Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Biosimilars in the U.S. - the long way to their first approval ***

Dr. Mayte Bewersdorff (Abschlußjahr: 2016)

Summary
Language: English
The first biosimilar approval in the United States (U.S.) has been awaited for a long time. Europe already started approving biosimilars in 2006. In contrast, in the U.S. the first biosimilar was only granted marketing authorization (MA) in 2015. This first abbreviated biologic license application (aBLA) was submitted to the FDA by Sandoz seeking licensure in the U.S. for their filgrastim going by the brand name Zarxio and can be regarded as a model case for the biosimilar approval process in the U.S. because neither guidance documents were published nor the regulatory aBLA pathway was established at the time Sandoz started their development program of Zarxio. The FDA had the opportunity to learn from this aBLA and to define and optimize their requirements for submission of an aBLA. This learning process is partly reflected in the finalized guidance documents published after the approval of the first biosimilar. Due to the ongoing learning process of the FDA while already assessing aBLAs, the publication of further guidance documents has been slowed down. There are key issues which the FDA still needs to decide on, e.g. extrapolation of data to indications of use which have not explicitly been tested in clinical trials and naming of biosimilars.
Comparing the approval process of Sandoz’ filgrastim in the U.S. with the approval process in Europe reveals that the basic situation at the beginning of the development program was similar in terms of lacking finalized guidance documents and the lack of already approved biosimilars to learn from. Both procedures were of comparable duration. The main difference was the successive implementation of the procedures. Apparently the documentation submitted in the U.S. was more extensive than the European one, most likely due to improved test methods and additional "bridging studies" demonstrating high similarity of the European approved reference product, the U.S.-licensed reference product and the proposed biosimilar. It seems as if the FDA was more thorough in assessing the provided data than the EMA. Nonetheless, both agencies basically followed the same ideas which are reflected by the updated European guidelines of 2015 and the finalized U.S. guidance documents of 2015.
Looking at the ongoing biosimilar biologic product development (BPD) programs and the aBLAs already submitted to the FDA, more biosimilar approvals can be expected in the near future in the U.S.. However, due to patent protection and patent issues it might take some time until the next biosimilars are being placed on the market in the U.S..
Analyzing the potential causes for the delay of the approval of biosimilars in the U.S. revealed that there is no "one reason". Several points have to be considered which add up to delaying the whole process. First of all, the need for an abbreviated pathway for biosimilar approval was noticed later than in other countries, e.g. in Europe, and therefore, the process of establishing the legal basis for an abbreviated pathway started later in the U.S.. The "litigation culture" in the U.S. forces the FDA to create a more solid basis for the assessment of biosimilars for prevention of being sued, supporting the cautious behavior of the FDA in publishing finalized guidelines and approving biosimilars. In addition, the following issues contribute to the delay of biosimilar approval:

• the so-called "patent dance"
• internal and external discussions about the acceptability of extrapolation of data to indications of use which have not explicitly been tested in clinical trials
• defining the requirements for interchangeability/substitution of biosimilars
• the immunogenicity potential of biosimilars which might impact the safety of the product
• the "Nonproprietary Naming of Biological Products"

Some of these issues have yet to be resolved. Additional approved aBLAs will be required until the FDA will have finally defined the assessment process for biosimilars fully. The FDA will need to publish additional guidance documents during their learning process which will clarify their view on the outstanding issues and might affect the future of biosimilars and the abbreviated biologics license pathway according to 351(k) of the PHS Act in the U.S..
Pages: 84