Optimizing The Clinical Efficacy And Safety Of Biological Medicines And Their Biosimilars Within Available Resources In Europe

Allocati, Eleonora (2023). Optimizing The Clinical Efficacy And Safety Of Biological Medicines And Their Biosimilars Within Available Resources In Europe. PhD thesis The Open University.


Introduction: Biological medicines contain active principles made by large and complex molecular structures, produced or extracted from a biological source. Biosimilars offer significant opportunities to reduce the price of biological medicines especially in an area of spiralling healthcare expenditure. Given the complexity of these medicines, their role in the management of many diseases, and their high price, there is the need to promote their appropriate use and develop tools and policies to increase access to high quality and affordable medicines.

Aims: With a multidisciplinary approach, I took into account different facets this topic.
1. Analysis of the development and marketing authorisation of biosimilars in the EU to explore how the regulatory framework affects biosimilar clinical development, policies and uptake.
2. Analysis of the evidence supporting the switch between originator and biosimilars and the switch among biosimilars, in chronic clinical conditions.
3. Development and testing of an innovative analytical technique to monitor the appropriate use of biological medicines in order to maximise patient outcomes.
4. Development of education and training programmes for healthcare professionals regarding biological medicines and biosimilars in collaboration with local health authorities.

Methods: I applied a combination of different methodologies, tailored to each different aim.
1. Analysis of pivotal clinical trials of EU approved biosimilars that compare their efficacy and safety to originators.
2. Series of systematic reviews that evaluate efficacy and safety of switching between biologics and their biosimilars of insulin analogues and anti-TNFs. Identification of studies through systematic searches on Medline, EMBASE, and The Cochrane Library. Update of anti-TNFs review (2022) to retrieve studies on switching among biosimilars.
3. Measurement of serum concentrations of therapeutic antibodies and anti-drug antibodies using the innovative Surface Plasmon Resonance-based immunoassay.
4. Definition of training objectives and modalities of educational sessions on biological medicines. Identification of clinical areas where these medicines are commonly used. Development of key metrics of prescription performance used as starting point for the course content.

Main results:
1. Up to April 2022, I retrieved 68 biosimilars approved in the EU, corresponding to 18 active principles. The comparability exercise and subsequent approval of the majority of them is based on one or more pivotal phase III trials comparing their clinical efficacy to the originators. Often trials adopted an equivalence design, while insulin analogue biosimilars approval based on non-inferiority trial design. Two third of these trials included data on immunogenicity. The requirement for showing similarity in terms of clinical efficacy and safety provides a robust demonstration of comparable clinical outcomes.
2. I retrieved 22 studies addressing the insulin review questions. Three randomised controlled trials, on insulin glargine, collected evidence on equivalent efficacy, safety and immunogenicity when switching to biosimilar. Data on switching between different analogues, or from analogues to human insulins are very limited (one RCT).
Studies comparing switching from originators to biosimilars of anti-TNF (infliximab, adalimumab, etanercept) in chronic inflammatory diseases are many and consistent. I included 32 records, corresponding to three systematic reviews, 14RCTs, 8 OLEs and three cohort studies. Substantial amount of evidence from RCTs is available for IFX and ADMB, versus one RCT of ETN. All these studies suggest switching is safe and effective. With regards of switching among biosimilars, I included 19 clinical studies: 11 cohort studies and 8 single-arm studies: none of these studies highlights significant concerns on switching between biosimilars.
3. The study involved 76 patients receiving infliximab for IBD. Concentration of biological drug and anti-drug-antibodies in each sample determined by SPR in triplicate by two researchers with different experience. Measurements with both ELISA and SPR indicated very similar IFX serum concentrations, with differences of ADA. All the sera showing ADA by ELISA also showed ADA by SPR. 8 patients showed ADA only with SPR: these ADA had significantly faster dissociation rate constants than those detectable by both methods. Measurement of IFX and ADA can support informed decisions for a more rational management of biological therapies.
4. Education programme was replied four times with 30-40 participants each. There was a case-mix of specialties: gastroenterologists, dermatologists, rheumatologists but also oncologists, internal medicine physicians and general practitioners. The majority was confident in prescribing biosimilars in naïve patients, with some restraint to switching. All the participants were in favour of better integration of the gained experience with different specialities.

Conclusions: Altogether, the different strategies exploited in my project could support a clinical decision-making based on a more rational use of biological medicines, with benefits for both the patient’s outcome and the health budgets.

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