Abstract
A new era of gene and cell therapy for treating human diseases has been envisioned for several decades. However, given that the technology can alter any DNA/cell in human beings, it poses specific ethical, legal, and social difficulties in its application. In Malaysia, current bioethics and medical ethics guidelines tackle clinical trials and biomedical research, medical genetic services, and stem cell research/therapy. However, no comprehensive framework and policy is available to cater to ethical gene and cell therapy in the country. Incorporating ethical, legal, and social implications (ELSI) would be crucial to guide the appropriate use of human gene and cell therapy in conjunction with precision medicine. Policy experts, scientists, bioethicists, and public members must debate the associated ELSI and the professional code of conduct while preserving human rights.
BACKGROUND
The use of genomic information has rapidly grown since the completion of the Human Genome Project (HGP). 1 Since then, several advances in genomic medicine have been developed, including precision medicine, multiomics approaches, and genetic testing. Precision medicine involves understanding patients' genetic and genomic information to make effective prevention, diagnosis, and treatment decisions with the most negligible side effects for the patient. 2 Meanwhile, multiomics aims to identify molecular markers across diverse omics layers that increase the diagnostic yield for health and improve disease prognosis via a robust understanding of the genotype-to-phenotype relationship. 3 Clinical molecular genetic testing is helpful for various applications, such as rare disease diagnostics, predictive testing for common disorders, and health care management. 4 Therefore, integrative panomics potentially leads to the discovery and application of novel biomarkers and targeted therapeutics for each patient. 5
Another recent technology, a key player that may change the face of precision medicine, the revolutionary CRISPR/Cas9 gene-editing tool, enables precise edits to be made in the genome. 6 Gene editing holds much promise for human gene and cell therapy as it aims to correct the underlying genetic cause of diseases and serves as a one-shot cure. As of 2019, more than a 1,000 gene and cell and therapy trials were reported, with oncology, cardiology, central nervous system, musculoskeletal, and infectious diseases being the top 5 fields dominating the U.S. market. 7 At a global level, China has established itself as a world leader in genome editing, harnessing CRISPR in various disciplines, including medicine. 8 Moreover, China was the first in the world to treat people with cells modified using CRISPR/Cas9. 9 It is also known for the most prominent controversy in health science for making the world's first CRISPR-edited babies twin girls to disable HIV infection. 10
In Malaysia, gene and cell therapy to accelerate precision medicine is still in its infancy, and more research should be conducted on par with other developed countries. 11 We previously discussed that the transparency on the outlook on gene editing in the country could be improved, and the relevance of the existing regulatory, biosafety, and biosecurity aspects suffice to govern the technology. 12 As Malaysia is a multicultural country bound by societal norms, it is crucial to consider the ethical, legal, and social implications (ELSI) arising from the science of genetics and the uses of genetic technologies known as genethics. 13 Comprehensive guidelines and legal policies must be established to tackle the challenges and risks associated with the technologies. Therefore, this review aims to highlight the ELSI of gene and cell therapies toward adopting precision medicine in Malaysia.
THE LANDSCAPE OF PRECISION MEDICINE IN MALAYSIA
In the past, clinical medicine was practiced according to the symptoms presented by the patient, based on the physician's knowledge (intuition medicine). 14 Clinical practices are currently based on scientific research evidence, including clinical trials (evidence-based medicine). On the contrary, future clinical medicine will consider the patient's characteristics, such as their genome, epigenetics, and lifestyle (precision medicine). Precision medicine has many applications in diagnostic and therapeutic fields, such as cancer, infectious diseases, and other multisystemic chronic diseases. However, the adoption of precision medicine remains limited in Malaysia, as efforts that apply genomics, transcriptomics, proteomics, and metabolomics are confined at the institutional level and not harnessed for clinical applications. 15
To encourage universities, research institutes, companies, and health care centers to practice precision medicine, the Ministry of Health (MOH), Malaysia, proposed six focus areas to accelerate Health care 4.0: (i) quality and safety of care, (ii) illness to wellness, (iii) health care back to communities, families, and individuals, (iv) inclusive innovations and intelligent solutions, (v) collaborative partnerships, and (vi) public-private integration. The current ecosystem of precision medicine in Malaysia is summarized in Table 1.
The present ecosystem of precision medicine in Malaysia in terms of data/registry, biobank, professional courses, experts, and genetics/genomics services
Adapted and modified from Academy of Sciences Malaysia. Precision Medicine Initiative in Malaysia. 15
CRM, Cancer Research Malaysia; IMR, Institute for Medical Research; MGI, Malaysia Genome Institute; MGRC, Malaysian Genomics Resource Centre; MOH, Ministry of Health; MOSTI, Ministry of Science, Technology, and Innovation; SJMC, Subang Jaya Medical Centre; UKM, Universiti Kebangsaan Malaysia; UM, Universiti Malaya; UMBI, UKM Medical Molecular Biology Institute; USM, Universiti Sains Malaysia.
As part of the precision medicine initiatives in Malaysia, there were four significant advancements and developments in genetics and genomics. First, the MyGenome project completed its 100th human genome from a diverse Malaysian population to represent patterns of shared and clinically relevant genetic variations. 16 Second, The Malaysian Cohort, based at Universiti Kebangsaan Malaysia (UKM), Medical Molecular Biology Institute, recruited 106,527 participants to identify risk factors, study gene–environment interaction, and discover biomarkers for the early detection of cancers and other diseases. 17 Third, the Malaysian Node of the Human Variome Project (MyHVP), based at Universiti Sains Malaysia (USM), developed a specialized database that enables gene variation associated with the health and diseases of Malaysian ethnic groups to be collected, stored, and shared by all disciplines. 17,18
Fourth, the development of a medical genetics services partnership between the University of Malaya Medical Centre, USM and UKM teaching hospitals, and the national tertiary Hospital Kuala Lumpur enable medical genetic services to be available across Malaysia's public health system. 19 These efforts complemented each other and addressed many of the critical focus areas proposed by the MOH Malaysia.
Genetic testing allows the health care practitioner to determine the best therapeutic options for individuals, advancing precision medicine initiatives. Medical genetic services are provided in a multidisciplinary setting, in which genetic counseling is the leading service conducted by medical geneticists and genetic counselors. 19 Medical geneticists play an essential role in the establishment and/or confirmation of a genetic diagnosis based on the results of medical examinations, ordering of genetic testing, and genetic test results disclosure. In contrast, genetic counselors emphasize reinforcing genetic information through genetic education and providing ongoing psychosocial support to the patients. Malaysia only has about 14 clinical geneticists and 9 genetic counselors to serve the population. 20,21
To better understand the potential growth of medical genetic services, a survey estimated the Malaysian growth in demand for all human disorders-related genetic tests from 2012 to 2016. 22 Seventy-five percent of genetic tests were molecular genetics, whereas 25% of tests were either cytogenetic or molecular cytogenetic techniques. There was an increasing demand for genetic testing, with the growth rate at 4.4%, 42.5%, 31.8%, and 34.5% from 2013 to 2016, respectively. The study concluded that the demand for genetic counseling is estimated to increase more than expected. The need for genetic counseling has grown exponentially, and the role of genetic counselors in managing emerging technology issues such as gene and cell therapy is also evolving.
A study that deep-dived into medical genetic services offered reported clinical and health (wellness and lifestyle) tests and DNA sequencing as standard genetic services in Malaysia. 23 Although many genetic laboratories offer “DNA Test Reports” accompanied by methods to interpret them, the lack of genetic counseling services raises critical concerns about consumers' capability to understand the test results in decision-making related to health. Moreover, most laboratories provide limited information about DNA isolation, informed consent, sample storage, and privacy policy issues. Thus, numerous legal and ethical issues arise from these genetic testing and counseling services in Malaysia, which calls for immediate action.
In Malaysia, similar to many other countries, referrals to specialists are advised mainly by physicians. A study evaluating physicians' knowledge and perception of gene profiling in Malaysia found that physicians were not well-informed about gene profiling, and none had ordered genetic tests for their patients. 24 Surprisingly, the physicians were unfamiliar with the available genetic tests and were uncertain about the readiness of genetic technologies to be considered an essential element of their practices. Furthermore, inadequate documentation and evidence on clinical validity and utility could cause physicians to express less interest in adopting new genetic technologies.
A cross-sectional comparative study among junior and senior medical students at the International Medical University, Malaysia, revealed that only about one-third of the 356 respondents had heard of precision medicine. 25 However, 92.7% expressed interest in learning more about precision medicine. Both junior and senior medical students had positive attitudes toward adopting genome-guided prescribing and precision medicine; however, they were uncomfortable with their knowledge of genomic testing. Also, junior and senior students were largely well-grounded in understanding possible ethical dilemmas and concerns associated with precision medicine. Overall, precision medicine knowledge is low, and future medical practitioners are not adequately prepared to apply genomics to clinical practice.
It is not just the health care providers' knowledge that is crucial; examining the intention of patients with genetic diseases or family members to adopt genetic testing and its associated predictors in Malaysia is also critical to bringing medical genetics forward. For example, a study reported that the respondents demonstrated a solid intention to adopt genetic testing, expressed a high trust in key players involved in medical genetics, and claimed that the application could be accepted on religious grounds. 26 Furthermore, the respondents agreed that genetic testing offered high benefits but perceived that the test might have moderate risks, such as genetic discrimination and privacy issues associated with genetic information, which could impact insurance policies or job security. Thus, intentions to adopt genetic testing are multidimensional, and further efforts must be taken to overcome the public concern for successful implementation.
Another study assessed the knowledge, awareness, and perception of genetic testing among the general public in Malaysia. 27 The study revealed that most of the Klang Valley public have adequate knowledge of genetic testing, and half of the respondents were willing to undergo genetic testing. In addition, more than half of the respondents recognized the importance of genetic testing and its use for preventive care. They also agreed that it is necessary to increase awareness of genetic testing and implement laws and policies by the government to address the ethical issues concerning genetic testing. However, some respondents were unaware of or negatively perceived genetic testing. Hence, more efforts should be undertaken, such as a media campaign to educate and decrease any stigma associated with genetic testing.
Precision regenerative medicine, through targeted and engineered cellular and acellular therapy specific to individuals or disease states, has gained attention in Malaysian clinical settings as an alternative approach to current treatment modalities, particularly hematopoietic stem cells and mesenchymal stem cells. 28 Approximately 11 public and private hospitals/centers perform hemopoietic stem cell transplants. 29 Moreover, numerous facilities are offering clinical stem cell services in Malaysia, including Hospital Ampang, Hospital Pulau Pinang, Hospital Likas, National Cord Blood Bank in National Blood Centre (PDN), Hospital Sultanah Bahiyah, and Stem Cell Laboratory in Institute for Medical Research.
Many institutions are studying stem cell biology, characterization, genetic stability, and differentiation into cell types such as heart muscle, neurons, liver, kidney, and cartilage. The number of patients receiving stem cell transplantation for leukemias, lymphomas, solid tumors, and several genetic diseases is increasing. Stem cell treatment for heart failure, stroke, spinal cord injuries, and organ failure is in the developmental stage, and Malaysians could benefit from such therapies in the future.
A study was conducted to ascertain the industry's readiness for regulating cell and gene therapy products (CGTPs) regarding awareness of the guidelines, challenges, and acceptance of the regulatory requirements in Malaysia. 30 The findings indicate that 73.3% were aware of the Malaysian guidance document and guidelines, and 56.7% were aware of the differences in registration requirements between class I and II CTPs. However, only 36.7% of respondents agreed that the document was clear and understandable, whereas 50% were neutral regarding the clarity and understandability of the guidelines. Many CGTPs were in the early development phase, and the most challenging registration barriers were dossier preparation and compliance with the preclinical and clinical requirements. This study provides a snapshot of the industry's current regulation preparedness to accelerate CGTPs in Malaysia.
IMPLEMENTING PRECISION MEDICINE IN MALAYSIA: ELSI
Since the inception of HGP, ELSI aspects such as fairness in using genetic information, privacy and confidentiality, psychological impact and stigmatization, clinical issues, and conceptual and philosophical implications were among the essential elements addressed. 31 Similarly, critically reflecting on existing responses and bringing together multidisciplinary critical perspectives would help move forward ethical gene editing through 32 : (i) evaluating and guiding current and prospective developments in gene editing, (ii) reviewing existing theoretical literature on ELSI of genetic interventions on human beings, (iii) developing a robust framework for future discussions and evaluations on gene editing development, (iv) ensuring responsible governance framework for scientists, biotech companies, and public research institutions, and (v) improving the discourse between key stakeholders, including scientists, clinicians, bioethicists, policymakers, and the society.
Ethical consideration in precision medicine
The National Institutes of Health (NIH), MOH was established in 2003 to support medical research in Malaysia. 33 Under NIH, the National Medical Research Register (NMRR) and Medical Research and Ethics Committee (MREC) were set up to regulate all research conducted in MOH institutions and facilities. 34 Any MOH personnel conducting studies in MOH facilities must be registered with NMRR for review and approval. 35 Meanwhile, any research involving human subjects by MOH researchers and non-MOH must obtain prior review and permission from MREC. Decisions from MREC are guided by World Health Organization (WHO)'s operational guidelines, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and Malaysian Guidelines for Good Clinical Practice (GCP).
The GCP was implemented under the control of the National Committee for Clinical Research. 36 The document ensures that all clinical trials conducted in Malaysia are per the ICH E6 GCP and considers local practices and issues. This document also safeguards humans from the effects and safety of compounds used in trials, human rights protection of trial participants, and the roles of clinical research investigators, clinical trial sponsors, and clinical research associates. The central dogma of this guideline is that the well-being of the study subject must be prioritized over the interest of science. Although the guidelines outline principles for clinical trials, they can also be applied to other clinical interventions involving the subjects' safety and well-being.
The Malaysian GCP encompasses 13 core ICH GCP principles to ensure subject protection and reliability of trial results. 37 These principles can be summarized by 38,39 : “all clinical trials should be conducted in accordance with ethical principles, sound scientific evidence, and clear, detailed protocols. The benefits of conducting trials should outweigh the risks. The rights, safety, and well-being of trial participants are of paramount importance, and these should be preserved by obtaining informed consent and maintaining confidentiality. Care must be given by appropriately qualified personnel with adequate experience. Records should be easily accessible and retrievable for accurate reporting, verification, and interpretation. Investigational products should be manufactured according to good manufacturing practice (GMP).”
Besides that, the Clinical Trials and Biomedical Research (MMC Guidelines 009/2006) was established to guarantee the ethical principles and the code of conduct for clinical trials and research involving human subjects by the Independent Ethics Committee. 40 The activities monitored by the ethics committee which aim to reduce risk to the study subjects include (i) all clinical trials and biomedical research involving human subjects intended for discovering clinical, pharmacological, and/or pharmacodynamic as well as adverse effects of an investigational product, (ii) additional procedures such as invasive or medication above the standard care, (iii) questionnaires involving patients or their relatives, (iv) patient data outside of the investigator's professional custody, and (v) research that may include children, prisoners, and adults not capable of providing consent, particularly on permission for genetic material usage.
On the contrary, the government of Malaysia introduced four frameworks when inferring stem cells therapy, such as National Guidelines for Hemopoietic Stem Cell Therapy (2009), National Standard for Cord Blood Banking and Transplantation (2009), National Standards for Stem Cell Transplantation (2009), and Guidelines for Stem Cell Research and Therapy (2009), which oversee collection, processing, transplantation of stem cells, as well as regulate what is allowed and what is prohibited. 41,42 Notably, the Stem Cell Research and Stem Cell Therapy (MMC Guidelines 002/2009) outlined the social, religious, and ethical controversies arising from stem cell activities such as the creation, usage, and destruction of human embryonic stem cells in Malaysia. 43
The Medical Genetics and Genetic Services (MMC Guidelines 010/2006) was established to address genetic screening, prenatal diagnosis, DNA banking, DNA profiling, and medicolegal and paternity disputes. 44 This guideline safeguards the genetic profile of the individual and family, discoveries that may predict future adverse health events of an individual or family member, and the genetic profile and choices that may affect the future generation. Similarly, Guidelines on Ethical Issues in the Provision of Medical Genetics Services in Malaysia (2019) caters to genetic counseling and testing, prenatal and preimplantation diagnosis, banked DNA, and informed consent and confidentiality. 45 It covers the ethical aspects of genetic health care delivery concerning health and diseases, which ensures all the practices align with the prevailing legal, religious, and cultural beliefs.
The Malaysian Guideline on the Use of Human Biological Tissues for Research was released to cover issues related to 46 : (i) researching stored/archived human biological tissues that were collected during routine investigation/treatment, (ii) collecting biological tissues from patients undergoing routine investigation and treatment which may be used for future research, and (iii) conducting research involving a planned prospective collection of human tissues, including those for biobanking. According to the guidelines, biosamples include “organs, tissues, bodily fluid, teeth, hair, and nails; but not established cell lines. Many of the principles in this guideline could apply equally to extracted material such as DNA and RNA.” 47
However, the guidance does not cover using biosamples for medical diagnostics, disease surveillance, teaching, or stem cell applications, and therefore, archived biosamples are not governed in Malaysia. 15 In such circumstances, adopting some international governing laws, such as 48 (i) The Biobanks Act of Iceland of 2000, (ii) Swedish Biobanks in Medical Care Act of 2003, (iii) Act Relating to Biobanks of Norway 2003, (iv) Estonia Human Genes Research Act, 2000, and (v) U.K. Human Tissue Act 2004, would be an excellent standard framework for addressing such drawbacks.
The ethical issues surrounding stem cells and embryo research have been a significant factor in Malaysia. 49 Human stem cell research using adult stem cells is more ethically acceptable and less controversial. Nevertheless, legislation in Malaysia does not cover the research on stem cells, and there are no definite statutory provisions for stem cell therapy, except that practices must adhere to the Private Healthcare Facilities and Services Act 1998. Malaysian and western contemporary stem cell ethics incorporated ethical universalism and ethical relativism arguments on the permissibility of human embryonic stem cell research. 50 The ethical relativism arguments related to ethnicity, culture, religion, and country, while ethical universalism in the context of the embryo's moral status, can be based on science or what constitutes virtuous or dutiful.
Malaysia's stem cell technology is neither liberal nor tightly regulated and, therefore, hampers the effort in harmonizing global laws or policies for interoperability. Some countries have tightly regulated the technology due to their conservative perspective and remaining with liberal policies with no restrictions.
In the Southeast Asian region, Singapore is the sole country that has taken the initiative to draft a precision medicine-specific provision standard incorporating ELSI in health care and genetic data. 51 First, the Genome Institute of Singapore (GIS), funded by the Agency for Science and Technology Research (A*STAR), uses genomic sciences to improve human and public health. Second, the Personalised OMIC Lattice for Advanced Research and Improving Stratification (POLARIS) and GIS and SingHealth research to deliver better patient outcomes. Third, the Surveillance and Pharmacogenomics Initiative for Adverse Drug Reactions (SAPhIRE), in collaboration with the Biomedical Research Council, Health Sciences Authority, GIS, and the Translational Laboratory for Genetic Medicine, developed an active surveillance network for monitoring and discovery of genomic biomarkers that is predictive of specific adverse drug reactions (ADRs).
SingHealth Duke-National University Singapore Institute of Precision Medicine (PRISM) standardized precision medicine and precision health to improve patient care, focusing on diseases relevant to the Asian population. Overall, the ethics of emerging technology must become fundamental to its governance and policy development, which encourages international collaboration of gene and cell therapy projects with countries of different regulatory positions and grants some consistency.
Legal consideration in precision medicine
In general, the regulatory framework for Malaysian medical professionals is provided by three central bodies 25 : (i) the MMC is involved in the registration of medical practitioners intending to practice in the country with reasonable and acceptable standards, (ii) the Malaysian Medical Association is a representative body of the medical profession, and (iii) the MOH which regulates at the ministerial and state level. In clinical settings, the MMC ensures the highest standards of medical ethics, education, and practice in the interest of patients, the public, and the profession. The Code of Professional Conduct (2019) guides the behavior of registered medical practitioners in their clinical practices. 52,53 Meanwhile, the Good Medical Practice (2001) provides the moral and professional obligations expected from medical practitioners. 54
Furthermore, medical practices in Malaysia are governed by the Medical Act 1971 (Act 50) 55 and the Medical Regulations 1974. 56 On the July 1, 2017, the Medical (Amendment) Act 2012 (Act A1443) 56 and the Medical Regulations 2017 57 were enforced to address the current needs of medical practice and to ensure safe and quality medical care are provided to the public. Existing laws can be inferred to regulate precision medicine in Malaysia, although they are generic and does not cater for the use and applicability of genomic medicines in this country. 58 For instance, the Human Tissue Act 1974 caters for the use of parts of human bodies of deceased persons for therapeutic medical education and research purposes. 59 However, this Act only relates to cadaveric donors, whereas live donors fall within the purview of the common law. 60
On the contrary, the Biosafety Act 2007 (Act 678) 61 was established to strike a balance between promoting modern biotechnology and protecting against its potential environmental and human health risks in Malaysia. 62 As per the law, the application of genetically modified organisms (GMOs) is based on the recommendation of the Genetic Modification Advisory Committee (GMAC). 63 GMAC monitors and handles inquiries, proposals, and approvals concerning GMOs' use, release, and introduction. However, their recommendations are based purely on scientific assessments, while ethical judgments are not considered. The members of GMAC mainly comprised life scientists (i.e., molecular biology, genetics, animal, plant, environmental, food, microbiology), and ethical considerations by other experts should be included. 64
In contrast, the European Union incorporated ethical considerations into their socioeconomic concerns provisions in their national biosafety laws. 65 Similarly, Norway caters to bioethics in their biosafety laws, in which the GMO assessment must be based on scientific evidence and ethical consideration. 66
National Pharmaceutical Regulatory Agency (NPRA) took the first step toward regulating CGTPs by publishing the Malaysian Guidance Document and Guidelines for Registration of CGTPs in 2016. 67 This document outlines the concept and basic principles of CGTPs, introduces the registration framework and guidelines to be applied, and provides relevant scientific data and information. Beginning January 1, 2021, the manufacture and sale of gene and cell therapy products must be approved by the Malaysian Drug Control Authority (DCA), of which the NPRA serves as the secretariat. 46,68,69 Therefore, the Guidance Note for CGTPs Manufacturing Facility in Malaysia was established in 2021. 70 Notably, the class II CGTPs must be registered with the DCA, including combination and gene therapy products of high-risk products. 71
However, this guideline only specifies that facilities producing CGTPs must comply with GMP, and a more focused policy is deemed necessary to ensure a higher standard for creating CGTPs as it involves handling live. 28 Since CGTPs are still unregulated due to the absence of apparent laws or policies in Malaysia, there is a higher chance of ethical exploitation and medical malpractice. 42,72 Therefore, navigating through regulatory framework between countries that have well-established CGTPs frameworks would accelerate global adoption and harmonization of cell and gene therapy, as shown in Table 2. 68,73 –77
The summary of the regulatory agencies and frameworks related to gene and cell therapy in Malaysia, the United States, the European Union, Japan, Australia, and Singapore
ACB, Advisory Committee on Biologicals; ATMPs, advanced therapy medicinal products; CAT, Committee for Advanced Therapies; CBER, Center for Biologics Evaluation and Research; CGTPs, cell and gene therapy products; CHMP, Committee for Medicinal Products for Human Use; COR, comparable overseas regulators; CTGTPs, Cell, Tissue, and Gene Therapy Products; DCA, Drug Control Authority; EMA, European Medicines Agency; EU, European Union; FDA, Food and Drug Administration; HSA, Health Sciences Authority; MHLW, Ministry of Health, Labour, and Welfare; NPRA, National Pharmaceutical Regulatory Agency; OCTP, Office of Cellular and Tissue-based Products; OGTR, Office of the Gene Technology Regulator; OTAT, Office of Tissues and Advanced Therapies; PMDA, Pharmaceuticals and Medical Devices Agency; RMAT, regenerative medicine advanced therapy; TAC, Therapies Advisory Committee; TGA, Therapeutic Goods Administration; TRG, Tissue Reference Group.
Data confidentiality in precision medicine
Regarding Malaysian DNA legislation, two prevailing laws, the DNA Identification Act 2009 (Act 699) and the DNA Identification Regulations 2012 [PU. (A) 274/2012] were enacted. Act 699 tackles the establishment of a Forensic DNA Databank Malaysia (FDDM), the collecting of DNA samples, forensic DNA analysis, and the use of DNA profiles and information, 78 while DNA Identification Regulations 2012 cater authorization and consent, the procedure of collecting and storage of samples, as well as DNA profiling into the databank. 79 FDDM legally stores DNA profiles and related information for human identification in forensic investigations. 80 Under Section 7 of Act 699, access to the DNA databank is limited only to a gazetted officer, the head of the DNA databank, the deputy head, or the officers designated by the home affairs minister.
The DNA bill was first read in the Parliament of Malaysia on August 18, 2008, and was much contested. 81 Among the matters raised during the debate was that the Personal Data Protection (PDP) Act should be passed and implemented before the DNA Bill. Their primary concerns centered around collecting personal data and that the DNA databank must be organized according to data protection principles. Some worried that collecting and profiling of intimate samples (i.e., blood, semen, or any other tissue or fluid) and nonintimate samples (i.e., any hair except pubic hair, samples that are taken from or under a nail, and saliva and buccal swabs) without a PDP in place might not protect the person's privacy and liberty. Therefore, in 2000, the Malaysian government introduced a draft PDP Bill based on the European data protection standards. 82
A new proposed Bill was tabled before the Parliament of Malaysia, and in 2010, the Bill was passed as the PDP Act 2010 (Act 709). 83 –85 In the context of genetic research, when a DNA sample is analyzed and a DNA profile is created, it falls within the domain of the PDP Act.
Genetic data are classified as sensitive personal data, so it would also be subjected to stricter requirements under section 40 of the Act. Under section 40(1): “a data user shall not process any sensitive personal data of a data subject except in accordance with the following conditions: (i) the data subject has given explicit consent to the processing of the personal data, and (ii) the processing is necessary for medicinal purposes and is undertaken by either a healthcare professional or a person who in the circumstances owes a duty of confidentiality which is equivalent to that which would arise if that person were a healthcare professional.” 82
Similarly, other Asian countries also established laws that protect genetic privacy 86 : (i) China's Personal Information Security Specification (2020) and Regulation of the People's Republic of China on the Administration of Human Genetic Resources (2019); (ii) Hong Kong's Personal Data Privacy Ordinance (1996); (iii) Japan's Act on the Protection of Personal Information (2017); (iv) Philippines's Data Privacy Act (2012); (v) South Korea's Personal Information Protection Act of 2011 (2017); (vi) Singapore's Genetic Testing and Genetic Research (2005) and PDP Act (2012); and (vii) Taiwan's PDP Act (2012). Although these policies regard genetic information as sensitive and personal, there is no absolute right to confidentiality.
There is a widely held rebuttable assumption that data obtained during a therapeutic intervention will be held in confidence by the person who obtains it unless there is a reason for disclosing it. 87,88 Thus, the PDP Act has some shortfalls that need to be cleared, including the contradictions between total exclusion for research and human dignity. Furthermore, the noncommercial collection of personal data and the usage of such data by the Federal and State Governments is another discrepancy in human rights and integrity.
Genetic information can also be used for nonmedical purposes, such as in life insurance for underwriting or when applicants disclose their genetic status to pay cheaper premiums. 89 The Financial Services Act 2013 (Act 758) ensures fair, responsible, and professional business conduct in the banking and insurance industry and protects the rights and interests of financial consumers. 90 Under section 133(1): “no person who has access to any document or information relating to the affairs or account of any customer of a financial institution…shall disclose to another person any document or information relating to the affairs or account of any customer of the financial institution.” 91
The public often fears that their genetic data could be used as a discrimination point in employment and various forms of insurance, including life, health, disability, and long-term care. 89,92 Notably, a person with a complex genetic result may be denied insurance coverage or charged excessively high premiums, making many hesitant to seek testing. To cater to this issue, the Guidelines on Ethical Issues in the Provision of Medical Genetic Services in Malaysia outline some critical points. 45 Insurers should not refuse health insurance coverage or charge higher premiums based on a family history of genetic disorders. Most importantly, mandatory genetic testing for insurance purposes should not be permitted. Anyone considering genetic testing must be informed of insurance companies' potential use of that information while protecting the information's confidentiality.
Nonetheless, an Islamic medical insurance system in Malaysia, known as “takaful,” made it a prerequisite that all applicants (i.e., medical takaful) disclose a range of details. 93 The applicants are limited to revealing their personal information and medical conditions and declaring their spouse and family health history. Disclosing genetic information by takaful applicants may serve as a selection criterion in granting insurance coverage and as a determinant of the insurance premium. Notably, the policyholder with perceived genetic risk is technically discriminated to contribute more to the Participants' Risk Account, as any claim due to indemnification will be made from this fund. However, in addressing takaful companies' requirements and the issue of genetic discrimination in their underwriting process, both seem unavoidable and necessary.
At an international level, the U.S. Department of Health and Human Services issued the Health Insurance Portability and Accountability Act (HIPAA) 1996 to protect sensitive patient health information from being disclosed without the patient's consent or knowledge. 94,95 Various entities such as health care providers, health plans (insurers, health maintenance organizations), and business associates are subjected to HIPAA's privacy rules. Besides that, the Genetic Information Nondiscrimination Act (GINA) was enacted in 2008 aimed to 96 (i) prohibit group and individual health insurers from using a person's genetic information in determining eligibility or premiums, (ii) prohibit an insurer from requesting a person to undergo a genetic test, (iii) prohibit employers from using a person's genetic information in making employment decisions such as hiring, firing, and job assignments, and (iv) prohibit employers from requesting, requiring, or purchasing genetic information about persons or their family members.
Nevertheless, GINA provides no protections against genetic discrimination for life insurance, disability insurance, or long-term care insurance. 97,98 Furthermore, the law only protects individuals predisposed to certain genetic diseases without overt symptoms. Thus, complementary protection to GINA, such as the Americans with Disabilities Act in employment settings and HIPAA and the Affordable Care Act, were introduced in the context of health insurance.
Religious and social consideration in precision medicine
The public's acceptance or rejection of medical sciences is also primarily influenced by the role played by the world's major religions and their belief structures. 99 All religions react to new genomic technologies and concepts in their own way, and there is rarely a universal consensus on every issue. Malaysia is a multicultural and religio-ethnic country comprising Malays, Indians, Chinese, and other ethnicities, practicing various religions such as Islam, Christianity, Buddhism, Hinduism, and Sikhism in relative peace and harmony. 100 Religious ethics play a crucial role in Malaysian stem cell ethics and its regulation, whereby the original Guideline on Stem Cell Research and Therapy (2006) was established after consultation with the Malaysia National Fatwa Council, which stipulates research activities that are permissible and prohibited based on Islam. 50,101
Later, the guideline was revised in 2009 by including the value of other religions in Malaysia, such as Hinduism, Buddhism, Taoism, Sikhism, Catholicism, and Christianity, by approaching the Malaysian Consultative Council of Buddhism, Christianity, Hinduism, Sikhism, and Taoism (MCCBCHST).
A study conducted in a tertiary care hospital in Malaysia reported that nearly all patients and physicians reported a high prevalence of religiosity. 102 Even though religion is vital to many patients and physicians, half of them ignore it in their clinical practice due to lack of time to converse, lack of training in obtaining a religion and spirituality (R/S) history, and trouble identifying patients who want to discuss R/S issues. Hence, R/S beliefs and practices at both the patient and provider levels may expedite a greater degree of precision medicine and effective treatment. 103 Another study among USM undergraduate nursing students revealed that the population's religion, cultural, social, and behavioral determinants could encourage a more positive attitude toward stem cells in medicine. 104
From the perspective of Islam, humans do not “own” their bodies because the actual “Owner” is God, who created these bodies law. 105 Humans can still make decisions about their bodies in the capacity of God's trustees, as long as they do not infringe the Owner's instructions by exposing their bodies to unjustified risks. For example, gene manipulation is not permissible in Islam if it undermines the dignity of human subjects and does not comply with the “Syariah” law. The National Fatwa Deliberation Committee (2005) agreed that therapeutic cloning is permitted when done for medical purposes, such as generating new cells or replacing damaged organs, while being aware of the limits within Islamic law. 106 Moreover, the Mufti Department of Selangor stated that stem cells from specified sources will be used for medical treatment and research through fatwa legislation number 13. 28
Meanwhile, Christianity depends on biblical parameters about the moral status of that human subject, such as applying technology to the embryo. 107 Christians are called to love and ought to use technology to prevent disease. They should be wary of excessive technological optimism, primarily when the technology violates essential Christian values. Buddhism believes that genetic manipulation is ethically acceptable only if it releases the suffering of an individual and promotes a “life of enlightenment and compassion,” in line with the “Four Noble Truths.” 108 However, as the technologies for this therapy are imperfect, every effort must be made to ensure the patient's safety. Like other religions, Hindu values support gene editing based on its principles of beneficence (therapeutic), obligation (survival), and justice (ethics). 109 Furthermore, the application of technology must also be based on the principle of consequentialism (karma) and balance (benefits vs. risk), as the long-term effects of this technology have yet to be determined.
There are increasing concerns about the power and technicality of gene and cell therapy, such as on-target editing efficiency or incomplete editing (mosaicism) in an organism. 110 A study was conducted to identify the intention of Malaysian health care providers and patients and the predicting factors associated with adopting gene therapy. 111 The findings revealed that although the respondents perceived gene therapy as highly beneficial and acceptable from a religious perspective, they were still cautious. Despite acknowledging the moderate risks, this was reflected in their strong intentions to adopt gene therapy. Most of them perceived that gene therapy would benefit future generations by making people healthier and enhancing their quality of life. 112
However, there were worries about the consequences of the technology, safety, and long-term effects, as gene editing is poorly understood compared to many other medical procedures. Thus, when moving the technology from bench to bedside, every effort must be taken to document the spectrum of off-target effects while acknowledging the reality of a certain degree of risk.
A significant goal for gene and cell therapy is to edit somatic cells in patients suffering from inherited diseases and cancers by targeting the affected tissue. 113,114 From an ethical viewpoint, somatic gene editing is not a considerable debate, as the subjects receiving the technology can give informed consent, and the resulting modified human cells will not contribute to the human gene pool. On the contrary, germline gene editing would present unique challenges, as the germ cells or embryo will be altered and likely propagate into future generations. 115,116 Moreover, if germline editing succeeds in only some cells but not others, the embryo will be a mosaic, potentially introducing unanticipated harm. Thus, there was a call to adopt a moratorium on all clinical uses of germline editing under such circumstances. 117,118
To gauge the global acceptance of germline gene therapy, a survey was conducted among 106 countries on the governance of human germline and heritable genome editing. 119 The research categorized the usage of heritable editing for reproduction purposes, while germline editing was for nonreproduction purposes. The study showed 19 out of 106 countries (including Malaysia) and 70 out of 106 countries (including Malaysia) prohibited human germline and heritable gene editing, respectively. These data suggest an international consensus on the prohibition of heritable human gene editing that would result in a child's birth with a modified genome.
On the contrary, 11 countries, such as the United States, the U.K., and China, permit germline editing and impose strict limits on this technology. 118 For example, in the United Kingdom, human embryo research is permitted under the Human Fertilisation and Embryology Act (HFE Act) 1990, allowing research licenses involving human embryos outside the body for specified purposes. Nonetheless, the safety, efficacy, risk, and benefits must be sufficiently addressed, and the decision must be based on scientific, medical, and ethical principles.
While various gene and cell therapy strategies are being translated from the laboratory to the clinic through in vivo or ex vivo approaches, these methods have great potential to be developed into tissue-based therapy in treating genetic diseases. 120,121 However, the ethical use of such interventions, either for curative (therapy) or noncurative (enhancement) purposes, is often debated. 122,123 Gene therapy focuses on maintaining or restoring bodily organization and function, while gene enhancement involves alteration to improve average organization, appearance, health, and function. The distinction between these two interventions is unclear, as therapies and enhancements often present as a continuum. 124,125 The desire to improve endurance and performance, memory, intelligence, and appearance poses important ELSI issues that must be acknowledged to maintain bioethics principles.
The National Anti-Doping Agency of Malaysia recently reported that gene doping had infiltrated the Malaysian sports ecosystem and may pose a considerable problem as it is not easily detected. 126 Approximately 200 fitness-related genes increase red blood cell activity/delivery and enhance skeletal muscle size, strength, and endurance. 127,128 The biological techniques to introduce these genes into athletes are developing rapidly. Hence, the World Anti-Doping Agency prohibits doping as it is unethical, and all athletes should rely on their natural ability, strength, and training under equal conditions. 129
The ease of gene editing has influenced the push for designer babies. Generally, designer babies are created from an embryo selected by preimplantation genetic diagnosis or genetic modification to develop heritable, disease-free babies. 130 However, objections have been raised against gene editing due to unknown risks and safety, gene enhancement, and the belief that it is dehumanizing. Under such circumstances, there should be a substantial debate on where the line should be drawn when manipulating the genes and attributes of an individual. 131 For example, while people may be more accepting of gene editing that prevents diseases, some parents are willing to spend excessive money to obtain a child with specific traits and demonstrate a desire for perfectionism.
Often, these parents pick genes associated with characteristics such as memory, intelligence, height, or athletic ability and perform this alteration without their child's knowledge and consent. 132 Who gets to decide about interventions during a child's development? And would this result in children becoming more like commodities than precious gifts? Under such circumstances, the Assisted Reproduction (MMC Guidelines 003/2006), Malaysia clearly states that “preimplantation diagnosis to create ‘designer babies' (those with specific physical, social, or specific gender characteristics and not for the reason of avoiding serious medical illnesses), are ethically unacceptable and are prohibited.” 133
BRINGING PRECISION MEDICINE TO THE FOREFRONT OF CARE IN MALAYSIA
Currently, Malaysia has no robust national plans or large-scale research initiatives on precision medicine. Nevertheless, the pipeline for precision medicine to be fully adopted in Malaysia has been outlined, which may take about 7 years to be fully implemented, as several key areas need to be focused on. 15 Five key strategies have been proposed to make Malaysia's precision medicine initiative successful. 134 First, a clear policy agenda and strategic plan must be established through collaboration between the Academy of Sciences Malaysia and MOH, which was presented to the National Science Council. Second, the national genome sequencing projects would generate evidence that precision medicine is cost-effective, improve the outcome and quality of life, and fill the knowledge gap.
Third, strengthening information and communication technology, data science, data analytics, and artificial intelligence encourage collecting and storing large-scale datasets. Fourth, precision medicine can be affordable and accessible to everyone if sustainable funding and reimbursement systems such as health insurance schemes are available. Fifth, the quadruple helix collaboration approach between the government, academia, industry, and civil society would accelerate the precision medicine ecosystem, as shown in Fig. 1.
The quadruple helix approach to implement precision medicine in Malaysia. Precision medicine is based on six major key areas fueled by government, academia, industry, and civil society.
Advances in genetic and genomic technology have accelerated the introduction of medical genetics into the health care system in the Asia-Pacific region. 135 However, some of the current shortcomings faced include (i) the lack of awareness of cultural beliefs in genetic health care, (ii) the varying stages of socioeconomic development and educational background that lead to increased demand and misuse of genetic technologies, (iii) the role of women in society and the crisis of gender selection, (iv) the lack of preventive and care services for genetic, (v) the issue of gene ethics in medicine, and (vi) the lack of understanding of some religious practices. Tackling these challenges would allow Malaysia to reduce inequalities and ensure a more inclusive, ethical, and cost-effective medical genetics practice in the region.
Identifying the intrinsic and extrinsic ethical concerns arising from cell and gene therapy in Malaysia is also crucial (Amin, 2009). Intrinsic concerns focus on people's beliefs about what is morally acceptable and how they evaluate biotechnology products. Extrinsic concerns deal with the possible risks of different biotechnology applications, consumer rights, and patenting issues. As bioethics and medical ethics concerning gene and cell therapy in Malaysia are relatively new, public engagements and recommendations to oversee GMOs' research and clinical uses should be expanded. The National Bioethics Council (NBC) was established to advise, resolve, and manage bioethical issues in Malaysia. 136 The council members, who are bioethicists, scientists, nonscientists, policymakers, and stakeholders, are collectively entrusted with studying topics related to new technologies. The launching of NBC was to be on par with the international practices of examining, reporting, and advising on bioethics issues and ensuring that breakthroughs in health research in Malaysia are standardized. 137
There is also a considerable need for an ethics panel to consider practitioners' lack of understanding of ELSI and how they share information with their patients. 138 Under such circumstances, ethics education and training are crucial for clinicians and researchers to effectively assess and resolve the issues presented to them. 139 A survey was conducted among preservice science teachers at Malaysian Education Institutions to investigate the awareness and perception of bioethical issues. 140 The findings revealed that understanding bioethical issues among preservice science teachers was very high due to exposure to the curriculum. Moreover, the awareness level for cloning, organ donation, genetic modification, stem cells, and abortion was very high compared to gene therapy, gene screening, and euthanasia. Overall, this study suggests the importance of equipping science teachers with knowledge of bioethics, as they have an immense role in shaping society by changing students' awareness and perception of ethical issues.
Incorporating ethics education in medical schools, clinics, and hospitals would allow the practitioner to continuously update medical genetics' ethical and legal obligations. 141 A study was conducted among 11 Malaysian medical schools, comprising 6 public and 5 private institutions. 142 All except one school implemented a formal bioethics curriculum. Clinicians and lawyers taught various bioethics topics in the medical program. The most common teaching and assessment methods were lectures and attendance. The study concluded that bioethics education in Malaysia was new and limited mainly by qualified teaching staff, no established curriculum to follow, limited financial resources to hire qualified staff, and no consensus among the faculty members.
Informed consent is essential to safeguard an ethical and legal requirement for research and for the participant to understand and voluntarily confirm their willingness for the trial. 143 In Malaysia, practitioners and patients have an observable discrepancy in understanding the consent form. 144 The patients showed a lack of understanding of the consent information, while the practitioners tended to overlook the signed consent as patients fully understood the issue in question. Thus, the current initiatives of informed consent in medical genetics include consent forms' communicative and social functions. 145 Regarding communicative functions, follow-up and interactive support must be offered to the participants. Mainly, the involvement of family members would provide additional insights during decision-making. On the contrary, the social functions predominantly inform participants of associated social risks such as genetic discrimination, sample, and data sharing and emphasize the role of an ethics committee.
A guideline and an informed consent template were developed in 2012 by the USM Human Research Ethics Committee to tackle genomics studies. 146 The guidelines are divided into six chapters covering definitions, general issues, consent, sample/data storage, research withdrawal, results disclosure, and public data release. In particular, the informed consent process must assess the competence of research participants, the amount and accuracy of the information, and the participant's ability to understand the information. In addition, the process should also demonstrate participants' voluntariness and active authorization of the consent. Otherwise, genetic information may be abused by third parties such as insurers and employers (i.e., granting access during the application process), resulting in discriminatory treatment and loss of confidentiality. Under such circumstances, it is essential to explore further how the public perceives sharing their genetic information as a threat, which may hinder participation in genetic research and genetic testing in the future.
Moreover, the safety concerns associated with gene and cell therapy are not new and have been highly publicized. For instance, the tragic death of Jesse Gelsinger in late 1999 during an early trial of gene therapy highlighted the need for more focus on safety. 147 There was a lack of long-term safety and efficacy data, which must be considered and transparently conveyed to participants or families in such research before obtaining informed consent. Although advances have been made in managing acute effects, the potential for delayed adverse events remains a concern. 148 Therefore, care should be taken not to draw premature conclusions about the safety of this emerging therapy, which may impede the substantial progress seen in the field so far.
Viewing the situation globally, in the United States, President Obama introduced the Genomics and Personalized Medicine Act of 2006 to realize the promise of personalized medicine by expanding genomics research. 149,150 In 2010, the Act was reintroduced, and several initiatives were implemented. 151 For example, the Food and Drug Administration (FDA) published “Paving the Way for Personalized Medicine: FDA's Role in a New Era of Medical Product Development,” which outlined the plan to implement a regulatory framework that supported the codevelopment of companion diagnostics and therapeutics as well as genomic-based medicine. 152 Besides that, the WHO introduced the Human Genomics in Global Health Initiative to address the ethical and regulatory issues arising from genomic research and its clinical applications. 153 Overall, such initiatives at an international level can be adapted to establish a responsible, ethical, and culturally appropriate precision medicine that are legalized under the Malaysia's law.
Notably, the U.S. National Academies of Sciences, Engineering, and Medicine (NASEM) established a new comprehensive report on “Human Genome Editing: Science, Ethics, and Governance” to accommodate the issues of benefits and risk, regulation, and societal values in the application of genome-editing technologies. 154 The context of public engagement is essential to shape the ethical debate and influence the patient's choice. There are three principles recommended to guide public participation in gene editing 154 : (i) the quality of the research program, which largely depends on weighing the risks and benefits, potential policy options, and the anticipation by lay public to ask questions and suggest solutions, (ii) the legitimacy of outcome which is grounded in transparency, competency, interest, and concerns of all interested parties, and (iii) the administrative efficiency which is critical to ensure that decisions are undertaken promptly, while safeguarding against overshadowing public opinions.
Therefore, public engagement measures are built through (i) communicating ethical, regulatory, and political decisions to the maximum number of society, (ii) consulting and conveying relevant information from a maximum number of affected public to sponsors/regulatory agencies, and (iii) participating and exchanging all related information and value among a maximum number of public and policymakers through appropriate dialogue. Therefore, the NASEM committee identified seven principles that many countries, including Malaysia, could use to govern ethical human genome editing. 155
CONCLUSION AND FUTURE DIRECTIONS
Based on the discussion above, the current Malaysian bioethics and medical ethics framework cater to clinical trials, biomedical research, medical genetic services, and stem cell research/therapy. 18,156 Currently, there are no comprehensive policies and guidelines, a lack of membership diversity in ethics committees, and limited human and financial resources to tackle gene and cell therapy as part of precision medicine in the country. 157 With many ethical issues surrounding the applications, a comprehensive legal and governance framework emphasizing ELSI is crucial. The privacy framework that safeguards personal identification and genetic information should also be considered.
Integrating bioethical concerns into biosafety law would promote sustainable development. 158 For instance, a balanced inclusion of bioethical considerations in the Biosafety Act 2007 would ensure advancement in Malaysia. Bioethical issues should be addressed in the decision-making process, and the role and function of NBC should be expanded to provide advice, resolve, and manage bioethical aspects. Legal policies regarding the scope and role of ethical issues must be made clear to avoid uncertainty. There is no doubt that gene and cell therapy will continue to present intriguing challenges for 21st century scientists and ethicists. Thus, education and significant respectful discourse are required to tackle such complex ethical issues, so that Malaysia can successfully apply this modern technology in this country.
Gene/cell manipulation is also frequently portrayed as “playing God” and is influenced by the belief that no one has the right to create humans except God. 159,160 Any attempts to do so or to modify human nature will cause harm. Moreover, there is public fear that redesigning the human genome and creating humans with desired traits may turn procreation into a manufactured product. Researchers may regard genetically enhanced humans as subjects of experiments with high commercial values rather than a being. Furthermore, there is concern over “Frankenstein,” who may abuse science for their interests and be destructive to humankind.
In such a context, addressing the ethical issues may require a series of questions 161 : (i) what is the harm envisaged? (ii) what information do we have? (iii) what ethical principles should guide us? and (iv) how do we reach moral closure in decision-making? Answering these questions will potentially eliminate sweeping generalizations of modern biotechnology, allowing for a comprehensive and transparent assessment of gene editing in a clinical setting. For Malaysia to outline its guidelines on ethical gene and cell therapy, the country must consider training more genetic counselors and specific ethical training and adopting the existing international framework.
All responsible parties, such as MOH personnel, policymakers, bioethics, geneticists, lawyers, physicians, and nongovernmental organizations, should create a forum to discuss such recommendations to formulate a firm ELSI framework in Malaysia. The future of precision medicine is now and expected to transform the health care system in Malaysia and value for the individual patient, the health of the community, and the economy growth.
Footnotes
ACKNOWLEDGMENTS
V.K. was supported by the Fundamental Research Grant Scheme (203/CIPPT/6711845) during his candidature.
AUTHORs' CONTRIBUTIONS
V.K. contributed to the conception and wrote the article. K.T.D. participated in drafting the review and revising it critically for important intellectual content. All authors reviewed the final article to be submitted.
AUTHOR DISCLOSURE
No competing financial interests exist.
FUNDING INFORMATION
This work was supported by KT's grants—Ministry of Higher Education Malaysia for Fundamental Research Grant Scheme with Project Code: FRGS/1/2020/SKK0/USM/02/9 and Universiti Sains Malaysia for Research University Grant with Project Code:1001/CIPPT/8012333.