to innovator biologics, which may accelerate their development. For instance, choice of their dose and biomarkers in both nonclinical and clinical studies is simpler, and prior knowledge from the innovator biologic may reduce the scale/duration of clinical trials and safety monitoring focused on known side effects of the target pathway.
1.4 Differences Between Biosimilars and Generic Medicines
Significant differences exist between biologic medicines including innovator biologics, biosimilars, and biobetters compared with chemically synthesized or isolated small molecule drugs (SMDs) and their generics. Biologics and biosimilars are in a different league to their chemical pre‐predecessors in terms of molecular complexity and natural variability.
Table 1.3 Pivotal differences between biologics and small molecule drugs.
| Biologics | Small molecule drugs (SMDs) |
|---|---|
| Large/complex molecules or mixtures of these molecules | Well‐defined chemical structures |
| Product is the process: >1000 process steps | Manufactured by chemical synthesis: specific agents are used in an ordered/sequential manner |
| Living processes that are very sensitive to minor changes in manufacturing: may alter the product and its function (efficacy, safety) | Well‐defined chemical synthesis or isolation: subject to lower batch‐to‐batch variability |
| Product quality, purity, and function are ensured by “stable” or “consistent” manufacturing | Each individual component of the finished drug product is identified and quantified |
| Unwanted immune reactions are common | Unwanted immune reactions are rare |
First and foremost, biologics are produced in living cells or organisms and are not chemically synthesized. Many of the other factors that hinder the full acceptance of biosimilars stem from these critical differences in the properties of biologics and SMDs. A summary of the pivotal differences between biologics and SMDs is provided in Table 1.3. Pharmacists and doctors need to keep these key differences in mind when having conversations about biosimilar medicines.
1.5 Interchangeability, Switchability, and Substitution
1.5.1 Interchangeability
Interchangeability is defined as the medical practice of changing one medicine for another to achieve the same clinical effect in a given clinical setting and patient, on the initiative of, or with the prescriber's agreement. An interchangeable product is a biosimilar that produces the same clinical outcome in any given patient. Demonstration of interchangeability presents many challenges.32
In the United States, registration of a biosimilar does not imply interchangeability and another class of biosimilars, “interchangeable biosimilars” have been introduced into the regulatory framework. To meet this interchangeability designation, a sponsor must demonstrate that the biosimilar produces the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of switching between the biosimilar and reference product is not greater than the risk of maintaining the patient on the reference product. No biosimilar has been granted interchangeability status so far.
1.5.2 Switchability
Switching, on the other hand, is a decision by the physician to exchange one medicine for another with the same therapeutic intent in a given patient. Alternation also refers to switching.33 Another term in this context is non‐medical switching (NMS) referring to when a patient whose current therapy is effective and well‐tolerated is switched between therapies, such as an innovator biologic to its biosimilar for an economical, formulary, or other nonmedical reasons, i.e. for reasons other than the patient's health and safety.34 Generally, NMS may be initiated by a hospital pharmacist, based on the local formulary, or the insurance company providing health insurance in consultation with the patient and the physician. The Biologics Prescribers Collaborative (BPC), representing specialist/general physician prescribers, and Alliance for Patient Access (AfPA) have developed NMS principles and guidelines.35
Shared decision‐making between physicians, pharmacists, and patients is crucial for successful switching.36 Patients' attitudes and level of satisfaction with switching to a biosimilar is related to being provided with necessary information about their health.37 A comprehensive review concluded that evidence gaps around efficacy and safety of switching still exist.38
1.5.3 Substitution
Substitution refers to dispensing one medicine instead of another equivalent/interchangeable medicine by the pharmacist without consulting the prescriber.
In some jurisdictions/countries, interchangeability and switching are only permitted or recommended in some patients/conditions and at different treatment periods (for example, initiating therapy versus continuation of therapy).39 Switch comes with challenges, so there needs to be clear local and national biosimilar substitution and switching policies and switch management strategies are important.40 Pharmacists should play a pivotal role in patient empowerment as well as raising awareness of biosimilars among physicians and patients and reducing scepticism about the safety of biosimilars.
Key challenges for the integration of biosimilars into routine biologic therapy include questions around interchangeability, switching, and automatic substitution. Additional switch studies and drug registries may enhance our understanding of the safety and effectiveness of switching and a key hurdle to broader adoption of biosimilars is lack of interchangeability with reference biologics.41
Chapter 7 deals with interchangeability principles and evidence.
1.6 Other Clinical Considerations with Biosimilars
1.6.1 Indication Extrapolation
For innovator biologics, efficacy and safety must be demonstrated separately for each clinical indication. In contrast, biosimilar clinical trials are not required for all indications approved for the innovator biologic. Indication extrapolation is defined as approval of biosimilars for all indications of the innovator product even though the biosimilar may not have been studied in all indications.42 The molecular similarity is the key guiding principle for extrapolation to multiple indications; it is an important concept in biosimilar development and is permitted by regulatory agencies, provided it is scientifically justified.43
1.6.2 Nocebo Effect
The nocebo effect is defined as a negative treatment effect that is induced by a patient's expectations that are unrelated to the pharmacologic actions of a medicine.44 In any switching study, the subsequent biologic prescribed (like a biosimilar) is perceived to exert a lower therapeutic benefit due to this nocebo effect. The attitudes of doctors, patients, and payers are therefore crucial for the full acceptance of biosimilars because of the nocebo effect.45
1.6.3 Immunogenicity Reactions
An
