Considerations for accelerated development

How will an accelerated pathway change the way you outsource?

‘The exception to the new paradigm: the added compression of accelerated pathways means process development will likely continue post approval’

One of the features of the drug R&D pipeline is that new therapies are increasingly for orphan and rare diseases and, in fact, accelerated pathways of some kind are estimated to affect 50% of drugs in clinical trials. The implication for such a development timeline is that the drug sponsor needs its CDMO partner to deliver a close-to-commercial ready formulation, without slowing development. In the case of many accelerated trials, this means jumping from an early phase scale to Phase III and missing out on a significant amount of potential development time.

Valdas Jurkauskas, Senior Vice President at Pardes Biosciences, highlights the challenges of initial work. He says: ‘For the last three years now, especially in view of the pandemic, we more and more often find ourselves in a situation where we are asked to enable the very first investigational drug application in record time. And the time between development candidate nomination and submission of the first IND is further shortened when the discovery team takes a long time to select the lead candidate. The IND-enabling timeline is almost always less than 12 months. So, when selecting a CDMO we need to consider the chemical process and analytical development capabilities and resources, as this is going to be, for lack of a better term, a catch-up endeavour. The CDMO process chemistry experience and capabilities are key to the success of the programme, as is its formulation development since most new molecules today have low solubility and may require enhancement technologies.’

Because accelerated pathways force sponsors to take a different approach to their clinical study data, the ability to handle risk through the pathway becomes extremely important. Drug sponsors should be clear on their risk tolerance as it relates to each of their partners along the supply chain (if there are multiple), as well as being able to assess the risk/benefit associated with getting therapies to patients as quickly as possible.

According to Hajir Mokhtari, Senior Manager, Program Management at Thermo Fisher Scientific: ‘In a fast-track approach you need a partner who can effectively balance the risk and speed. Obviously, speed becomes a priority, but the risks of quality and the product integrity remaining intact should not be compromised. So, the CDMO partner in that case becomes someone who can balance that risk versus speed more effectively. And with that comes the need to select a partner that has the experience and proven track record with expedited approval processes.’

So, how can innovators align the competing goals of developing more robust pathways, while hitting incredibly tight timelines and managing risk? Stephanie Gaulding, CQA, CPGP, Managing Director at Pharmatech Associates, sees a third way. In this case, you will still need pharma-ready formulations to get you through approval, but the innovator accepts that once through to commercial (inside 6-12 months) they are going to have to continue to work on the formulation and process.

Crucially, the innovator would have to plan for a post-approval change, wherein they can introduce improvements into the manufacturing process. Gaulding notes that when it comes to compressed timelines, the odds of further refinement being needed after approval are high.

She says: ‘Typically I would say within the first year or so the majority of those that are going through accelerated pathways do see some level of change associated with the manufacturing process. In my experience, it's hard to get the process fully optimised from the get-go.’ She recommends that the sponsor accepts this as part of their strategy, and potentially considers conducting parallel programmes in later development – one for approval and one for post approval process improvements.

Finally, our experts advise sponsors to assess organisational capacity and availability of relevant personnel when considering CDMO partners for an accelerated pathway.

According to the anonymous Big Pharma Director: ‘My number one piece of advice I would give to a biotech or anyone undertaking fast track in conjunction with an external partner - don’t just look at the reactors and scale, look at the body of scientists and labs that support that. Even your project manager at the CDMO, how many other projects do they work on? What is the time dedicated your product? You need them to have attention on all parts of the programme.’