Challenges and advances in biotech drug regulation

Hannah Blake interviews Mark Richardson

Richardson Associates Regulatory Affairs Ltd

Mark Richardson shares his views on the regulatory landscape, with regards to the biotech industry, and how important it is for pharma to have a good relationship with their regulatory team starting with product development through to distribution and marketing.

Ahead of Management Forum’s Biotechnology for the non biotechnologist event, we speak with independent regulatory affairs consultant, Mark Richardson, about the regulatory aspect of the biotech industry.

Mark explains some of the regulation trends in the EU, compared with those in the USA and also shares his thoughts on what advances in biotech regulations we can expect to see in the next decade.

Interview summary

HB: Hello Mark thanks for taking part in this interview. Could you start by explaining your current role, please?

MR: Thank you for inviting me to contribute. I am an independent regulatory affairs consultant specialising in the development of small molecule, biotech and advanced therapy products. I provide advice and support to a range of organisations from academic spin-off virtual start-ups to blue chip global (bio) pharma companies, from clinical contract research organisations (CROs) to law firms and the European Commission. The majority of my clients are based in the EU and the US. The nature of the work varies considerably, compiling technical documents for clinical trial applications, programme compliance / gap analysis, advising on regulatory strategy, meetings with national and regional regulatory authorities, paediatric investigation plans, regulatory due diligence on licensing opportunities, orphan drug designations, expert witness in litigation, CRO business development and training in regulatory affairs. I work from my home just outside Oxford in the UK.


“What works well is enabling the regulatory team to be proactive in informing development decisions…”


HB: How important is it for pharma to have a good relationship with its regulatory team?

MR: Of course it is very important, as are all of the relationships in a project team. Regardless of how the relationship is structured in terms of responsibilities, management and reporting lines, it is critical that there is open, continuous and clear communication between the regulatory function and the other elements of the development team. What works well is enabling the regulatory team to be proactive in informing development decisions by ensuring it has all of the facts at its disposal. It is not the role of the regulatory function to determine the development pathway, but it is important that the pathway should be fully illuminated to see the way ahead and to identify future potential hazards.

What works less well is when the project team uses the regulatory function as a post hoc compliance checking mechanism for isolated decisions taken out of the wider context of the programme. In these circumstances, the input might well be appropriate within the confines of the specific issue at hand, however it might not take into account related but (to the regulatory team) unknown activities or information which might have a consequential impact.

HB: How has the biotech regulation landscape in Europe changed in the past decade?

MR: In the past decade there has been nothing less than an avalanche of new regulation of medicinal products in the EU. We have seen a radical overhaul of the system of clinical trial regulation and the introduction of paediatric drug regulations, both of which have had a major impact on the development of all medicinal product types, Europe has led the world in the creation of a new and effective regulatory pathway and a library of guidance enabling the development and approval of biosimilar products, and it has established a body of regulation for the sector of highly innovative biological drugs known collectively as advanced therapies which were not previously well served.


“The success is manifested in the opening of the EU market for biosimilars in 2006…”


Some of these new regulations have been more successful than others. At the top of the successful list must be the endeavour in biosimilars where Europe has effectively created the framework for regulators worldwide. There are now unambiguous expectations of the standard of similarity required between a biosimilar and the marketed reference product of which it is a copy version, and clear guidance on how to achieve this standard. The success is manifested in the opening of the EU market for biosimilars in 2006 and is being consolidated by the widening of the body of technical guidance to include more product types and the revision and updating of the existing guidance on the basis of the experience gained to date. The next significant landmark in this story will be the approval of the first biosimilar monoclonal antibody product, a copy of infliximab, which is currently under evaluation at the EMA.

The development of the biosimilar regulations and guidance has been rigorously science-led, a feature which the new advance therapies regulations also shares. This class of medicines includes cell and gene therapies and tissue engineered products, all highly innovative and technically very complex. In their case, the new tranche of regulation was required because the existing regulatory framework, which serves conventional small molecule and biotechnology derived protein products well, does not take into account the different level of complexity and diverse origin of the biological materials of which they are composed. In addition to the regulatory control of these different product specific attributes, there was also the need to “close the gap” between the regulation of medicinal products and the regulation of medical devices, historically entirely separate regulatory domains in EU law. This becomes necessary because of the hybrid nature of matter and use of some tissue engineered products, for example matrix-supported tissue implants, which straddle the regulatory divide.

The greater harmonisation of clinical trial regulation across the EU in 2004 has been helpful, but needs to be further streamlined and the remaining differences between individual Member States must be mitigated or eliminated, a new framework has been published. The paediatric regulations have a clear and laudable purpose to ensure the appropriate development of paediatric drugs but their expectations are burdensome, inflexible, sometimes inconsistently applied and are very time and resource intensive.

HB: How does this compare with the regulatory trends in the US market?

MR: The US regulatory landscape over the last decade has been more tranquil in comparison to the EU. Unlike the EU, there has been no driver for fundamental change to clinical trial regulation. However, there has been the institution of broadly equivalent regulation ensuring the development of paediatric drugs under the Pediatric Research Equity Act, although this has a much lighter and more flexible framework which is far easier to navigate and comply with.


“The development of the biosimilar regulations and guidance has been rigorously science-led…”


But the standout difference between the two jurisdictions over the decade is on biosimilars. The historical and legal origins of the regulation of small molecule drugs and generics (by CDER) and biologics (by CBER) effectively prevented the framing of a biosimilar pathway until there was a very significant change in the law in March 2010. FDA guidance followed in February 2012. The pathway and requirements for biosimilars in the US are broadly similar to those in the EU, but there are two categories of biosimilars. One which is equivalent to the EU standard of similarity and in a second, higher standard a biosimilar is “interchangeable” with the reference product. Interchangeability enables drug selection (but not initial prescription) to be taken out of the hands of physicians, as is the case for generic medicines.

HB: What are the differences between regulating small molecule generics and biosimilars?

MR: The principle difference is that a small molecule generic can be manufactured and demonstrated to be essentially identical to its reference product and only very limited clinical bioequivalence studies can support approval. Neither of these is true for biosimilars because they are complex, heterogeneous products of inherently variable biological systems in which they are manufactured. Small differences between a biosimilar and the reference product (including the types of impurities) can have significant biological, immunological and / or clinical consequences. The demonstration of biosimilarity must therefore be a rigorous comparative assessment which demonstrates that, if there are any differences, the biosimilar must be indistinguishable in its clinical effects from the reference product. This is the focus of biosimilar regulation.

HB: One of the biggest challenges for start-up biotech companies is in understanding regulatory requirements and processes – how best can this challenge be overcome?

MR: Start-up managements must recognise that regulation starts with the idea of the product and compliance must be built in at the very outset of the programme. They must obtain enabling advice by accessing the appropriate experienced resource. This is an integral part of the planning and the cost of the initiation of a development programme to avoid an early wrong turn.


“It remains to be seen whether or not EU biosimilar regulation will follow the “two standard” model of the US…”


HB: How can biosimilar products stand out in the competitive space, in order to achieve commercial success?

MR: This is much more a question of commercial and marketing strategy than of regulatory control. EU level regulation and legislation does not determine how or where biosimilars are priced, sold or prescribed. In essence, they are developed to be lower cost alternatives to their corresponding reference products which no longer have patent protection, in these respects biosimilars are no different from small molecule generic drugs. Their only differentiating characteristic when they first hit the market is price. It might be that subtle differences in safety and efficacy emerge as clinical experience accrues which could affect prescribing decisions, but any such claims would need to be very diligently substantiated.

HB: What advances in biotech regulations do you expect we will see over the next 10 years?

MR: I am encouraged to believe that advances and refinement of regulation in the biologicals and biotech sector in the EU will continue to be science-led. The evidence from the biosimilar and advance therapies regulations has demonstrated this principle well in the last decade. It remains to be seen whether or not EU biosimilar regulation will follow the “two standard” model of the US, which is clearly driven by pharmaco economics. We can expect more tractable clinical trial regulation. The more foreseeable significant shift in the regulatory landscape has already begun where the science is leading, that is in personalised (or biomarker directed) medicines. One thing is absolutely for sure, there is unlikely to be less regulation.

HB: Thank you for your time, Mark.




About the interviewee:

Mark Richardson, PhD FTOPRA, is a Drug Development Regulatory Affairs Consultant and is also Director of Richardson Associates Regulatory Affairs Ltd.

After postdoctoral research in molecular biology at the Universities of Dundee and California at Berkeley, Mark joined British Biotech in 1988 to work on recombinant vaccines before becoming Head of Assay Development, then Biopharmaceutical Development Manager and subsequently moving into Regulatory Affairs with responsibility for rDNA products in preclinical and clinical development. In 1997 he moved to Groupe Fournier as Head of the Gene Therapy Development Unit to lead a European oncology clinical development programme. Joining the CRO sector in 1999, first with Orion Clinical Services and later with i3 Research, Mark headed and expanded the Regulatory Affairs departments providing advisory and regulatory support for global development and clinical investigation of recombinant proteins, gene and cell therapy products, as well as for small molecule drugs. In September 2008 Mark established the consultancy Richardson Associates Regulatory Affairs Ltd.


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This interview was coordinated by Management Forum.

How do you think biotech regulations will evolve in the next decade?