A Look at Biosimilars

The advent of biologics has had a huge impact on the treatment of various diseases including lymphomas and will continue to do so. With the arrival of biosimilars, these types of treatments will become even more accessible to patients.

However before a biosimilar comes to market, it has to go through a development and approval process created by health authorities like the European Medicines Agency(EMA) and the U.S. Food and Drug Administration(FDA). This article gives an overview of what is entailed in bringing a biosimilar to market.

Terminology

The following list provides a list of terminology and their meanings; it may be useful to refer to this list when reading the article:

Term

Definition

“Alternative” biologic

Usually indicates the product is different from the original product. The development process of an alternative biologic is less formal than that followed for the development of a biosimilar. An alternative biologic may not have been compared in direct clinical trials with the original product. Alternative biologics will have a different name and be a different product.

Biosimilar

Copy biologic

Follow-on biologic

Biosimilars are not generics; rather they are similar but not identical to the original biologic product. A biosimilar is a biologic medical product where the active substance is either made or derived from a living organism. After the expiry of the patent of an approved biologic, a biotech company can produce a biosimilar. Biosimilars may also be referred to as copy biologics or follow-on biologics.

Pharmacodynamics (PD)

The study of the biochemical and physiological effects of drugs and the mechanisms of actions, including the correlation of their actions and effects with their chemical structure.

Pharmacokinetics (PK)

The study of the movement of drugs in the body, including the processes of absorption, distribution, localization in tissues, biotransformation (i.e., chemical alteration of the drug within the body), and excretion.

Progression-free survival (PFS)

Signifies the chance of staying free of disease progression for a group of individuals suffering from a cancer after a particular treatment. It is the percentage of individuals in the group whose disease is likely to remain stable (and not show signs of progression) after a specified duration of time. PFS rates are an indication of how effective a particular treatment is.

Response rate (RR)

Percentage of patients experiencing a complete or partial response to treatment.

Overall survival (OS)

Denotes the chances of survival for a group of individuals suffering from cancer. It represents the survival percentage of individuals in the group after a particular duration of time.

End point

What a clinical trial is trying to measure or find out; in essence, the goal of the trial. It is scientifically very important that the goals for clinical trials be selected and clearly defined in advance. Typical end points include measurements of toxicity, response rate and survival.

 

Biosimilar Development Guidelines

Biosimilars are successors to biologics that have lost their patent. Unlike simple generics, such as Aspirin which is a small chemical molecule that is chemically synthesized, biologics and biosimilars are complex structures owing to their size, structure and manufacturing process. They are developed either in yeast or bacteria resulting in a simple biologic, e.g., calcitonin, or in mammalian cells resulting in a complex biologic, e.g., Rituxan/MabThera/rituximab. When biologics are developed, this is the process that is followed:

  1. Host cells are modified to produce recombinant proteins (a manipulated form of protein generated in various ways to produce large quantities of the protein);
  2. Cells are grown under controlled conditions (fermentation);
  3. The drug substance is extracted, refolded and purified;
  4. Drug substance is formulated to the stable finished product and distributed in the form of a vial, syringe or cartridge.

Recognising the importance of ensuring that biosimilars are efficacious as well as safe and tolerable, numerous countries have developed guidelines and regulations for their development. When establishing guidelines, the usual process is for a country’s health authority to develop them. Before they are approved, outside input is requested (e.g., the pharmaceutical industry has an opportunity to review them and make suggestions for modifications) and then a final document is implemented. Patient organisation input is not typically requested. Once that process is complete, the guidelines are formalized. Figure 1 shows the countries that have guidelines for the development of biosimilars.

 

FIGURE 1

 

When a country is developing a biosimilar, the guidelines for the country in which the product will be launched are followed, e.g., if the biosimilar will only be made available in South Korea, only those guidelines are followed. If the intent is for the biosimilar to be made available elsewhere, then the development guidelines for those countries apply.

Biosimilar Approval Requirements

Approval of a biologic is by means of following a government’s regulatory pathway. Biosimilars have to demonstrate comparability with the original biologic including efficacy, safety and tolerability. Table 1 provides a comparison of the marketing authorization requirements for a generic, biosimilar and a new product.

Table 1: Comparison of marketing authorisation requirements

Generic

Biosimilar

New Product (new clinical entity)

Quality

  • “Standalone” program (i.e. the first step in which all needed quality attributes of the product are controlled)
  • Comparison with original product
  • “Standalone” program (i.e. the first step in which all needed quality attributes of the product are controlled)
  • Very comprehensive comparison with original product

“Standalone” program (i.e. the first step in which all needed quality attributes of the product are controlled)

Preclinical

No data needed

Abbreviated program; depends on complexity of molecule

Full preclinical program

Clinical

  • Bioequivalent study
  • No phase I
  • No phase II
  • No phase III
  • Phase I: PK/PD study
  • Phase II: Not needed
  • Phase III: Study in one representative indication
  • Phase I: PK/PD study
  • Phase II: Not needed
  • Phase III: Study in one
  • representative indication 
  • Risk management plan that includes pharmacovigilance activities to identify, prevent, characterise or minimise the risk of a drug
  • Phase I
  • Phase II
  • Phase III in all indications
  • Risk management plan that includes pharmacovigilance activities to identify, prevent, characterise or minimise the risk of a drug

Abbreviations: PD = pharmacodynamics; PK = pharmacokinetics

As seen in Table I, when developing a biosimilar for lymphoma for example, phase II trials are not needed and a phase III trial need only be undertaken in one representative indication, i.e., only have to show efficacy, tolerability and safety in one type of lymphoma as all required clinical trials have already been done prior to the product coming to market. Typically, by not having to undertake a phase II study and only one phase III study in one indication, there is potential for cost savings.

Development of a Biosimilar: a four-step process

The clinical program undertaken to demonstrate a biosimilar’s comparability with the original product needs to be agreed with the country’s health authorities. This includes agreement on the indication, trial design and end points to be validated. The scope of the clinical program will depend on the degree of similarity with the original product. As well, the clinical program needs to support extrapolation to nonstudied indications and interchangeability with the original product.

Table 2 outlines the development process of a biosimilar. The process comprises four steps that start with a preclinical phase, proceeding to the pharmakokinetic/pharmacodynamic phase, followed by a phase III study. Following approval of the biosimilar, postapproval trials are required to meet regulatory needs. Table 2 outlines the four-step process.

Table 2: Biosimilar development process

Average Time

Characteristics

Step 1: Preclinical

6–12 months

Abbreviated preclinical program

  • Toxicology, efficacy/safety in relevant species models

Step 2: Phase 1 (PK/PD)

9–12 months

  • Demonstration of PK/PDequivalence in a sensitive population (can be healthy volunteers)
  • Same dosing is appropriate as confirmed by bioequivalence studies

               • No phase II dose-finding studies needed

Step 3: Phase III (confirmatory)

2–4 years

  • Demonstration of similarity in terms of efficacy and safety in ONE indication, but not patient benefit per se
  • “Sensitive” primary end points may be different from those used in originator trials
  • Sufficient for extrapolation across indications, based on high degree of similarity and same mechanism of action

Step 4: Postapproval trials

Variable

Additional data to meet regulatory needs

Abbreviations: OS = overall survival; PD = pharmacodynamics; PFS = progression-free survival; PK = pharmacokinetics; RR = response rate

The original trials for the product will likely have measured all the end points noted in Step 3 in Table 2. Based on the requirements of the country’s health authorities, not all the same end points will need to be assessed. Given that the biosimilar will be very similar to the original product with the same mechanism of action, results from the phase III study are extrapolated across all indications for that drug.

In summary…

The development of biosimilars entails following the country’s health authority guidelines to ensure equivalent efficacy, tolerability and safety. Throughout the year, as new guidelines become available around the world and clinical trials are started examining biosimilars, LC will keep you informed.

 

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