Can Phase III Biosimilar Studies be Eliminated?

History repeats itself, and all indications are that biosimilars are, in meaningful ways, following a similar path to small-molecule generics. Many in the biopharmaceutical realm would likely dispute the comparison as biologics are considerably more complex, and demonstrating comparability is quite challenging.

However, similar arguments were made in the late 1960s when the FDA developed the abbreviated new drug application for the approval of generic drugs. In 1984, the Drug Price Competition and Patent Term Restoration Act, commonly known as Hatch-Waxman, facilitated approval of generic versions of brand-name drugs released after 1962 without repeating efficacy and safety studies.

Unsurprisingly, this move was not popular among originator drug companies, and they argued vehemently, although unsuccessfully, that there would be widespread drug safety issues and patients’ lives would be jeopardized.

In the end, many originators in the small molecule space began marketing generic versions of their brand-name drugs after patent expiration, albeit at lower price points and with lower profit margins.

When the Biologics Price Competition and Innovation Act (BPCIA) of 2009 was signed into law in March of 2010, creating the framework for biosimilars, the arguments were very similar.

Biologics Are Different

While the arguments made by small molecule drug innovators in the 1960s and biologics innovators in the early 2000s were similar, the position of innovator biopharmaceutical companies was stronger. The structures of biological drugs are not fixed in the same way chemically synthesized compounds structures are. Additionally, the manufacturing process controls, reagents, and other inputs essential for biopharmaceuticals’ successful and safe production are more complex.

The reality is, even as large numbers of biologics began making their way to the market twenty to thirty years ago, critical quality attributes of many molecules were not well understood.

However, just as it took a bit of time for generic small-molecule drugs to gain a foothold, the same has been true for biosimilars. Today, biosimilars are gaining momentum and market share.

Over the last two decades, ProtaGene has supported more than 80 biosimilar programs. First-generation programs included Filgrastim, EPO, and Insulin, later flanked by the first mAbs like Adalimumab, Trastuzumab, and finally turning to immune checkpoint mAbs or biospecifics. Some of our colleagues still remember how partly unreal yet overly satisfying it felt to hold the first biosimilar drug pack in their hands.

20 Years of Biosimilar Development, 20 Years of Progress


Twenty years ago, we knew very little about biosimilars, specifically, how to best analyze and characterize molecules. Analytical technologies have come a long way in 20 years, as has the experience and holistic knowledge of biologic molecules. Additionally, legislative frameworks and regulatory guidances were created and have matured.

You merely have to reverse engineer the chemical structure for small molecule generics, completely replicating the innovator’s product. When the structure is the same, you can be confident that the product will perform the same. However, biologics do not work this way.

When working with biologics, you have to determine which characteristics deliver the needed therapeutic performance and safety profiles. When biosimilar development started 20 years ago, the analytics programs were massive. We were trying to fully characterize every aspect of the molecule because the industry and regulators lacked confidence regarding the specific characteristics driving the desired mechanisms of action. These early analytical programs were extensive, time-consuming, and costly.

Today, we are much more confident in our understanding of these molecules. Biosimilars analytics and characterization programs are now much more manageable, faster, and more cost-effective. This progress, coupled with process development and manufacturing process understanding, is truly helping to advance the field.  


Are Phase III Biosimilars Studies Still Needed?

Leading global regulators and industry are collaborating to conclude whether current characterization, analytical capabilities, and biologics understanding are now strong enough to support the elimination of phase III, comparative efficacy, studies.

While the FDA and EMA remain undecided on the issue, the UK’s MHRA has concluded that clinical comparability should always include pharmacodynamic markers if available but has determined that a comparative efficacy trial may not be necessary if sound scientific rationale supports the elimination of the study.

We agree with the MHRA’s position. At least speaking for the ProtaGene organization, we are confident that our characterization capabilities and expertise are robust enough to support the elimination of phase III in many cases.

These studies cost a great deal. If the product’s critical quality attributes are well-characterized and well-understood, and the phase I trial confirms the product’s safety, we have found that little additional knowledge is gained from phase III trials.

Phase III studies add costs and lengthen the time to market, delaying patients’ access to needed therapeutics.

Leveraging 20 Years of Biosimilar Development Experience

Being involved since the formation of the biosimilars market, ProtaGene has amassed a great deal of experience and expertise. We have made significant investments to prepare for the pending biopharmaceutical patent cliff driving the next wave of biosimilars market growth. Contact us if we can help support your biosimilars development program.

About the Author

André Abts, PhD

André Abts, PhD, is the Vice President of Project Management CMC at ProtaGene. He is a CMC expert with over eight years of experience leading the implementation, optimization, and harmonization of project management processes across the organization. Dr. Abts manages NBE and biosimilar projects of different stages, from early development to Phase III and market approval under GMP. He also plays a key role in collaborating with international pharmaceutical clients and authoring regulatory documentation for health authorities. Dr. Abts joined Protagen Protein Services GmbH in 2014, where he served as a Project Manager of Biotherapeutics and later as the Head of Project Management of Biologics.

Dr. Abts holds a PhD in Biochemistry and a Diploma in Chemistry from Heinrich-Heine-University Düsseldorf, where he engaged in protein and peptide research in the field of antibiotics and antimicrobial peptides at the Institute for Biochemistry.

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