First monoclonal antibody biosimilars: tackling the challenge of substitution

The global biologics market—which is forecast to be worth $250 billion in 2020 (i.e. 18% of the overall pharmaceutical market)¹—is currently undergoing a profound upheaval following its opening-up to the biosimilars competition (copies of off-patent biologics)². After losing a certain number of European and American patents related to biologics such as EPO (erythropoietins), G-CSF (Granulocyte-Colony Stimulating Factors), and GH (Growth Hormones) over the past decade, patents related to leading and costly monoclonal antibodies (mAbs) are now disappearing—e.g. Remicade (infliximab), rituximab (Mabthera), bevacizumab (Avastin), etanercept (Enbrel), or adalimumab (Humira) used in oncology, for inflammatory, rheumatic, chronic, or skin diseases. This current situation now gives a new momentum to this market³. Healthcare payers are, thus, eagerly awaiting the arrival of such a competition in the highly innovating mAbs sector in order to drive down drug prices and increase the patients’ access to these medicines. However, as for biosimilars already on the market, healthcare institutions and professionals must wonder whether or not the mAb biosimilar can be substituted for the mAb originator at the pharmacy level (when the mAb originator was prescribed). The stakeholders are currently wondering the following: does substituting biosimilars for the originators (or vice versa) increase the safety risks—particularly the immunogenicity risk—or reduce efficacy at a higher proportion than what would be expected with repeated administrations of the originators? Which medical and economic criteria should be taken into account to compare branded products and biosimilars with a view to a potential tender?

The first mAb biosimilar to be approved in Europe and elsewhere was the infliximab biosimilar (Inflectra and Remsima), which originator is Remicade. In October 2013, after the European Medicines Agency (EMA) gave a positive opinion for infliximab biosimilars, the European Commission granted a marketing authorization (MA) for these two biosimilars in the various therapeutic indications that are authorized for Remicade (i.e. indications in gastroenterology, rheumatology, and dermatology). As for previously approved biosimilars, the two aforementioned European institutions did not make a stand on the issues of substitution, and with good reason, as answering these questions does not fall within their areas of expertise and is the sole responsibility of EU Member States⁴. Nevertheless, governments, national or local authorities in various EU countries only made recommendations with respect to whether or not they should authorize the substitution between biologics, but did not set any national legal frameworks for these practices to date. In most European countries, the health authorities all distinguish two cases in their recommendations: substituting the biosimilar for the originator for naive patients or substituting the biosimilar for the originator for patients that were previously treated with the branded product. The majority of competent authorities recommend the substitution only for naive patients but, to this day, only France enshrined this principle in law. However, no decree implementing this measure was yet published, making this French law not applicable today.

As these biologics are mainly hospital prescription products and in view of the lack of stance of governments and national institutions on substitution for biosimilars, hospitals and healthcare structures logically took up these major issues. Even if building a consensus on substitution practices among physicians, pharmacists, and administrative departments in health facilities seems quite difficult, the recent experience of the Assistance-Publique Hôpitaux de Paris (AP-HP)—that includes 37 French public hospitals—in this area shows that it is, however, possible.

The AP-HP is the largest public hospital group in Europe, with 22,000 beds; it cares for 12 million patients annually. The Committee on Medicinal Products (COMED) of AP-HP—in charge of listing the medicines on the hospital drug formulary or making a decision on whether drugs and therapeutic equivalents should enter into a competition—recently met the challenge of assessing the infliximab biosimilars marketed in the EU from a medical point of view and had to position itself on the interchangeability and substitution issues of biosimilars within the hospitals of the AP-HP. In 2015, the COMED decided that infliximab biosimilars and their originator (Remicade, corresponding to a 42-million-Euro expense per year for AP-HP) could be considered as therapeutically equivalent and, thus, could be authorized to participate in the same tender. By reaching this conclusion, the COMED followed a rigorous decision-making process made up of several steps, which we shall detail here.

In early 2015, the COMED consulted AP-HP physicians working in hospitals for adults and pediatric hospitals specializing in therapeutic areas corresponding to the indications of infliximab: gastroenterology (Crohn’s disease and ulcerative colitis); rheumatology (rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis); dermatology (psoriasis); and hospital pharmacists. The COMED presented to the experts the policy it had applied since 2009 with G-CSF and EPO biosimilars (i.e. the recognition of a therapeutic equivalence between biosimilars and originators and the possibility of substituting a biosimilar for the originator). The EMA’s scientific approach and requirements for pharmaceutical firms to get MA for mAbs biosimilars were also clearly explained to these experts (in comparison with Remicade in a comprehensive set of physicochemical and biological assays to determine whether the products were “highly similar”, demonstrations of pharmacokinetic and pharmacodynamics similarity and also by therapeutic equivalence, clinical efficacy, and safety trials on the most sensitive patient population—here in the population of patients with rheumatoid arthritis and ankylosing spondylitis)⁵. Finally, on the basis of several arguments, the experts felt that there was no reason to question the initial COMED policy for biosimilars:

• As a European agency, they consider that the clinical data provided by laboratories demonstrate some therapeutic equivalence between the two infliximab biosimilars and the originator (2-year data without switches and 1-year data with switches in ankylosing spondylitis and rheumatoid arthritis).

• They believe that there is sufficient experience in using infliximab biosimilars in Europe (countries such as Portugal and some Eastern Europe countries where the Remicade patent expired several years ago).

• They mention that the risk management plan for infliximab biosimilars was strengthened compared to Remicade, which can ensure effective monitoring of the efficacy and safety in using these treatments, whether in cases of switch or not (post-marketing studies required by EMA consist in open-label clinical trial with long-term follow-up and registries both for rheumatismal and inflammatory bowel diseases⁶).

• They note that immunogenicity data of biosimilars provided by laboratories would not suggest any difference between the originator and the biosimilar, either in terms of appearance of neutralizing antibodies or in terms of clinical impact of seroconversion. The experts also stressed that this finding was also true in the case of switch, as shown by some recent observational studies in patients with rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease^7–10.

• They also felt that there might be medical and organizational difficulties related to the listing of several infliximab products on the hospital drug formulary, and support the limitation of their number to better control the switch between infliximab products.

• The various experts highlight that the potential savings generated by this competition between infliximab products would economically be very positive for the AP-HP. This is shown by the results of a budget impact analysis that was presented to them¹¹.

In addition to its decision, the COMED made two recommendations:

• A vigorous post-approval surveillance (full traceability) of these products should be implemented in AP-HP following the tender.

• Physicians should be encouraged to take part in the registries that will be implemented by the medical disciplines concerned in the AP-HP.

The tender related to infliximab products in AP-HP was actually only implemented for naive patients, as the current French law does not allow the switch from branded biologics to biosimilars for “pre-treated” patients. An infliximab biosimilar finally won the tender that resulted in an estimated 45% discount of the price, equivalent to an estimated €6-million gain per year for AP-HP¹². On top of that, the re-negotiation of the branded infliximab price generated more than €1-million savings for the institution.

It is interesting to compare this price discount obtained by AP-HP in 2015 to that obtained in Norway where it reached 69% in the same year. Today, the four Norwegian regions recommend switching Remicade with its biosimilars, with the assumption that a biosimilar is indeed substitutable for its originator¹³. It can be noted that the National Institute for Health and Care Excellence (NICE)’s position is more moderate on this issue, as it determines this switch to the implementation of a biological and clinical monitoring in patients before and after the switch in the UK. For the NICE, the ongoing data collected has to be regularly reviewed by the medical team as a part of a risk management strategy¹⁴.

The US and the EU currently absorb most of the cost burden for biologics. This makes them simultaneously the most attractive places of opportunities for biosimilar manufacturers and the most critical markets for innovating manufacturers to protect their reference products. As it was the first to introduce scientific and regulatory requirements for the approval of biosimilars in 2004, the EU has emerged as a testing ground for biosimilars. EU and US biosimilar regulatory frameworks are very similar (same quality and scientific requirements in demonstrating the biosimilarity of a therapeutic protein to a reference product). Unlike the European legislator who did not mandate the EMA to rule on the question of substitution, the US legislator mandated the FDA to rule on the “interchangeability” issue (i.e. the substitution in the European sense) at a federal level. For now, two types of follow-on biologics can emerge from the US pathway: (i) biosimilars—same terminology as in Europe, corresponding to the same scientific and regulatory requirements to be authorized; (ii) and interchangeables—i.e. biosimilars that can safely be substituted for the originators—that meet higher regulatory standards¹⁵. However, the FDA has not yet clarified the level of evidence required for a product to get the interchangeable designation. At the beginning of 2016, the US is currently lagging behind the EU in the field of biosimilars, and only one biosimilar (not interchangeable, i.e. not pharmaceutically substitutable) was commercialized in the US (Zarxio, which is a G-CSF Neupogen biosimilar)¹⁶. It can also be noted that the FDA arthritis advisory committee recently voted 21–3 in favor of full approval for biosimilar infliximab, and that a final decision from FDA is pending.

At a time when the biosimilar market is just beginning to take shape in the EU and is in the early stages of development in the US, answering the questions of substitution for biosimilars is of particular importance. For now, as the AP-HP experience shows, a local or regional consensus-based decision-making process involving both physicians and hospital pharmacists and a balanced multi-criteria assessment on biosimilars is an original way to encourage their use. Without this impetus provided by hospitals and healthcare facilities, there are concerns that the biosimilar market shall not develop and that the enormous savings expected from biosimilars shall not be forthcoming. In order for biosimilars to keep their promises, hospitals and decentralized structures shall have to define the conditions and the rules of a possible substitution between branded biologics and biosimilars.

François Bocquet and Pascal Paubel
Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cité, Paris, France
Health Law Institute, Inserm, UMR S 1145, Paris Descartes University, Sorbonne Paris Cité, Paris, France
General Agency of Equipment and Health Products (AGEPS), Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
[email protected]

Transparency

Declaration of financial/other relationships

The authors report no conflicts of interest. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of funding

No sources of funding were used to conduct this study.

Acknowledgements

The authors are grateful to I. Fusier and A.L. Cordonnier for the organization of the expert group meeting on infliximab biosimilars in AP-HP and their advices.