Making sense of the regulatory web governing biosimilars development across APAC

In recent years the Asia-Pacific (APAC) region has represented an area of growth in the biopharmaceutical sector, with expanding drug production and development — including in the area of biosimilars. Designed to closely emulate biological products (often called reference products) whose patents have expired, biosimilars can improve patient access to treatment and lower the cost of care. However, because it is impossible to exactly replicate a biological entity, there are strict regulations that surround the approval of any biosimilars.

The European Medical Agency (EMA) was the first regulatory agency to introduce guidelines on the approval of biosimilars, setting a precedent in 2005. In many cases, those preexisting regulations served as a template for APAC countries to develop their own — leading to strong similarities in requirements for the approval of a biosimilar.

Overall, biosimilars must demonstrate high levels of comparability to the reference product in terms of chemistry, manufacturing and controls, composition, preclinical pharmacology and toxicology, efficacy and clinical studies. Because immunogenicity, or immune response to a substance, is of particular concern for biological products, it is also typical to require post-market monitoring for safety data.

Nevertheless, regardless of these broad similarities, individual countries have their own unique regulatory nuances — and this is certainly the case in the APAC region. Included here is an exploration of some of the key differences for biosimilar approval processes and requirements in major regulatory agencies in the APAC region, as compared to EMA and the U.S. Food and Drug Administration (FDA) regulatory guidelines.

China

Perhaps the most noteworthy aspect of biosimilar regulations in China is the approval pathway. Because biosimilars are meant to emulate an existing therapeutic, rather than innovating new approaches to treatment, the EMA and FDA provide an abbreviated pathway to approval. China’s National Medical Products Association (NMPA), however, requires biosimilars to be submitted through the same pathway as innovative biologics, though with an adjusted set of data requirements.¹ This means that approval may take longer than in countries that do provide a condensed pathway for biosimilars: Some estimates place standard biologic approval in China at up to two years versus close to one year in the US and Europe.

It is also important to be aware that the reference product must be approved by the NMPA prior to entering any comparative clinical studies for the biosimilar. This is in contrast to EMA and FDA policies, which allow for reference products approved by other reputable authorities as long as a bridge is established with a product that has been approved by the relevant regulatory agency.

India

In 2016, India’s Central Drugs Standard Control Organization released an updated biosimilar guidance that helped it align more closely with World Health Organization (WHO) biosimilar standards than previous regulations had. Although this move brought India’s biosimilar regulation nearer into accordance with international standards, there are areas in which requirements are not quite as stringent. For example, while EMA and FDA policies call for clinical studies with “adequate power” — or a sufficient sample size to reasonably detect any meaningful difference between the biosimilar and reference product — India only requires a sample size of at least 100 Indian patients in the test group.² As a result, sample sizes may not be large enough for high confidence in biosimilar and reference product comparability. Such differences mean that biosimilars initially approved in India may face scepticism from international regulators if brought to the global market.

Japan

In January of 2024, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) removed a requirement that all biosimilar clinical studies be conducted with Japanese subjects.³ However, sponsors must still evaluate whether ethnic factors might impact clinical trial results, such as by analysing the available evidence from the reference product. Depending on the resulting conclusions, sponsors must be prepared to either explain that there is no significant difference for the Japanese population or proceed with clinical studies involving Japanese participants.

Upon a biosimilar’s submission for market approval, the PMDA conducts site visits and meets with sponsors, in addition to reviewing submitted materials. The timeline for biosimilar approval in Japan is likely to be relatively short: Typical new drug approvals occur within twelve months, with biosimilar submissions requiring a less lengthy process. However, timelines may vary depending on the product.

Singapore

While Singapore’s Health Sciences Authority (HSA) biosimilars regulation is highly aligned with international standards — and, in fact, utilises International Council for Harmonisation forms for applications — it does have a few notable requirements. One of these is that a biosimilar product must be approved by regulatory agencies in the US, Canada, Australia, the EU or the UK before it can be submitted as a biosimilar in Singapore — otherwise it must be submitted as a new biological product. Additionally, there are two types of applications available for biosimilars: NDA-2, for the initial biosimilar approval, and NDA-3, for any subsequent variations on the biosimilar’s strength.⁴

Singapore offers an abridged approval pathway for biosimilar products. From the time of receipt, the HSA estimates a timeline of 230 business days to conduct screening and an evaluation of the application, placing this process at under one year for completion.

South Korea

Harmonised with WHO guidelines, biosimilar regulation in South Korea is relatively straightforward for sponsors familiar with international standards. South Korea’s Ministry of Food and Drug Safety (MFDS) places a particular emphasis on biosimilars that are recombinant DNA protein products, though it does note that in principle biosimilars might be any type of biological product.⁵ In general, the MFDS processes submissions relatively quickly, with approvals typically taking less than one year.

Interchangeability

Many APAC countries, including most of those named above, have no guidelines regarding biosimilar interchangeability, in which a biosimilar so closely emulates a reference product that it may be substituted for the reference product without a doctor’s approval. In the US, the requirements for achieving interchangeability are even stricter than for biosimilar approval, while in the EU member states are responsible for their own individual standards.

Preparing to enter the APAC market

The APAC region is vast, with numerous unique variations on the approach to biosimilars. As sponsors consider entering into this dynamic and growing area, it is important to carefully consider a country’s individual regulatory requirements, timing and other factors that may impact biosimilar approval. Through preparation and careful planning, biosimilar developers can create a plan that best prepares their product for success. If you would like to understand how ICON's Centre for Biosimilar Drug Development can assist, please contact us.

References:

¹Xu, Gangling, and Junzhi Wang. “The Current Status of the Biosimilars Landscape in China.” Biologicals, vol. 85, Feb. 2024, p. 101744, https://doi.org/10.1016/j.biologicals.2024.101744.

²Central Drugs Standard Control Organization. (2016). “GUIDELINES ON SIMILAR BIOLOGICS: Regulatory Requirements for Marketing Authorization in India, 2016.”

³Kuribayashi, Ryosuke, et al. “Revisions to the Requirement of the Japanese Clinical Study Data for Biosimilar Developments in Japan.” Expert Opinion on Biological Therapy, vol. 24, no. 7, July 2024, pp. 637–45, https://doi.org/10.1080/14712598.2024.2377300.

⁴“HSA | Biosimilar Product Application.” HSA, 31 Oct. 2018, https://www.hsa.gov.sg/therapeutic-products/register/guides/biosimilar-products.

⁵Ministry of Food and Drug Safety: National Institute of Food and Drug Safety Evaluation. (2022). “Biosimilar Product Evaluation Guide.”