Choice of Drug Discovery CROs
John Dixon

Choice of Drug Discovery CROs

In today's high-stakes world of early drug discovery, high-value CROs are often the voice of experience. So be selective.

There is a wide choice of CROs these days dealing with all aspects and stages of Pharmaceutical R&D. When it comes to drug design and discovery it is common to focus on Medicinal Chemistry first. However we must remember drug discovery was always an integrated and equal partnership of several disciplines. Other key activities are DMPK (ADME) and Biology (particularly Pharmacology). DMPK weakness was a classical limitation in drug discovery, bringing failure over many decades. It is clear this problem still exists and might be increasing. Alarmingly, inexperienced people regard DMPK measurements as unwanted cost to be incurred by as few compounds as possible. Pharmacological rigour is an essential source of judgement about suitability of drug candidates. It was never strongly taught in all countries and there are major deficiencies in pharmacological standards both in clients and CROs.

The extent to which these are born in mind varies amongst clients since variety of clients is just as broad as that of CROs.

Many clients have limited drug discovery experience. Academic and virtual organisations are either inexperienced or too small to possess all of components. Naturally they make up for this with consultants. Such consultants are employed on an occasional basis and not expected to make daily contributions. Frequently they bring unwelcome news. Few clients want to be told that further time and effort is needed to find the right compound. With the exception of major pharma companies who retain the required expertise, lack of experience in many client companies seems likely to continue. If so this inexperience must be alleviated by careful choice of the most suitable CRO.

There is a tendency to assume drug discovery can be complete in a limited (frequently unrealistic) time period with limited budget. This would be quite laughable if it was not so serious. Scientific problems are not all the same. To assign two years money to a five year problem is all too common. Such exercises might be seen later as failure (not poor judgement). However all too often they are claimed as successes when a candidate drug emerges with suboptimal properties from incomplete optimisation.

The true objective of drug discovery is a compound with the robust characteristics needed to survive the rigours of drug development (where >90% of all candidate drugs fail). Borderline compounds will not do! It is essential to assemble maximum strength and judgement to have any chance of success (particularly within limited time and budget).

It follows that choice of CRO is absolutely critical. In many cases the CRO is the only real source of strength and experience. Increasingly some have far more experience than their clients will ever have. In some cases CROs can be relied upon to manage projects for clients. Such CROs concentrate and accumulate experience whilst many new clients will have worked on few projects.

Experienced CROs with strength and integrated disciplines necessary to bring maximum value to all client categories are relatively few. They might appear expensive particularly to clients unfamiliar with realities of drug discovery and development. It must be worth paying more for increased chance of success! In earlier days cost was an important driving force. Many low cost CROs expanded accordingly. With major clients who remained strong and merely sought additional capacity particularly in chemistry this was workable. However with inexperienced clients and unrealistic timescales the low cost approach was far less likely to succeed.

Of course it depends how we define success. Major pharma companies measure success as compound survival in development. After all we are trying to find new medicines to treat sick people (aren't we?). Less experienced short term organisations may regard success as an early financial exit when a candidate drug with all its strengths and limitations is passed on elsewhere. To be fair many smaller and newer organisations have no development experience. They possess limited knowledge of what is needed to avoid borderline compounds destined to fail at a subsequent more expensive stage.

So here is another characteristic that some CROs bring to inexperienced clients, namely anticipation of development issues. Lets remember toxicology is performed at toxicological doses (by definition much higher than therapeutic levels). Let's also remember early clinical studies are performed on small patient numbers at doses permitted by earlier toxicology. We need maximum drug concentrations over a significant time sufficient to show statistical benefit in (small numbers of) patients without intruding into concentrations likely to bring safety problems. This requires robust candidate drugs with exemplary performance characteristics. Central to this need is ability to bring DMPK influence to bear on design of compounds that do not yet exist (not simply measure properties of those already made).

This additional requirement allows us to further discriminate between CROs. Many CROs have few if any staff familiar with drug development. In CROs largely based on chemistry this may be even greater. There are geographical considerations. Many CROs are located in countries with limited pharmaceutical R&D history where development experience is less available. Highest quality CROs are not equally distributed across the globe.

Returning to discovery integration we must not simply assume it comes from key disciplines coexisting in the same place. Many CROs claim to be integrated on this basis but true integration involves inter disciplinary partnership and continuous mutual influence resulting in better compounds. CROs that recently assembled these components will take longer to justify integration claims. Even in countries with a strong pharmaceutical industry history we can see CROs that are truly integrated and some that are not. If we consider the additional dimension of development understanding then we see a wider range.

After over 10 years of outsourcing we can ask whether it is making any difference to this high-risk poorly productive industry.

Major pharma companies continue to use low cost CROs in a big way. Early mistakes have been corrected but it is still not clear if success is maintained. In any event it is unlikely to be greater when outsourced. If so then cost of failure has presumably reduced. Was this worth10 years turmoil and job losses?

The real benefit of outsourcing lies elsewhere. New participants have entered the field together with new sources of investment. Such organisations lack staff numbers, experience and/or laboratories but can participate in the complex world of drug discovery and development. This is a major positive development and must be good news for patients in the long term. These new sources of enterprise and investment must make the most of the best CRO experience to succeed. We must see more effort put into careful CRO selection particularly by newer client organisations. Minimising cost does not enhance success.

There are wide varieties of both CROs and client categories. Endless permutations are possible.

It follows that not all client CRO combinations will succeed and some are very unlikely to succeed (within limited time and budget).

How to cite:

Dixon, John. Choice of Drug Discovery CROs. Eureka blog. July 22, 2015. Available: