Extrapolation of a biosimilar to indications for which it was not tested during the clinical trial program is common practice in Europe. Many of the currently available biosimilars were approved in every indication of the originator after testing in a single indication. For the recently approved biosimilar mAbs Remsima™ (Celltrion) and Inflectra™ (Hospira), approval was granted for all indications of the originator Remicade® (infliximab, Janssen) after a phase I trial in ankylosing spondylitis and a phase III trial in rheumatoid arthritis. Extrapolated indications include ulcerative colitis, Crohn’s disease, psoriatic arthritis, and plaque psoriasis [26, 27]. According to the EMA guidelines, extrapolation of biosimilar data to other indications of the originator is allowed, provided the mechanism of action is the same in each indication and/or adequate scientific justification can be provided based on the totality of evidence, including experience gained with the reference product and good clinical efficacy and safety data for the biosimilar . The precise mechanism of action for trastuzumab is unknown. Several putative mechanisms of action for trastuzumab have been identified, and it may be that any combination of these mechanisms results in the antibody’s efficacy. It is also likely that these mechanisms may contribute differently for each indication of trastuzumab .
Indication extrapolation forms the basis of the biosimilar concept, and without it there would be minimal financial benefit associated with biosimilars . Current opinion regarding extrapolation of indications for biosimilar mAbs holds that if the clinical efficacy and immunogenicity testing are done in the most sensitive patient population, it would be appropriate to extrapolate to other indications of the reference antibody . For HER2-positive breast cancer, this would mean clinical testing of a biosimilar trastuzumab in the adjuvant or neoadjuvant setting, with extrapolation to metastatic breast cancer. The converse, a biosimilar tested in the metastatic setting extrapolated to early breast cancer, would not be acceptable. As discussed above, the metastatic setting does not allow for appropriate evaluation of immunogenicity signals because many patients with metastatic breast cancer are immune compromised. Extrapolating a biosimilar trastuzumab tested in metastatic breast cancer to early breast cancer means an increased risk of unpredictable immune responses that could reduce efficacy and increase adverse events. A trial in the neoadjuvant setting is highly recommended in order to justify the use of biosimilar trastuzumab in the adjuvant setting.
All biologic manufacturers must submit a pharmacovigilance plan as part of the marketing authorization application. This plan comprises pre- and post-authorization immunogenicity testing, a risk management plan based on safety issues identified during the clinical trials, and post-marketing safety commitments such as targeted questionnaires, phase IV studies, and specialized follow-up for long-term use [9, 31]. The goal of this plan is to identify any product-associated safety risks not observed during clinical testing and provide a framework to rapidly report and manage such incidences.
Central to the pharmacovigilance plan is the need to be able to accurately trace which medicines a patient is given. Many medicines are prescribed by international nonproprietary name (INN), which provides information regarding the composition and type of drug. For biologics and biosimilars, the situation is more complicated. Like generics, biosimilars are given the same INN as the originator . While generics are identical to their originators, and in many cases can be used interchangeably, biosimilars are not. When tracking the adverse events and other safety concerns associated with a biosimilar or biologic, it is of utmost importance that the appropriate drug is identified. Thus, prescription by brand name is recommended by several regulatory agencies within Europe [33, 34] and by the EMA. Because of this, in 2013, the summary of product characteristics, or label, of two biologic products was altered to include the statement “in order to improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file” [35, 36]. It is expected that this statement will be added to other biologic labels in the future, including Herceptin’s.
The contents of the Herceptin label are of interest with regard to biosimilar trastuzumab, because biosimilars currently receive very similar labels to those of their originators . The label for a biosimilar product may not identify that it is a biosimilar, what clinical studies have been done to validate its comparability, or which indications are extrapolated. This is worrisome, as it is essential that, when administering any drug to a patient, a clinician have as much information as possible about that. Information on comparability trial data and extrapolation can be found in a biosimilar medicine’s European Public Assessment Report. However, this is difficult to access and interpret, and many community physicians are not fully aware of the information contained in this document. The label for each drug is the primary source of information for the practicing clinician and should be as clear and complete as possible. Because of this, we recommend the label for any approved biosimilar trastuzumab be altered to identify that the product is a biosimilar. Importantly, the clinical trial data to justify comparability and extrapolation should be included. The document should also be updated with results of the post-approval pharmacovigilance activities once this information is available .
Interchangeability, substitution, and switching
Interchangeability has been an issue of serious concern for biosimilars since the approval of the first biosimilar medicines nearly a decade ago. Because generic medicines are therapeutically equivalent to their originators, they are often considered interchangeable with the originators. Because biosimilars are not therapeutically equivalent to their originators, many physicians feel strongly that biosimilars should not be considered interchangeable. Others argue that interchangeability is essential to the incorporation of biosimilars into clinical practice and is an obvious consequence of the biosimilarity exercise . Currently, each country in the European Union (EU) is allowed to decide individually which medicines are interchangeable.
Interchangeability becomes an issue when the traceability of a biologic product is compromised through automatic substitution or switching. When products are interchangeable, the patient may receive either the biosimilar or the originator, regardless of what the physician has prescribed and recorded. If the patient later develops an adverse reaction to the drug, the physician may incorrectly attribute the source because of this automatic substitution. It is also possible that the patient may be switched back and forth between the biosimilar and the originator, either due to poor record keeping as a result of automatic substitution or because the drugs are considered interchangeable. Switching between two similar biologic drugs increases the risk of anti-drug antibodies, which can lead to adverse immunologic reactions and decreased drug efficacy. Because the patient has received multiple drugs, the origin of these adverse events cannot be traced.
There is no EU-wide policy on automatic substitution. Automatic substitution is regulated at the national level and varies by country . Currently no country has passed legislation allowing this practice with biologics, and many have specifically prohibited it. We agree with this action, as we feel that automatic substitution and switching with biosimilars are risky behaviors that preclude successful pharmacovigilance activities. A biosimilar trastuzumab will never be therapeutically equivalent to the originator, and so these medicines should not be considered interchangeable. Because trastuzumab is used to prolong survival in patients with a fatal disease, it is irresponsible to take risks that might impair the efficacy and safety of the patients’ treatment.