Overcoming regulatory and economic challenges facing pharmacogenomics

The number of personalized medicines and companion diagnostics in use in the United States has gradually increased over the past decade, from a handful of medicines and tests in 2001 to several dozen in 2011. However, the numbers have not reached the potential hoped for when the human genome project was completed in 2001. Significant clinical, regulatory, and economic barriers exist and persist. From a regulatory perspective, therapeutics and companion diagnostics are ideally developed simultaneously, with the clinical significance of the diagnostic established using data from the clinical development program of the corresponding therapeutic. Nevertheless, this is not (yet) happening. Most personalized medicines are personalized post hoc, that is, a companion diagnostic is developed separately and approved after the therapeutic. This is due in part to a separate and more complex regulatory process for diagnostics coupled with a lack of clear regulatory guidance. More importantly, payers have placed restrictions on reimbursement of personalized medicines and their companion diagnostics, given the lack of evidence on the clinical utility of many tests. To achieve increased clinical adoption of diagnostics and targeted therapies through more favorable reimbursement and incorporation in clinical practice guidelines, regulators will need to provide unambiguous guidance and manufacturers will need to bring more and better clinical evidence to the market place.     

Molecular tools for companion diagnostics

The heterogeneous nature of cancer results in highly variable therapeutic responses even among patients with identical stages and grades of a malignancy. The move towards personalised medicine in cancer therapy has therefore been motivated by a need to customise therapy according to molecular features of individual tumours. Companion diagnostics serves to support early drug development, it can provide surrogate markers in clinical trials, and also guide selection of individual therapies and monitoring of responses in routine clinical care. The era of companion diagnostics can be said to have begun with the introduction of the HercepTest - a first-of-a-kind diagnostic tool developed by DakoCytomation in 1998 to select patients for therapy with the anticancer drug Herceptin (trastuzumab). Herceptin and the paired test proved that companion diagnostics can help guide patient-tailored therapies. We will discuss herein technologies to analyse companion diagnostics markers at the level of DNA, RNA or protein, focusing on a series of methods developed in our laboratory that can facilitate drug development and help stratify patients for therapy.     

The pinpoint promise of nanoparticle-based drug delivery and molecular diagnosis

Nanotechnology, or systems/device manufacture at the molecular level, is a multidisciplinary scientific field undergoing explosive development. The genesis of nanotechnology can be traced to the promise of revolutionary advances across medicine, communications, genomics and robotics. Without doubt one of the greatest values of nanotechnology will be in the development of new and effective medical treatments (i.e., nanomedicine). This review focuses on the potential of nanomedicine as it specifically relates to (1) the development of nanoparticles for enabling and improving the targeted delivery of therapeutic agents; (2) developing novel and more effective diagnostic and screening techniques to extend the limits of molecular diagnostics providing point-of-care diagnosis and more personalized medicine.     

Impact of the US Patent System on the Promise of Personalized Medicine

The biotechnology revolution promises unfathomable future scientific discovery. One of the potential benefits is the accelerated introduction of new diagnostics and treatments to the general public. The right medication for the right patient is the goal of personalized medicine, which directly benefits from many of biotechnology's biggest and most recent advances. The US patent system rewards innovation in medicine and other arts and sciences by granting innovators, for a period of time, the right to exclude others from using what was invented. One of the purposes of the patent system is to trade that right to exclude, and in its stead obtain the patent holder's obligation to fully and publicly disclose the essence of the innovations so that they can be improved, thus advancing the common welfare. A tension exists between personalized medicine's need for access to and use of scientific advances and the patent system's reward of exclusive use or nonuse to innovators. This tension may result in fewer diagnostic and therapeutic tools brought to the market and generally adopted. The risk seems particularly acute with respect to the diagnostic and therapeutic tools arising from genetic testing that hold specific value for a subset of the population. The judicial system has introduced ethical exceptions that overcome a patent holder's right to exclude; these judicial overrides relate to the provision of certain types of medical procedures and the development of certain types of new drugs, and not, apparently, to the use of diagnostic and therapeutic tools essential to the success of personalized medicine. A serious question exists as to whether legislative action is necessary to increase public access to genetic testing.     

Semiconductor quantum dots for in vitro diagnostics and cellular imaging

The need for companion diagnostics, point-of-care testing (POCT) and high-throughput screening in clinical diagnostics and personalized medicine has pushed the need for more biological information from a single sample at extremely low concentrations and volumes. Optical biosensors based on semiconductor quantum dots (QDs) can answer these requirements because their unique photophysical properties are ideally suited for highly sensitive multiplexed detection. Many different biological systems have been successfully scrutinized with a large variety of QDs over the past decade but their future as widely applied commercial biosensors is still open. In this review, we highlight recent in vitro diagnostic and cellular imaging applications of QDs and discuss milestones and obstacles on their way toward integration into real-life diagnostic and medical applications.     

Co-development of a companion diagnostic for targeted cancer therapy

Oncology drug development is a long and costly process associated with a success rate of 5-10%. The parallel development of companion diagnostic tests that will identify patients most likely to receive benefit has the potential to increase the success rate for oncology drugs and decrease development time and associated costs. Metastatic melanoma is a challenging disease that has been associated with poor survival. Identification of a mutated BRAF kinase gene in many cases of melanoma provided a promising therapeutic target. Here we describe the successful co-development of vemurafenib, a first-in-class selective inhibitor of oncogenic BRAF kinase, and its companion diagnostic, the cobas(?) 4800 BRAF V600 Mutation Test. Key success factors in the development process included early identification of the BRAF V600E biomarker, early development of the diagnostic test, and early and close collaboration between the pharmaceutical and diagnostic development teams. This focused and integrated process resulted in the first personalized medicine for the treatment of metastatic melanoma less than five years after the Investigational New Drug Application, a remarkably short time.     

Preclinical strategies to define predictive biomarkers for therapeutically relevant cancer subtypes

Defining key driver mutations in cancer, the resulting aberrations in molecular mechanisms and the subsequent phenotype underpins the development and implementation of novel personalized medicine strategies. The literature is replete with biomarkers of prognosis and therapeutic responsiveness identified in single cohorts of patients that have not been independently validated and as a consequence, not developed. Integrating companion biomarker discovery with therapeutic development at the preclinical stage creates the opportunity to identify candidate biomarkers early, which would significantly facilitate both biomarker and therapeutic development. Advances in “-omic” technologies have led to large-scale efforts in characterizing and cataloguing the full range of aberrations in cancer. These include the International Cancer Genome Consortium and The Cancer Genome Atlas, which aim to comprehensively catalogue the range of genomic aberrations for large numbers of cancers for a progressively increasing range of cancer types and subtypes. The technical challenges associated with achieving these goals in some instances have required the generation of primary xenografts and cell lines. These extensively characterized model systems will provide an unprecedented resource for the discovery of biomarkers of therapeutic responsiveness for established therapies, and the development of companion biomarkers linked with preclinical novel therapeutic development in the future.     

Best practices for companion diagnostic and therapeutic development: translating between the stakeholders

By 2012 the pharmaceutical industry has generally recognized the value proposition offered through 'personalized medicine': shorter regulatory reviews and higher prices as a tradeoff for a more specific patient market. Examples of companion diagnostics (Cdx) exist not only in oncology, but across therapeutic areas that allow us to define treatment benefit and identify the 'best patients' for a given treatment approach or combination thereof. In the 13 years since the co-approval of trastuzumab (Herceptin(?)) from Genentech and the HercepTest(?) from Dako, the regulatory and commercial environments have yet to adopt a standard methodology for co-development and co-approval. Furthermore, a one-size-fits-all approach is unlikely to emerge despite attempts by various stakeholders to create an environment of conformity for approval and reimbursement issues. What has emerged, however, is the experience of clinical developers and commercial teams in bringing these products to market. In this article, we focus on the many factors that should be considered to successfully develop and market a companion diagnostic, based on lessons learned from recent case studies. A proposed framework of questions to be addressed at the various stages of developing highly effective companion diagnostic products is also presented.     

Looking forward, looking back

Amgen's retrospective sortie into personalized Vectibix treatment poses some difficult questions for regulators concerning the oversight of companion diagnostics.     

Cancer genomics: from discovery science to personalized medicine

Recent advances in genome technologies and the ensuing outpouring of genomic information related to cancer have accelerated the convergence of discovery science and clinical medicine. Successful examples of translating cancer genomics into therapeutics and diagnostics reinforce its potential to make possible personalized cancer medicine. However, the bottlenecks along the path of converting a genome discovery into a tangible clinical endpoint are numerous and formidable. In this Perspective, we emphasize the importance of establishing the biological relevance of a cancer genomic discovery in realizing its clinical potential and discuss some of the major obstacles to moving from the bench to the bedside.     

SNP array analysis in constitutional and cancer genome diagnostics--copy number variants, genotyping and quality control

Array-based comparative genomic hybridization analysis of genomic DNA was first applied in postnatal diagnosis for patients with intellectual disability (ID) and/or congenital anomalies (CA). Genome-wide single-nucleotide polymorphism (SNP) array analysis was subsequently implemented as the first line diagnostic test for ID/CA patients in our laboratory in 2009, because its diagnostic yield is significantly higher than that of routine cytogenetic analysis. In addition to the detection of copy number variations, the genotype information obtained with SNP array analysis enables the detection of stretches of homozygosity and thereby the possible identification of recessive disease genes, mosaic aneuploidy, or uniparental disomy. Patient-parent (trio) information analysis is used to screen for the presence of any form of uniparental disomy in the patient and can determine the parental origin of a de novo copy number variation. Moreover, the outcome of a genotype analysis is used as a final quality control by ruling out potential sample mismatches due to non-paternity or sample mix-up. SNP array analysis is now also used in our laboratory for patients with disorders for which locus heterogeneity is known (homozygosity pre-screening), in prenatal diagnosis in case of structural ultrasound anomalies, and for patients with leukemia. In this report, we summarize our array findings and experiences in the various diagnostic applications and demonstrate the power of a SNP-based array platform for molecular karyotyping, because it not only significantly improves the diagnostic yield in both constitutional and cancer genome diagnostics, but it also enhances the quality of the diagnostic laboratory workflow.     

A critique of race-based and genomic medicine

Now that a composite human genome has been sequenced (HGP), research has accelerated to discover precise genetic bases of several chronic health issues, particularly in the realms of cancer and cardiovascular disease. It is anticipated that in the future it will be possible and cost effective to regularly sequence individual genomes, and thereby produce a DNA profile that potentially can be used to assess the health risks for each person with respect to certain genetically predisposed conditions. Coupled with that enormous diagnostic power, it will then depend upon equally rapid research efforts to develop personalized courses of treatment, including that of pharmaceutical therapy. Initial treatment attempts have been made to match drug efficacy and safety to individuals of assigned or self-identified groups according to their genetic ancestry or presumed race. A prime example is that of BiDil, which was the first drug approved by the US FDA for the explicit treatment of heart patients of African American ancestry. This race-based approach to medicine has been met with justifiable criticism, notably on ethical grounds that have long plagued historical applications and misuses of human race classification, and also on questionable science. This paper will assess race-based medical research and practice in light of a more thorough understanding of human genetic variability. Additional concerns will be expressed with regard to the rapidly developing area of pharmacogenomics, promoted to be the future of personalized medicine. Genomic epidemiology will be discussed with several examples of on-going research that hopefully will provide a solid scientific grounding for personalized medicine to build upon.     

Role and implications of nanodiagnostics in the changing trends of clinical diagnosis

Nanodiagnostics is the term used for the application of nanobiotechnology in molecular diagnosis, which is important for developing personalized cancer therapy. It is usually based on pharmacogenetics, pharmacogenomics, and pharmacoproteomic information but also takes into consideration environmental factors that influence response to therapy. Nanotechnology in medicine involves applications of nanoparticles currently under development, as well as longer range research that involves the use of manufactured nano-robots to make repairs at the cellular level. Nanodiagnostic technologies are also being used to refine the discovery of biomarkers, as nanoparticles offer advantages of high volume/surface ratio and multifunctionality. Biomarkers are important basic components of personalized medicine and are applicable to the management of cancer as well. The field of nano diagnostics raises certain ethical concerns related with the testing of blood. With advances in diagnostic technologies, doctors will be able to give patients complete health checks quickly and routinely. If any medication is required this will be tailored specifically to the individual based on their genetic makeup, thus preventing unwanted side-effects.     

Predictive diagnostics and personalized medicine for the prevention of chronic degenerative diseases

Progressive increase of mean age and life expectancy in both industrialized and emerging societies parallels an increment of chronic degenerative diseases (CDD) such as cancer, cardiovascular, autoimmune or neurodegenerative diseases among the elderly. CDD are of complex diagnosis, difficult to treat and absorbing an increasing proportion in the health care budgets worldwide. However, recent development in modern medicine especially in genetics, proteomics, and informatics is leading to the discovery of biomarkers associated with different CDD that can be used as indicator of disease's risk in healthy subjects. Therefore, predictive medicine is merging and medical doctors may for the first time anticipate the deleterious effect of CDD and use markers to identify persons with high risk of developing a given CDD before the clinical manifestation of the diseases. This innovative approach may offer substantial advantages, since the promise of personalized medicine is to preserve individual health in people with high risk by starting early treatment or prevention protocols. The pathway is now open, however the road to an effective personalized medicine is still long, several (diagnostic) predictive instruments for different CDD are under development, some ethical issues have to be solved. Operative proposals for the heath care systems are now needed to verify potential benefits of predictive medicine in the clinical practice. In fact, predictive diagnostics, personalized medicine and personalized therapy have the potential of changing classical approaches of modern medicine to CDD.     

Pros and cons of using aberrant glycosylation as companion biomarkers for therapeutics in cancer

Cancer treatment has been stratified by companion biomarker tests that serve to provide information on the genetic status of cancer patients and to identify patients who can be expected to respond to a given treatment. This stratification guarantees better efficiency and safety during treatment. Cancer patients, however, marginally benefit from the current companion biomarker-aided treatment regimens, presumably because companion biomarker tests are dependent solely on the mutation status of several genes status quo. In the true sense of the term, "personalized medicine", cancer patients are deemed to be identified individually by their molecular signatures, which are not necessarily confined to genetic mutations. Glycosylation is tremendously dynamic and shows alterations in cancer. Evidence is accumulating that aberrant glycosylation contributes to the development and progression of cancer, holding the promise for use of glycosylation status as a companion biomarker in cancer treatment. There are, however, several challenges derived from the lack of a reliable detection system for aberrant glycosylation, and a limited library of aberrant glycosylation. The challenges should be addressed if glycosylation status is to be used as a companion biomarker in cancer treatment and contribute to the fulfillment of personalized medicine.     

Society as Cause and Cure: The Norms of Transgender Social Medicine

This article analyzes how trans health was negotiated on the margins of psychiatry from the late 1970s and early 1980s. In this period, a new model of medical transition was established for trans people in Norway. Psychiatrists and other medical doctors as well as psychologists and social workers with a special interest and training in social medicine created a new diagnostic and therapeutic regime in which the social aspects of transitioning took center stage. The article situates this regime in a long Norwegian tradition of social medicine, including the important political role of social medicine in the creation of the postwar welfare state and its scope of addressing and changing the societal structures involved in disease. By using archival material, medical records and oral history interviews with former patients and health professionals, I demonstrate how social aspects not only underpinned diagnostic evaluations but were an integral component of the entire therapeutic regime. Sex reassignment became an integrative way of imagining and practicing psychiatry as social medicine. The article specifically unpacks the social element of these diagnostic and therapeutic approaches in trans medicine. Because the locus of intervention and treatment remained the individual, an approach with subversive potential ended up reproducing the norms that caused illness in the first place: “the social” became a conformist tool to help the patient integrate, adjust to and transform the pathology-producing forces of society.

     

Assessing the value-adding impact of diagnostic-type tests on drug development and marketing

OBJECTIVE AND METHODS: We explore the cash value of the companion diagnostics opportunity from the perspective of the pharmaceutical partner. Cashflow-based modeling is used to demonstrate the potential financial benefits of key relationships between the pharmaceutical and diagnostics industries. RESULTS: In four scenarios, the uplift in the net present value (NPV) of a proprietary medicine can exceed $US1.8 billion. By simple extrapolation, the uplifted NPV calculations allow realistic and plausible estimates of the companion diagnostic opportunity to be in the region of $US40 billion to $US90 billion. CONCLUSION: It is expected that such market valuation could drive a macroeconomic change that shifts healthcare practice from reactionary disease-treatment to proactive health maintenance.     

Translational genomics in personalized medicine – scientific challenges en route to clinical practice

Background

In the area of omics and translational bio(medical)sciences, there is an increasing need to integrate, normalize, analyze, store and protect genomics data. Large datasets and scientific knowledge are rationally combined into valuable clinical information that ultimately will benefit human healthcare and are en route to clinical practice. Data from biomarker discovery and Next Generation Sequencing (NGS) are very valuable and will combine in comprehensive analyses to stratify medicine and guide therapy planning and ultimately benefit patients. However, the combination into useful and applicable information and knowledge is not trivial.

NGS in personalized medicine

Personalized medicine generally promises to result in both higher quality in treatment for individual patients and in lower costs in health care since patients will be offered only such therapies that are more effective for them and treatments that will not be safe or effective will be avoided. Recent advancements in biomedical and genomic sciences have paved the way to translate such research into clinical practice and health policies. However, the move towards greater personalization of medicine also comes along with challenges in the development of novel diagnostic and therapeutic tools in a complex framework that assumes that the use of genomic information is part of a translational continuum, which spans from basic to clinical research, preclinical and clinical trials, to policy research and the analysis of health and economic outcomes. The use of next-generation genomic technologies to improve the quality of life and efficiency of healthcare delivered to patients has become a mainstay theme in the field as benefits derived from such approaches include reducing a patient’s need to go through ineffective therapies, lowering side- and off-target effects of drugs, prescribing prophylactic therapies before acute exacerbations, and reducing expenditures.

Economic challenges

As such, personalized medicine promises to increase the quality of clinical care and, in some cases, to decrease health care costs. Besides the scientific challenges, there are several economic hurdles. For instance, healthcare providers need to know, whether the approach of personalized healthcare is affordable and worth the expenses. In addition, the economic rationale of personalized healthcare includes not only the reduction of the high expense of hospitalizations, the predictive diagnostics that will help to reduce cost through prevention or the increased efficacy of personalized therapies needs to offset prices of drugs. There are also several factors that influence payer adoption, coverage and reimbursement; the strength of evidence drives payers‘ decisions about coverage and reimbursement, varies widely depending on the personalized healthcare technology applied and regulation and cost-effectiveness seem to be increasingly associated with reimbursement, which is strongly influenced by professional society guidelines. In general, we see the following main obstacles to the advancement of personalized medicine: (i) the scientific challenges (a poor understanding of molecular mechanisms or a lack of molecular markers associated with some diseases, for example), (ii) the economic challenges (poorly aligned incentives), and (iii) operational issues in public healthcare systems. The operational issues can often be largely resolved within a particular stakeholder group, but correcting the incentive structure and modifying the relationships between stakeholders is more complex.

En route to clinical practice

This article focuses on the scientific difficulties that remain to translate genomics technologies into clinical practice and reviews recent technological advances in genomics and the challenges and potential benefits of translating this knowledge into clinical practice, with a particular focus on their applications in oncology.

Electronic supplementary material

The online version of this article (doi:10.1186/1877-6566-6-2) contains supplementary material, which is available to authorized users.