Model or Gospel

Model Clinical Trial Agreements (mCTAs) were developed in February 2003 by the Department of Health and the Association of the British Pharmaceutical Industry (ABPI) with the dual aim of expediting and improving the contracting process to allow approved trials to begin more quickly. A further objective is to save money for the National Health Service (NHS), sponsors, and CROs by removing the need for legal review of trial-specific agreements.

Revised versions of the mCTA for research sponsored by pharmaceutical and biopharmaceutical companies in NHS hospitals were launched on October 30, 2006. The revised mCTAs were further developed by a number of health care organizations, including the ABPI; the BioIndustry Association (BIA); the Department of Health for England; the devolved administrations of Wales, Northern Ireland, and Scotland; the Council Heads of Medical Schools; the NHS Research and Development Forum; and the UK Clinical Research Collaboration. The mCTA is based on English law and governance arrangements, but individual mCTAs have been adapted for use in Northern Ireland, Scotland, and Wales.

(PHOTOGRAPHY: PHOTODISC ILLUSTRATION: PAUL A. BELCI)

Model overview

The revised mCTAs build on the original versions and introduce changes to take into account new legislation and research governance requirements, changes that have taken place in the NHS (in particular, the creation of Foundation Trusts), and the NHS and industry's experience with the first versions.

The mCTAs contain references to standards for the management and governance of commercial clinical trials that are either mandatory or reflective of industry agreed levels of good practice. These include the ICH-GCP harmonized tripartite guideline for good clinical practice; the good clinical practice guidance published pursuant to European Directive 2001/20/EC (relating to the implementation of GCP in clinical trials) and Commission Directive 2005/28/EC (also relating to GCP); the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended); various UK Research Governance Frameworks; and patient indemnity arrangements and accountability through NHS bodies' chief executives for clinical research involving NHS patients.

The mCTAs also deal with industry undertakings to register clinical trials and publish research findings (as set out in the Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases).

Agreement specifics

The mCTA is designed to be used for Phase I to Phase IV trials undertaken in NHS hospitals involving NHS patients. It should not be used in connection with Phase I trials involving healthy volunteers; for noncommercial studies sponsored by charities, government departments or research councils; or for clinical trials performed by private institutions with patients recruited independently of their treatment within the NHS.

The guidance issued at the launch of the mCTA explains that use of the model agreement is not mandatory for either NHS hospitals or member companies of the ABPI or the BIA. However, its routine use is "strongly recommended" by the Departments of Health in England, Wales, Scotland, and Northern Ireland. These bodies recommend that no changes be made to the mCTA other than filling in trial specific details such as the title of the trial, the contracting parties, the identity of the principal investigator, the financial terms, and the subject recruitment arrangements.

In our experience, certain NHS Trusts have followed that guidance to the letter and have been reluctant to entertain any negotiations in relation to changes to the mCTA. They argue that the mCTA has been prepared by industry representatives, and therefore no changes should be required to the approved form document. This argument misses two points.

The first is that sponsors of clinical trials did not personally take part in the preparation of the mCTA (even if they are members of one or both of the professional organizations representing the pharma industry), so they had no direct input into its content. The second is that the agreement is a model—only a model. Like all standard form contracts, it is open to amendment depending on the background circumstances to entry into the contract, the commercial objectives, and bargaining positions of the parties.

The new mCTA contains a number of amendments that affect the bargain struck between the NHS Trust and the sponsor, particularly relating to the allocation of risk and intellectual property provisions.

Indemnity issues

The key changes from the sponsor's point of view are the new limits on hospital liability. There are two caps, depending on the nature of the breach committed by the NHS Trust.

In the event of willful and/or deliberate breaches of the agreement and any breach relating to clauses 6 (Confidentiality, Data Protection, and Freedom of Information), 8 (Publication) and/or 9 (Intellectual Property), the NHS Trust's liability is limited to a maximum of twice the value of the contract. The contract value is the total payment to be made by the sponsor to the NHS Trust if the targeted number of patients is recruited. The second cap covers all other breaches of the agreement by the NHS Trust and limits the NHS Trust's liability to a maximum of the contract value.

These caps are clearly inadequate; the losses that sponsors may face if a clinical trial is not carried out in strict accordance with the protocol in the clinical trial agreement may be greater than the total contract value by several orders of magnitude. Furthermore, these clauses require a court to decide whether a breach of contract was deliberate, a concept that is rather alien to English law. The guidance issued with the new mCTA recognizes that:

"...for a number of possible types of breach (for example, the loss of important Intellectual Property Rights or the release of strategically important information) it is arguable that these provisions might not fully compensate the sponsor to the extent of their loss. However, it is considered that paying compensation on the basis negotiated would be an additional incentive to encourage hospitals to take every reasonable precaution to prevent a breach. These precautions could include: having robust research governance arrangements; instituting training programs for researchers undertaking commercial trials; publicizing to researchers and their staff the crucial importance of protecting the integrity of sponsors' confidential information; and taking disciplinary action in the event of a willful or reckless breach of the provisions of clinical trial agreements."¹

These precautions are required to ensure the careful running of trials, but are not much comfort to sponsors in the face of substantial financial loss. The new mCTA places the onus on the sponsor to have deep pockets or rock solid insurance.

Intellectual property clause

The new intellectual property clause is based on the principle that each party retains ownership of any pre-existing intellectual property or know-how owned by it or licensed to it. The sponsor owns any intellectual property or know-how relating to the clinical trial, the investigational medicinal product or the trial protocol. The sponsor does not gain any rights to any clinical procedures or improvements to such procedures.

This seems sensible in most cases, but may lead to difficulties if, for example, the method of administration of the investigational medicinal product is novel or complex. The NHS Trust and the principal investigator are obliged to disclose to the sponsor any know-how arising from the trial.

Information disclosure

Several changes were made to the new mCTA that may lead to disclosures that are to the detriment of the sponsor. The obligations relating to confidential information are restricted to a 10-year period in both clause 6.3.4 and clause 20. Lifting the obligations of confidence at the end of this period might well conflict with the sponsor's rights to data exclusivity.

The new clause 6.2.6 of the mCTA, which was inserted to deal with the Freedom of Information Act 2000 (FOIA), is unbalanced. In particular, there are certain exemptions to the obligation to disclose information set out in the FOIA, but in the mCTA the decisions as to whether these exemptions apply is left purely in the hands of the site conducting the trial. The agreement should at the very least include a clause that permits the sponsor to make an application to the court or the Information Commissioner for the purpose of preventing a potentially damaging disclosure. This will be particularly important if the FOIA can be used by generic companies to obtain data relating to trials.

Publications, recruitment, and terminations

In clause 8.4, there is a danger that publication of a summary of study results before publication of the full study might undermine the sponsor's right to preserve its intellectual property rights. As a result, the sponsor will need to ensure that the protocol deals comprehensively with the rights to publication. Note, however, under clause 3.6 of the new mCTA, in the event of conflict between the protocol and the mCTA itself, the terms of the mCTA prevail.

The rationale behind clause 8 of the mCTA is that publications based on limited and perhaps unrepresentative subsets of data from one or a limited number of trial sites should not be published before the multicenter data. A dissenting interpretation of the trial's data may be published after the main report, if the procedures in clause 8 are adhered to. (The mCTA allows the sponsor a 60-day period for review of the publication, plus a delay of up to six months from the date of submission of the draft publication so that it can take steps to protect its proprietary rights, intellectual property, and know-how.)

The mCTA does not deal with the issues of competitive recruitment between different sites or the consequences of a trial becoming full before the site that has entered into the mCTA has managed to recruit its proposed allotment of study subjects. This may have consequences on trial remuneration and expenses, which should be addressed.

An amendment is required to clause 12.8 of the mCTA, which deals with early termination. The clause should state that termination of the mCTA is without prejudice to the accrued rights and liabilities of the parties under the agreement and to those rights and obligations, which are preserved pursuant to clause 20 or which by their nature are intended to survive termination. The additional wording (in italics) points to clause 20, which sets out the rights that are expressed to survive termination and widens the net to include any rights that are not included in clause 20 but should also survive termination.

Principal investigator

An additional issue is that the new mCTA does not oblige the NHS Trust to ensure that the principal investigator is aware of and complies with their obligations in the conduct of the study.

As the principal investigator is not a party to the mCTA, the sponsor has no direct recourse against the principal investigator in the event that he or she breaches a term of the agreement. The NHS Trust represents that the principal investigator has the necessary skill and expertise to perform the clinical trial and that he or she is made aware of its obligations contained in Appendix 6 to the mCTA. However, the NHS Trust is not required to carry out any investigation to check that the principal investigator does not have any conflicts of interest.

Fate of the UK

Aisling Burnand, chief executive of the BIA, commented at the launch of the new mCTAs that "the universal endorsement of this agreement is a tremendous achievement which will strengthen the UK's position as a world leading location for medical research. The use of this template contract will significantly accelerate the initiation of trials and allow patients faster access to innovative treatments." However, this optimism is tempered by the guidance issued with the mCTAs, which neatly sets out the problem faced by the UK:

"In recent years, the performance of UK sites involved in these international clinical trials has declined in terms of the speed of trial site initiation, patient recruitment, and quality of data generated, while trial costs have, in general, risen faster than in comparable countries. With increasing competition from research sites in the developing world and states in Eastern Europe, it has become more difficult for pharmaceutical companies to justify the inclusion of UK sites. Unless their performance improves, the extent of UK participation in international trials will continue to decline, with possible adverse consequences for the UK Pharmaceutical Industry more generally, as well as the status of the UK as a centre of medical and research excellence."

So, will the new mCTAs ultimately help or hinder the development of the UK pharmaceutical industry?

The new mCTAs tip the scales in favor of the NHS Trusts to the detriment of sponsors. If a sponsor insists on adequate contractual protection in the form of indemnities, requiring the negotiation and amendment of the mCTA, then the attempted streamlining of the contractual process has backfired.

We have seen sponsors dropping certain trial sites that are unwilling to make any revisions to the mCTA. This erodes the goodwill and connections established in prior collaborations between such sites and the sponsors and places future collaborations in jeopardy. Certain pharmaceutical companies are just not prepared to bear additional financial risks in what is already a risky business. If that reaction is widespread, the UK may become a less attractive location for clinical trials, despite its current reputation for clinical excellence.

If in the long term fewer trials are being conducted in the UK, then British-based scientists may miss out on exciting new developments, which may ultimately undermine the UK's reputation for clinical excellence.

Mark Lubbock* is a partner and head of the health care group at international law firm Ashurst, email: mark.lubbock@ashurst.comLindsey Depuydt is an associate in the technology and commercial department at Ashurst.

*To whom all correspondence should be addressed.

Reference

1. The Guidance on Use of the mCTA for Pharmaceutical and Biopharmaceutical Industry Sponsored Research in NHS Hospitals, paragraph 7.11 (2006 version), available at: www.nihr.ac.uk/.