Introduction
To develop a biosimilar you are basically copying an existing product to make your own product. Is this an easy way to have a new product on the market, in a short time frame? Are there any problems? A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized original biological medicine product, the reference product, in the European Economic Area (EEA) and/or an FDA-licensed biological product. A reference product approved in another country could be used, but will add to the the requirement to show that the reference product fulfills the requirement for being approval by FDA and/or EMA, which is not recommended, and will create problems. It does not have to be a problem making a biosimilar, but there are a number of issues that have to be solved, to prove that your proposed biosimilar is similar to the product on the market, the reference product and achieve approval from the regulatory authorities. An extensive knowledge about product characterization, process development, industrial manufacturing, regulatory and clinical trials, is required. The number of clinical trials, if any, is dependent on how well the comparability with the reference product is made.
Requirements for a Biosimilar
There are two major activities needed to bring a biosimilar to market; developing and setting up the manufacturing process and showing biochemical and clinical comparability, with the reference product. A good collaboration and contact with regulatory authorities are also crucial for success. The company developing a biosimilar has to have the required biopharmaceutical know-how, the requirements are on the same level as developing a new product or maybe even higher. For a startup company interested to go the biosimilar route, it is a must to employ extensive external help.
It is important to use a stepwise comparison with the reference product. The FDA encourages sponsors to consult with the agency, for each step in the development, to present their results and plans for the next step, for approval of the results and plans. Because of the the FDA’s present view on biosimilar it is crucial for a successful approval of the biosimilars to have good contact with the FDA. The FDA requires information demonstrating that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product.” The stepwise approach should also be used for Europe, close contact with EMA directly, and/or the report country is necessary.
The Marketing Authorization (MA) application dossier of a biosimilar medical product must provide a full quality dossier, CTD Module 3, as detailed as for current legislation with the addition of a demonstration of bio similarity to the reference medical product by using appropriate physico-chemical and in vitro biological tests, non-clinical studies and clinical studies. If the comparability studies show a relevant difference between the biosimilar and the reference product, making it unlikely that the bio similarity will be established, a stand-alone full Marketing Authorization Application should be considered.
A biosimilar could not be better than its reference product. If so it can be registered as a new product according to normal procedures. The biosimilar product can be improved after registration without the requirement to show similarity with the reference product. The regulation for changes of a commercial product applies.
Reference Product
When choosing the reference product, it is necessary to ensure that the product is registered in the European Economic Area (EEA) and/or an FDA-licensed biological approved product, preferably by both the FDA and the EMA, for the same indication and dose, at least by the EMA. If there is more than one product on the market for the same indication, one has to be chosen as the reference product. You must secure that there are no known serious adverse events and immunogenicity issues. The chosen product should be a highly purified product in order to establish bio similarity.
Establish Bio Similarity with the Reference Product
A stepwise approach is recommended for evaluation of the similarity of the biosimilar and the reference product. To be able to successfully demonstrate bio similarity the reference product has to be a well characterized highly purified product, which is the case for most biotechnology products. Before starting the development of the biosimilar, inform yourself when the agencies are willing to collaborate, before the patent protections ends or only after the protection ends for the reference product.
Manufacturing Process
A requirement is that the biosimilar have a considerably lower COGs compared to the reference product. A lower price compared to the reference product is the only way to compete for the biosimilar product and motivate the existence of the bio similar. New technology should be used to create an optimal up-to-date process, fulfilling the requirement for low COGs. A detailed specification for the biosimilar has to be set up, based on the characterization of the reference product. This specification must be the goal for the process development. The formulation of the biosimilar can be improved, using modern state-of-the-art technology, but it does not have to be identical to the reference product, as long as it does not affect potency, stability or safety. The comparison with the reference product should be made with the biosimilar product produced by the intended commercial process. This means that the manufacturing process has to be set up at commercial scale, at risk.
Manufacturing Cost, COGs
The cost for biopharmaceuticals is regarded as being high. It is based on the cost for product developed over 20 years ago. The manufacturing knowledge for biopharmaceuticals 20 years ago was limited, it was a new field, and new principles had to be developed from scratch. The process produced the product but at a high cost.
Therefore the manufacture of biosimilar is so interesting, for two reasons, first it can reduce the cost of treatment for society and the patient and secondly, more patients can be treated with the low cost biosimilar.
The biosimilar has to compete with price. Modern process development can develop a process with significant lower COGs. This especially applies for antibodies. Fifteen years ago the expression levels were in the range of 0.3 – 1 g/L, today they are in the range of 5 – 10 g/L. Having an expression level above 3 g/L gives an enormous cost reduction.
Non-Clinical Studies
In Vitro studies
To design the non-clinical program a comprehensive understanding of the reference product characteristic is required, taking into account efficacy and safety. The required number of batches analyzed depends on the complexity of the reference product, it must be sufficient to make meaningful conclusions. Any difference in the reference product caused by the age of the product should be investigated. The variability of the reference product should be established. The results will define the goal and specifications for the process development. An extensive structural and functional characterization of the reference product to define the target quality profile has to be done. The same characterization should be done for the biosimilar. The analytical methods used should be scientifically valid and suitable for their purpose. The assays should cover the pharmacological/toxicological aspects known to be of relevance for the reference and the bio similar. Since in vitro studies are more sensitive they should preferably be used to detect difference, instead of studies in animal.
The Need for In Vivo studies
All comparability aspects may not be covered in in vitro studies; therefore in vivo studies may be needed, if there is a relevant in vivo model. Any difference, like the glycosylation pattern can create a need for in vivo studies. If the biosimilar comparability studies in step one gives satisfactory results and no issues are identified in step two, an in vivo animal study is usually not necessary. However, a scientific justification is needed. Nonclinical safety pharmacology, reproductive and development toxicity and carcinogenicity studies are not required when comparability with the reference product has been established.
In Vivo Studies
If in vivo studies are regarded as necessary, the focus of the studies should be pharmacokinetic PK and/or pharmacodynamics PD and safety. The PK and PD should preferably be quantitatively compared for the reference and the bio similar.
Immunogenicity
The immunogenicity of the biosimilar should be evaluated in clinical trials and compared to the reference product. The purpose is to show if there are any potential difference between the reference and the biosimilar. Immunogenicity data should be collected, if feasible from all clinical studies, and must be followed up during the post approval phase.
Impurities
The impurities, product and process related should be characterized, quantified and preferably identified both for the reference product and for the biosimilar. The biosimilar can have a lower content of impurities, but if there are significant differences in amounts or new impurities, this has to be investigated. Additional pharmacological/toxicological studies or other studies have to be performed.
Clinical Studies
It is expected that the biosimilar manufacturing process will be optimized during process development. However, it is recommended to generate the clinical data from the intended commercial manufacturing process product, representing the quality profile of the commercialized product. It is crucial that the product used for the previous step is comparable/ similar with the product used for the clinical studies. The manufacturing process has to be developed and scaled up before comparison studies can start. Indicative studies can be done with material produce by the process under development.
The comparability studies should be performed stepwise, starting with pharmacokinetic PK and feasible pharmacodynamics PD. Next step would be clinical efficacy and safety trials to demonstrate clinical biosimilarity.
The clinical studies should be designed to show whether there are clinically meaningful differences between the reference and the biosimilar. The biosimilar should not be superior or inferior to the reference product. The PK studies should be designed to demonstrate similar PK profile for the biosimilar and the reference.
The PD makers/biomarkers should be added to the PK studies. The PD makers should be selected based on their relevance to the clinical outcome.
The PK/PD studies can be sufficient to demonstrate clinical comparability. The selected PD maker/biomarker
- Is an accepted surrogate marker, related to patient outcome
- Is relevant for the pharmacological action, clear dose-response or a concentration response is demonstrated
Efficacy Trials
If there are no surrogate makers, comparability has to be demonstrated by comparative clinical trial(s), preferably double blind.
Efficacy Endpoints
The purpose is not to demonstrate efficacy, it is already done for the reference product, but to confirm comparable clinical performance for the reference and the biosimilar. It should be shown that the chosen model/study design is relevant and sensible to detect potential differences, for efficacy and safety. Comparability specifications and margins should be pre-specified and justified. The specifications should be set up based on data from the reference product, using statistical tools and clinical and scientific data. The assays used should have the required sensitivity.
Clinical Safety
Clinical safety should be covered by the PK and/or the PD studies and also the clinical efficacy studies.
Extrapolation From One Therapeutic Indication to Another
If the reference product is registered for more than one indication, extrapolation of clinical data for the biosimilar to the other indications could be acceptable, but needs to be scientifically justified.
Pharmacovigilance
The comparability studies are probably insufficient to identify rare adverse effects. Clinical safety of biosimilar must be monitored closely on an ongoing basis during the post approval phase.
Present and Future Potential for Biosimilars
In Europe five product groups are approved by the EMA at present. But ten years ago EMA was, if not negative, at least not positive to biosimilars, but they have changed their minds. The coming two years will be crucial. Will the trend with biosimilars continue in Europe? If so, there is a possibility that the biosimilar can be approved without clinical trials, if the biochemical comparability comparisons are performed in a proper way. There was no problem in the clinical trials for the approved bio-similar, which would further reduce the cost; the clinical trials are the most expensive part of the development of a biopharmaceutical.
The situation in North America is different. The FDA is not really interested in biosimilars, they are in the same position as the EMA was ten years ago. One biosimilar is approved by the FDA, but a legal battle is still ongoing. The FDA has still not decided on how the inspections for a biosimilar manufacturing facility should be performed. Will it take the FDA ten years to come to the position Europe is at today? Hopefully not, the USA is the largest market for pharmaceuticals and is therefore important for driving the biopharmaceutical development.
Market Penetration for Biosimilars
The price for a small molecule drug goes down when the patent ends, but that does not happen for large molecules. One explanation is that the manufacturing cost is still high; the opportunity to significantly lower the price is not there. But a biosimilar can be sold at a much lower price; there are examples of price reductions of up to 80%. A biosimilar does not add a new better product on the market, but it will decrease the cost for society (needed) and give more patients the opportunity to be treated with the drug. But it requires society to be active, to require that a change to the biosimilar is done. In a country where this is made, the shift to the biosimilar can happen within a half year. However, in country where the decision is made by the people prescribing of the drug, nothing changes.
Conclusions
Developing a biosimilar is not an established way for creating a new product, but if the present trend continues in Europe it will be. In the USA it is however still an open question if/when it will be. A biosimilar is an important benefit for society; a product with a lower price than the product on the market and for the patient, more patients can be treated at a lower cost. Therefore the biosimilar is needed for the future pharmaceutical treatment, where costs will have an even higher importance than today. The benefit for the company is that the clinical efficacy has already been shown and toxicology and clinical studies for the substance have been performed. The requirement for clinical trials is reduced. However, to show similarity with the reference product is an extensive activity. The manufacturing process has to be developed and set up before evidence of similarity can be achieved, at a risk. Suitable biosimilar products are human endogenous substances, they are always needed. The owner of the reference product also has the opportunity to develop a biosimilar, with their product knowledge they can develop the biosimilar more easily. This can be done so that the biosimilar is ready to be put on the market then the patent expires. When choosing which biosimilar to develop, make sure there is an expected need for the product during the coming ten years. There is a risk that a new better product for the indication will be launched on the market, making the biosimilar of less interest for the patient and maybe also for the society.
Jan Gunnar Gustafsson is a versatile and highly accomplished Senior Executive Management Professional offering over 32 years of experience in the areas of Regulatory, Strategic Planning, Process Development, CMC, Creative Solution Development, Manufacturing, Organizational Health & Safety Management, Contract Negotiation, Quality Assurance and Project Management and regulatory in the Bio Pharmaceutical industry. He has worked with process devel-opment and comparability issues for Biosimilars.