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615 ISSN 2041-5990 10.4155/TDE.10.68 © 2010 Future Science Ltd Therapeutic Delivery (2010) 1(5), 615–619 SPECIAL FOCUS: PERSONALIZED MEDICINE FOREWORD The right drug for the right patient at the right time for the right period of time is the basic premise of personalized medicine. There are many definitions of personalized medicine but for the purpose of this editorial, we will adopt the definition suggested at a meeting in November 2006 co-organized by Harvard Medical School and Harvard Business School. Thus, personalized medicine refers to “the management of a patient’s disease or disposi- tion by using the best molecular knowledge to achieve the best medicinal outcome for that individual.” Personalized medicine is the foun- dation of global health. Indeed, the steady rise in life expectancy worldwide since the dis- covery of penicillin owes it to a succession of innovative medicines. The right drug for the right patient at the right time for the right period of time is the basic premise of personalized medicine. During the past decade, drug development has become alarmingly costly and inefficient, requiring US$1.8 billion over 10–12 years with a probability of success averaging 10% [1] . This is the consequence of higher safety hurdles required for regulatory approval in a health- care environment far more complex than we ever imagined before the completion of the Human Genome Project. Nevertheless, despite stringent regulatory scrutiny, adverse drug reactions still occur, including fatalities that eventually lead to withdrawal of drug products. Personalized medicine has the potential of nar- rowing this gap in drug safety between what is projected from clinical trials and what actually occur in practice. Moreover, by keeping our focus on meeting the patient’s needs, rather than on only the details of the drug product or the disease, we may be able to improve the effi- ciency of future drug development. This will be indicated by a higher success rate at a fraction of today’s costs in a fraction of today’s time – without compromising drug safety. Personalized medicine: it takes more than genomics The worldwide fascination with personalized medicine is fuelled by impressive advances in genomics, including the prospect of resequenc- ing of whole genomes at the population level for a modest fee. The impact of genomics can be felt through either genetic mutations of a constitutive protein in the target cell (targeted molecular therapeutics pathway) [2] or the pro- teins responsible for the absorption, distribu- tion, metabolism and elimination of the drug (pharmacogenomics pathway) [3] . Examples of the former pathway include the tyrosine phos- phatase inhibitors in the treatment of chronic myelogenous leukaemia and the monoclonal antibody trastuzumab against HER-2, the human epidermal growth factor receptor that is overexpressed in certain breast cancer cells. Examples of the latter pathway include genetic polymorphisms of the cytochrome C drug- metabolizing enzymes [4] such as CYP2D6, CYP2C19 and CYP3A4, and of the drug efflux transporters [4] P-glycoprotein and multidrug resistance protein [5] . Pharmacogenomics is an active area of research. An important resource in this arena is the Pharmacogenomic Knowledge Base (PharmGKB [101]), which was created in 2000 to catalog links between human genetic varia- tion and drug response. This powerful resource not only provides high-quality information, but also brings researchers together to share ideas and collaborate. In fact, the National Institutes Personalized medicine: transforming drug development and healthcare Personalized medicine will have the same impact on the efficiency of drug development as aviation has on business, mobility of the work force and advancement of science. Vincent H L Lee School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong Tel.: +852 260 968 62 Fax: +852 260 352 95 E-mail: [email protected] Keywords: barriers to personalized medicine n genomics n lifestyle n variability in drug response For reprint orders, please contact [email protected]

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Page 1: Personalized medicine: transforming drug development and healthcare

615ISSN 2041-599010.4155/TDE.10.68 © 2010 Future Science Ltd Therapeutic Delivery (2010) 1(5), 615–619

Special FocuS: perSonalized Medicine

Foreword

The right drug for the right patient at the right time for the right period of time is the basic premise of personalized medicine. There are many definitions of personalized medicine but for the purpose of this editorial, we will adopt the definition suggested at a meeting in November 2006 co-organized by Harvard Medical School and Harvard Business School. Thus, personalized medicine refers to “the management of a patient’s disease or disposi-tion by using the best molecular knowledge to achieve the best medicinal outcome for that individual.” Personalized medicine is the foun-dation of global health. Indeed, the steady rise in life expectancy worldwide since the dis-covery of penicillin owes it to a succession of innovative medicines.

“The right drug for the right patient at the right time for the right period of time is the basic

premise of personalized medicine.”

During the past decade, drug development has become alarmingly costly and inefficient, requiring US$1.8 billion over 10–12 years with a probability of success averaging 10% [1]. This is the consequence of higher safety hurdles required for regulatory approval in a health-care environment far more complex than we ever imagined before the completion of the Human Genome Project. Nevertheless, despite stringent regulatory scrutiny, adverse drug reactions still occur, including fatalities that eventually lead to withdrawal of drug products. Personalized medicine has the potential of nar-rowing this gap in drug safety between what is projected from clinical trials and what actually occur in practice. Moreover, by keeping our focus on meeting the patient’s needs, rather than on only the details of the drug product or

the disease, we may be able to improve the effi-ciency of future drug development. This will be indicated by a higher success rate at a fraction of today’s costs in a fraction of today’s time – without compromising drug safety.

Personalized medicine: it takes more than genomicsThe worldwide fascination with personalized medicine is fuelled by impressive advances in genomics, including the prospect of resequenc-ing of whole genomes at the population level for a modest fee. The impact of genomics can be felt through either genetic mutations of a constitutive protein in the target cell (targeted molecular therapeutics pathway) [2] or the pro-teins responsible for the absorption, distribu-tion, metabolism and elimination of the drug (pharmacogenomics pathway)[3]. Examples of the former pathway include the tyrosine phos-phatase inhibitors in the treatment of chronic myelogenous leukaemia and the monoclonal antibody trastuzumab against HER-2, the human epidermal growth factor receptor that is overexpressed in certain breast cancer cells. Examples of the latter pathway include genetic polymorphisms of the cytochrome C drug-metabolizing enzymes [4] such as CYP2D6, CYP2C19 and CYP3A4, and of the drug efflux transporters [4] P-glycoprotein and multidrug resistance protein [5].

Pharmacogenomics is an active area of research. An important resource in this arena is the Pharmacogenomic Knowledge Base (PharmGKB [101]), which was created in 2000 to catalog links between human genetic varia-tion and drug response. This powerful resource not only provides high-quality information, but also brings researchers together to share ideas and collaborate. In fact, the National Institutes

Personalized medicine: transforming drug development and healthcare

“Personalized medicine will have the same impact on the efficiency of drug development as aviation has on business, mobility of the work force and advancement of science.”

Vincent H L LeeSchool of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong Tel.: +852 260 968 62 Fax: +852 260 352 95 E-mail: [email protected]

Keywords: barriers to personalized medicine n genomics n lifestyle n variability in drug response

For reprint orders, please contact [email protected]

Page 2: Personalized medicine: transforming drug development and healthcare

Foreword | Lee

Therapeutic Delivery (2010) 1(5)616 future science group

of Health has just funded 14 more scientific projects and seven network resources to fur-ther accelerate the pace of translating genetic information into practice.

As depicted in Figure 1, factors other than genomics also shape the evolution of personalized medicine. Thus, the stratification of patients on the basis of genomic differences in target recep-tor proteins, or proteins tied to drug pharmaco-kinetics calls for radical changes in the design of clinical trials and the choice of business model to manage drug development. While the random-ized controlled clinical trial will remain the gold standard in drug development in the foreseeable future, several alternatives have been proposed to streamline the procedure and to make allow-ance for challenging at-risk populations [6]. The shrinking of the size of the target patient popula-tion will inevitably stimulate innovative changes in the ways drugs are developed and regulated. Commercially, the infrastructure that has sup-ported the blockbuster model of drug develop-ment may not be resilient enough to adapt to a new culture created by the pursuit of person-alized medicine. Therefore, 30 years after the birth of the biopharmaceutical industry, a new industry to translate evidence-based personal-ized medicine into improved human therapeu-tics is gaining momentum. Whether this new pharmaceutical industry will follow the path of remarkable transformation of the telecom-munication industry from landline to wireless is left to the imagination and the commitment

of the pioneers in personalized medicine. What is certain to happen is that, by necessity, drug development will be multidisciplinary and bet-ter co-ordinated. It will draw extensively upon knowledge existing in house and in the public domain. Hopefully, it will bring the drug to the market sooner, p referably within 3–5 years.

Personalized medicine & drug safetyBy matching the drug to the right patient, a con-sequence of personalized medicine is improved drug safety. A metaphor for meeting this chal-lenge is the civil aviation system. From the design of airplanes to the professionals working in the system, safety is the prime focus and is achieved to a near perfect degree while the system oper-ates economically and generally efficiently and reliably. Engineers use mathematical models to achieve optimal balances between cost and safety when designing and building airplanes and phar-macoeconomics could likewise be used to balance these competing factors in drug design, testing and prescribing. Aircrafts are built with redun-dant systems and warning mechanisms to prevent foreseeable failures, and pilots are highly trained to check and respond, using well-tested protocols, to every possible warning signal. Similarly, mul-tiple redundant warning mechanisms could be developed to detect any foreseeable adverse drug reactions and pharmacists and physicians could be trained to systematically check and respond to every possible warning signal. Air traffic con-trollers play a critical role in preventing ‘adverse aircraft interactions’ and this professional dedica-tion, backed by radar and other technology, nearly eliminates collision risk. However, adverse drug interactions kill far more people than airplane collisions. Eliminating this risk could be accom-plished by giving high priority to pharmacists as drug traffic controllers and developing protocols as clear as those used for air traffic. Meteorologists and pilots report weather hazards in real time to the system and to other pilots behind, who imme-diately seek approval from air traffic control to adjust flight plans to prevent harm. By analogy, during drug development, testing and routine use, adverse events could be reported, analyzed and used to adjust practice in real time to prevent harm, minimize cost and increase effectiveness.

There is, however, a limit to which drug safety can be designed into a molecule based on physicochemical and pharmacokinetic con-siderations. Consequently, additional inter-ventions are required. They include designing targeted drug-delivery systems tagged for the

Personalized medicine

Genomic advances

Drug development

Innovative clinical trials

Informatics

Patient education

Customizingdosage

Drug regulatorsand policy makers

Economics

Mathematics

Life sciencesChemistry

Healthcareprofessionals

Engineering

Figure 1. Multifactorial input to personalized medicine.

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target cells [7]; genetic profiling of patients to match the pharmacokinetic characteristics of the drug [8]; behavior modifications of the patient and training by pharmacists on the pur-pose, proper usage, precautions and side effects to be expected. A seamless communication network connecting the patient, pharmacist and physician would facilitate the monitoring of progress of therapy and timely rendering of corrective actions. Upon replication worldwide, much can be learned of the clinical efficacy and tolerability of a drug product in a hetero-geneous population. This knowledge would be useful for not only the management of existing drug products, but also the design and testing of new drug products.

The requirements of personalized medicineOur working model of personalized medicine is predicated on our ability to select the right patient for the drug, to customize dosage regimen, to noninvasively monitor drug movement in the body, to archive information on drug response for unique patient attributes, and to develop simu-lation models to guide the design and interpreta-tion of clinical trials in the context of drug safety. Towards that end, four requirements are integral to personalized medicine, as follows.

� Biomarkers Developing disease-specific biomarkers for iden-tifying the stage of disease at the time of first diagnosis and for quantifying disease progres-sion thereafter is an important requirement [9]. Equally as important is developing physiologically responsive drug carriers to tailor the drug release profile to the specific diseases and maximize the therapeutic benefits. Research in identifying and verifying disease-specific biomarkers would be extremely useful to manage the complexity of disease, as well as in enabling earlier detection of disease and hence initiation of drug therapy. The high attrition rate of drug candidates in Phase III is due, in part, to the reliance on late-stage dis-ease models when symptoms first become detect-able [10]. However, at such an advanced stage the patient is not likely to respond dramatically to therapeutic intervention. This is exemplified by the repeated frustrations in the development of more efficacious drugs for Alzheimer’s disease [11]. The very recent report of a serum protein-based algorithm for the detection of Alzheimer’s disease offers hope for the improved management of this debilitating disease [12].

� Drug monitoringConstant feedback on the progress of drug ther-apy to the patient and the physician is rare today. In contrast, drug monitoring will be an integral component of personalized medicine. Indeed, developing drug specific point-of-care diagnos-tics to quantity the drug response is a logical follow-on development to diagnostic screening kits based on biomarkers. This will provide use-ful feedback to the patient and the healthcare professionals responsible for his/her care, espe-cially when there are no obvious signs or symp-toms characteristic of the disease. Moreover, if the drug response signal can be digitalized for transmission over the internet to a server for data warehousing, it may be possible to look for trends of efficacy as well as toxicity to make adjustments in therapy. Companion noninvasive molecular imaging would be an equally valuable tool for mapping drug distribution in the body, particularly access to target. Such information, together with the design of new biomaterials and nanotechnology, would provide critical insight to guide the design of targeted drug-delivery systems. The incorporation of these technolo-gies earlier in the drug-development cycle will increase the chance of success by maximizing the therapeutic benefits and minimizing side effects, and will increase the economic return by broad-ening the range of therapeutic indications. The wealth of clinical and pharmacokinetic informa-tion can be archived for subsequent use to test disease simulation models. This is the essence of informatics, a potentially useful tool for identi-fying at-risk patients for monitoring of adverse drug reactions monitoring.

� Smart drug-delivery systemA new generation of drug-delivery systems radi-cally different from the fixed-dose tablets and capsules is needed. Ranging from microneedles to a modified inkjet printer, these new technolo-gies are designed to enable flexibility in dispens-ing dosages of multiple medications for the con-venience of the patient, particularly the elderly. Drug-dosage customization can be indexed to the stage of the disease, co-existing diseases (and hence other drugs) and the genetics and life style of the patient. Ten or more medications are not uncommon for the elderly

� Regulatory renaissanceThe regulatory infrastructure and philosophy must be modernized to cope with the avalanche of new drug product applications focusing

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on subpopulations, including setting stan-dards for products with unmet public health needs and enhancing safety and health through informatics. In order to render regulatory deci-sion on a timely basis, regulatory agencies may have to create incentives to recognize the spon-sor’s sustained leadership in innovation, quality assurance and corporate social responsibility. A well-designed demonstration project that will shed some light on the wisdom of a de facto honor system of regulatory oversight is a must.

Regulatory agencies themselves must be prepared to undergo a transformation from a reactive to a proactive mode of operation and from embracing a discontinuous to a continu-ous mode of innovation and refinement. Thus, regulatory agencies are expected to identify problematic areas in drug manufacturing, championing and rewarding innovations in drug development and manufacturing, and assuring compliance of drug product manufacturing with international standards.

Research priorities: the never-ending marathon Of the many priority research areas inspired by personalized medicine, three seem to stand apart from the others, as follows:

� Restructuring drug developmentCurrent drug development is fragmented, heavy in documentation and secretive. It is best described as assembly-line drug development, with a huge inertia to turn back upstream when the system does not behave as planned. Ideally, modern drug development should be interactive, collaborative and communicative. We expect regular open crosstalk between clinicians and basic scientists, which would accelerate our pace of innovation. A possible configuration of the restructured drug development process is to combine preclinical, Phase I and II studies into a new discovery phase. The current Phase III and IV would then become the development phase.

Concerning clinical trials, the targeted popu-lation model of drug development has an inher-ent challenge of recruiting the number required for clinical trials from a smaller pool of volun-teers. This limitation may spur the development of alternatives, including a virtual network of volunteers in their own homes all over the world.

Given the pivotal role played by diagnostic tests in identifying responders to drug therapy, it would be worthwhile for the stakeholders to con-vene and discuss regulatory standards, criteria for

demonstrating value-added service and incentives for the manufacturer to embark on the develop-ment. Commercial development of diagnostic kits is best characterized as proceeding with caution. Clarity in regulatory philosophy and physician adoption of this new technology will play a major role in moving it forward.

� Harnessing bioinformatics for predictive medicine An extremely valuable resource from the per-sonalized medicine initiative is a comprehensive database depicting the collective influence of drug-, patient- and environment-related fac-tors in drug response. This resource should be useful for flagging adverse drug reactions, for identifying unmet medical needs, and for streamlining clinical trials. Sophisticated text and data mining tools will emerge to enable virtual control groups in clinical trials and adverse event data mining. A daunting chal-lenge is willingness of the private enterprise to share proprietary knowledge, an important step to minimize duplication and dead ends. A mechanism to link up fragments of informa-tion that will feed into a broad knowledge base is required to deliver personalized healthcare to patients. Ultrafast computing is required to support software designed to visualize increas-ingly complex data-rich, dynamic systems, allowing real-time predictions at all levels, from molecular to whole person.

A trusted partnership between academia and industry is absolutely essential to sustain the paradigm shift in drug development in the era of personalized medicine. The future pharma-ceutical industry is likely to be organized as a network, whereby academia will drive innova-tions and industry will focus on development and commercialization. There must be a mutual feeling of shared ownership in the genesis and subsequent application of new concepts, new tools and, ultimately, new medicine. This mandates a new way to look at intellectual property, access to data and business models to sustain innovation.

� Healthcare reformAn often-overlooked factor in personalized medicine is the healthcare team and its relation-ship with the patient. The goal of personalized medicine will fall short, however powerful the planned therapy is, unless the doctor, nurse, pharmacist and other healthcare professionals on the healthcare team understand and accept their

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individual roles. The pharmacist plays a key role in recommending and monitoring drug ther-apy, and should be on the alert for drug–drug, drug–herb and drug–nutrient interactions.

There are several other possible trend-setting research areas:�More relevant preclinical drug testing models,

including the use of zebra fish and stem cells to modernize toxicology and hazard assess-ment;

�Better evaluation tools, including biomarkers for disease progression and side effects;

�Employing drug-delivery technologies to sup-port drug development;

�Fostering the development of microprocessor-controlled personalized medicine dispensers;

�Supporting development of innovative tech-nology to detect, as well as to deter counterfeit drugs, that are a threat to global health.

In summary, personalized medicine is more than a therapeutic novelty. It is a call for vision-ary leadership and bold action from the rank-and-file to chart a new pathway of drug development

capable of meeting the needs unique to subpopu-lations in a therapeutic community. To draw anal-ogy to public transportation, personalized medi-cine will have the same impact on the efficiency of drug development as aviation has on business, mobility of the work force and advancement of science. For the time being, the full impact of personalized medicine is far from clear given the backlog in analyzing and interpreting the wealth of genomic information collected.

AcknowledgementsThe author wishes to acknowledge the input of Larry Baum, Vivian Lee and Ying Chau to an earlier draft of the manuscript.

Financial & competing interests disclosureThe author has no relevant affiliations or financial involve-ment with any organization or entity with a financial inter-est in or financial conflict with the subject matter or materi-als discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t estimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Bibliography1 Trusheim MR, Aitken ML, Berndt ER.

Characterizing markets for biopharmaceutical innovations: do biologics differ from small molecules? Forum Health Econ. Policy 13(1), article 4, (2010).

2 Phillips K, Van Bebber S, Issa AM. Diagnostics and biomarker development: priming the pipeline. Nat. Rev. Drug Discov. 5, 463–469 (2006).

3 Lammers L, Mathijssen RH, van Gelder T et al. The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer. Br. J. Cancer 103, 765–771 (2010).

4 Kramer J, Sagartz JE, Morris DL. The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat. Rev. Drug Discov. 6, 636–649 (2007).

5 Zolk O. Current understanding of the pharmacogenomics of metformin. Clin. Pharm. Ther. 86, 595–8 (2009).

6 Wilson C, Schulz S, Waldman SA. Macroscopy regulation: individualization of medicine lost in translation. Clin. Pharm. Ther. 81, 153–155 (2007).

7 Schilsky RL. Personalized medicine in oncology: the future is now. 9(5), 363–366 (2010).

8 Ratain MJ. Personalized medicine: building the GPS to take us there. Clin. Pharm. Ther. 81, 1–2 (2007).

9 Scherer HU, Dörner T, Burmester GR. Patient-tailored therapy in rheumatoid arthritis: an editorial review. Curr. Opin. Rheu. 22, 237–45 (2010).

10 Schuster D, Laggner C, Langer T. Why drugs fail – a study on side effects in new chemical entities. Curr. Pharm. Design 11, 3545–3559 (2005).

11 Carter MD, Simms G, Weaver DF. The development of new therapeutics for Alzheimer’s disease. Clin. Pharm. Ther. 88(4), 475–486 (2010).

12 O’Bryant S, Xiao G, Barber R et al. A serum protein-based algorithm for the detection of Alzheimer’s disease. Arch. Neurol. 67, 1077–1081 (2010).

� Website101 PharmGKB.

www.pharmgkb.org