If all molecules in discovery and development were added together over recent years and compared to the number of successful drug approvals each year, the ratio is (approximately) 10,000:1. In other words, for every 10,000 molecules entering drug discovery, 9,999 will fail during some stage of the development process. Evidently, developing a molecule that has a desired, efficacious yet safe effect in humans is a remarkable achievement considering the lengthy, complex and expensive process.
So how can we turn these odds a little more in our favor? Can we de-risk molecules from failure during drug development? Is it possible to select new molecules that will have a greater than 1:10,000 chance of progressing through development and creating a successful, safe, marketed product?
It’s important that we understand what de-risking is and the risk areas where molecules fail. By applying appropriate experimental resources to identify potential exposure to these risks early in the development process, we can help identify molecules that have a better chance of survival.
What is de-risking?
De-risking represents a relatively new and developing strategy designed to quickly assess if a new drug has a metabolic liability making it potentially susceptible to being approved with restrictive conditions or labelling, not being approved, complex clinical development or being withdrawn from the market once it’s been approved for a wider population.
De-risking, in this article, refers to the intelligent application of early in vitro testing to investigate areas of major risk. Noteworthy, is that this type of testing is not absolutely quantitative, it’s not necessarily 100% predictive of a definite yes or no, it’s about generating information which allows you to make better informed decisions regarding ‘the likelihood’ of risk.
Benefits of early de-risking
Benefits of early de-risking are far and wide. The greatest benefit of course is improving patient safety which is the primary concern. Also, a natural byproduct will add value to your molecule. Take a compound that has a low drug-drug interaction profile and low liver toxicity potential; this is seen as considerably de-risked from non-approval and/or withdrawal post-market, making it more valuable.
Essentially, de-risking provides confidence to invest in that molecule not only in terms of capital investment but also in terms of people and time.
Crucial to applying a de-risking screening strategy is to understand the major risks for drug developers and where/when they occur.
What are the major risks and risk drivers of de-risking?
The risk-liabilities in one instance are metabolically-driven. Another major risk area, beyond the scope of this post, is lack of clinical efficacy reflected by failure to transit from Phase II to Phase III during clinical development.
As the above table suggests, the stages of drug development can be separated into three categories: new drug application (NDA), approval, and post-market. Each of these phase developments have risks and risk drivers associated to them. When we look at the drivers, it really does underpin the importance of drug metabolism because all of the drivers here are metabolically based.
It’s these risk drivers; metabolites in safety testing, drug-drug interaction and drug induced liver injury that will help us to identify risk and essentially recognize molecules that have a better chance of survival.
Here is just a short summary of each of the risk drivers. You can find more information on these in our pharma de-risking journal article.
Metabolites in safety testing (MIST)
The principle recommendations of the FDA’s guidance regarding the concept of MIST guidance are:
- To encourage the identification of differences in drug metabolism between animals used in non-clinical safety assessments and humans as early as possible during the drug development process
- Generally, metabolites present at disproportionately higher levels in humans than in any of the animal test species should be considered for safety assessment
- Human metabolites that can raise a safety concern are those formed at greater than 10 percent of total drug related exposure
Drug-drug interaction (DDI)
The assessment of pharmacokinetic-based drug-drug interactions (DDI) is a major element of modern drug development. As populations expand and individuals live longer, the occurrence of patients being prescribed multiple concurrent medications (polypharmacy) is increasing. Consequently the risk of adverse drug reactions due to DDIs is also increasing and this area of drug development is coming under increasing regulatory scrutiny. Drugs with a high DDI potential (particularly as a victim drug) may be at risk of non-approval, excessive labelling or post-market withdrawal.
Drug induced liver injury (DILI)
Drug-induced liver injury is a major concern for the Pharma industry. It is the single biggest cause of liver transplant in humans and a major cause of safety-related drug withdrawal post-market. It is also a major cause of drug attrition during development.
Its low frequency means that often it is not detected during clinical trials. Hence detection often occurs once the drug is approved and moves into a much larger patient population, sometimes becoming a major reason for post-market withdrawal. The decision to progress a molecule that is displaying DILI-positive characteristics is an extremely high risk decision.
Read more about the potential impact of DILI scenarios in our de-risking white paper.
For more detail about de-risking and drug metabolism, listen to the webinar series by Guy Webber.
About the author
Guy Webber, Scientific Manager, In vitro and drug-drug interaction sciences at Envigo, has 25 years’ experience in Pharma and Contract Research, working on hundreds of drug molecules for many different clients.