Guidelines are Not Recipes: Biowaivers and Beyond

Ahead of the 2nd Annual Bioequivalence and Bioavailability Studies conference, Pharma IQ caught up with Anders Fuglsang from FuglsangPharma. Fuglsang is a former EU regulator (clinical assessor) and managed the international group of assessors that established the EU guidelines for proof of therapeutic equivalence that came into force in 2009. He was an expert advisor to the WHO, member of the Efficacy Working Party at EMEA (EMA), member of the PK subgroup, and has worked with both generic and innovator companies. 

Pharma IQ: What are the potential benefits for companies using biowaivers?

A Fuglsang:
Biowaivers obviously allow companies to avoid the cost that is otherwise associated with a clinical trial (PK, PD etc). Instead of such trials, biowaivers allow them to rely on in vitro experiments which are less labor intensive, cheaper and oftentimes faster. Ethically, this makes good sense as it also implies that less human exposure takes place.

Pharma IQ: What are the potential risks for companies using biowaivers?

A Fuglsang: Generic and innovator companies alike are very interested in bringing down the time and cost associated with the development of medicines. They therefore do argue strongly for use of biowaivers. However, at the end of the day, it is up to the regulators if they will accept documentation based on in vitro (or in silico) studies. There's no guarantee for it.
Taking a gamble may result in headaches down the road.

Pharma IQ: What challenges do companies face with regards to understanding the current regulatory thinking and implications for the pharma industry?

A Fuglsang: Guidelines are not recipes. They are not algorithms. There is always that element of interpretation that needs to be done. A possible solution is to seek scientific advice, either nationally or centrally at the European Medicines Agency. On top of that comes that scientific advice is not binding on applicant or agency, and there may be differences in the views between the various agencies. The existence of referrals at CMD(h) illustrates this. This is a real challenge on both sides.

Let me add, I do not think this the need for interpretation signifies a gap in the guidelines; I have the highest respect for regulators developing guidance. It is a very difficult task and there are many factors that need to be taken into consideration. Some of them are scientific, and some relate to e.g. legal or practical issues. Guidelines evolve as we generate and share knowledge. What regulators think depends strongly on the information that is available to them. Therefore it is crucial that companies be willing to share data with regulators. In the recent years, I believe we have seen battles between innovator and generic companies where both sides have tried to influence regulators in the direction that is appropriate for their own business ambitions. Thereby the data shared with regulators may not always be purely scientific and objective but may be biased. I think regulators to some extent are aware of it, and I think this phenomenon has the potential to complicate their development of guidance, unfortunately. Money talks. Perhaps it even screams?

Pharma IQ: How would you assess the near, mid and long term impacts of biowaivers?

A Fuglsang: They will continue to get a lot of attention and find wider use.

In the long term, I imagine that we will see biowaivers entering innovator dossiers which will bring down the costs of phase I and phase II trials. Regulators and the industry have previously been flirting a lot with the use of biosimulation etc. which are techniques that one way or another may give the answers to questions that today can only be answered by means of studies on humans beings. This is not just around the corner, though, but years ahead. In silico trials as of today are not trusted to any great extent by regulators.

Consider the explosion in genetic knowledge that took place from the mid 90'ies, when the first pathogenic bacterium was sequenced. Suddenly everybody had available the entire genetic sequence of an organism causing trouble. The genotype, after all, determines the phenotype and the pathogenecity. The thinking was, and still is, that when you understand the genes then you understand the infectious diseases and can take measures to prevent them. This was thought to be a turning point in the fight against infections. Thousands of papers have since then been published, and we know the genomes of thousands of viruses, bacteria, humans and even more complex genomes. And yet, we have not understood well how to use the primary sequence information to battle infections. Along similar lines I think there is a long way to go before any regulators can accept in silico trials as biowaivers: understanding the processes that govern ADME and affect safety and efficacy in humans is just not a picnic.

Short- and mid-term: We will see various updates to guidelines. In principle, all guidelines are under continuous development. I would expect that biowaivers on a smaller scale will find their way (or be expanded upon) into guidelines dealing with equivalence concepts. Locally acting products, modified release, immediate release, biosimilars, transdermals make good candidates.

An example where things have gone in the opposite direction is development of medicines for children: In the past in Europe, medicines for adults were not always too thoroughly tested in children. In stead, posologies could be approved based on down-scaling of an adult dose of basis of a child's weight or body surface. Regulators have started moving away from that with new regulation for pediatric developments and PIPs etc. So in principle this is an area where there used to be biowaivers, albeit implicit, but where the rules are now being tightened somewhat. 


Interview conducted by Andrea Charles