Clinical combinations: ever increasingly, two study products are better than one

24.05.2024

Forgive the poetic licence but it feels like almost every week a new agreement for a clinical combination therapy lands on our desks.

Drug combination therapy has been a popular approach to clinical research and treatment for decades now, with many notable successes showing improved treatment response for patients or the reduction of adverse events. However, from an eye-ball test at least[1], clinical combinations appear to be increasingly commonplace – particularly in the field of oncology – and we seem to be advising on these agreements far more frequently in recent times.

Therefore to aid readers about to start, or perhaps already in the midst of, negotiating a clinical combination therapy agreement, we thought it would be helpful to identify, and offer some guidance on, three of the key topics we regularly encounter when advising clients on these arrangements.

Conduct of the Study

Naturally, one of the main points to agree in any clinical combination agreement is to decide the process for the running and conduct of the study itself.  In particular, the parties will need to determine which company will be the actual regulatory sponsor of the study and agree the governance procedures and scope of decision-making authority for each party.

In terms of the study protocol, we would typically expect to see this being mutually agreed between the parties and, once agreed, the sponsor would be contractually restricted from making any changes to the protocol unless agreed to by the non-sponsoring party (or as required by a regulator).   Note that for multi-arm studies where the combination therapy is only a part of the overall study, the agreement should make clear that the definition of the “Study” and applicable rights regarding the protocol, regulatory authority interactions and other matters under a party’s decision-making authority apply only to the specific combination therapy arm – and, ultimately, do not unduly fetter the rights of the sponsor to run and manage the wider study.

Generally, we would expect the sponsor to have the final decision making authority in respect of the running of the study and all related operational issues.  However, it would be customary for the non-sponsoring party to have a right to veto certain issues – including any matters which materially impact, or relate to the dosing of, its study drug or which could otherwise materially increase the scope and costs of the study.

Intellectual Property and Clinical Data

It wouldn’t be a Bristows article if we didn’t mention intellectual property and data!  However, the use and ownership of the clinical data, and any inventions which may potentially arise as a result of the combination, go to the very heart of an agreement of this nature.

Typically, except for very limited and clearly defined purposes (as further detailed below), each party will be unable to use and disclose the data arising under the study until such data is published in accordance with the agreed publication regime.  As a side note (but notably one which is often overlooked), it’s important for the drafting to clearly define whether a party is free to use and disclose all data once the results of the study are published or whether this permission only applies to the specific items of data that have been published.   However, in almost all cases, a party will need to be free to use and disclose the data for (a) the purpose of conducting the study, (b) seeking regulatory approvals (including seeking label extensions) and complying with applicable laws and regulations and (c) filing for patents on any inventions generated in accordance with the agreement.  Of particular importance for those smaller biotechs who are constantly seeking new or enhanced investment rounds, a party will also typically want to be able to disclose the data and the terms of the agreement itself, under obligations of confidentiality, to existing and potential investors. While the parties most often agree, in principle, to this type of disclosure, it is common for the specific details of this clause to be heavily scrutinised by, and negotiated between, the parties.

The likelihood of any inventions arising out of the combination trial depends largely on the nature of the combination and the field of treatment – and, often most importantly, whether the proposed combination is novel or already well-known. Nevertheless, the agreement will need to detail each party’s ownership rights in respect of the clinical data and any inventions which may arise.  While there is no hard-and-fast rule, it is not unusual to see parties agree something along the lines of the following: (a) all clinical data will be jointly-owned between the parties (subject to the restrictions detailed above); (b) any inventions which solely relate to a party’s study drug will belong to that party; and (c) all other inventions will be jointly-owned (with each party being free to exploit such inventions, without restriction, as they see fit).  Note also that it wouldn’t be surprising for a collaboration partner to insist that any patents for joint inventions – where those patents cover the combination of the parties’ two different classes of drugs – should not be used to give their competitors freedom to operate to develop or exploit a rival combination.

However, ultimately, the IP/data ownership arrangements will always be a matter of negotiation between the parties (tailored to the specific circumstances and wider commercial context) and no two agreements are likely to ever be exactly the same.

The Path Forward?  

As mentioned above, the parties will typically want to make clear that each party has the ongoing right to reference the other party’s drug product for the purpose of label extensions.  However, normally, the parties will not seek to document in the agreement the terms of any future combination studies (e.g. a subsequent Phase II/III trial).  That said, there is no harm in including some language in the contract which makes clear that any agreements for future trials in respect of the combination will be based on substantially the same terms as the current contract – with the aim of trying to short-circuit future negotiations between the parties.

While certainly not common, we have seen some parties insist on having harder obligations in respect of future agreements for subsequent trials – the fear being that the other party will have a change of circumstances or strategy and leave them high and dry.  For example, if the parties are unable to agree the terms for a future agreement within a reasonable time period, then the initiating party will have the right to pursue its own subsequent trial with the other party being required to provide a reasonable amount of study drug for such trial.  In this case, a well-advised non-initiating party will not want to agree to a potentially onerous, uncertain or open-ended commitment and should seek to ensure that there are suitable contractual protections put in place – such as (just to mention a few): (a) including a time bar on the right for the other party to communicate its decision and/or commence the subsequent trial; (b) ensuring that it has the right to reject any such future agreement if it is no longer developing or commercialising the relevant drug or if it reasonably believes the proposed study is not feasible or could endanger patients; (c) committing the other party to pay its reasonable costs and expenses of supplying the drug; and (d) guaranteeing that it receives the same access and IP rights to the clinical data and inventions as under the original agreement.

These three topics are, of course, just a summary of some of the key negotiation points we see between parties embarking upon a clinical combination collaboration.  The relevant agreement will need to cater for a range of other topics such as the position on cost-sharing, the mechanics for supply of the relevant drug products, publication strategy, safety reporting, data privacy compliance, termination rights and an appropriate liability regime etc.

We look forward to advising many more clients on these type of agreements and, if we see any other interesting or new themes emerge in this space over the coming months, we’ll be sure again to share our thoughts.

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[1] Although note there does seem to appear to be academic research supporting this view, see for example the following article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10441974/#:~:text=Combination%20therapies%20are%20increasingly%20prevalent,rational%20design%20and%20industry%20trends)