Critical Points to Consider about Biosimilars

Biosimilars will play an important role in treating rheumatic diseases. Some predictions show that biosimilars could cost less than biologics and as such, will open the floodgates to patients who previously couldn’t afford the hefty price tag associated with biologics.

“Rheumatologists will be at the forefront of the use of biosimilar monoclonal antibodies/soluble receptors,” write the authors of a review published online March 8 in the Annals of the Rheumatic Diseases. Led by Dr. Thomas Dorner of Charite Universitatsmedizin in Germany, the review summarizes the status of biosimilars worldwide and issues not so unique to individual countries weighing similar issues from interchangeability to costs to pharmacovigilance and safety.

In recent years, 20 biosimilar products have been approved in countries throughout the world, including the first biosimilar monoclonal antibody (mAb) CT-P13 (biosimilar infliximab), which is available in more than 70 countries worldwide and approved in Europe for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease and ulcerative colitis. In February, an FDA advisory committee recommended it for approval of all indications of the reference product.

There are over 700 biosimilar products in preclinical and clinical trials. To date, 30 applications for biosimilar products have been evaluated in the European Union and 22 were approved across six classes. In the United States, the Food and Drug Administration’s Center for Drug Evaluation and Research reports that 59 proposed biosimilars for 18 different reference products are enrolled in its Biosimilar Product Development Program.

In rheumatic disease, adalimumab is leading the way with seven biosimilar molecules under study (data has been published in peer-reviewed journals or presented at scientific meetings); followed by etanercept with four; infliximab with four; and, rituximab with three. In February, the biosimilar CT-P13 was recommended for approval in the U.S. by an FDA advisory committee. 

THE REGULATORY ENVIROMENT

The authors write that regulatory agencies have described the analysis of biosimilar trials as a “paradigm shift in drug development, occurring at variable rates in different countries around the world.”[[{"type":"media","view_mode":"media_crop","fid":"46920","attributes":{"alt":"@DmitryKalinovsky/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_6991438847579","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5482","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"@DmitryKalinovsky/Shutterstock.com","typeof":"foaf:Image"}}]]

The European Medicines Agency (EMA) first developed guidelines for biosimilars in 2005. The 2013, European Public Assessment Report (EPAR), allowed CT-P13 for all indications of its reference product despite only having had conducted clinical trials in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). In terms of naming, the EMA recommends the use of trademarks.

In the U.S., there are eight FDA guidance documents on biosimilars. A draft guidance on Clinical Pharmacology Data in 2014 added a requirement for comparison between multiple lots of the biosimilar with both U.S. and former U.S.-licensed reference products. A draft guidance on Reference Product Exclusivity (2014) prevents application for and approval of a biosimilar until four years and 12 years after the initial approval of the reference product, respectively. In 2015, the FDA addressed labelling requiring biosimilars use the proper name with a four-letter suffix and include data only for the reference product. The FDA has not yet issued guidance on interchangeability.

CLINICAL TRIAL DESIGN

The authors write about the need for equivalent trial designs.

The EMA, FDA and other regulatory agencies require a pharmacokinetic/pharmacodynamics (PK/PD) study in humans and at least one clinical trial to demonstrate equivalent efficacy and immunogenicity and comparable safety of the biosimilar and its reference product.

The FDA has stated that for biosimilars that can be administered by subcutaneous or intravenous routes, the PK study should be performed using a single subcutaneous injection, since this route is considered to be more likely than intravenous administration to uncover potential differences in immunogenicity between the biosimilar and the reference product.

CHALLENGES IN CLINICAL PRACTICE

The authors highlighted several issues:

The absence of regulatory guidelines for switching between reference products and biosimilars. Most clinical trials investigating transitioning to a biosimilar have been based on only one switch. Other studies are underway to collect “real-world” data about switching treatments:  the NOR-SWITCH study and the PLANETAS study.

“Although close analytical similarity of the critical attributes of a biosimilar with its reference product  suggests that clinical differences will be unlikely, RCTs for biosimilars, which typically enroll fewer than 600 participants, are underpowered to identify unexpected rare adverse events. Thus, careful postmarketing pharmacovigilance is important for both biosimilars and reference products,” the authors wrote.

Naming issues:  It is expected that biosimilars and reference products will eventually be substituted repeatedly as will other biosimilars of the same reference product.

“There will be a need to introduce new ways to track and document which products a patient receives. For example, patient passports or similar traceability methods. Such strategies for drug monitoring and immunogenicity assessments before and after switching will facilitate mandated as well as voluntary pharmacovigilance,” the authors wrote.

COSTS

“The expense of biologic agents is a major issue. What should a biologic disease-modifying anti-rheumatic drug (bDMARD) really cost? How much shareholder value above and beyond the return of investment should society pay? What should subsequently marketed biosimilars cost given that the first has already led to a price reduction?” the authors wrote.

One study showed that patients who were switched to CT-P13 for RA in the UK, Italy, France and Germany is estimated over 5 years to offer savings of 20 to 30 percent.

“Clinicians are said to be more willing to use biosimilars if their patients are beneficiaries of the cost savings. Alternatively, if a biosimilar has no clinically meaningful difference in efficacy or safety with the reference product, then cost saving should be sufficient moral reason to promote its use in a world where medical resources are finite. The availability of biosimilars will allow patients to receive  medications that might otherwise be unaffordable to them,” the authors wrote.

References:

Thomas Dörner, Vibeke Strand, et al.

"The changing landscape of biosimilars in rheumatology,"

online March 8, 2016.

Annals of the Rheumatic Diseases

. doi:10.1136/annrheumdis-2016-209166