The concept of personalized medicine (PM), which is the use of the right drug for the right patient at the right dose, is not a topic new in the field. PM is a concept that is developing over the decades with PM drugs already available in the market. While there have been articles on either ethical or legal aspects/implications of PM, there are very few recent articles discussing both of them simultaneously. This article aims to discuss both the legal and ethical aspects of PM, with personal insights.
In a commentary in the prestigious journal, Nature Medicine,1, the preeminent oncologist Professor Brian J. Druker, shared his personal story and research experience where among the staggering amount of work he published, the best celebrated one would perhaps be the development of the tyrosine kinase inhibitor, imatinib2 in 1996 for the treatment of chronic myeloid leukaemia (CML). The 2-phenylaminopyrimidine derivative imatinib, specifically targets and inhibits the activity of the BCR-ABL fusion kinase, with complete cytogenetic response in the majority of newly diagnosed patients with chronic-phase CML3. This represents a typical example of molecular targeted therapy in personalized medicine (acronymized here as PM, also otherwise known as precision medicine). The era of PM, involving the administration of tailored drugs to the right patient according to their genetic susceptibility4, is a departure from the conventional “one size fits all” treatment approach which can have adverse reactions and reduced drug efficacy in some patients5,6. For instance, patient sensitivity to the anticoagulant warfarin7, is influenced by genetic polymorphisms of the enzyme CYP2C9b and VKORC1c. These put the spotlight on PM, which is highly regarded to transform drug development and treatment approaches8 by leveraging on the groundwork laid by the completion of the Human Genome Project more than a decade ago9. To date, adoption of PM has yielded numerous benefits for the treatment and diagnosis of several pathologies ranging from kidney diseases49, sclerosis50, cardiovascular diseases51 and in particular, oncology52-56. Trastuzumab, an example of PM, is a monoclonal antibody targeting the extracellular domain of ERBB2 protein57. ERBB2 (also known as HER2) is one of the most frequently mutated gene amplified in women with breast cancer. In female patients with metastatic HER2-overexpressing breast cancer receiving trastuzumab treatment, a notable response rate of 35% was reported59. The mechanism of action underlying trastuzumab has been reviewed in the literature60. Combinatorial administration of trastuzumab with chemotherapy61, pertuzumab62,63 and other PM drugs have produced beneficial clinical outcomes. Considering the mounting importance of PM in modern medicine, the ethical and legal aspects of PM need a comprehensive discussion – in which this essay aims to achieve.
aAn indication of the absence of Philadelphia chromosome (a reciprocal translocation between chromosome 9 and chromosome 22) in all 20 bone marrow metaphases (metaphase cells) by cytogenetic analysis (eg: karyotyping).
The emerging clinical evidence supporting the use of PM to treat various pathologies have convinced superpower countries to invest greatly in PM drug development. For instance, the UK and US have announced plans in 2015 to commit huge amount of funds for PM development64 – with a staggering investment of £13·7 million and $215 million respectively. The state of California in particular, have revealed a $3 million plan65,66, named “California Initiative for Advancing Precision Medicine” in 2015 to resolve ethical, legal and other associated public concerns on PM and the ambitious goal of speeding up the development of PM drugs. China, another formidable country in scientific research has been reported to launch a more ambitious project that will be heavily funded and invested in70. The project aimed to focus on sequencing genomes and deepen understanding on the genetic basis of cancers70. This initiative by China is expected by experts to booster research in PM and hasten the discovery of new PM in the drug pipeline. Looking at Europe68, a series of PM workshops have been organized, with European health ministers meeting on PM, and the EU research and innovation program Horizon 2020 and the EU IC PerMed project introduced. The innovation program Horizon 2020 has the funding of €3 billion68 to invest in the various aspects of PM. All of these represent the significant efforts made by the European government to promote PM. Shifting our attention to the Nordic region69, Denmark has their Danish National Biobank containing 8 million patient specimens, ranging from urine to serum. In addition, Denmark also have several other biobanks such as Bio- and Genome Bank Denmark and the Danish Neonatal Screening Biobank. Other countries such as Estonia have biobanks and personalized medicine programmes67. The list of population-based cohort studies and biobanks available in the Nordic region has been summarized elsewhere in the literature69 and will not be discussed further. All of these approaches and initiatives will undoubtedly contribute to the development and adoption of PM as a therapeutic treatment option.
bCytochrome P450 family 2 subfamily C isoform 9 enzyme
cVitamin K epoxide reductase
For PM to exert its therapeutic effects on the intended patient population, a colossal database containing various bio-information of patients must be readily available to pharmaceutical companies and developers before any rational drug design/formulation can be laid down. In realisation of this, there are advocations for the creation of the databanks for the PM field5,10,11, where its benefits and the challenges have been discussed in detail. The inception of the PM database starts with the collection of patient information, which has been subjected to ethical concerns on informed consent12,13 and legal regulations11,12,14. For example15,16, the Icelandic Healthcare Database by deCODE Geneticsd, has been controversial partially due to its assumption of “presumed consent” where health information of all Icelandic citizens are automatically integrated into the database unless an opt out is requested13. On this issue, critics have lambasted that the approach limited the autonomy an individual has on the control of their materials and the willingness to participate in the research after having key project details informed17. Defenders of embracing presumed consent have instead, pointed out the drawbacks of individuals-based informed consent in biobanking, where wastage of resources (e.g. time and funds) and impediment of vital research for remaining medical materials without consent from the respective participants18. Exacerbating the situation for researchers, getting informed consent from participants (an information required for PM) across countries for biobanking is legally challenging with different rules and regulations on the mode of consent required by the relevant authorities12,14. Taking France and Japan for comparison, specific informed consent and broad consent is required respectively for biobank-based research12,14. Therefore, standardization on the mode of informed consent adopted across countries is a potential future direction worth implementation.
Given the prodigious amount of data to be stored, many have also expressed privacy and confidentiality as ethical concerns on the obtained health information10,19,20 for the construction of PM databases. Privacy concerns on personal medical-associated information in the database is best-illustrated in the Iceland’s deCODE database case21, where a plaintiff initiated the lawsuit in objection of including her deceased father’s medical record in the database, with the belief that she could be at risk of her health particulars being identified based on such information, causing an uproar13 on the violation of personal privacy, leading to the eventual decision by Iceland’s supreme court to rule the established database as unconstitutional22. In an attempt to resolve this, a “Bio-PIN” concept, which is a unique identifier derived from the individual’s biological data, has been suggested23 as a potential solution to reduce the limitations in biobank-based research while also simultaneously addressing ethical and legal issues surrounding confidentiality, informed consent as well as data security. It is noteworthy that complete anonymization remains arduous as identification of individuals based on biological data such as SNPeis possible24. Nevertheless, the introduction of privacy-securing technologies is an encouraging move to solve the various ethical as well as legal issues entangling the deployment of biobanking in PM.
Commercialisation of patient data in the database is another ethically disputed subject based on the information generated in PM. Using the same case of the Icelandic Healthcare Database by deCODE Genetics as mentioned previously, it has been reported21,25 that deCODE Genetics will be given a 12 year exclusive right to commercialise the database with a portion of the profits shared with the healthcare system – a move that infuriated the community and sparked criticisms on exploitation, where it is believed patient data should not be used as a tool for a company gains26.
Besides all of the above-mentioned ethical and legal implications, the usage of the term PM has also gained considerable opposition. Judging solely by the information extracted from the term, it is inevitable for the members of public to misinterpret it as developing drugs only for certain privileged individuals – a grave misunderstanding that objectors of the term have attempted to address to justify their advocations for the adoption of term “precision medicine” instead27,28. In addition to the discussion on the accuracy of the terminology, affordability of PM has also been intensively debated with worries on rising healthcare costs29,30 due to smaller intended patient population after stratification while others foresee the deployment of PM to slash treatment costs8,31 based on the idea that unnecessary costs from inefficacious treatments would be avoided by directing appropriate drugs for the suitable population and thus reducing financial expenditure on medical treatments in the long run32. The practice of patient stratificationf in PM has been another topic of ethical dispute in addition to the above-mentioned cases of contestation, in which worries on possible social complications were raised33,34. For this reason, the term “stratified medicineg” is sometimes used interchangeably with PM35.
Opining on the possible ethical dilemmas budding from the practice, the possibility of patients to be denied access by clinicians or insurance companies to potential PM based on the presumption of inaptness or drug toxicity has been suggested36. Justifiers of patient stratification in PM on other hand, have vocalised its importance in medical research36.
One of the key tools driving PM development is accurate and reliable biomarkers. In PM, biomarkers are considered as a pre-requisite where they are used in patient stratification to identify and classify patients into subpopulations based on treatment responses and possibility of experiencing adverse reactions35. These biomarkers can take the form of gene expression patterns, protein and histological markers amongst the many others. To illustrate how biomarkers are implicated in PM, the example of PD-L1 levels as a biomarker to evaluate patient response to therapeutics targeting the PD1– PDL1 pathway in cancer is given, where it has been reported37 that higher percentage of patients with tumours that are positive for PD-L1 achieved the objective response compared to those patients with tumours negative for PD-L1, highlighting the role of biomarkers in predicting therapeutic response. To achieve the aim of patient stratification in PM (to administer drugs to patients who are mostly like to benefit), companion diagnostic tests which relies on biomarker-dependent subgrouping of patients, are fundamental38. As such, pharmaceutical companies usually co-develop PM together with its respective companion diagnostic devices (also referred to as in vitro diagnostic (IVD) companion diagnostic devices according to FDAh”. With relation to the legal aspects of this process, safety, accuracy and efficacy-associated information for both PM and its companion diagnostic tests are required to be submitted to regulatory such as FDA for approval. In a survey conducted by the Tufts Center for the Study of Drug Development39, it was found that the majority of the participating biotechnology-pharmaceutical companies lack companion diagnostics or had no specific target patient populations using biomarkers, in which scepticism on regulatory pathways exists at the time. With the intention of better elucidating the regulatory and legal requirements for the co-development of PM and the complementary diagnostics, there has been rigorous discussion of the potential challenges and solutions for the approval process (in this case, by FDA). In legal aspects, a pharmaceutical company should provide evidences demonstrating the analytical and clinical validity of the companion diagnostic. Also included in the discussion is the evolution of regulations concerning PM companion diagnostics, for instance the FDA’s 2012 draft guidance documenting the enrichment strategies for clinical trials (elucidating guidelines for different phrases of clinical trials); predictions on the FDA’s approval of multi-marker diagnostic development (where obtaining investigational device exemption for a multi-marker screening platform has been suggested as a potential solution) as well as registrations addressing queries regarding the selections of positive/negative diagnostics. According to the legal regulations in the draft guidance, it is permitted to restrict the target patient population to those likely to benefit (biomarker-positive) and use algorithm to predict patient response for stratification40. Collectively, it can be said that information generated and involved in PM has been subjected to considerable number of legal challenges since its introduction.
Eliciting a fierce ethical and legal altercation, the topic of patentability has captivated immense amount of attention, particularly from pharmaceutical companies and researchers working on developing PM. For PM pharmaceutical companies, it is statutory that they provide cogent evidences (information) proving the pre-emption of fundamental principles, novelty, non-obviousness, to satisfy the requirements of “machine or transformation test” as well as high-level of utility of their companion diagnostics in order to be considered as a strong candidate for patent-eligiblility41. The legal imperativeness of such requirements has been highlighted in the recent decade where patent lawsuits has risen exponentially and legal uncertainties for the pharmaceutical companies have lurked. To name a few, in the Mayo Collaborative Services v. Prometheus Laboratories Inc 2011 case, the US Supreme Court has ruled against Prometheus after deeming the methodology developed for optimising treatment efficacy to be unpatentable based on the “laws of nature”. Diagnostic methodologies are patentable in Europe only if they are in vitro in essence, and the boundaries defining criteria for the patentability of diagnostic methods varies considerably across countries42. Taking a look in another similar case, Association for Molecular Pathology v. Myriad Genetics, Inc., the US supreme court ruled that isolated BRCA1 and BRCA2 DNA sequences are not eligible to be patented on the basis of “laws of nature” and “natural phenomenon” while cDNA will be considered patentable on the basis that it is not “naturally-occurring”71. This decision by the court has been viewed to be a welcomed approach by some while others fear that it will possibly aggravate uncertainty on the patentability of gene-associated subject matter given the great variability of patent eligibility across countries and around the world71. There have been viewpoints that the ruling would cause consternation in the biotechnology field and would hinder possible investments in drug-related product development. As a result, the industry may be forced to rely on trade-secrecy and other measures to ensure profits71. All of these have highlighted the roadblocks for PM drug development and implementation. Likewise, the legal limitations in reimbursement and the complementary regulations for diagnostic tests represents another challenge for PM although these are predicted to change soon43. Taken together, all of these may lead to dubiety on PM diagnostics development and discourage innovation in the biotechnology community44. It is undeniable that continued and sustainable investments in the biotechnology industry would be critical to the successive development of new drugs for better management of disease pathologies. However, if such investments are over-dependent on patents and active assertion of patent rights, patient accessibility to newly introduced drugs would also inevitably be decreased as the cost of drug development continue to rocket up. This “unhealthy” cycle would eventually deny certain patient groups of critical treatments and defeat the core principle of drug development to cure pathologies.
Offering a closer look at the current progress of implementing PM in Southeast Asia, a study has concluded that Singapore has been one of the countries notable for its efforts for encouraging PM, demonstrated by the presence of relevant PM healthcare services and job positions45. From the study45, it is however evident that majority of the Southeast Asia countries, including Singapore, are ill-prepared for the era of PM as seen by the lack of PM research-governing regulations, for instance. Viewing from a legal perspective, the lack of legislations for PM pose a huge challenge for PM as information required for legal approval of PM is non-existent, thus hindering as well as diminishing the willingness of companies to invest in research and development for PM, The true potential of PM has thus, yet to be realised in Southeast Asia. Hence, it is irrefutable that Southeast Asia countries need to invest more resources for full PM implementation in order to offer higher quality of healthcare to its patients.
ddeCODE Genetics is a biotechnology company.
eSNP is an acronym for single nucleotide polymorphisms, which are single base pair differences in genomic DNA sequences between individuals.
fPatient stratification refers to the stratification of patients into subgroups on the basis of disease susceptibility, treatment response and clinical prognosis.
gStratified, personalized, individualized, precision medicine are 4 terms that are often used interchangeably in the literature.
hFDA refers to United States (US) Food and Drug Administration
Looking back at the decades of PM development, we have witnessed the emergence of new targeted drugs such as gefitinib, trastuzumab and erlotinib for cancer therapy46.47 with the trend of PM currently also being pursued for the treatment of neurological, metabolism, pulmonary and myriad of diseases48. In the near future, there will be a sharp increase in the integration of new technologies such as artificial intelligence, machine learning, wearable technology and 3D printing in facilitating the development of PM. This is because currently, there are reports on the use of these technologies for personalised medicine72-80. Additionally, given the nature of PM in which biobanks and clinical data are heavily relied on, the application of data-processing technologies such as machine-learning would definitely be critical for the advancement of the PM field. It would, therefore, be only a matter of time before they are finally utilised in the field of PM.
Distractingly, a variety of ethical concerns as well as legal regulations on information generated in PM have to a certain extent, hindered the progress of the developing personalised drugs for various pathological disorders. In the future, it can be envisaged that universal patent rules and regulation would be created if countries wish to further encourage investments in the research and development of PM drugs - although such initiative would not be possible anytime soon. Universal legislations governing PM would need to be introduced – one that would ease the difficulties of PM developers in filing applications and adhering to the relevant healthcare guidelines. For example, the guidelines for acquiring patient consent will need to undergo reforms to unify the type of consent required across countries before conducting clinical trials in humans. Government legislations will also need to carefully revise the patent eligibility criteria while also maintaining a tight balance between industry, healthcare insurance companies and patients so that the cycle of PM development is sustainable, and the ultimate goal of benefitting patients can be achieved. Affordability and accessibility to all patients and all countries (whether under-developed or developed) should hence be the fundamental principle to bring PM from bench to bedside. Lastly, it can be foreseen that a new clinical management system would need to be created to resolve patient and public concerns on the transparency of drug development associated information as well as handling of patient data. Taken together, all of this accentuates the fact that expediting the establishment of more comprehensive guidelines and legislations for PM would be paramount in our race against health illnesses.
This work is self-funded. This article is a personal endeavour of a Diploma in Biomedical Science graduate of Republic Polytechnic.
The author declares no conflict of interest. The article publishing charge for this article is waived as the author was unemployed.
Len J S crafted, edited and prepared this manuscript
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