Non-clinical Development

Activities required by the regulator, often in a formal regulatory environment and conducted according to Good Laboratory Practice (GLP). These are often conducted in an accredited lab at a Contract Research Organisation (CRO).

They will usually focus on safety and toxicity of the therapeutic under development but can include biodistribution and/or pharmacokinetic studies. Studies may be required in one or more species.

This can be a very costly phase and it is important to ensure that the work being undertaken is appropriate to enable a Clinical Trial Authorisation (and beyond).

The overall aim of this phase is to provide robust assurance that the treatment is likely to be safe and effective in the clinic. Conducting these important studies to GLP standard means that the regulator can be confident that there is little risk of errors or miscalculations. Organisations that hold GLP accreditation are inspected and highly regulated.

This phase may or may not be necessary, depending on what data are available for the medicine in its existing use, and how relevant that is to the new use. For example, if the new use needs a different dose, length of use or formulation, or there are significant additional risks in the new patient population then it is likely that this phase will be required before authorisation is given to proceed with a clinical trial. It is always best to check with the regulator on what is required before embarking on this phase.

Main activities and considerations:

If you are engaging a CRO to conduct this phase (which most will be) they may be able to offer advice on what studies could be required. However, it is always prudent to engage with the regulator when planning these potentially costly and time-consuming studies.

Which studies and which species are required?

  • From a 3Rs perspective as well as a cost perspective lower order species should be considered, if suitable. If a specific species is required by the regulator for a particular study, for example a distribution study, it may be possible to conduct sufficient safety/toxicity evaluation in that single species too. What is required will also depend on what data are already available for the therapeutic that you are seeking to repurpose. Visit NC3Rs for further information.

Choosing a CRO

  • There are several considerations when selecting a CRO, including:
    • Do they have prior experience in generating similar data?
    • Are the assays and models already established or will development be required?
    • How accurate is their price quote and how long is it valid for? What factors may make the quote subject to change?
    • When are they able to conduct the work? Can they commit upfront to a timeslot?
    • What form will their reporting take?
    • Will reports and documents be “regulatory submission ready”? This saves time and avoids unexpected costs.
    • Is the pricing schedule reasonable? You may wish to obtain 2-3 quotes to check if pricing is competitive, but be careful to ensure that they are all quoting for the same scope of work.
    • Are there penalties for late or non-delivery included in the contract?
    • Does the CRO meet UK standards for the 3Rs (replacement, reduction and refinement of the use of animals) as set out by the National Centre for the 3Rs (NC3Rs). This is important even if the CRO is based overseas. NC3Rs have resources to support selection of a CRO .
    • Do they have a reputation for timely delivery, or otherwise?
    • If samples are to be shipped to or from the CRO are there processes in place for this? Are permits required?
    • What are the CRO's GLP sample and document retention schedules and prices?
    • The following sources may be useful when looking for a CRO:

Contracting with the CRO

When engaging with service providers and/or collaborators legal agreements are usually required. If you are part of a university then your technology transfer office should be able to help you with this. Alternatively, funders may be able to advise at a high level (though would not usually sign off on these agreements)). It is important to consider contractual requirements in plenty of time as preparation and execution of these documents can be time-consuming.

  • CDA/NDA

    Usually, the first step when engaging with a Contract Research Organisation (CRO) would be to put a Confidential Disclosure Agreement (CDA) in place between the involved parties. A CDA (or NDA) is a legal contract between at least two parties that outlines confidential information that the parties wish to share with one another for certain purposes, but wish to restrict access to by third parties. Having a CDA in place should allow you to share confidential information about your project freely. Many institutions have their own template CDAs that can be used as a starting point, but often terms are negotiated until both parties are happy.

  • Statement of Work (SoW) and quote

    Once you have your CDA in place you can begin discussions about the scope of work that you wish the CRO to undertake. If the work is required from a regulatory perspective, for example safety/toxicology for your new indication, you should consult the MHRA before you plan this work (Visit Resources - MHRA for further information). It is important to define the scope of work in as much detail as possible at this stage, so that it can be costed as accurately as possible. If possible, try to negotiate a longer timeframe for validity of the quote, so that it has not expired (and the price increased) by the time you are ready to contract the work.

  • Material Transfer Agreement (MTA)

    A Material Transfer Agreement (MTA) is a contract that governs the transfer of materials between two organisations, for example an animal model or a cell line. The MTA defines the rights of the provider and the recipient with respect to the materials and any derivatives.

  • Contract

    The Statement of Work will form part of the wider contract. In most cases where a CRO is used it will be a fee-for-service arrangement, but in some cases it could be a collaboration agreement. Contractual terms will differ between providers and with the nature of the work. Your TTO and/or Contracts office should negotiate these terms on your behalf, but your input may be needed. Particular points to look out for include:
    • Costs and payment schedule: Is this reasonable? A percentage of costs up front is reasonable to reserve slots or purchase consumables etc. Preferably a portion of the costs should be reserved until after all deliverables have been met.
    • IP ownership terms:
      • Who will own arising IP?
      • Ownership of any relevant background IP will usually be stated in the contract.
      • If the work is being conducted on a fee-for-service basis the entity contracting the work (perhaps a university) will usually own the arising IP.
      • If there is significant intellectual input from the CRO they may wish to negotiate for ownership of arising IP.
      • If you are in a university your Contracts office or TTO should lead these discussions. If you are a charity or a patient group, LifeArc or another funder, may be able to assist.
      • Be aware that funders may have requirements or expectations about the basis on which a CRO would be appointed (such as on a fee-for-service basis with no preferential access to arising IP) and you should ensure you understand and comply with these.
      • If work is being done in a country whose primary language is not English, the CRO or collaborator may wish to have a translated version of the contract. The English language version would be the legally binding version.
    • Timelines:It is prudent to try to get timelines for delivery written into the contract.

Engaging consultancy support

In some instances it may be worthwhile engaging a specialist consultant to advise you on regulatory requirements. You should consider the source of funding to support the cost of this, and the appropriate timing to seek such support. In some cases, funders may be able to support these costs as part of a project.
You may wish to consult The Organisation for Professionals in Regulatory Affairs (TOPRA) or search their Services Directory when looking for a consultant