Special feature: Top 10 clinical trial mistakes

This special feature is brought to you by James Cameron of McCullough Robertson.

Clinical trials play a vital role in the development of safe treatments and medical devices and it is no surprise that the experimental nature of human research makes clinical trials a heavily regulated field.

The documentation associated with preparing for and managing a clinical trial creates a number of legal obligations and rights between investigators, sites, sponsors, contract research organisations (CROs), ethics committees and the Therapeutic Goods Administration (TGA).

Often the pressure to avoid delay in commencing a clinical trial can lead to legal and contractual aspects of the process being overlooked. These simple oversights can be costly to the parties involved and may hinder or prevent approval by legal and regulatory authorities such as the TGA and the US Food and Drug Administration (FDA).

Here are 10 common clinical trial mistakes you should avoid.

1) Agreements not reflective of GCP responsibilities

The ‘Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), annotated with TGA comments’ (GCP Guideline) and the National Statement 2007 (National Statement) set out the key responsibilities of each party involved in a clinical trial in Australia.

Compliance with these documents is mandatory. Both the sponsor and principal investigator for a clinical trial certify that they will conduct the clinical trial in accordance with these documents when they notify under the CTN scheme.

In the haste to initiate a trial site or negotiate a CRO agreement, parties often make the mistake of failing to consider whether the outline of their roles and responsibilities is consistent with the GCP Guideline, the National Statement and other applicable guidelines.

A clinical trial agreement, protocol or CRO agreement should only be negotiated by persons trained in good clinical practice (GCP) that have a strong understanding of the roles and responsibilities of each party under GCP. Ideally any clinical trial agreement and protocol should include provisions that resolve inconsistency in a manner that is compliant with GCP.

2) Non-compliant ICFs

Informed consent related issues are among the most commonly cited deficiencies in GCP compliance inspections of clinical trial investigators and sites. The GCP Guideline sets out requirements for the form and content of Informed Consent Forms (ICFs).

Common mistakes made in drafting ICFs include:

• failing to address the requirements of the GCP Guideline
• inadequate explanation of compensation rights for injury and who will cover those costs
• explanation of risks in the ICF not matching those set out in the Investigator Brochure
• inaccurate or misleading statements in respect of privacy law and access to patient records
• failing to use plain English to explain issues in a way the patient can understand
• poor layout that makes the ICF difficult to read

3) Failing to consider relevant regulatory documentation

The regulations and guidelines relating to clinical trials are numerous and dynamic. While the clinical trial agreements published by Medicines Australia require compliance with the GCP Guideline, there are a number of other regulatory documents applicable to clinical trials in Australia.

Both sites and sponsors often make the mistake of failing to properly acknowledge the key regulatory documents relevant to clinical trials in Australia. These include:

• the GCP Guideline
• the National Statement
• the Declaration of Helsinki 2008
• the Australian Code for the Responsible Conduct of Research (mandatory compliance for NHMRC funded research)

There is also a plethora or other guidelines issued by the TGA in respect of particular products and devices.

Regulatory documents are frequently updated or superseded so it is important to ensure that references to those documents are references to the correct edition, even when using clinical trial agreements approved by Medicines Australia.

Not all regulatory documents require mandatory compliance, so consideration should also be given to whether all terms of a particular code or guideline should apply to the particular clinical trial in question.

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4) Intellectual property rights

Properly dealing with the nuances of intellectual property in a clinical trial is important but often overlooked.

While a site needs to ensure that the intellectual property it might contribute to the clinical trial (often termed ‘Background IP’) is not transferred to the sponsor, a sponsor may require a right to licence that intellectual property for the commercialisation of its drug or medical device. The sponsor will also want to ensure that it owns all intellectual property arising from the clinical trial.

Common mistakes in dealing with intellectual property in clinical trial agreements include:

• failing to appropriately distinguish between background intellectual property and newly developed intellectual property
• failure to secure the chain of title of ownership, particularly where the investigator is not an employee of the site
• failure of the sponsor to secure a licence to the background intellectual property of the site if needed
• failure of the site to request warranties from a sponsor that the sponsor’s intellectual property does not infringe third party rights
• clauses preventing a site from sublicensing intellectual property rights
• failure to adequately identify the intellectual property being licensed for the clinical trial

It should be noted that even commonly used documents, such as the clinical trial agreements published by Medicines Australia, fail to address some of these issues. So called ‘standard’ agreements rarely suit all parties and they should be reviewed and considered just like any other legal contract.

5) Inappropriate or inadequate indemnification

It is a prerequisite for ethics approval under GCP that the sponsor signs the ‘Medicines Australia Form of Indemnity for Clinical Trials’ in favour of the Human Research Ethics Committee (HREC) and the site. The indemnity is a separate document to the clinical trial agreement.

Many sites make the mistake of believing that the Medicines Australia indemnity protects them from any loss or damage, when in fact it is limited to claims made by or on behalf of subjects. The indemnity does not address loss or damage suffered as a result of:

• intellectual property infringement claims by third parties
• a breach of the clinical trial agreement by the sponsor or its CRO
• the negligence or wilful misconduct of the sponsor or its CRO
• personal injury to the employees or agents of the site as a result of using the trial product
• damage to the property of the site as a result of using the trial product

By drafting indemnities in the clinical trial agreement that are complementary to the Medicines Australia Form of Indemnity for Clinical Trials, a site can improve the remedies available to it for loss or damage it may suffer as a result of the clinical trial.

6) Protocol deviations and violations

Under GCP, a site must not implement any deviation to the protocol without the prior approval of the sponsor and the ethics committee. Changes to eliminate hazard must be submitted as soon as possible to the sponsor, ethics committee and the TGA.

Unfortunately, departures from protocols outside those permitted by the GCP Guideline often occur. These can range from protocol ‘deviations’ that are unlikely to put subjects at risk through to ‘violations’, which may place both subjects and the integrity of data at risk.

A sponsor should ensure that its clinical trial agreements are drafted appropriately to provide it with rights and remedies for departures from the protocol. If using a CRO, a sponsor should also carefully draft clauses that transfer obligations relating to permitted protocol deviations to the CRO.

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7) Failing to address and understand privacy law

Clinical trials involve the collection of sensitive personal information (primarily health information) about subjects. Privacy laws and standards in force in Australia heavily regulate the circumstances in which sensitive personal information may be collected, used and disclosed by organisations.

In general, consent must be obtained from each subject for each action in respect of his or her personal information. The privacy section of an ICF should therefore:

• identify which privacy laws and standards apply to the particular information
• set out in detail what personal information (including photographs) will be collected from each subject
• set out each use and disclosure of the information that the collector may undertake including disclosure to sponsors and government and regulatory bodies and any publication that may occur
• describe when and how the information will be de-identified
• inform the subject about their right to access the information that has been collected about them

Ideally ICFs should also require subjects to sign-off on each of these items, as a ‘bundled consent’ may not constitute adequate consent in the case of health information.

8) Inappropriate publication rights

As clinical research is often performed by institutions that rely on the promotion of research in order to secure funding, the publication clauses in a clinical trial agreement are often contentious and heavily negotiated.

Mistakes often seen in the drafting of publication clauses include a lack of certainty in respect of:

• what information is allowed to be published
• triggers and timeframes for review by the sponsor
• what right the sponsor has to amend, delete or remove information on review
• acknowledgement of authorship

Both sites and sponsors should carefully consider whether the publication clause in the clinical trial agreement they are negotiating is appropriate to their needs.

9) Failure to consider insurance

Most clinical trial agreements (including those published by Medicines Australia) require the sponsor to provide evidence of its clinical trial insurance. However it is also important to go beyond merely checking that a policy is in place and consider such things as:

• whether the policy is in fact a dedicated clinical trial insurance policy
• whether the policy is ‘occurrence-based’ or a ‘claims made and notified’ policy
• checking whether the limit of the policy is sufficient ($10M or $20M is usual)
• whether the particular trial in question has been listed on the policy
• whether the policy correctly names the sponsor entity as an insured
• checking that the policy covers the territory where the trial is taking place

Both sponsors and sites should also be aware that the drafting of indemnities and limitations of liability in a clinical trial agreement could interact with insurance policies. Depending on the drafting of the clauses in question, this can result in breach of the terms of the insurance policy and may limit or prevent recovery under the policy.

10) Failure to properly inform TGA

The Therapeutic Goods Act 1989 and its regulations require the TGA to be informed and notified within set timeframes of a number of issues before, during and after a clinical trial.

Approved forms are published by the TGA for many of the notifications it requires, from notification of the commencement of a trial through to the addition of new sites and trial closure.

TGA replacements or updates to forms can sometimes see CROs and sponsors use out of date forms. The TGA will usually reject incorrect forms and this can delay the progress of a clinical trial.

Conclusion

Whether your role is as a site, a sponsor or a CRO, the negotiation of documents in a clinical trial demands an understanding of the complex web of laws and regulations associated with good clinical practice. Further, so called ‘standard’ agreements are, at best, merely an approximation of what ought to be agreed between the parties.

To help minimise the potentially significant risks of non-compliance, expert legal advice should be sought in respect of the legal issues associated with a clinical trial, including the review, drafting and negotiation of the key agreements and documents entered into between the parties.