PhAMA Position on Biosimilar Medicines Ms. Leah Goodman

Contents Key Messages An Overview - Biological Medicines and their Regulatory Framework PhAMA Position and Recommendation on Biosimilars

An Overview - Biological Medicines and their Regulatory Framework

Biological Medicines: An Overview Biologics differ from generic chemical drugs with respect to their: Manufacturing processes Size and complexity Origin Composition and nature. Recombinant technology used to produce biosimilars has: Turned biologics into important therapeutic options. 1 Revolutionized the therapeutic course of intractable diseases such as cancer, 2 diabetes and rheumatoid arthritis. 1. Reichert JM. Trends Biotechnol. 2006;24:293– Mellstedt H, et al. Annals of Oncology. 2008;19:411–419.

Biosimilars vs. Generics BiosimilarsGenerics Manufacturing processComplex/multifacetedSimple/straightforward SizeLarge moleculesSmall molecules OriginManufactured from genetic material of living cell cultures or DNA technologies 1 Synthesized in a laboratory or extracted from natural sources Composition & Nature  Active ingredients are not identical to the innovator product  There is a strong relationship between the manufacturing process and the characteristics of the final product 2  Active ingredients are identical to the innovator product  The manufacturing process does not affect the final product 1.APG, Procurement and Prescribing Practices for Biologics in the UK, 29 June Schellekens H. Nat Rev Drug Discov. 2002;1:457–462.

Regulatory Framework of Biological Medicines In Malaysia, the National Pharmaceutical Control Bureau (NPCB) is responsible for granting marketing authorisations (MA) for biotechnology products. 1 Granting of MA for biosimilars is subject to strict regulatory approval, but assessments of substitution/interchangeability are not inclusive. NPCB recognised challenges posed by biosimilars for clinical practice: Safety and efficacy Pharmacovigilance Interchangeability and substitution Market competition Extrapolation of indications 1.National Pharmaceutical Control Bureau Malaysia. Guidelines on Registration of Biosimilar. 2.Suiz and Carlo. The Business Journal for the Generic Medicines Sector. 2011;8:4. Comprehensive knowledge of these challenges is crucial to ensure an appropriate place for biosimilars in the market. 2

NPCB Guideline on Interchangeability and Substitution of Biosimilars “Biosimilars are not generic products and cannot be identical to their reference products. Further, the formulations may be different and these can have profound effect on their clinical behaviour. In addition, biosimilars do not necessarily have the same indications or clinical use as the reference products. Therefore, given current science, they cannot be considered interchangeable with the reference product or products of the same class. Automatic substitution (i.e the practice by which a different product to that specified on the prescription is dispensed to the patient without the prior informed consent of the treating physician) and active substance-based prescription cannot apply to biologicals, including biosimilars. Such an approach ensures that treating physicians can make informed decisions about treatments is in the interest of patients’ safety.” 1.Mellstedt H, et al. The Challenge of Biosimilars. Annals of Oncology. 2008;19:411–419.

PhAMA Position and Recommendation on Biosimilars

Recommendation All biologic/biosimilar prescriptions should be written by brand name and not by International Non-proprietary Name (INN). A biologic or biosimilar medicine cannot be considered immediately interchangeable and therefore not automatically substituted without the knowledge and consent of the treating physician. Patients should be kept fully informed about their medication and should be consulted if changes to their treatment are made. The summary of medicinal product characteristics (SmPC) should clearly indicate the source of information contained within it, such as relevant clinical studies or that it has been derived from evidence about the originator product. Biosimilar medicines should be subject to clinical practice guidelines for the management of all relevant diseases where biosimilars exist in the treatment armamentarium. Tenders which are undertaken involving biological medicines should not seek to source a single product only. Extrapolation of indications for biosimilar products should be evaluated on a case by case basis.

1.Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community Code relating to Medicinal Products for Human Use, Article 102e. 2. National Pharmaceutical Control Bureau Malaysia. 3. Directive 2010/84/EU, Article 102e. 4. MHRA, Drug Safety Update. 5. British National Formulary, September To facilitate compliance with the patient safety, and pharmacovigilance identification and traceability requirements. To ensure there is no automatic substitution. To facilitate rigorous, appropriate and accurate post approval surveillance on the safety and efficacy of drugs. To help distinguish between biosimilar products and reference biologic medicines. All biologic/biosimilar prescriptions should be written by brand name and not by International Non-proprietary Name (INN). This recommendation is in line with that of EU legislation for Member States, 1 WHO, Australia’s drug regulatory agency, NPCB guidelines, 2-4 British National Formulary (BNF), 5 European Federation of Pharmaceutical Industries and Associations (EFPIA), and by the European Biopharmaceutical Enterprises (EBE).

1.Rumel D, et al. Revista de Saúde Pública. 2006;40(5):1–7. 2.Furberg CD, et al. Lancet. 1999;354(9185):1202– Bogaert P, et al. Biosimilar regulation: Important Considerations and Global developments. A biologic or biosimilar medicine cannot be considered immediately interchangeable and therefore not automatically substituted without the knowledge and consent of the treating physician. Drugs with similar pharmacodynamics do not necessarily ensure the same efficacy and safety even with simple molecules. 1,2 Automatic substitution can impact patient safety and post marketing surveillance. No country has declared biosimilars interchangeable with reference products. France, Germany, and Spain specifically prohibit substitution. Canada does not support it 1 and Japan avoids substitution during post-marketing surveillance. 3

Physician-patient conversations are crucial to aid a fully informed decision to take a biosimilar- International Alliance of Patient’s Organization 1 Patient could be fully aware of the advantages, disadvantages and any adverse reactions of therapeutic medicine. 1. IAPO Briefing Paper on Biological and Biosimilar Medicines, p fing%20Paper.pdf Patients should be kept fully informed about their medication and should be consulted if changes to their treatment are made. Decision to switch medications should never be based on cost alone, the prescribing physicians must employ appropriate clinical judgment based on evidence and patient specific therapeutic needs.

The summary of medicinal product characteristics (SmPC) should clearly indicate the source of information contained within it, such as relevant clinical studies or that it has been derived from evidence about the originator product. Source of information in SmPC is crucial as there have been instances where the terminology of SmPC sections for a biosimilar and its originator product were identical. It is imperative that the SmPC should clearly mention if the information was obtained from either studies investigating the biosimilar product or from evidence about the originator product.

HCPs need be educated on the integration of biosimilars into therapy, interchangeability, automatic substitution, immunogenicity and monitoring for adverse events. Educational activities will aid HCPs to promptly recognise emerging safety issues and address them through appropriate risk mitigation strategies. Biosimilar medicines should be subject to clinical practice guidelines for the management of all relevant diseases where biosimilars exist in the treatment armamentarium. PhAMA offers to assist MOH to co-design and conduct educational programs on the appropriate use of biologic medicines. PhAMA strongly encourages medical associations and Health Authorities to include a section on ‘Biosimilar Safety Considerations in Clinical Practice’ when updating their clinical practice guidelines.

Switching biological medicines between patients could be challenging as not all biological medicines may be suitable for all types of patients. Choice of medicines needs to be provided to permit physicians to customise treatment. Tenders which are undertaken involving biological medicines should not seek to source a single product only. PhAMA recommends that tenders must be conducted in a way that is consistent with the specific regulatory and pharmacovigilance requirements of biological medicines.

For regulatory approval, adequate scientific justification for extrapolation is needed in each of the claimed indications, in which, there is clinical data on the biosimilar itself. Regulatory approval should further be supported by post-authorisation monitoring and pharmacovigilance of the biosimilar. Extrapolation of indications for biosimilar products should be evaluated on a case by case basis. Appropriate scientific assessment of the comprehensive evidence (analytical, non- clinical and clinical) is needed to determine the acceptability of extrapolation depending on the type of product, nature of the indications, mechanism of action and overall weight of evidence.

Key Messages

Despite stringent regulatory framework, there appears to be marked differences in the perception of the value and use of biosimilars. PhAMA has thus made 7 recommendations to address challenges posed by biosimilars for clinical practice. The recommendations cover areas where action is needed by regulators, HTA agencies, MOH officials and healthcare professionals who prescribe or dispense these medicines. A rigorous implementation of these recommendations by all stakeholders is paramount to protect patients.

PhAMA Proposal PhAMA would welcome the opportunity for further dialogue with regulators, healthcare providers, patient groups and all other interested stakeholders to contribute to developing a sustainable framework for the use of biosimilars whilst encouraging scientific innovation, maintaining standards and patient safety. Thank You