drug abacavir (Ziagen /Epzicom ).23 The HLA-B*5701 mutation is presentin approximately five percent of HIV patients inthe U.S.Revealing Additional Targeted Uses forMedicines and Drug CandidatesMolecular testing can also help identify the mostappropriate uses for therapies that were initiallytargeted to the general population. The lungcancer drug gefitinib (Iressa ), for example, didnot demonstrate a survival advantage in a generalpopulation of lung cancer patients in clinical trials,and was withdrawn from the market in 2005after initially being granted accelerated approvalin 2003. However, continued clinical research
The Personalized Medicine Reportrevealed benefits in patients who test positivefor epidermal growth factor mutations. FDAapproved Iressa as a first-line treatment for thissubset of patients in 2015.Gene and protein analyses have also led to anevolution in the way tumors are evaluated andclassified. With an increasing body of knowledgeabout the underlying genomic alterations and theexpression of relevant biomarkers, tumor classification is shifting away from tissue of origin andtoward molecular taxonomy, which is having aprofound effect on the way that oncology treatment decisions are made. For example, trial resultssuggest that expression of the PD-L1 biomarker,which has been widely observed in cancers frommultiple tissues of origin, can help doctors makemore informed decisions about the use of somenovel immune checkpoint inhibitors.24 This has ledto expanded approvals for immune checkpointinhibitors like pembrolizumab (Keytruda ), whichwas initially approved in 2014 for melanoma.25FDA revised Keytruda’s label in 2015 for use innon-small cell lung cancer and has fast-trackedreview for its use in other indications.26, 27 Similarly,FDA has also approved the use of nivolumab(Opdivo ) for multiple indications.28, 29, 30, 31, 32Likewise, early studies indicate that crizotinib(Xalkori ), already approved to treat specific formsof non–small cell lung cancers, including those thatare EML4-ALK-positive, is also effective againstother types of tumors containing ALK alterations,such as aggressive forms of pediatric neuroblas-toma and anaplastic large cell lymphoma.33, 34FDA has fast-tracked regulatory review for theseexpanded indications, which some observersbelieve is a precursor to an era in which the agencyapproves all personalized medicines faster basedon the increased likelihood that a molecularlytargeted drug will be safe and effective.Increasing Patient Adherenceto TreatmentPatient non-adherence with treatment leads toadverse health effects and increased overall healthcare costs. When personalized therapies provemore effective or present fewer side effects,patients may be more likely to comply with theirtreatment regimens. The greatest impact could bein the treatment of chronic diseases, for which nonadherence commonly exacerbates the condition.For example, inherited forms of hypercholesterolemia (high cholesterol) can increase the riskof myocardial infarction before the age of 40 bymore than 50-fold in men and 125-fold in women.Knowledge of a genetic predisposition for hypercholesterolemia provides patients with a powerfulincentive to make lifestyle changes and managetheir condition with drugs. Patients with a geneticdiagnosis have shown more than 86 percentadherence to their treatment program after twoyears, compared to 38 percent prior to testing.3513
14The OpportunityFIGURE 3: A NEW TREATMENT PARADIGMWithout Personalized Medicine: Some Benefit, Some Do NotPatientsTherapySome patients benefit, some patients do not benefit, andsome patients experience adverse effectsWith Personalized Medicine: Each Patient Receives the Right MedicinePatientsBiomarkerDiagnosticsTherapyEach patient benefits from individualized treatmentAdapted with permission from: PhRMA. A New Treatment Paradigm. Accessed September 13, 2016at he-health-care-system.
The Personalized Medicine ReportAvoiding Invasive Testing ProceduresMolecular tests that simply require a blood samplecan also sometimes replace invasive and uncomfortable tissue biopsies. For example, Allomap ,a multi-gene expression test, detects whetherthe immune system of heart transplant recipientsis rejecting the new organ.36 Approximately 25percent of heart transplant patients experiencea rejection, which can prove fatal. To monitor forrejection, heart tissue biopsies are performed asfrequently as once a week after the transplant,and then every few months thereafter for severalyears. This invasive procedure requires inserting atube into a vein in the neck and threading it to theheart to obtain the biopsy, which is uncomfortablefor patients and has risks associated with injury tothe vein and heart. Patients who are monitored forrejection using Allomap have equivalent outcomesas those who receive heart tissue biopsies, butwithout the associated risks and complications.37, 38Helping to Control the OverallCost of Health CareBy introducing innovative science that can createefficiencies and sustainability, personalized medicine also has the potential to reduce health carecosts worldwide. As noted, incorporating personalized medicine into the fabric of the health caresystem can help decrease costs associated withmany embedded inefficiencies, such as trial-anderror dosing, hospitalizations due to adverse drugreactions, late-stage health condition diagnoses,and reactive treatment. Personalized medicine canalso play an important role in the implementationof value-based payment and delivery models, whichcan help coordinate patient care and reduce costs.As an example, data suggest that pharmacogenomic testing associated with the managementof dosing of the blood thinning drug warfarin caneliminate costs associated with hospitalizationsfor bleeding or thromboembolism. The MayoClinic and the pharmacy benefits manager Medcoput the model to the test in a 3,600-subjectprospective study. Hospitalization rates for heartpatients were reduced by about 30 percent whengenetic information was available to doctorsprescribing the drug.39 Additionally, breast cancertherapy guided by the Oncotype DX test hasbeen estimated to provide a net cost savings of 2,256 per patient tested, based on a reductionin chemotherapy use with an incremental costeffectiveness ratio of 1,944 per life year saved.40Another study found a 604 million annualsavings among all patients when treatment withpanitumumab (Vectibix ) or cetuximab (Erbitux )was limited to patients with metastatic colorectalcancer whose KRAS gene was not mutated.4115
16The Opportunity“It’s not really ‘should we do this.’ We haveto do this. We don’t get to decide whatthe biology of these diseases are, we justhave to work with it.” — Barbara Weber, M.D.Interim Chief Medical Officer, Neon Therapeutics
The Personalized Medicine ReportSCIENTIFICADVANCEMENTThe scientific tools necessary to realize thebenefits of personalized medicine are already atour disposal.PMC counts 132 personalized medicines, thatis, drugs that point to specific biomarker(s) intheir labels to direct use, currently on the market(Figure 4; Appendix), and recent estimates by thegenetic testing data company Concert Geneticsindicate that there are now no fewer than 65,000genetic tests available (Figure 5). Analysts peg themarket value for drugs reliant on companion diagnostics (CDx) at over 25 billion in 2015 (Figure 6).These numbers are likely to continue growing.A recent survey conducted by the Tufts Centerfor the Study of Drug Development showed that42 percent of the drugs in the development pipeline now include biomarkers in their research anddevelopment design. The survey also suggestedthat biopharmaceutical manufacturers have nearlydoubled their investment in personalized medicineover the past five years, and that these companiesexpect investment to increase by another 33percent over the next five years (Figure 7).Scientific developments in genomicsequencing, how an individual’s biology impactsdisease susceptibility, immunotherapy, genetherapy, and CRISPR-Cas9 gene editing are layingthe groundwork for a new era in medical discovery.17
18The OpportunityFIGURE 4: COMING OF AGENumber of Personalized Medicines Has Increased Steadily Since 2008*1321068136520082010201220142016Pe
The Personalized Medicine Report 5 INTRODUCTION When it comes to medicine, one size does not fit all. Treatments that help some patients are ineffective for others (Figure 1),1 and the same medicine may cause side effects in only certain patients. Yet, bound by the constructs of traditional care delivery models, many of today’s doctors still
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
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ii. personalized medicine from a regulatory perspective 5 1. defining personalized medicine 5 2. fda's unique role and responsibilities in personalized medicine 11 iii. driving toward and responding to scientific advances 14 1. building the infrastructure to support personalized medicine 16 2. recent organizational efforts 20 iv.
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. Crawford M., Marsh D. The driving force : food in human evolution and the future.
