Cell and Gene Therapy Regulation in Malaysia: Current Pathways and International Comparison

1. INTRODUCTION

“Cell and gene therapy products (CGTPs)”, “advanced therapy medicinal products”, “regenerative medicine advanced therapy (RMAT)’’ or “advanced therapy” represent an important advancement in medical science, providing promising therapeutic solutions for diseases previously considered incurable [1–4]. CGTPs are a diverse group of products that may originate from cells, tissues, or genes. They differ from traditional pharmaceuticals mainly because of the manipulation of living cells, the administration of genetically modified cells, and the expression of genes of interest in the human body [5,6]. As the discipline continues to evolve, regulatory frameworks must adapt to manage the scientific and clinical complexities while ensuring patient safety, treatment efficacy, and timely access [7–11].

In Malaysia, the regulation of CGTPs has increased in significance due to the worldwide progress in the field and the rising demand for innovative therapies. In response, the Malaysian Guidance Document and Guidelines for CGTPs were introduced in 2016, establishing the requirements for quality, safety, and efficacy [12,13]. This led to the initiation of mandatory product registration in January 2021, with full regulatory enforcement starting in January 2025 [14]. Notably, Malaysia’s regulatory framework is also influenced by international standards. Although Malaysia holds the status of observer, as opposed to a member in the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use as of February 2025, it is working towards aligning its regulatory framework in reference to those of established authorities, such as United States (US), European Union (EU), and Japan [15,16]. The US, EU, and Japan are the founding country members of the ICH.

However, despite these developments, challenges persist in balancing the approval of CGTP while maintaining strong regulatory oversight, particularly in adapting international regulatory frameworks to the local context [11,17,18]. Hence, this article aims to evaluate Malaysia’s regulatory framework for CGTPs, focusing on expedited review pathways such as priority review and the facilitated registration pathway. It further conducts a comparative analysis with regulatory systems in the US, EU, and Japan to identify structural differences and shared practices. The goal is to assess how Malaysia’s evolving regulatory approach fits within the global landscape and to highlight opportunities for potential alignment and enhancement.

2. METHODS

3. RESULTS

3.3. Oversight of CGTPs in Malaysia

The regulation of CGTPs has progressed through several milestones. In 2012, a technical working group was established, which led to the publication of guidance documents for CGTP registration in 2016 [25]. Furthermore, in 2017, Directive Bil 6/2017 introduced a voluntary registration process, in contrast to mandatory registration which was initially planned for January 2021 [12]. Directive Bil 19/2020, issued in 2020, allowed for transitional registration mechanisms, enabling CGTPs marketed prior to the full enforcement of regulations in 2021 to remain available under certain conditions [14].

This transition period, which extends from 2021 to 2024, aims to improve industry readiness while maintaining regulatory oversight, with the target for full compliance set for January 1, 2025[12,14,25]. During the transitional period, CGTPs marketed prior to 2021 may continue limited sales through a two-stage manual screening process. Stage 1 involves basic documentation, such as product information and evidence of safety, while Stage 2 requires more robust data, including completed nonclinical studies and ongoing early-phase clinical trials. Specifically, these mechanisms aim to prevent disruptions to patient access while encouraging the industry to prepare for full compliance [14]. Figure 1 below illustrates the regulation timeline for CGTPs in Malaysia.

Figure 1. A chronology on the CGTP Regulation Timeline summarized from NPRA directives. [Click here to view]

Malaysia has introduced several expedited pathways (which will be explained further below), but current utilization for CGTPs remains limited. However, despite all efforts in facilitating CGTP registration, up to May 2025, only one CGTP product succeeded in gaining market access in Malaysia—for instance, Zolgensma, manufactured by Novartis Gene Therapies, Inc., Durham, US. Zolgensma, which is a gene therapy indicated for Spinal Muscular Atrophy (SMA), has been approved since February 2024. Notably, Zolgensma has been designated as an orphan drug and evaluated via the priority review pathway in Malaysia [26]. In its country of origin, the US, it has been approved since May 2019, followed by approval in the EU and Japan in March 2020 [26–29]. Apart from Zolgensma, no other CGTPs have been approved via the conditional or facilitated registration pathways to date.

4. EXPEDITED REGULATORY PATHWAYS AND ORPHAN DRUG DESIGNATION IN US, EU, AND JAPAN

The expedited regulatory pathways in the US, EU, and Japan share common goals of facilitating faster access to innovative therapies while balancing safety and efficacy. The US has multiple pathways, including RMAT, fast track, breakthrough therapy, priority review, and accelerated approval, providing different levels of support depending on the available data [50,51]. The European Union Priority Medicines (EU’s PRIME) scheme and accelerated assessment prioritize early engagement and regulatory support, while Japan’s SAKIGAKE designation fosters early innovation and conditional approval mechanisms for regenerative medicines [52–56]. Moreover, orphan drug incentives across all regions provide financial and regulatory benefits to support drug development for rare diseases [57–60]. The eligibility criteria and key benefits of each program in the US, the EU, and Japan are as described in Tables 3, 4, and 5, respectively.

Table 3. Eligibility criteria and key benefits for each program in US.

Source: US Food and Drug Administration [50,51,59].

Table 4. Eligibility criteria and key benefits for each program in EU.

Source: European Medicine Agency [52,53,57,58,62]

Table 5. Eligibility criteria and key benefits for each program in Japan.

Source: Japan Ministry of Health, Labour and Welfare [55,56,61,63,68].

5. DISCUSSION

The discussion now shifts from reporting regulatory pathways to analyzing their alignment and divergence with international practices, as well as evaluating Malaysia’s position in facilitating access to advanced therapies.

However, while there might be similarities between these pathways and those in other ICH countries (i.e., the US, the EU, and Japan), the FRP is unique to Malaysia. Unlike expedited pathways in the US (e.g., RMAT) or Japan (e.g., SAKIGAKE), which emphasize early access based on limited clinical data, Malaysia’s FRP accelerates market entry by leveraging prior approvals from recognized reference authorities, conserving regulatory resources, and focusing internal review efforts on higher-risk products [30]. The list of eligible reference authorities has been expanded beyond the original scope of just the US and EU, to include those recognized by the WHO, JAs from ASEAN member states, and other reference countries accepted by the DCA. Consequently, this demonstrates Malaysia’s move toward broader regulatory harmonization. Hence, PRH should take this opportunity to make use of the program, which will eventually lead to faster market access in Malaysia.

The priority review program in Malaysia is parallel to the priority review in the US and Japan, and it includes an accelerated assessment in the EU. All pathways reduce assessment timelines to 120 working days, 6 and 9 months, and 150 days as opposed to 245 working days, 10 and 12 months, and 210 days for standard reviews, respectively [2,33,50,53,61]. Specifically, in Malaysia and the US, eligibility criteria for serious or life-threatening diseases are prioritized, although Malaysia additionally considers local context as a criterion, e.g., local manufacturing site [33,50]. Unlike the US, which mandates superiority over existing therapies, Malaysia’s and the EU’s frameworks emphasize the absence of treatment alternatives [33,50,53]. Compared to Japan’s approach, it only limits priority review to orphan drugs or significant improvements in clinical care [2,61]. On the other hand, Malaysia’s approach aligns with global trends in expediting critical therapies, but is broader in scope as it incorporates domestic health priorities. Malaysia would benefit from more stringent prioritization criteria to optimize resource allocation. Additionally, Malaysia would have a strengthened system by implementing greater transparency in review outcomes (e.g., the number of products granted priority review and their outcomes, or the incorporation of regulatory pathway approval status in product technical assessment summaries), which are elements increasingly standard in mature regulatory systems. The differences associated with the pathways are tabulated in Table 6 below.

Table 6. Comparison of priority review pathways.

Source: US Food and Drug Administration, [50] European Medicine Agency, [53] Japan Ministry of Health, Labour and Welfare, [56, 61, 63, 68] National Pharmaceutical Regulatory Agency, Ministry of Health, Malaysia [33].

The conditional registration pathway, which accepts Phase II clinical trials for review in Malaysia, shares considerable similarities to the EU’s conditional marketing authorization and the US’s accelerated assessment designation [31,50,62]. All accept surrogate or intermediate endpoints under conditions of unmet need and require post-marketing commitments. Moreover, as the guideline for conditional registration in Malaysia was developed in reference to the guideline in the EU, it is not unexpected that there are many similarities to the pathway in the EU. Both Malaysia and the EU require a product to be for a serious or life-threatening target disease, for a limited orphan patient population, and with no alternative treatment options at the point of submission [31,62]. Furthermore, all programs require a post-marketing study for confirmation of efficacy and safety [2,31,51,61,62]. The validity of the conditional approval is 1 year in the EU, while in Malaysia, it is 2 years [31,53]. In the US, accelerated approval does not carry a defined validity period. However, it is contingent upon the timely completion of post-marketing confirmatory trials. Approval may be revoked if these trials fail to confirm clinical benefit, if the product is deemed unsafe or ineffective, or if the sponsor does not fulfill post-approval obligations. Additionally, misleading promotional activities may also warrant withdrawal [50]. In Japan, the pathway is only applicable to regenerative medicine products [63]. These comparisons indicate Malaysia’s alignment with global conditional approval practices, while also highlighting areas for ongoing regulatory refinement. Table 7 below tabulates the differences regarding the conditional registration pathways.

Table 7. Comparison of conditional registration pathways.

Source: US Food and Drug Administration, [50] European Medicine Agency, [62] Japan Ministry of Health, Labour and Welfare, [61, 63, 68] National Pharmaceutical Regulatory Agency, Ministry of Health, Malaysia [31].

The orphan drug designation systems in Malaysia, the US, the EU, and Japan share a common objective of promoting treatment, including diagnosis, for rare and serious diseases, albeit having differences in eligibility thresholds and the breadth of incentives offered. In particular, the definition of rare diseases, ranging from fewer than 1 in 4,000 in Malaysia to fewer than 200,000 people in the US, was based on the prevalence of the countries [45,46,59,64]. Moreover, extensive support was provided in the US, EU, and Japan, including tax benefits, user fee exemptions, regulatory guidance, and market exclusivity of up to 10 years [58,59,63–67]. Additionally, Japan further extends its support through financial subsidies and priority review specifically for orphan drugs [68]. Both the EU and Japan add regulatory support, which is an important tool in increasing the likelihood of registration approval in the respective countries. It is also worth noting that the US, EU, and Japan work closely on the issues related to orphan medicines [64–66,68]. However, Malaysia’s mechanism of orphan drugs remains modest, offering possible GMP inspection fee waivers, reduced data requirements, and priority review. Unlike other systems, Malaysia incorporates approval from the national expert committee, highlighting its emphasis on localized evaluation [45,46]. In summary, the differences mentioned reflect varying levels of regulatory maturity and strategic priorities in addressing rare disease treatment access. The comparison regarding the orphan drug designation in the US, EU, Japan, and Malaysia is as per Table 8 below.

Table 8. Comparison for orphan drug designation.

Source: US Food and Drug Administration, [59, 64] European Medicine Agency, [57, 58] Japan Ministry of Health, Labour and Welfare, [68] National Pharmaceutical Regulatory Agency, Ministry of Health, Malaysia [46, 47].

In relation to the early engagement strategy, Malaysia’s Pre-Submission Meeting (PSM) is a voluntary consultation service that serves as an avenue for applicants to clarify regulatory or technical issues [69]. Although it is not tied to any pathways, it echoes the supportive functions of the US Breakthrough Therapy (or RMAT for Regenerative Medicines), the EU’s PRIME, and Japan’s Sakigake Designation [50,52,55,63,70,71]. These international pathways, however, include formalized processes and regulatory assignment of an FDA senior manager, a Committee for Medicinal Products for Human Use rapporteur, or PMDA concierge, consequently providing structured guidance [50–52,55,69]. Malaysia’s PSM, though helpful, lacks similar strategic integration into product development timelines, representing an area for potential enhancement [69].

6. LESSONS FROM INTERNATIONAL CGTP IMPLEMENTATION

The regulatory experiences of advanced jurisdictions, namely the US FDA, EMA, and PMDA, offer valuable lessons on the challenges of implementing expedited pathways for CGTPs. Nevertheless, while these frameworks highlighted the advantage of faster access to novel therapies, they also come with trade-offs related to regulatory rigor, post-approval monitoring, and the reliability of clinical evidence [72]. One of the critical issues worth focusing on is the conditional regulatory pathway, whereby surrogate endpoints are often used in early-phase trials to predict clinical benefit in place of traditional, long-term efficacy and safety data [73].

Additionally, the use of surrogate endpoints has been associated with a lack of ability to predict meaningful clinical outcomes consistently [73]. Surrogate endpoints also have limited validity in the context of long-term safety and efficacy [73]. This is exemplified by the product, Kymriah, which was approved based on surrogate markers like B-cell aplasia, but its sustained efficacy beyond short-term remission remains under post-marketing evaluation [73].

In Japan, conditional approval of HeartSheet based on limited early-stage data raised concerns about the reliability of non-randomized trials in predicting therapeutic benefit. Although post-marketing studies were required, their implementation was delayed, reflecting a common challenge in CGTP approvals where early patient access often occurs before comprehensive real-world validation [74]. Furthermore, products such as Temcell and reclassified therapies like JACE have demonstrated impediments in ensuring long-term safety oversight and in adapting established treatments to fit within accelerated regulatory pathways.

Additionally, manufacturing and quality control challenges in CGTPs also complicate accelerated approvals [75]. Therapies granted breakthrough or Sakigake designations have encountered difficulties maintaining their quality control, also known as Chemistry, Manufacturing, and Controls standards [75]. This is exemplified by the need to resolve issues with the manufacturing process, including product stability, short half-life, and analytical validation [71]. This post-approval commitments require specifications and test-methods revision, which further demands specialized regulatory and scientific capacity [71].

Beyond scientific uncertainty, accelerated approvals transfer a significant burden of evidence generation to the post-marketing phase, which requires high levels of workforce and financial commitment from sponsors [70,73]. Between 2018 and 2022, up to 70% of FDA approvals required confirmatory Phase III trials. Many of the trials were delayed, inconclusive, or failed to verify anticipated benefits [73]. Moreover, this burden is anticipated to be particularly heavy for CGTPs due to the complex manufacturing processes and individualized treatment protocols. Resource strain is experienced by sponsors, marketing authorization holders, and regulatory agencies, particularly due to the obligation to meet statutory review timelines while managing increased volumes of post-market follow-up commitment [17,70,76].

Collectively, the risks mentioned underscore the need for Malaysia and other emerging regulators to balance the speed of access with scientific caution, ensuring the benefits are not limited to only faster patient access, but more importantly, are safe, transparent, and evidence-driven. Additionally, this should be considered without overextending regulatory personnel or compromising staff sustainability.

However, while the above were derived from the international regulatory models, the regulatory adaptation must also be considered within the context of the ASEAN level. There is a glaring challenge regarding regulatory harmonization in ASEAN. In particular, each country in the ASEAN region has its own framework with specific guidelines (if any) and requirements for CGTPs, making it challenging to create a unified regulatory approach for CGTPs. This includes differences in regulating development plans, clinical research, market approval, and ultimately patient access [15,76–79].

Additionally, a significant inequality in infrastructure, including laboratories and experienced technical personnel among ASEAN member states, creates a barrier for harmonization. These are exemplified by differences in stem cell processing facilities, technical expertise, and resources available for CGTPs regulation and oversight [78,80].

It has also been reported that ethical considerations, particularly in the use of autologous cells and innovative practices, require careful regulation to ensure safety and efficacy. Differences in ethical standards, such as views on gene editing, stem cell use, and human tissue sourcing, pose challenges in regional harmonization. Some countries are more restrictive than others, leading to fragmented policies and regulatory uncertainty for developers [81].

From a domestic standpoint, Malaysia faces unique implementation challenges, despite having introduced the CGTP regulatory framework in 2016. Hence, it has been highlighted that there is a significant gap in the nation’s regenerative medicine ecosystem, including the lack of clear clinical and manufacturing standards and ethical controversies [82]. Additionally, there is institutional fragmentation between regulatory, research, and health service bodies. This is particularly evident with the use of embryonic stem cells [82]. Apart from this, lack of funds, specialized equipment, and skilled personnel contribute to the challenge in CGTPs development [82]. Overall, this may inhibit or delay the complete optimization of the expedited pathways that are currently in place in Malaysia.

7. FUTURE RECOMMENDATION

In light of the challenges previously mentioned, Malaysia should approach the development of its own CGTP regulatory framework with strategic caution and incremental steps. As opposed to immediate replication of CGTP-specific, fast-track programs like the FDA’s RMAT or Japan’s conditional and time-limited designation, Malaysia could begin by establishing a conditional approval mechanism tied to post-marketing obligations. It draws from the strengths and learning from the limitations of established systems. Early regulatory collaboration with mature agencies, the use of shared scientific assessments, and the adoption of risk-based evaluation models can help reduce the review burden while maintaining quality. Moreover, the introduction of a national CGTP registry and active surveillance infrastructure would be essential to track real-world outcomes and fulfill post-approval commitments. By focusing on validation of surrogate endpoints, harmonized standards, and transparency in regulatory expectations, Malaysia can build a robust, agile, and trusted system that facilitates innovation without compromising patient safety or clinical credibility. Over time, with accumulated regulatory experience and industry feedback, Malaysia may consider introducing a formalized expedited pathway for CGTPS, tailored to local health system needs, resource constraints, and pharmacovigilance capacity.

8. CONCLUSION

In summary, Malaysia has established a range of regulatory pathways that align with international standards while addressing local requirements. The regulatory oversight of CGTP is evolving in response to scientific advancement, providing a structured framework for its regulation. Nevertheless, despite CGTP regulations being in place since 2021, only one product, Zolgensma, has been successfully registered to date, a considerably lower number compared to other biologics [25]. Further investigation is warranted to understand the factors limiting CGTP approvals in Malaysia and, consequently, their availability to patients. CGTPs offer the potential to eliminate or repair disease-causing cells, providing curative approaches that address unmet medical needs and enable highly personalized precision medicine [83].

Unlike the US and Japan, which offer specific programs like RMAT designation and conditional or time-limited approvals for CGTPs, Malaysia currently lacks a dedicated program for these therapies. However, applicants can utilize existing pathways that offer various benefits and considerations to streamline the approval process. Therefore, enhancing and expanding these mechanisms could improve Malaysia’s capacity to support the safe and efficient development of CGTPs, ultimately enhancing patient access to these advanced treatments.

9. ACKNOWLEDGMENTS

The authors thank the Director General of Health Malaysia for his permission to publish this article. The authors also thank all past and present colleagues from within their work organization for valuable information, some of which contributed to the writing of this review article.

10. AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work. All the authors are eligible to be an author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.

11. FINANCIAL SUPPORT

This research article was financially supported by Universiti Teknologi MARA and Institute of Postgraduate Studies UiTM.

12. CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

13. ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

14. PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not necessarily represent those of the publisher, the editors, or the reviewers. This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

15. USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY

The authors declare that they have not used Artificial Intelligence (AI) tools for writing and editing of the manuscript, and no images were manipulated using AI.

16. DISCLAIMER

The views expressed in this article are the personal views of the authors. They may not be understood or quoted as being made on behalf of or reflecting the position of the Ministry of Health, DCA, or NPRA.

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