perspec tives ACKNOWLEDGMENTS A.S.K. is a Greenwall Faculty Scholar and has received a career-development award from the Agency for Healthcare Research and Quality (K08HS18465-01) and a Robert Wood Johnson Foundation Investigator Award in Health Policy Research.
5.
CONFLICT OF INTEREST The authors declared no conflict of interest.
6.
© 2014 ASCPT
7.
1. Brief of Pharmaceutical Research and Manufacturers of America as Amicus Curiae in Support of Respondent, Mayo Collaborative Services v. Prometheus Laboratories, 132 S. Ct. 1289 (2012) (No. 10-1150) (November 2011). 2. PerkinElmer v. Intema, 496 Fed. Appx. 65 (Fed. Cir. 2012). 3. Hennekens, C.H. & Ridker, P. Systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases
4.
8. 9. 10.
and as tools to aid in the selection of agents to be used for the prevention and treatment of atherosclerotic disease. US patent 6,040,147 (21 March 2000). Man, A. & Spector, N.L. Predictive biomarkers in cancer therapy. US patent 7,794,960 (14 September 2010). Laboratory Corporation of America Holdings v. Metabolite Laboratories, 548 US 124 (2006) (per curiam). Mayo Collaborative Services v. Prometheus Laboratories, Inc. 566 U.S. ___ (20 March 2012). Fox, J.L. Industry reels as Prometheus falls and Myriad faces further reviews. Nat. Biotechnol. 30, 373–374 (2012). Association for Molecular Pathology v. U.S. Patent & Trademark Office, 689 F.3d 1303 (Fed. Cir. 2012). Classen Immunotherapies v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011). Kesselheim, A.S. & Karlawish, J. Biomarkers unbound—the Supreme Court’s ruling on diagnostic-test patents. N. Engl. J. Med. 366, 2338–2340 (2012).
Personal DNA Donation to Energize Genomic Medicine WJ Lu1,2 and DA Flockhart1,2 Immense strides toward improved human genomic sequencing have been made over the past decade, but significant obstacles to clinical research and translation are now evident. Novel approaches able to traverse financial, regulatory, and ethical obstacles on behalf of patients and the public health are needed. We propose a novel approach to the collection and annotation of personal genomic data using an organized donation program analogous to the national organ-procurement system. Our understanding of disease has progressed markedly since the first draft of the human genome. Multiple novel genomic associations have been discovered, and unforeseen new therapies targeted at distinct genetic subpopulations have been developed.1 Progress in pharmacogenomics has been unprecedented.2 Genomic research has now reached a stage where an explosion of new diagnostics and therapeutics seems imminent, and the US Supreme Court ruling bar-
ring the patenting of human DNA adds to this momentum. However, several obstacles now present themselves. Prominent among these are emerging regulatory challenges, mounting clinical research costs, and complex ethical issues. Current genomic research faces an unavoidable catch-22: as increasingly detailed genomic data become available, phenotypic detail is being simultaneously removed to protect privacy, making the discovery of useful associations more dif-
1Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; 2Indiana
Institute for Personalized Medicine, Indianapolis, Indiana, USA. Correspondence: WJ Lu ([email protected]) doi:10.1038/clpt.2013.131
ficult. Simultaneously, genomic research is approaching a more expensive phase necessitated by the need to study rare variants, the complexity of multivariate associations, and the large number of trials required to assess the clinical significance of a daunting number of associated variants.3 It will not be practical to carry out randomized, prospective trials to validate the majority of these associations. Indeed, it is increasingly evident that classic prospective trials designed to study a discrete phenotype using tight exclusion criteria are slow, costly, and often too “exclusive” to be broadly generalizable. In addition, access to patient data sets and samples on a larger scale than previously imagined will be essential to future progress. As health-care spending in the United States comes under greater pressure from other sectors of the economy, it is clear that the genomic research community needs to find more cost-effective ways to discover and validate important associations with clinical outcomes. To overcome these prominent barriers, a novel data collection and curation system modeled on the existing national organ donation organization could be put in place. We envision a program that encourages individuals to non-anonymously donate their DNA sequences and electronic health records (EHRs) for research—a DNA Donor Program (DDP). If individuals consent to make their data publicly available, the need for restraints to protect privacy would be significantly reduced, as has been the case for the Personal Genome Project (PGP; http://www.personalgenomes. org). Numerous eminent scientists followed by more than 2,000 participants in the PGP have consented to publish their genomic sequences and personal health information. In the same way that the PGP envisions broad scientific involvement, the DDP envisions broad public involvement, although not every consented donor would have his or her genome sequenced, just as not every organ-donor registration results in a successful transplant. The purpose of a DDP would be to provide a centralized and accessible EHR database from which research groups could request consented samples to be sequenced. DNA samples
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 2 | FEBRUARY 2014
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perspec tives will be requested from consented living donors or will be stored when donors die. The DDP would be a nonprofit initiative with organized data procurement and data centralization as its core missions. Because the general public would be important participants in the DDP, it will be critical that an effective and transparent oversight mechanism, involving donor representatives and appropriately qualified experts in genomic science, ethics, and the law, be established. An accountable committee would oversee the following functions: (i) identify high-priority research needs and select appropriate DNA samples to be stored or sequenced; (ii) develop pathways to solicit and educate minority communities and promote a diverse donor pool; (iii) ensure balanced and educated consent of donors; (iv) ensure high-quality EHR data acquisition; (v) authorize data and sample access only to qualified researchers, medical providers, and donors themselves; and (vi) protect and advocate for donors’ family members. Restrictive penalties that bar access to data would be put in place for those who misuse DDP resources. Fundamentally, donors and their families could be protected by these measures, along with current doctor–patient confidentiality laws, and by the Genetic Information Nondiscrimination Act of 2008, which makes genetic discrimination in employment or health insurance illegal.4 An effective data access portal able to import both genomic data and EHRs with high integrity would be the cornerstone of such a donation program. It would incorporate cutting-edge efficiencies of access and retrieval that would simplify inquiries by researchers. As the number of donors increases, the increasing data could be a source of genomic associations with clinical outcomes throughout life. In these respects it would represent a significant advance over existing databases that are private, difficult to access, or limited in scope. It would allow genetic and phenotypic information to be reused multiple times and thus maximize its research value. Individual donors’ phenotypic outcomes could be updated by donors at specified age increments (e.g., every five years) or automatically as EHR systems become more interoperable. A donor’s final EHR 130
at death could be retrieved by the DDP as provided for in the donor’s consent. The EHR data generated by the DDP would also be available to donors and their primary healthcare providers to facilitate the use of readily available genomic data. Cost is an increasing concern for genomic science. Although the cost of sequencing continues to decrease, we desperately need solutions that will similarly minimize the costs of obtaining samples and phenotypic data. In the United States, patients do have legally sanctioned access to their own medical records and have the right to gift their own EHRs. These records represent a large potential asset to researchers, and personal donation of such EHRs would markedly reduce the normally high costs of data acquisition incurred by clinical trials. However, current EHRs exist in a series of fragmented systems that have been challenging to amalgamate or to access on a large scale. The DDP we envision would exploit the gathering momentum toward making information exchange between EHRs easier and more accurate. The National Coordinator for Health Information Technology’s system already encourages the development of health information exchanges that can import data from multiple institutions and providers into a standard format.5 Standardized datacapture systems, such as the Electronic Source Data Interchange Document (http://www.cdisc.org/esdi-document), have already been developed to enable the integration of clinical care and clinical research.6 The movement toward adoption of EHRs that can effectively communicate with data access portals such as that we propose is challenging but inexorable. A centralized portal that accesses multiple EHR databases would markedly reduce the myriad costs currently associated with data acquisition from complicated clinical systems. The deployment of a system that exploits the interoperability of EHR databases would be critical to the mission of the DDP and would ultimately allow more efficient and cost-effective solutions for genomic researchers. Genomic research today often requires the gathering and rigorous curation of data across several studies to allow replication and validation. Researchers must
often navigate disparate hospital systems, multiple institutional gatekeepers, physicians’ offices, institutional review boards, and complex medical record systems. The process of identifying patients and defining relevant data is therefore slow and complicated, and the time taken represents an impediment to progress. Because the DDP could catalyze the collection of data and the creation of a centralized data access portal, it would avoid redundancies inherent in any “cottage industry” type of data-gathering approach. Others already recognize the value of an organized approach that links genomic data to EHRs. Institutions in the National Human Genome Research Institute’s Electronic Medical Records and Genomics (eMERGE) Network (http://www. genome.gov/27540473) are charged with combining DNA biorepositories with electronic medical record systems involving 13 specific human traits for largescale, high-throughput genetic research with the goal of returning genomic testing results to patients in a clinical care setting. The Million Veteran Program (http://www.research.va.gov/mvp) has a similar goal, using the Veterans Administration’s EHR system. The DDP would be synergistic with such efforts. The time savings derived from a simpler and more consistent process would be important. In addition, the DDP would be consistent with the growing movement toward patient-centered care. In the same way that the creation of the national organdonation system catalyzed public education and increased awareness of the possibility of transplantation, and thus increased the number of transplant organs available, the DDP we envisage could actively educate the public about the practical, clinical value of genomic science. A designation of “DNA Donor” status on a driver’s license could be used to engage the public and facilitate their involvement. The DDP would actively solicit organizations representing ethnic minorities and that advocate for patients with rare diseases to organize donations, and these groups would be empowered to contribute to future discoveries directly relevant to them. Overall, a consented DDP could energize genomic and pharmacogenomic
VOLUME 95 NUMBER 2 | FEBRUARY 2014 | www.nature.com/cpt
perspec tives research by optimizing data sharing, controlling costs, saving time, educating the general public, and facilitating translation of new discoveries. There are strong natural incentives for both public and private stakeholders to participate in such an initiative. Initial funding could come from funding agencies or disease-group consortia who wish to exploit this resource to address specific research questions or to promote the use of data from unique communities. Individual research proj ects could then fund the sequencing and data interpretation. The scale of the DDP could be large. The genomic community would stand to benefit from an effective DNA-procurement system analogous to what is now a highly organized national organ-procurement system for transplants. We believe that the educational efforts of the DDP could act as a catalyst to bring about what has long been anticipated: a new societal approach to genomic research and personalized medical care. ACKNOWLEDGMENTS The authors thank Raymond L. Woosley and William Tierney for providing critical review and input into this article. CONFLICT OF INTEREST The authors are partners in Clinical Equilibrium Consulting, LLC, a company that provides clinical pharmacology, pharmacogenetic, and drug-interaction consulting services. D.A.F. is, or has been, a paid consultant or member of the scientific advisory boards for the following organizations involved in the development and implementation of pharmacogenomic tests: the Coriell Institute for Medical Research, Medco Health Solutions, Affymetrix, Quest Diagnostics, and LabCorp. © 2014 ASCPT
1. Lander, E.S. Initial impact of the sequencing of the human genome. Nature 470, 187–197 (2011). 2. Giacomini, K.M., Yee, S.W., Ratain, M.J., Weinshilboum, R.M., Kamatani, N. & Nakamura, Y. Pharmacogenomics and patient care: one size does not fit all. Sci. Trans. Med. 4, 153ps18 (2012). 3. Bush, W.S. & Moore, J.H. Chapter 11: genomewide association studies. PLoS Comp. Biol. 8, e1002822 (2012). 4. Allain, D.C., Friedman, S. & Senter, L. Consumer awareness and attitudes about insurance discrimination post enactment of the Genetic Information Nondiscrimination Act. Familial Cancer 11, 637–644 (2012). 5. Blumenthal, D. Stimulating the adoption of health information technology. N. Engl. J. Med. 360, 1477–1479 (2009).
See article page 147
Integrated Efficacy to Effectiveness Trials RM Califf1,2 Experts in clinical research, therapeutic development, and comparative effectiveness are continually frustrated in their attempts to fit the square peg of therapeutic development into the round hole of clinical trials. Trials can be optimized to provide signals in highly controlled experiments or to estimate an intervention’s effect in poorly controlled real-world settings, but not both simultaneously. Selker and colleagues propose a continuum that creates a smooth transition from controlled experiments to realworld, real-time studies within a single mechanism. The “efficacy-to-effectiveness (E2E)” approach described in this issue of Clinical Pharmacology & Therapeutics by Selker et al.1 describes a new paradigm for therapeutic development that is both consistent with current thinking and sensible from a conceptual standpoint. It is also timely, as our current system for developing and testing new medical technologies is clearly on an unsustainable trajectory.2 Drug developers face dire challenges within an environment where investment in new therapeutics is jeopardized by sharply rising costs of development—an escalation that has grown particularly acute for laterphase clinical trials. Advocacy groups understandably want swift access to potentially useful therapies and a better understanding of the comparative safety and effectiveness of technologies. Clinicians seek to narrow the range of uncertainty in their recommendations. And payers and health systems would prefer to pay only for therapies that provide a favorable balance of risk and benefit. All these factors were reflected in the report of the special subcommittee of the President’s Council of Advisors on Sci-
ence and Technology (PCAST) in 2012.3,4 Prompted by an exodus of high-paying pharmaceutical and biotechnology jobs from the United States, 5 the PCAST subcommittee included industry executives, academic leaders, government and policy experts, and patient advocates. Fundamentally, the committee recommended a more continuous approach to technology approval in which the level of uncertainty is continuously narrowed by a series of studies and permission for marketing occurs earlier in the cycle but is accompanied by a robust commitment to continuous postmarketing evaluation.3 In the E2E model,1 the developmental path for a novel technology starts with an efficacy study designed to optimize detection of a signal for a favorable benefit/ risk balance. Once this initial hurdle is cleared, the trial would evolve through a carefully planned, systematic process into a comparative effectiveness trial. This trial would be conducted in a population that represented the breadth of the technology’s intended use and would have a duration and sample size adequate for informing its rational use in practice. The eminent sensibility of these proposals is unsurprising
1Duke Translational Medicine Institute, Duke University, Durham, North Carolina, USA; 2Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA. Correspondence: RM Califf ([email protected])
doi:10.1038/clpt.2013.232
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 2 | FEBRUARY 2014
131
5.
CONFLICT OF INTEREST The authors declared no conflict of interest.
6.
© 2014 ASCPT
7.
1. Brief of Pharmaceutical Research and Manufacturers of America as Amicus Curiae in Support of Respondent, Mayo Collaborative Services v. Prometheus Laboratories, 132 S. Ct. 1289 (2012) (No. 10-1150) (November 2011). 2. PerkinElmer v. Intema, 496 Fed. Appx. 65 (Fed. Cir. 2012). 3. Hennekens, C.H. & Ridker, P. Systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases
4.
8. 9. 10.
and as tools to aid in the selection of agents to be used for the prevention and treatment of atherosclerotic disease. US patent 6,040,147 (21 March 2000). Man, A. & Spector, N.L. Predictive biomarkers in cancer therapy. US patent 7,794,960 (14 September 2010). Laboratory Corporation of America Holdings v. Metabolite Laboratories, 548 US 124 (2006) (per curiam). Mayo Collaborative Services v. Prometheus Laboratories, Inc. 566 U.S. ___ (20 March 2012). Fox, J.L. Industry reels as Prometheus falls and Myriad faces further reviews. Nat. Biotechnol. 30, 373–374 (2012). Association for Molecular Pathology v. U.S. Patent & Trademark Office, 689 F.3d 1303 (Fed. Cir. 2012). Classen Immunotherapies v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011). Kesselheim, A.S. & Karlawish, J. Biomarkers unbound—the Supreme Court’s ruling on diagnostic-test patents. N. Engl. J. Med. 366, 2338–2340 (2012).
Personal DNA Donation to Energize Genomic Medicine WJ Lu1,2 and DA Flockhart1,2 Immense strides toward improved human genomic sequencing have been made over the past decade, but significant obstacles to clinical research and translation are now evident. Novel approaches able to traverse financial, regulatory, and ethical obstacles on behalf of patients and the public health are needed. We propose a novel approach to the collection and annotation of personal genomic data using an organized donation program analogous to the national organ-procurement system. Our understanding of disease has progressed markedly since the first draft of the human genome. Multiple novel genomic associations have been discovered, and unforeseen new therapies targeted at distinct genetic subpopulations have been developed.1 Progress in pharmacogenomics has been unprecedented.2 Genomic research has now reached a stage where an explosion of new diagnostics and therapeutics seems imminent, and the US Supreme Court ruling bar-
ring the patenting of human DNA adds to this momentum. However, several obstacles now present themselves. Prominent among these are emerging regulatory challenges, mounting clinical research costs, and complex ethical issues. Current genomic research faces an unavoidable catch-22: as increasingly detailed genomic data become available, phenotypic detail is being simultaneously removed to protect privacy, making the discovery of useful associations more dif-
1Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; 2Indiana
Institute for Personalized Medicine, Indianapolis, Indiana, USA. Correspondence: WJ Lu ([email protected]) doi:10.1038/clpt.2013.131
ficult. Simultaneously, genomic research is approaching a more expensive phase necessitated by the need to study rare variants, the complexity of multivariate associations, and the large number of trials required to assess the clinical significance of a daunting number of associated variants.3 It will not be practical to carry out randomized, prospective trials to validate the majority of these associations. Indeed, it is increasingly evident that classic prospective trials designed to study a discrete phenotype using tight exclusion criteria are slow, costly, and often too “exclusive” to be broadly generalizable. In addition, access to patient data sets and samples on a larger scale than previously imagined will be essential to future progress. As health-care spending in the United States comes under greater pressure from other sectors of the economy, it is clear that the genomic research community needs to find more cost-effective ways to discover and validate important associations with clinical outcomes. To overcome these prominent barriers, a novel data collection and curation system modeled on the existing national organ donation organization could be put in place. We envision a program that encourages individuals to non-anonymously donate their DNA sequences and electronic health records (EHRs) for research—a DNA Donor Program (DDP). If individuals consent to make their data publicly available, the need for restraints to protect privacy would be significantly reduced, as has been the case for the Personal Genome Project (PGP; http://www.personalgenomes. org). Numerous eminent scientists followed by more than 2,000 participants in the PGP have consented to publish their genomic sequences and personal health information. In the same way that the PGP envisions broad scientific involvement, the DDP envisions broad public involvement, although not every consented donor would have his or her genome sequenced, just as not every organ-donor registration results in a successful transplant. The purpose of a DDP would be to provide a centralized and accessible EHR database from which research groups could request consented samples to be sequenced. DNA samples
Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 2 | FEBRUARY 2014
129
perspec tives will be requested from consented living donors or will be stored when donors die. The DDP would be a nonprofit initiative with organized data procurement and data centralization as its core missions. Because the general public would be important participants in the DDP, it will be critical that an effective and transparent oversight mechanism, involving donor representatives and appropriately qualified experts in genomic science, ethics, and the law, be established. An accountable committee would oversee the following functions: (i) identify high-priority research needs and select appropriate DNA samples to be stored or sequenced; (ii) develop pathways to solicit and educate minority communities and promote a diverse donor pool; (iii) ensure balanced and educated consent of donors; (iv) ensure high-quality EHR data acquisition; (v) authorize data and sample access only to qualified researchers, medical providers, and donors themselves; and (vi) protect and advocate for donors’ family members. Restrictive penalties that bar access to data would be put in place for those who misuse DDP resources. Fundamentally, donors and their families could be protected by these measures, along with current doctor–patient confidentiality laws, and by the Genetic Information Nondiscrimination Act of 2008, which makes genetic discrimination in employment or health insurance illegal.4 An effective data access portal able to import both genomic data and EHRs with high integrity would be the cornerstone of such a donation program. It would incorporate cutting-edge efficiencies of access and retrieval that would simplify inquiries by researchers. As the number of donors increases, the increasing data could be a source of genomic associations with clinical outcomes throughout life. In these respects it would represent a significant advance over existing databases that are private, difficult to access, or limited in scope. It would allow genetic and phenotypic information to be reused multiple times and thus maximize its research value. Individual donors’ phenotypic outcomes could be updated by donors at specified age increments (e.g., every five years) or automatically as EHR systems become more interoperable. A donor’s final EHR 130
at death could be retrieved by the DDP as provided for in the donor’s consent. The EHR data generated by the DDP would also be available to donors and their primary healthcare providers to facilitate the use of readily available genomic data. Cost is an increasing concern for genomic science. Although the cost of sequencing continues to decrease, we desperately need solutions that will similarly minimize the costs of obtaining samples and phenotypic data. In the United States, patients do have legally sanctioned access to their own medical records and have the right to gift their own EHRs. These records represent a large potential asset to researchers, and personal donation of such EHRs would markedly reduce the normally high costs of data acquisition incurred by clinical trials. However, current EHRs exist in a series of fragmented systems that have been challenging to amalgamate or to access on a large scale. The DDP we envision would exploit the gathering momentum toward making information exchange between EHRs easier and more accurate. The National Coordinator for Health Information Technology’s system already encourages the development of health information exchanges that can import data from multiple institutions and providers into a standard format.5 Standardized datacapture systems, such as the Electronic Source Data Interchange Document (http://www.cdisc.org/esdi-document), have already been developed to enable the integration of clinical care and clinical research.6 The movement toward adoption of EHRs that can effectively communicate with data access portals such as that we propose is challenging but inexorable. A centralized portal that accesses multiple EHR databases would markedly reduce the myriad costs currently associated with data acquisition from complicated clinical systems. The deployment of a system that exploits the interoperability of EHR databases would be critical to the mission of the DDP and would ultimately allow more efficient and cost-effective solutions for genomic researchers. Genomic research today often requires the gathering and rigorous curation of data across several studies to allow replication and validation. Researchers must
often navigate disparate hospital systems, multiple institutional gatekeepers, physicians’ offices, institutional review boards, and complex medical record systems. The process of identifying patients and defining relevant data is therefore slow and complicated, and the time taken represents an impediment to progress. Because the DDP could catalyze the collection of data and the creation of a centralized data access portal, it would avoid redundancies inherent in any “cottage industry” type of data-gathering approach. Others already recognize the value of an organized approach that links genomic data to EHRs. Institutions in the National Human Genome Research Institute’s Electronic Medical Records and Genomics (eMERGE) Network (http://www. genome.gov/27540473) are charged with combining DNA biorepositories with electronic medical record systems involving 13 specific human traits for largescale, high-throughput genetic research with the goal of returning genomic testing results to patients in a clinical care setting. The Million Veteran Program (http://www.research.va.gov/mvp) has a similar goal, using the Veterans Administration’s EHR system. The DDP would be synergistic with such efforts. The time savings derived from a simpler and more consistent process would be important. In addition, the DDP would be consistent with the growing movement toward patient-centered care. In the same way that the creation of the national organdonation system catalyzed public education and increased awareness of the possibility of transplantation, and thus increased the number of transplant organs available, the DDP we envisage could actively educate the public about the practical, clinical value of genomic science. A designation of “DNA Donor” status on a driver’s license could be used to engage the public and facilitate their involvement. The DDP would actively solicit organizations representing ethnic minorities and that advocate for patients with rare diseases to organize donations, and these groups would be empowered to contribute to future discoveries directly relevant to them. Overall, a consented DDP could energize genomic and pharmacogenomic
VOLUME 95 NUMBER 2 | FEBRUARY 2014 | www.nature.com/cpt
perspec tives research by optimizing data sharing, controlling costs, saving time, educating the general public, and facilitating translation of new discoveries. There are strong natural incentives for both public and private stakeholders to participate in such an initiative. Initial funding could come from funding agencies or disease-group consortia who wish to exploit this resource to address specific research questions or to promote the use of data from unique communities. Individual research proj ects could then fund the sequencing and data interpretation. The scale of the DDP could be large. The genomic community would stand to benefit from an effective DNA-procurement system analogous to what is now a highly organized national organ-procurement system for transplants. We believe that the educational efforts of the DDP could act as a catalyst to bring about what has long been anticipated: a new societal approach to genomic research and personalized medical care. ACKNOWLEDGMENTS The authors thank Raymond L. Woosley and William Tierney for providing critical review and input into this article. CONFLICT OF INTEREST The authors are partners in Clinical Equilibrium Consulting, LLC, a company that provides clinical pharmacology, pharmacogenetic, and drug-interaction consulting services. D.A.F. is, or has been, a paid consultant or member of the scientific advisory boards for the following organizations involved in the development and implementation of pharmacogenomic tests: the Coriell Institute for Medical Research, Medco Health Solutions, Affymetrix, Quest Diagnostics, and LabCorp. © 2014 ASCPT
1. Lander, E.S. Initial impact of the sequencing of the human genome. Nature 470, 187–197 (2011). 2. Giacomini, K.M., Yee, S.W., Ratain, M.J., Weinshilboum, R.M., Kamatani, N. & Nakamura, Y. Pharmacogenomics and patient care: one size does not fit all. Sci. Trans. Med. 4, 153ps18 (2012). 3. Bush, W.S. & Moore, J.H. Chapter 11: genomewide association studies. PLoS Comp. Biol. 8, e1002822 (2012). 4. Allain, D.C., Friedman, S. & Senter, L. Consumer awareness and attitudes about insurance discrimination post enactment of the Genetic Information Nondiscrimination Act. Familial Cancer 11, 637–644 (2012). 5. Blumenthal, D. Stimulating the adoption of health information technology. N. Engl. J. Med. 360, 1477–1479 (2009).
See article page 147
Integrated Efficacy to Effectiveness Trials RM Califf1,2 Experts in clinical research, therapeutic development, and comparative effectiveness are continually frustrated in their attempts to fit the square peg of therapeutic development into the round hole of clinical trials. Trials can be optimized to provide signals in highly controlled experiments or to estimate an intervention’s effect in poorly controlled real-world settings, but not both simultaneously. Selker and colleagues propose a continuum that creates a smooth transition from controlled experiments to realworld, real-time studies within a single mechanism. The “efficacy-to-effectiveness (E2E)” approach described in this issue of Clinical Pharmacology & Therapeutics by Selker et al.1 describes a new paradigm for therapeutic development that is both consistent with current thinking and sensible from a conceptual standpoint. It is also timely, as our current system for developing and testing new medical technologies is clearly on an unsustainable trajectory.2 Drug developers face dire challenges within an environment where investment in new therapeutics is jeopardized by sharply rising costs of development—an escalation that has grown particularly acute for laterphase clinical trials. Advocacy groups understandably want swift access to potentially useful therapies and a better understanding of the comparative safety and effectiveness of technologies. Clinicians seek to narrow the range of uncertainty in their recommendations. And payers and health systems would prefer to pay only for therapies that provide a favorable balance of risk and benefit. All these factors were reflected in the report of the special subcommittee of the President’s Council of Advisors on Sci-
ence and Technology (PCAST) in 2012.3,4 Prompted by an exodus of high-paying pharmaceutical and biotechnology jobs from the United States, 5 the PCAST subcommittee included industry executives, academic leaders, government and policy experts, and patient advocates. Fundamentally, the committee recommended a more continuous approach to technology approval in which the level of uncertainty is continuously narrowed by a series of studies and permission for marketing occurs earlier in the cycle but is accompanied by a robust commitment to continuous postmarketing evaluation.3 In the E2E model,1 the developmental path for a novel technology starts with an efficacy study designed to optimize detection of a signal for a favorable benefit/ risk balance. Once this initial hurdle is cleared, the trial would evolve through a carefully planned, systematic process into a comparative effectiveness trial. This trial would be conducted in a population that represented the breadth of the technology’s intended use and would have a duration and sample size adequate for informing its rational use in practice. The eminent sensibility of these proposals is unsurprising
1Duke Translational Medicine Institute, Duke University, Durham, North Carolina, USA; 2Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA. Correspondence: RM Califf ([email protected])
doi:10.1038/clpt.2013.232
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