Common Hiccups in Safety Assessment
When trying to turn inventions into drugs, who you partner with matters. Four things that can slow down drug development.
I have spent much of my career working with start-up companies. They are often virtual, outsourcing all their drug development projects, and in some cases have never moved a drug into clinical trials. I have also had the pleasure of talking to some very entrepreneurial post-graduates who are looking to turn their inventions into drugs.
My primary role is to provide advice to sponsors who are looking to assess the non-clinical safety of their products, and the work I do is exciting and rewarding I am able to do what I always wanted to do when I first discovered a passion for science: work with the brightest minds in research, on the cutting edge of technology and innovation.
But we all know that getting a drug to market can be a monumental struggle at times. One of the questions that I often get asked by those who are newer to drug development, or one I bring up as a reality check, is a deceptively simple one: What factors cause drug development to falter? Here are a few common reasons:
A Sponsor doesn’t always understand what they want or need
It is increasingly the case that Sponsors are developing extremely complex and innovative products, where the development pathways are not straightforward and are therefore open to interpretation. This is particularly the case when innovation precedes regulation.
The new class of drugs called CAR-T is one example. A clear regulatory pathway for development of CAR-T cells is still being established, but robust fundraising by biotechs has enabled many small and virtual businesses to move their products into early development. By necessity, these smaller biotechs rely on the expertise of a CRO to guide them and help them to define their non-clinical safety strategy. So choosing the right CRO to partner with matters. A CRO needs a range of internal experts who understand how to move a Sponsor’s innovative products to the clinic. They also need to be up-to-date on the regulatory thinking and novel technological approaches to safety assessment. Having these skills ensures that Sponsors receive the best advice possible, and when those chemistry and skill sets aren’t there, the project suffers.
Late delivery of API
Whether a drug is manufactured by a contract manufacturer or a pharmaceutical company, late delivery of the Active Pharmaceutical Ingredient (API) is a fairly common reason why preclinical programs are delayed. One of the many reasons for API delays is the process of scale-up to produce the quantities of material needed for the preclinical safety studies.
When CROs invest the time and money to improve the way they schedule studies, it makes it easier for them to adapt to changes in API delivery dates and to reschedule studies with minimal impact on program timelines. CROs with a large network of sites can also use their size to their advantage to reduce delays, in contrast to smaller service providers that don’t have the resources to do so.
One of the most common issues delaying drug development is formulation. Pharma did a lot to address the issue of bioavailability in the 1990s, yet there is still a misperception among those less experienced in drug development that formulations suitable for efficacy studies are also suitable for GLP toxicology studies. This is sometimes the case, but when a drug has a good therapeutic window, the required dose levels for toxicology studies are significantly higher and hence a higher formulation strength will be required. This can often require reformulation work, which may affect bioavailability and cause delays in the initiation of the toxicology program. My advice: consider this early to avoid some sleepless nights!
Bioanalytical method development
I have worked in the CRO industry for over 20 years, and one of the key challenges has always been bioanalytical method development. There are four main aspects to this:
- Understanding your molecule. This is something that I have learned the hard way. Not all molecules are equal, and knowing whether a molecule will be an analytical challenge will enable you to decide early on what the best analytical approach should be, and will help you be realistic about development and validation timelines.
- Equipment failures. Smaller CROs tend to have very limited equipment, meaning that when a mass spectrometer breaks down there is lack of spare capacity and an inevitable delay in getting key PK or TK results. CROs with many mass spectrometers have many more options, and the analysis can be moved to another machine to avoid delays.
- Expertise in method development. The more experience the method development team has, individually and collectively, the more likely that method development will progress smoothly.
- Scheduling. Allow plenty of time for any hiccups.
We are working at the cutting edge of science with novel molecules or other therapeutic approaches, and we are assessing their safety in extremely complex biological systems. This means that there will always be unexpected findings. Understanding quickly what they are and how we deal with them defines how successful the development program will be. Anticipating possible findings, including appropriate endpoints, and having a supportive network of specialized experts to discuss findings will all help to increase the chance of a positive outcome when the unexpected occurs.
Peter Gaskin, PhD, is Senior Director of Scientific Advisory Services at Charles River Laboratories. He has over 25 years of experience in biotechnology and pharmaceutical drug development, having successfully designed and led the non-clinical programs for many products from lead optimization to market. For more information check out our Charles River Scientific Advisory Services or how we can help plan your IND-enabling studies.