The importance of interchangeability in the procurement of medications: Biosimilar case

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1 The importance of interchangeability in the procurement of medications: Biosimilar case ALIMS Congres, Kragujevac, November 6, 2015 Prof. Borut Štrukelj, PhD

2 Brief CV Current position: professor, Pharmaceutical biotechnology, University of Ljubljana, Faculty of Pharmacy Visiting professor: Duquesne University, Pittsburgh, USA Former expert: EMA, Biotech Working Party (BWP) ; European Pharmacopoeia, Biologicals; Disclosure: occasionally lecturer sponsored by Janssen, Pfizer, Abbot, Abbvie, Alkaloid, Eli Lilly, Sandoz

3 Biologicals at a glance First drugs: 1982 (recombinant human growth hormone, recombinant insulins) More than 220 products, marketed worldwide App. 250 products are in development Since year 2002, first patents of biologicals expired

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5 Production of biologicals is a complex biotechnological process: Expression system Upstream processing Downstream processing formulation + Host+ vector with gene Cell line, MCB, WCB Biological drug substance Purified drug substance) Biological drug product Selection of gene, vector and host Optimization of production conditions Development of biofermentation Optimization and scale up Isolation and purification Identification and characterization (In-process analysis)

6 Biological medicines are made in living organisms: process directs the product! From relatively simple case to.. Process: Gene information, cloning Vector selection Host selection (bacteria, yeast, mammal cells) Expression conditions Purification Formulation

7 The most advanced technological proces: mab

8 PRODUCTION, PURIFICATION AND CHARACTERIZATION OF BIOLOGICALS- Toolbox of complex processes A) Production and purification (production by living host cells, removal of product-related, host-related and process-related impurities) B) Characterizaton (3-D structure, glycosylation sites, isoform profile) and physico-chemical properties (UV, CD, IR, NMR, HPLC, peptide mapping, sugar mapping, SDS-PAGE, IEF, X-ray, mass spectrometry)

9 Proteins vs SCE: complexity Epoetin Aspirin Size Structure Stability Glycosylation, acylation, etc. Denaturation, Aggregation, Degradation, Oxidation,...

10 C) Stability (oxidation, truncated forms, hydrolysis, dimerization, aggregation) D) Immunogenicity (nature of the protein, impurities, formulation, route of administration, dose and regime) Production Quality Purification Biological activity Efficacy Formulation Handling Safety

11 IMMUNOGENICITY Factors that might trigger immunogenic reaction: - sequence variation - type of protein - glycosylation - host cells - contaminants - process-related impurities - formulation -handling and storage

12 Based on the above data, REGULATORY AUTHORITIES (EMA, FDA) recognised that the market approval process to generic drugs can not be applied to biosimilars! Due to complex structure, production and characterisation is is very unlikely that a biosimilar is identical to the original biologic medicine!

13 Prerequisites for the SCE generic marketing authorization: Time Patent expiry Registration of generics: If reveal identical structure, potency in pharmaceutical form, may obtain the MA after: Small chemical entity Bioequivalence study Without any clinical study! Based on the file of innovative reference drug

14 Small chemical entities innovative generic Due to probably different structure, different expression system and probably different formulation, within biological drugs GENERICS can not exist: BIOLOGICALS innovative biosimilar generic

15 The occurence and clinical consequence of immunogenicity in humans remains unpredictable The immunogenicity profile of biologicals and biosimilars can only come from laborous clinical trials and robust post-marketing programs In 2012, EMA launced a guideline related to mabs immunogenicity risk: Companies requesting mabs registrations should develop Risk Management Plan to guarantee not only risk identification and characterization, but also risk minimizing, monitoring and mitigation startegies for post-marketing surveillance

16 Assesment of similarity:biosimialar comparability tests : A comprehensive series of comparability tests and studies.these tests must demonstrate that a biosimilar exhibits comparable quality, safety and efficacy to the reference medicine. complex process + clinical studies! According to SANDOZ, the cost of developing a generic SCE is around 2-3 million Eur, whereas biosimilars have been estimated to cost around million Eur

17 Interchangeability Most generics are considered to be structurally identical and therapeutically equivalent=interchangeable with their reference products Contrary, biosimilars are similar to their reference products, they are not structurally or clinically identical, therefore automatic substitution from biologicals to biosimilars and vice versa (!) is not recommended (delayed side effects- traceability) Interchangeability: the reference product can be substituted for another that is expected to achieve the same clinical effect and in any patient on the initiative, or with the agreement of the prescriber. Substitution: Practice of dispensing one medicine instead of another drug at the pharmacy level without consulting the prescriber. patient may potentially receive a different brand every time their medicine is dispensed!

18 Intercangeability, cont Interchangeability of biosimilars or biologicals can be problematic due to: 1) A lack ot traceability in the case of adverse event 2) Confusion in tracking the cause of delayed adverse event. Biologicals are complex proteins that my initiate immunogenic adverse reactions that may occur several months after treatment. With switching, a patient may receive several different products prior to immunogenic reactions are detected. Many of health professional decisionmakers do not recommend that patients are switched back and forth between a biosimilar and the reference medicinal product

19 Regulatory view of interchangeability U.S.-FDA Europe- EMA WHO The FDA can designate a biosimilar as an interchangeable biologic when the following criteria are met: 1) The biologic product is biosimilar to the reference biologic product and 2) It can be expected to produce the same clinical results as the reference product in any given patient 3) For a biological product that is administered more than once to a patient, the risk in terms of safety or diminished efficacy of switching between the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. Decisions on substitution are made at national level: UK and Belgium recommend prescribing by brand name Spain, Germany and France prohibit automatic substitution Ireland, Poland, Slovenia and Portugal: no clear position The WHO does not define standards on interchangeability for biologic medicines. It should be defined by the national authorities

20 EPO and pure red cell aplasia (PRCA) case

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23 % of ADA after 50 weeks of treatment is similar between infliximab and CT-P13: app 30% patients (spondylitis) or 50% of patients (arthritis) developed antibodies against the medicine!

24 LACK OF CLINICAL DATA!

25 Indication extrapolation When a reference medicine is approved for use in more than one therapeutic indication, a biosimilar may not be required to demonstrate efficacy in all indications. When a biosimilar has been shown to have comparable performance in a most sensitive patient population, it may then be approved in some or all of the indications approved for the reference product, without the need for further clinical comparability trials. For extrapolation to be acceptable, the medicine must have the same mechanism of action in each indication and extrapolation is only approved by regulatory authorities on a case by case basis, taking into account the justification provided. Examples (sensitive patient populations that are immuno compromized): - early versus meastatic breast cancer, - patients with chronic inflammatory diseases with or without chemical immunosupresors

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27 Novel group of biologicals: NON-COMPARABLE BIOLOGICS! A new group of biologicals that: -have not been directly compared and analyzed against an already licensed reference biotherapeutic product (RBP); - and have not been approved via a regulatory pathway that is in alignment with World Health Organization Similar Biotherapeutic Product guidelines that ensure quality, safety, and efficacy (EMA, FDA)

28 Isoelectric focusing of different erhytropoietins from China, India, Russia and Argentina, comared with the standard (EPREX) Standard EPO

29 Conclusions 1. Immunogenicity is one of the most specific and severe adverse effects that might occur in treatment with biologicals and biosimilars 2. Detailed pharmacovigilance and traceability plans shoud be prepared for eash biological and biosimilar. Traceability by using solely INN is not a satisfactory criterium! 3. From the safety point of view automatic interchangeability is not recommended for biologicals and biosimilars 4. As the biosimilar market expands and biosimilars become more complex, it is necessary to clarify the prescribing regulations