Regulatory requirements for the acceptance of foreign comparator products in the participants of the International Generic Drug Regulators Programme

Submitted: 4 March 2019; Revised: 25 April 2019; Accepted: 27 April 2019; Published online first: 30 April 2019

The availability of quality generic drug products plays an increasingly important role in promoting access to medicines worldwide and in helping to address rising healthcare costs. This, however, has led to significant pressures on medicines regulatory authorities charged with the review and approval of these products.

The Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP, previously International Generic Drug Regulators Programme) aims to promote greater collaboration, regulatory convergence and potential mutual reliance on respective bioequivalence assessments in the longer term. This group is composed of the following regulators/agencies: Brazilian Health Regulatory Agency (Agência Nacional de Vigilância Sanitária, ANVISA, Brazil), Federal Commission for the Protection against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios, COFEPRIS, Mexico), European Commission/European Medicines Agency (EC/EMA), Health Canada (HC), Health Sciences Authority (HSA) Singapore, National Food and Drug Surveillance Institute (Instituto Nacional de Vigilancia de Medicamentos y Alimentos, INVIMA, Colombia), South African Health Products Regulatory Authority (SAHPRA), Medsafe (New Zealand), Ministry of Food and Drug Safety (MFDS, South Korea), Pharmaceuticals and Medical Devices Agency (PMDA, Japan), Swissmedic (Switzerland), Taiwan Food and Drug Administration (TFDA), Therapeutic Goods Administration (TGA, Australia), United States Food and Drug Administration (US FDA), as well as an observer from the World Health Organization (WHO).

The acceptance of foreign comparator or reference products is one of the topics addressed in the BEWGG since it could be considered the most limiting factor for the development and regulatory assessment of generic medicines marketed globally. Generics companies commonly have to repeat bioequivalence studies with the respective local comparator products of each country or jurisdiction because regulatory agencies are either unaware if the comparator product from other countries is the same product as their own or, if this is known, are unable to use that information for reasons of confidentiality and/or legal restrictions. This results in the duplication of efforts by regulators and industry alike, as well as unnecessary risks to study subjects.

The BEWGG of IPRP published the current regulatory requirements with respect to the acceptability of foreign comparator products of oral dosage forms among the regulators/agencies that participate actively in the BEWGG [1] to identify those participants that may accept a foreign comparator product under certain conditions. The sharing of the relevant information contained in their respective regulatory guidance documents and policies is a first step towards regulatory convergence in this area.

General aspects

Brazil, Colombia, the European Union Member States, Japan, Mexico, South Korea and the US do not accept foreign comparators and accept bioequivalence studies involving only their local comparator products, i.e. comparator products sourced from within their corresponding jurisdictions. In contrast, Australia, Canada, New Zealand, Singapore, South Africa, Switzerland and Taiwan accept studies with foreign comparator products under certain conditions. Only WHO lists specific comparators from different countries for the Prequalification of Medicines and for developing generics of essential medicines.

Origin of the foreign comparator product

Most participants limit the origin of the foreign comparator to countries with a comparable regulatory system. While WHO, South Africa and Switzerland accept comparator products from a list of countries, Australia, Canada and New Zealand have not defined the countries. On the other hand, Singapore and Taiwan do not impose any restrictions relating to the comparability of regulatory systems or agreements with the originating country or jurisdiction. Instead, emphasis is placed on comparing the manufacturing sites of the foreign and local comparator products. Some jurisdictions also have requirements at the company level. Australia, Canada, Singapore, South Africa, Switzerland and Taiwan require that the foreign comparator and the local comparator have to be marketed by the same corporate entity, although Australia, New Zealand, Singapore and South Africa also accept a different corporate entity if there is a licensing arrangement between the local and the foreign companies.

Additional restrictions

Some countries have specific restrictions specific to drug substance or drug product properties which additionally govern the situations in which foreign comparator products can or cannot be used. For example, in terms of drug substance properties, Australia, Canada and Singapore do not accept foreign comparator products containing narrow therapeutic index drugs (NTIDs) or drugs that require patient monitoring in order to avoid the consequences of under- or over-treatment. Australia and Canada do not accept foreign comparators of drugs with complicated pharmacokinetics, variable or incomplete absorption or absorption window or substantial first pass metabolism. Canada also limits the acceptance of foreign comparator products to those that contain highly soluble drugs. In contrast, there are no exclusion criteria with respect to drug substance properties in New Zealand, South Africa, Switzerland and Taiwan. In terms of drug product properties, Canada only accepts foreign comparator products for immediate release formulations, while Australia accepts immediate and enteric/delayed release products and may accept a foreign comparator product for sustained release products on a case-by-case basis. On the other hand, New Zealand, Singapore, South Africa, Switzerland and Taiwan do not have restrictions based on the release profile of the drug product.

Supportive documentation

Most participants require details regarding the source of supply, batch information and the foreign innovator company. In addition, the labelling and the Certificate of Analysis (CoA) of the foreign comparator product batch employed in the bioequivalence study is commonly required. Notably, Canada requires that product samples in their original container closure systems be made available upon request. Also, in New Zealand, reduced data requirements are applied to foreign comparator products sourced from the Australian market, provided evidence of harmonisation of the comparator product between the two markets can be demonstrated. Acceptable evidence supporting harmonisation between the New Zealand and Australian innovator products includes copies of the labelling or package inserts that demonstrate co-marketing in both countries.

Comparison of comparator product characteristics

The formulations of the local and the foreign comparator product should be compared for all participants. All seven countries require a qualitative comparison of the excipient composition. For Australia, Canada and New Zealand the local and the foreign comparator product have to have the same size, weight, shape, colour, scoring and type of coating. In contrast, Taiwan only requires them to have the same size, weight and type of coating, Switzerland requires them to have only the same size and weight, and Singapore and South Africa may accept differences as long as the release type is the same. Australia, New Zealand, Switzerland and Taiwan also require some physicochemical testing such as Fourier transform infrared spectra, near infrared spectra and powder X-ray diffraction spectra. All of these participants except South Africa also require the foreign comparator employed in the bioequivalence study to have the same strength as the local one. Interestingly, Australia is the only jurisdiction that requires a quantitative analysis in sufficient batches to determine batch-to-batch variability (often two to three batches) using validated test methods. In all these seven countries, it is necessary to demonstrate that the local and the foreign comparator product have similar dissolution profiles across the physiological pH range with 12 individual units per product. However, if it can be shown that the manufacturing site of the foreign and local comparator products are the same, then comparative dissolution data are not required by Singapore and Taiwan. Similarly, in New Zealand, if the foreign comparator product is sourced from the Australian market and harmonisation between the comparator products from New Zealand and Australia has been established, then physicochemical testing, e.g. dissolution, FTIR (Fourier-transform infrared spectroscopy) and XRD (powder X-ray diffraction), is not required.

These results demonstrate that the acceptability of foreign comparator products among BEWGG participants is not harmonised. While some countries do not accept this practice, other countries are open to the possibility of accepting foreign comparator products under certain conditions. However, the requirements to demonstrate that the foreign comparator and the local comparator are the same product in these countries differ widely. Importantly, for the WHO Prequalification Programme, both the European and the US comparator products are considered to be valid comparators because they ensure ‘prescribability’, i.e. an adequate safety and efficacy profile, even if they might exhibit different bioavailability and, consequently, the generics approved based on a comparison with the US comparator may not be ‘switchable’ with the generics approved based on a comparison with the European comparator.

It is interesting to note that the criteria of the BEWGG members appear to correlate reasonably well with the market size of the jurisdiction. Those jurisdictions with a large population (more than a hundred million inhabitants) require bioequivalence studies with their local comparator and generics companies are able to conduct the studies because they are profitable with those market sizes. In contrast, those countries with a smaller market size are open to accept bioequivalence studies with foreign comparators if these appear to be the same as the local ones. In those countries with middle size, the purchasing power of the population and the availability of local manufacturers may also play a role – South Africa (53 million) may accept foreign comparators, whereas Colombia (49 million) and South Korea (51 million) do not. Similarly, Australia and Canada, with 25 and 36 million inhabitants, respectively, impose important limitations for the acceptability of the foreign comparator. In countries that are smaller and with lower purchasing power than those participating in the BEWGG, it can be expected that generic drug products would not be developed with the local comparator products because those markets are not considered profitable enough for generics companies, e.g. Zimbabwe. These countries generally align with WHO and accept studies conducted with comparators from founding International Conference on Harmonisation (ICH) countries under the assumption that they will be the same in all the ICH countries, without any additional requirements as long as this foreign comparator is marketed by the innovator company.

Accepting foreign comparator products may bring about public health benefits by increasing the availability of generic medicines and thereby reducing healthcare costs. By decreasing the number of bioequivalence studies that industry is required to perform, regulators are able to lower barriers to generic drug applications while still maintaining the integrity and standards of safe, effective and quality generic drug products available for the people within their jurisdiction. On the other hand, the acceptance of foreign comparators in bioequivalence (BE) studies does have some risk in that the product may not be the same as the local comparator and may thus bring about switchability issues. Where a jurisdiction accepts the use of a foreign comparator, they apply restrictions to control the risk associated with switchability issues. Since greater restrictions on the use of a foreign comparator may also increase barriers to market entry for generic drug products, each jurisdiction must determine the appropriate approach for their healthcare system.

Those countries that require the exclusive use of their local comparator do so to ensure ‘switchability’ of all approved generics in their markets. For countries whose regulatory systems allow them to accept foreign comparator products, the acceptability of foreign comparator products is complicated by the absence of data confirming that the foreign comparator is identical to the local one. The sharing of confidential business information such as the composition, manufacturing process and specifications of the comparator products between regulators is not allowed by the present legislation of most countries. To overcome this obstacle, the legal systems would need to be modified to allow regulatory agencies to share needed confidential information about comparator products with other regulatory agencies.

Another potential approach to enhanced acceptance of foreign comparator products through sharing of information could involve the use of an independent third party, such as WHO, who could determine the similarity of comparator products. In this scenario, it would not be necessary to require the generics company to perform any comparability tests and restrictions on the acceptance of a foreign comparator could likely be eliminated.

Overall, in the presence of barriers which inhibit the acceptance of foreign comparator products, it will continue to be necessary to perform bioequivalence studies using the local comparator, or in some cases, to conduct a battery of in vitro tests to demonstrate the similarity/identity of the local comparator product to the foreign comparator product used in a bioequivalence study.

Competing interests: None.

Provenance and peer review: Article abstracted by Dr Alfredo García Arieta, Clare Rodrigues and Christopher Crane from a published paper [1]; internally peer reviewed.

Reference
1. García Arieta A, Simon C, Lima Santos GM, Calderón Lojero IO, Rodríguez Martínez Z, Rodrigues C, et al. A survey of the regulatory requirements for the acceptance of foreign comparator products by participating regulators and organizations of the International Generic Drug Regulators Programme. J Pharm Pharm Sci. 2019;22(1):28–36.

Disclosure of Conflict of Interest Statement is available upon request.

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