New EU rules to protect study volunteers

In early 2016, a French drug safety study made the headlines for all the wrong reasons. A candidate drug for a variety of diseases had gone through preliminary tests without producing any severe side-effects. It was then tested on a group of eight people via 10 daily doses. Five days into the study, one patient died and four others fell seriously ill.

The negligence that led to this tragedy caused outrage amongst the international pharmaceutical community, with France’s General Inspectorate of Social Affairs issuing a report that criticised the way the trial was designed and executed.

In response to the report, the European medicines Agency issued the “Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products” on 25 July this year, with the aim of protecting participants in early trials.

Calling for thorough preclinical tests and more stringent dosing, the guideline also advises trial staff and sponsors on how to deal with adverse events in a timely and adequate manner, minimising any damage done by harmful side-effects.

While the guideline is a welcome response to stakeholders’ uncertainty in the wake of clinical controversy, some healthcare experts claim that they don’t go far enough. Critics such as Joerg Hasford, chair of the Association of German Research Ethics Committees, suggest that the EMA still facilitates speed rather than safety in the clinical approach.

We examine the new guidelines and how they will affect the future of European trials, offering practical advice on reassuring stakeholders that patient safety is a top priority throughout the trial process.

What is an early-stage trial?

The majority of early-phase and first-in-human trials such as the controversial French trial in question use healthy participants, who take part in return for monetary remuneration, rather than ill patients. They’re designed to guide dose-selection, population and safety precautions for the rest of the trial, ensuring that ill patients are not put at unnecessary risk and that the data gleaned from the study is valid and high-quality.

Using healthy volunteers has a number of benefits, including speed of recruitment, ease of scheduling, and removing confounding variables such as other medications or disease pathology. Furthermore, the risk of adverse effects having long-lasting consequences is less in healthy volunteers.

While healthy volunteers are unable to receive any therapeutic benefits from joining a first-inhuman trial, they still risk negative effects. Ethical principles dictate that volunteers should only be exposed to minimal risk.

Responding to controversy

The main source of the controversy surrounding the death caused by the French trial was the testing of daily doses up to 100 milligrams - a dose far higher than necessary to completely inhibit the enzymes that the medication targeted.

The excessive dosage may have played a significant part in the death and neurological damage caused by the trial. In response, the new guidelines state, “to determine a safe starting dose, the methods used for determination of the strength and/or the potency of the product need to be relevant for the intended mechanism of action, reliable and qualified.”

Another critical problem with the French trial was physicians’ failure to react appropriately to the first signs of illness during the trial. The first volunteer to develop alarming symptoms was hospitalised, yet the remaining subjects received a further dose the next morning without being informed of the potential risk. This is seen as a violation of informed consent, as volunteers were unable to reassess their commitment in light of adverse effects.

Under the EMA's new rules, a serious adverse reaction in a single subject is considered reason to stop the trial entirely if there’s even a possible chance that the change in condition is related to the medication.

Minimising risks

The guideline outlines the fact that the wellbeing and safety of trial subjects must be a top priority of trial design and execution at every stage. It goes on to explain how strategies can be put in place to anticipate and characterise risks accurately, as well as how risks can be minimised and responded to.

In terms of trial design, the guideline focuses on determining the quality of medications offered to volunteers, and requires thorough preclinical data to prove an appropriate strength, potency and reliability in small doses. It goes on to cover healthy starting doses for healthy volunteers and patient participants, explaining that a defined No Observed Adverse Effect Level (NOAEL) needs to be demonstrated via animal trials and based on state-of-the-art statistical modelling before a trial design can be approved.

It also states that the increments at which a dosage is increased, and the maximum dosage not to be exceeded must be stated at the beginning of the trial, hopefully avoiding future instances in which dosage becomes excessive and dangerous without prior symptoms being shown.

Room for improvement?

While the European healthcare industry at large welcomes the changes, there are those who fear that the guideline is worded too softly, without appropriate focus on the potentially fatal consequences of failing to comply to the regulations.

Some critics suggest that the guideline lacks sufficient attention to the ethical problem of balancing risks and benefits. The candidate drug in the French trial, for example, had not been proved to be a particularly promising or beneficial candidate before first-in-human studies began. Researchers call for more certainty that such trials will benefit patients and the scientific community before they’re considered.

However, a spokesperson for the EMA responded that the guidelines cover a very broad range of trials and scenarios, and that they will need to be interpreted on a case-by-case basis, “proportionate to the level of uncertainty linked to the novel drug and the characteristics of the subjects.”

Reassuring stakeholders

While news of the French trial tragedy may have made patients and stakeholders uneasy, transparency is key to keeping everyone on board. Patients and volunteers need to be aware of the risks of a trial, and to feel that they’re treated as rational adults, capable of making educated decisions.

Supply patients and volunteers with a comprehensive overview of preclinical data, including rationale behind the dosages given and any potential adverse effects. Ensure that this data is presented in accessible language, without being patronising.

Reaffirm your commitment to stopping the trial at once should any serious adverse effect take place, and to informing all participants immediately, giving them an opportunity to reassess their involvement.

While the casualties of the French trial were tragic and avoidable, the controversy has been a rallying call for members of the clinical research community at all levels to work together and ensure standards are being met and patients are being put first.

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