OCTOBER 2013 Paving The Way For Personalized Medicine

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OCTOBER 2013Paving the Way forPersonalized MedicineFDA’s Role in a New Era of Medical Product DevelopmentU.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESU.S. FOOD AND DRUG ADMINISTRATION


Over the past few years, a number of products that signal a new era ofmedical product development have entered the market or come on thehorizon. In just the last two years, the FDA approved four cancer drugsfor use in patients whose tumors have specific genetic characteristics thatare identified by a companion diagnostic test. Last year, FDA approveda new therapy for use in certain cystic fibrosis patients with a specificgenetic mutation. Earlier this year, three-dimensional (3D) printing wasused to create a bioresorbable tracheal splint for treating a critically-illinfant.Each of these examples demonstrates the promise of “personalizedmedicine,” which is the tailoring of medical treatment to the individualcharacteristics, needs and preferences of each patient. The concept ofpersonalized medicine is not new: clinicians have long observed that patients with similar symptomsmay have different illnesses, with different causes; and similarly, that medical interventions may workwell in some patients with a disease but not in others with apparently the same disease. What is newis that advances in a wide range of fields from genomics to medical imaging to regenerative medicine,along with increased computational power and the advent of mobile and wireless capability and othertechnologies, are allowing patients to be treated and monitored more precisely and effectively and inways that better meet their individual needs.Long before I became commissioner, FDA was attuned to the promise and potential challengesof personalized medicine. As a result of this forward thinking, the Agency moved quickly to buildand shape a regulatory infrastructure to help make personalized medicine possible. I have madeit a priority to continue to evolve FDA’s regulatory processes in response to—and in anticipationof—scientific developments that are critical for the development of personalized therapeutics anddiagnostics.I am pleased to offer this report, Paving the Way for Personalized Medicine: FDA’s Role in a New Eraof Medical Product Development, as part of the Agency’s ongoing commitment to this important andemerging area of medicine. The report describes the ways in which FDA has worked to respond to,anticipate and help drive scientific developments in personalized therapeutics and diagnostics. Forthe first time, it provides a compendium of FDA’s many recent efforts to advance regulatory standards,methods and tools in support of personalized medicine and to further refine critical regulatoryprocesses and policies in order to bring about personalized medical product development. Thisthoughtful report should serve as a useful resource for those looking toward a future where all stagesof patient care—from prevention to diagnosis to treatment to follow-up—are truly personalized.Margaret A. Hamburg, M.D.Commissioner of Food and DrugsPaving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development2

I. INTRODUCTIONOn January 31, 2012, the FDA approvedwas patient-driven. The drug itself emergeda new therapy for cystic fibrosisout of a decade-long collaboration between(CF), a serious inherited diseasethe Cystic Fibrosis Foundation (CFF) and thethat impairs the lungs and digestive system.drug’s manufacturer, Vertex Pharmaceuticals.The drug, Kalydeco (known generically asThe Foundation had been at work severalivacaftor), was approved for patients with adecades previously, organizing and advocatingspecific genetic mutation – referred to as theon behalf of the patient community, fundingG551D mutation – in a gene that is importantresearch that led to the discovery of the gene infor regulating the transport of salt and water1989, building an extensive patient registry andin the body. There are hundreds of knownclinical trial network necessary for investigatingmutations that can lead to CF; the G551Dthe genetics of the disease, and efficientlymutation is responsible for only 4% of cases inrecruiting study participants and testingthe United States (approximately 1200 people).candidate drugs. Starting in the late 1990s, CFFIn these patients, Kalydeco works by helping tofunded a major drug screening effort that led torestore the function of the protein that is madethe discovery of the compound and invested aby the mutated gene. It allows a proper flowtotal of 75 million toward the development ofof salt and water on the surface of the lungsthe drug.and helps prevent the buildup of sticky mucusFinally, FDA approved Kalydeco in a verythat occurs in patients with CF and can lead toshort time. Elegant science and a well-designedlife-threatening lung infections and digestiveprogram of the drug sponsor allowed theproblems.agency to apply a number of mechanisms forThe Kalydeco story is compelling on severalstreamlining and expediting the review process.levels. First, Kalydeco is the first drug toFor one, the drug application was grantedaddress the underlying cause – rather than“priority review,” a designation that is giventhe symptoms – of CF. Skillful applicationto candidate drugs that offer major advancesof genomic science allowed researchers toin treatment or provide a treatment where nounderstand at a molecular level the reasonsadequate therapy exists. The time goal forwhy a protein fails to function, to discover andcompleting a priority review is six months, but adevelop a medicine specifically to improve itswell-prepared submission, strong evidence, andfunction, and to use the results of a genetic testa commitment on the part of all of the partiesto select the right patients for the drug. Whileinvolved enabled the review to be completed,it is too soon to say whether Kalydeco will beand the drug approved, in half that amountan all-out cure for those eligible to receive it,of time.patients are experiencing significantly improvedlung function and weight gain.Second, the path of development thatultimately led to the approval of KalydecoKalydeco is one of several “targeted therapies”approved in the past two years. Several cancerdrugs – crizotinib, vemurafinib, dabrafenib,and tremetinib – have each been approvedPaving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development3

for use in patients whose tumors have specificadvance medical practice, yet the challengesgenetic characteristics that are identified by aof understanding human health and diseasecompanion diagnostic test.remain sobering. Who we are, and whatMore broadly, Kalydeco is one of manyillnesses we suffer, depends not only on ourmedical products that point to the emergencegenes, but also on a complex intersection ofof a new era of personalized medicine.environmental, genetic, social and cultural“Personalized medicine” may be thought of asfactors. We have a great deal to learn abouttailoring medical treatment to the individualthe biological, anatomical and physiologicalcharacteristics, needs and preferences ofmechanisms that underlie disease. Realizingeach patient. “Personalized medicine” is nota truly personalized approach to patientlimited to pharmaceutical therapy. Advancescare will require fundamental advances inin computational power and medical imagingunderstanding each of these factors, as well asare paving the way for personalized medicalhow they impact one another.treatments that consider a patient’s genetic,The purpose of this report1 is to describe theanatomical, and physiological characteristics.unique and special role and responsibility thatThe advent of mobile and wireless capability,FDA has in helping to usher in the medicalbetter sensors, interoperable devices, and theproducts that are central to this larger effort.Internet have led to technologies that allowThe report describes the ways in which FDA hasfor more effective patient monitoring andevolved its regulatory processes in response to –treatment outside of traditional medical careand in anticipation of – scientific developmentssettings. And progress in regenerative medicinethat are critical for the development ofand stem cell research offers hope for some ofpersonalized therapeutics and diagnostics.the most personalized products imaginable –It describes in particular the ways in whichthe replacement or regeneration of missing orFDA has worked to bridge developments indamaged tissues.genomics and other relevant sciences to clinicalThe concept of personalized medicine is notpractice by advancing the tools necessary fornew: The practice of medicine has always beenevaluating targeted therapeutics and bringingabout treating each individual patient, andthem to market more efficiently, collaboratingclinicians have long observed that differentin key research, defining and streamliningpatients respond differently to medicalregulatory pathways and policies, and applyinginterventions. What is new is that paradigmaticnew knowledge in product reviews.developments in science and technology1offer new promise for developing targetedtherapeutics and tools for predicting who willrespond to a medical therapy or who will sufferill effects.The advances of the last few years inpersonalized therapeutics are testamentto the power of science to fundamentallyThis report was prepared by Tania Simoncelli, Senior Advisorin the Office of Medical Products and Tobacco, Office of theCommissioner. The following individuals contributed to itscontent and editing: Lisa Barclay, Khaled Bouri, KathleenBurns, Kate Cook, Ross Filice, James Fuscoe, Francis Kalush,Chava Kimchi-Sarfaty, Sheryl Kochman, Siyeon Lee, ErnestLitwack, Peter Lurie, William Maisel, Elizabeth Mansfield,Peter Marks, Donna Mendrick, Karen Midthun, Baitang Ning,Michael Pacanowski, Barbara Parsons, Karen Riley, ZubenSauna, Jeffrey Shuren, William Slikker, Jr., Stephen Spielberg,Julie Tierney, Weida Tong, Jill Warner, Carolyn Wilson, JanetWoodcock, Denise Zavagno, and Issam Zineh.Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development4

II. PERSONALIZED MEDICINE FROMA REGULATORY PERSPECTIVEWe all have a stake in personalizedand microscopy allowed scientists to beginmedicine. The way we viewto understand the underlying causes ofthe evolution of this area isdisease. From here, major advancementsinfluenced by our particular perspectivesin science and technology have allowed– for example, as patients, clinicians, drughealthcare decisions to become increasinglyor device manufacturers, informationgranular over time. With the growth of thetechnology specialists, healthcare providers,pharmaceutical and medical device industriesinsurers, educators, or regulators. Thisin the 20th century came the rise of genetics,section describes the concept of personalizedimaging, and data mining. Midway throughmedicine and some of the ways that the termthe century, observations of individualhas recently been used or defined. It thendifferences in response to drugs gave rise to aturns to a discussion of personalized medicinebody of research focused on identifying keyin the regulatory context, and describes FDA’senzymes that play a role in variation in drugunique perspective and responsibilities inmetabolism and response and that served ashelping to advance this important field.the foundation for pharmacogenetics. Morerecently, sequencing of the human genome atthe turn of the 21st century set in motion the1. DEFININGPERSONALIZED MEDICINEtransformation of personalized medicine froman idea to a practice. Rapid developments ingenomics, together with advances in a numberof other areas, such as computational biology,It’s far more important to know what personthe disease has than what disease the person has.– Hippocratesimedical imaging, and regenerative medicine,are creating the possibility for scientists todevelop tools to truly personalize diagnosisand treatment.The concept of personalized medicineDespite extraordinary advances that havedates back many hundreds of years. It wasbeen made to date in medical fields, wenot until the 19 century, however, thathave a long way to go in understanding whydevelopments in chemistry, histochemistrydifferent individuals experience diseasethPaving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development5

Early Examples of Personalized Medicine1907: Reuben Ottenberg reports the first known blood compatibility test for transfusion usingblood typing techniques and cross-matching between donors and patients to prevent hemolytictransfusion reactions.1956: The genetic basis for the selective toxicity of fava beans (“favism”) and the antimalarialdrug primaquine is discovered to be a deficiency in the metabolic enzyme, glucose-6-phosphatedehydrogenase (G6PD).1977: Cytochrome P450 2D6, a polymorphic metabolizing enzyme, is identified as the culprit forcausing some patients to experience an “overdose” or exaggeration of the duration and intensityof the effects of debrisoquine, a drug used for treating hypertension.or respond to treatment differently. Ourdescribed as providing “the right patient withcurrent lack of ability to predict an individualthe right drug at the right dose at the rightpatient’s treatment success for most diseasestime.”ii More broadly, “personalized medicine”and conditions means that clinicians havemay be thought of as the tailoring of medicalno choice but to follow a less than optimaltreatment to the individual characteristics,approach to prescribing drugs and otherneeds and preferences of a patient during alltreatment options. A patient being treated forstages of care, including prevention, diagnosis,high blood pressure, for example, might betreatment and follow-up.placed on one of a number of blood pressureSeveral terms, including “precisionmedications. The patient’s doctor makes amedicine,” “stratified medicine,” “targeteddecision about what medication to prescribemedicine,” and “pharmacogenomics,”based on only general information aboutare sometimes used interchangeably withwhat might actually work for that particular“personalized medicine.” “Precisionpatient. If the medication does not work aftermedicine” is perhaps most synonymousa few weeks, the patient might be switchedto “personalized medicine” and has beento another medication. This somewhatdefined by the National Academy of Sciences“trial-and-error” approach can lead to patient(NAS) as “the use of genomic, epigenomic,dissatisfaction, adverse drug responses andexposure and other data to define individualdrug interactions and poor adherence topatterns of disease, potentially leading totreatment regimens. The goal of personalizedbetter individual treatment.” iii “Stratification”medicine is to streamline clinical decision-refers to the division of patients with amaking by distinguishing in advance thoseparticular disease into subgroups, basedpatients most likely to benefit from a givenon a characteristic of some sort, whotreatment from those who will incur cost andrespond more frequently to a particularsuffer side effects without gaining benefit.drug or, alternatively, are at decreasedThe term “personalized medicine” is oftenrisk of side effects in response to a certainPaving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development6

After: personalized medicine (from genotype to 100 mg500 mg100 mg10 mgFigure 1. Representation of the trial-and-error or one-dose-fits-all approach versus personalized medicine. The left panel showsa situation in which everyone gets the same dose of a drug, regardless of genotype. The right panel shows a personalized medicineapproach in which the dose of the drug is selected based upon genotypical, and therefore phenotypical, variability of the metabolizingenzyme. (Source: Xie, H., Frueh, F.W., (2005). Pharmacogenomics steps toward personalized medicine. Personalized Medicine, 2(4), 333.)Describing Personalized MedicineThe definition and scope of the term personalized medicine varies widely, ranging from theextremely broad to the very narrow. These examples have been selected to demonstrate therange of definitions that have been proposed: “The use of new methods of molecular analysis to better managea patient’s disease or predisposition to disease.”– Personalized Medicine Coalition“Providing the right treatment to the right patient, at the right doseat the right time.” – European Union“The tailoring of medical treatment to the individual characteristicsof each patient.” – President’s Council of Advisors on Scienceand Technology“Health care that is informed by each person’s unique clinical, genetic, andenvironmental information.” – American Medical Association“A form of medicine that uses information about a person’s genes, proteins,and environment to prevent, diagnose, and treat disease.”– National Cancer Institute, NIHPaving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development7

treatment. Stratification can be thought ofWhile considerable attention inas a core element of personalized medicine.personalized medicine is currently being paid“Pharmacogenomics” (PGx) – the study ofto the use of genetic tests to guide therapeuticvariations of DNA and RNA characteristicsdecisions, a vast variety of medical devicesas related to drug responsecan be used in a personalized approach toiv– is a criticallyimportant area of personalized medicineimprove patient outcomes. Many medicalwhere significant progress has recentlydevice therapies are now capable of beingbeen made.tailored to specific patient characteristics.Personalized medicine generallyThese individual characteristics includeinvolves the use of two medical productspatient anatomy (e.g., size), physiology– typically, a diagnostic device and a(e.g., nervous and cardiovascular systems,therapeutic product – to improve patientmetabolism, reproduction) and environmentoutcomes. A diagnostic device is a type ofof use (e.g., intensive care unit, home use).medical device. Diagnostic devices includeAdditionally, physiological sensors canboth in vitro tests such as assays used inbe used to predict treatment responses formeasurement of genetic factors and in vivoindividual patients. For example, three-tests, such as electroencephalography (EEG),dimensional (3D) printing has been used toelectrocardiography (EKG), or diagnosticcreate personalized medical devices based onimaging equipment.imaging of a patient’s anatomy.PharmacogenomicsPharmacogenomics (PGx), the study of variations of DNA and RNA characteristics as relatedto drug response, is one of the most exciting areas of personalized medicine today. The fieldarises from the convergence of advances in pharmacology (the science of drugs) and genomics(the study of genes and their functions). Patients typically have variability in response to manydrugs that are currently available. It can be difficult to predict who will benefit from a medication,who will not respond at all, and who will experience adverse effects. PGx seeks to understandhow differences in genes and their expression affect the body’s response to medications.More specifically, PGx uses genetic information (such as DNA sequence, gene expression,and copy number) for purposes of explaining interindividual differences in drug metabolism(pharmacokinetics) and physiological drug response (pharmacodynamics), identifying respondersand non-responders to a drug, and predicting the efficacy and/or toxicity of a drug.Advances in PGx have opened new possibilities in drug discovery and development. PGx hasallowed for more tailored treatment of a wide range of health problems, including cardiovasculardisease, cancer, and HIV/AIDS. FDA’s Center for Drug Evaluation and Research (CDER)has supported pharmacogenomics for more than a decade by providing regulatory advice,reviewing applications, and developing policies and processes centered on genomics andindividualized therapeutics.Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development8

In addition, the advent of mobileoffices. Instead, more people are treatedand wireless capability, better sensors,at home and at work and are better able tointeroperable devices, and the Internet havemaintain their lifestyle and quality of life.led to technologies that allow for moreAs a result of these technological advances,effective patient monitoring and treatmentmedical diagnostics and therapeutics can beoutside the traditional medical care settings ofmore finely tuned to better meet the needs ofhospitals, chronic care facilities and physicianindividual patients.3D Printed Tracheal SplintPhysicians at the University of Michigan andAkron Children’s Hospital utilized a computedtomography image, computer-aided design,and 3D printing to create a bioresorbableairway splint to treat a critically-ill infant withtracheobronchomalacia – a life-threateningcondition that occurs when the airway wallsare weak and the airways collapse duringbreathing or coughing.The “personalized” tracheal splint for thepatient was constructed based on CT imagesof the patient’s airway and lungs. The deviceitself was “printed” by the 3D printer usingpolycaprolactone (PCL) – a degradablematerial that, over time, will dissolve,allowing the body to heal and grow aroundit. Upon receiving Institutional Review Boardapproval for use under FDA’s emergency-useprovisions, physicians successfully implantedthe tracheal splint overlying the patient’sairway, basically creating a placeholder forthe cells to properly grow around it. One yearafter surgery, imaging and bronchoscopyshowed an open airway while full resorptionof the bioresorbable stent is expected to take3 years.This story serves as a powerful exampleof how parallel advances in multiple fieldscan come together to result in extraordinaryadvances in personalized medicine, andoffers a glimpse into a future where trulyindividualized, anatomically-specific devicesmay become a standard part of patient care.Figure 1. Placement of the Printed Airway Splintin the Patient.Panel A shows the airway in expiration beforeplacement of the splint; the image was reformattedwith minimum-intesity projection. Panel B showsthe patient-specific computed tomography-baseddesign of the splint (red). Panel C shows an imagebased three-dimensional printed cast of the patient’sairway without the splint in place, and Panel Dshows the cast with the splint in place. Panel Eshows intraoperative placement of the splint (greenarrow) overlying the malacic left mainstem bronchialsegment. SVC denotes superior vena cava. Panel Fshows the bronchoscopic view, from the carina, of theleft mainstem bronchus after placement of the splint.Panel G shows the airway in expriration 1 year afterplacement of the splint; the image was reformattedwith minimum-intensity projection.From: Bioresorbable Airway Splint Created with a ThreeDimensional Printer N Engl J Med 2013; 368:2043-2045.Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development9

Examples of “Personalized” Medical DevicesTinnitus masker is personalized by the manufacturer to patient tinnitus. Thetinnitus treatment custom-tailors the audio signals to suit the individual patient’shearing requirementsPedicle screw spinal systems- Spinal systems consisting of a rod/screw/hook/connector kit are assembled by a surgeon to accommodate a patient’s uniqueanatomy/physiology using MRI/CT imaging.Software-based quantitative EEG analysis to predict an individual’s responseto various psychotropic drugs. The device provides the probability of response tovarious medications to guide clinician in decision making.The Zenith Fenestrated AAA Endovascular Graft is indicated for theendovascular treatment of patients with abdominal aortic or aortoiliac aneurysmshaving morphology suitable for endovascular repair. The fenestrated device allowsfor treatment of patients with shorter proximal neck lengths (i.e., length of healthyaorta between the renal arteries and the aneurysm) as compared to those who canbe treated using other endovascular grafts. Each device is tailored to the patient’sindividual aortic anatomy with openings in the graft material placed appropriately tomaintain blood flow to branch vessels of the aorta.The Artificial Pancreas Device System is a device under clinical investigationthat automatically monitors patient glucose levels and delivers patient-tailoredinsulin doses in people with diabetes. A computer-controlled algorithm connectsthe continuous glucose monitoring system and an insulin infusion pump to allowcontinuous communication between both devices and deliver a personalizedtreatment based on individual glucose patient readings.The success of personalized medicineIn the long run, personalized medicine seeksdepends on the development of accurate andto reduce the burden of disease by targetingreliable diagnostics and, in some cases, onprevention and treatment more effectively.the identification of predictive biomarkers.With the help of personalized medicine, theDiagnostics used in personalized medicinehealth care management paradigm will focusare generally intended to identify theon prevention, moving from illness to wellness,presence, absence, or amount of a biomarkerand from treating disease to maintaining(as in the case of in vitro diagnostics) or tohealth. By improving our ability to predictassess physiological or anatomical patientand account for individual differences incharacteristics (as in the case of EKG tracingsdisease diagnosis, experience, and therapyor imaging technologies). If the diagnosticresponse, personalized medicine offers hopetest is inaccurate, then the treatment decisionfor diminishing the duration and severitybased on that test may not be optimal. Forof illness, shortening product developmentexample, with an incorrect diagnostic result, antimelines, and improving success rates. At theunsuitable drug may be given to a patient whosame time, it may reduce healthcare costs bywill as a result, be harmed or will not benefit,improving our ability to quickly and reliablybecause the drug will cause an otherwiseselect effective therapy for a given patient whileavoidable side effect, will be ineffective for thatminimizing costs associated with ineffectivepatient, or both.treatment and avoidable adverse events.Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development10

2. FDA’S UNIQUE ROLE ANDRESPONSIBILITIES INPERSONALIZED MEDICINEFDA’s mission is to protect and promote thehealth of all Americans through assuring thesafety, efficacy, and security of drugs, biologics(such as blood products and vaccines), and Carefully consider benefits and riskswhen evaluating medical products toappropriately foster innovative productdevelopment while assuring adequatepatient protections; Stay abreast of rapid advances ininnovative science and technology; Provide clarity, predictability, andmedical devices, and the safety and security ofguidance to industry in order to helpfoods, cosmetics, and many other consumerencourage development in promising newgoods. In the U.S., FDA-regulated productsareas of medical product development;account for about 20 cents of every dollar Help ensure that information about thespent by American consumers each year. Inlatest science and technology is beingthe case of medical products, FDA determinesused appropriately and rationally tothat products are safe and effective beforeinform clinical trial design, drug andmarketing through a careful evaluation ofdevice development, and clinical practice;benefits and risks that considers the available Work together with university scientists,scientific data in the context of the underlyinggovernment agencies, including NIH,condition or disease. FDA also requirescompanies, standards organizations,manufacturers to follow quality manufacturingpracticing physicians, and patients topractices and processes, and conduct post-evaluate and validate new diagnostics andmarket surveillance. In addition FDA strives totherapeutics;advance the public health by helping to speedaccess to innovative medical products.FDA’s responsibility for ensuring that drugs, Help address the “pipeline” problem fordrugs and medical devices by identifyingopportunities for streamlining regulatorydevices, and biologics are safe and effectiveprocesses and advancing the science andprovides the agency with a unique perspectivetools that will help drive innovation.on both the successes and failures that occurFrom FDA’s perspective, personalizedin medical product development and specialmedicine promises to increase benefits andinsight into the emergence and directionreduce risks for patients by improving both theof the field of personalized medicine.safe

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.

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