Industry Focus: Life Sciences & Healthcare
What you need to know
- The tragedies that occurred in a recent new drug trial in France have again focussed attention on the safety of clinical trials, as the trial is the second in ten years to have involved significant serious adverse events.
- Those involved in human drug development will know that there are extensive regulations and guidelines that apply to the clinical trial landscape, and compliance with them is essential.
- The events in France have stimulated discussion, analysis and review of the sufficiency of some aspects of the current regulations and guidelines, and could potentially lead to change.
The recent death of a male participant in the Bial new drug trial in France is a tragic reminder that these types of trials are exactly what their name suggests - 'trials' of new drugs, or new aspects of already approved drugs (for example, new dosage regimes or delivery mechanisms, use for different indications, new combinations with other treatments, or use in different age groups). The event also made many in the life sciences industry shudder at the memory of the 2006 TeGenero clinical trial in London when six healthy volunteers suffered serious reactions within minutes of dosing, leaving them in intensive care with multiple organ failure (an incident described by some as the biggest setback for medical testing since thalidomide).
There are risks in all clinical trials, but there are also extensive regulations and standardised practices which must be followed to minimise those risks as much as possible and ensure that these types of tragedies are exceptionally rare.
This article provides a brief overview of the clinical trial landscape including some of its inherent risks, and offers insights on how the recent events in France could potentially lead to change.
The road to bringing a drug to market
R&D and pre-clinical testing
Research and development of new drugs or investigational medicinal products (IMPs) begins in the laboratory with scientists, including chemists and pharmacologists, who identify cellular and genetic factors that play a role in specific diseases and conditions. In the preclinical stage of drug development, an investigational or new drug must be tested extensively in the laboratory and using appropriate animal models to ensure it will be safe to administer to humans. Testing at this stage can take years and must provide information about the pharmaceutical composition of the drug, its safety (toxicology), how the drug will be formulated and manufactured, and how it will be administered to the first human subjects.
The next stage of drug development is the clinical trials. In most countries, the results of all pre-clinical testing together with other documentation must be provided by the sponsor of the proposed clinical trial (the drug company or its representative) to the appropriate regulatory agencies (for example, the FDA in the US and the EMA in the EU) to obtain authorisation to begin clinical testing in humans. In addition, all clinical trials must be approved by an ethics committee or internal review board which checks that the trial conforms with ethics requirements. The ethics committee may be a centralised body covering many hospitals, or the ethics committee of an individual hospital where the trial will take place.
Australia has a slightly different regime. Here, a sponsor has the option of submitting all information to the ethics committee first, and once its approval is obtained, having the doctor running the trial (known as the Principal Investigator) notify the Therapeutic Goods Administration (TGA) of the intent to conduct a clinical trial.
If the clinical trials are successful, the results of the trials together with other information relating to the drug are submitted to the relevant regulatory authority as part of an application for a marketing authorisation or licence to allow that drug onto the market.
Phases of clinical trials
Clinical testing is usually described as consisting of 'phases'. In each successive phase, increasing numbers of participants are tested. A clinical trial authorisation must be obtained from (or in Australia, notification may be given to) the relevant regulatory authority before the commencement of each phase of a clinical trial. There are four major phases of clinical testing.
- Phase I studies are designed to verify the safety and tolerability of the candidate drug in increasing doses in humans. They are also known as 'first in man' studies, conducted in a small number of healthy volunteers. Testing includes observation and careful documentation of how the drug acts in the body including how it is absorbed, distributed and metabolised.
- Phase II studies are designed to determine effectiveness and further study the safety of the candidate drug in participants suffering from the condition the investigational drug is designed to treat. This testing determines safety and effectiveness of the drug in treating the condition, and establishes the minimum and maximum effective dose.
- Phase III studies provide expanded testing of effectiveness and safety of an investigational drug, usually in randomised and blinded clinical trials in larger numbers of participants.
- Further testing may be undertaken post-approval in Phase IV trials, which expand testing of a proven drug to broader patient populations, and compare the long-term effectiveness (and cost) of the drug to other marketed drugs available to treat the same condition.
How risks are considered in clinical trials
Risks with a new drug (or new aspects of an existing drug) are usually considered in thorough scientific research and pre-clinical testing. Once the clinical trials stage begins, there are several ways in which risks are further considered, anticipated and handled. These include:
- selection of appropriate clinical trial sites and Principal Investigators
- careful preparation and compliance with the sponsor documentation including the Protocol to be followed for conducting the clinical trial, the Investigator's Brochure which sets out relevant background information and data, and the IMP dossier which contains information regarding the quality, manufacture and control of the IMP
- compliance with regulatory agency authorisation and ethics committee approval
- compliance with all legislation, regulations, guidelines and standard operating procedures (SOPs)
- compliance with Good Clinical Practice (GCP) guidelines as established on an international basis and applied within the relevant jurisdiction
- compliance with the World Medical Association's Declaration of Helsinki which sets out ethical considerations for experimentation on humans
- sufficient monitoring, keeping of detailed records (including the Trial Master File) and reporting of progress during the clinical trial, which includes safety reporting of adverse events (or reactions) in accordance with GCP as well as relevant legislation and guidance (pharmacovigilance)
- taking out and maintaining clinical trials insurance to cover all risks involved at a level that is sufficiently high for the trial, the Principal Investigator and its team, as well as the participants for any trial-related injuries
- detailed, finalised and executed clinical trial agreements with all trial sites, and sometimes separately with the Principal Investigators as well, setting out all relevant obligations including referencing those set out by law and guidance. Trial sites are usually hospitals but in the case of Phase I trials, some contract research organisations (CROs) have established Phase I units specifically designed for the conduct of Phase I trials only
- if the sponsor is using a CRO to conduct the clinical trial, an appropriately detailed, negotiated and executed CRO services agreement, and
- preparation of a detailed Informed Consent Form (ICF) for each participating participant. The ICF must have sufficient information to enable the potential participant to understand the details of the trial, the obligations and the risks involved. Each potential participant must also be given sufficient time to review the ICF and ask questions.
All of the above must be taken into account and taken seriously.
Lessons from the TeGenero clinical trial
Investigations into the 2006 TeGenero clinical trial raised issues regarding:
- inadequate pre-clinical in vitro testing, despite the minimum regulatory guidance at the time having been met
- participants having insufficient time to review and understand the ICF
- inadequate insurance
- lack of monitoring of participants who had suffered adverse reactions, and
- dosage timing issues, as all participants dosed in the affected cohort were dosed within one hour rather than sequentially to observe whether a reaction occurred before dosing the next participant.
After the TeGenero trial, Phase I clinical trials guidelines were heavily revised, particularly in relation to the timing of administering high doses of an IMP.
Bial's Phase I clinical trial
Bial, Portugal's largest drug company founded in 1924, outsourced the running of its Phase I clinical trial of new drug BIA 10-2474 (an experimental therapy for the treatment of various neurological conditions acting on the endocannabinoid system to target pain) to the well-established French CRO, Biotrial. Biotrial ran the trial in its Phase I unit within the Rennes University Hospital in France.
The overall trial began in July 2015 and the IMP had been given to 90 participants without any reaction prior to incident. More recently:
- On 6 January 2016, six participants designated to test the higher dosage regime started receiving their increased daily multiple doses of the IMP.
- On the evening of 10 January, one participant reacted badly and was hospitalised. The trial continued and the remaining five were given the next dose of the IMP the next morning on 11 January.
- Later in the day on 11 January, the hospitalised participant fell into a coma and subsequently died one week later.
- The remaining five participants were hospitalised between 13 and 15 January. Last reports available at the time of publication stated that of these five, three have been left permanently brain damaged, one is unaffected and one has neurological problems (although there are also conflicting reports stating that the remaining five are all slowly recovering).
Bial and Biotrial immediately suspended the clinical trial on 11 January when the first hospitalised participant fell into a coma, and they called in all trial participants for examination. Biotrial notified the French authorities of the serious adverse reactions on 14 January. The French authorities also moved quickly to investigate and have released initial findings, with a full report currently expected at the end of March. Initial findings state that no regulations were breached and Biotrial's certification to conduct clinical trials has been maintained.
However, questions have been raised by commentators and the French Health minister regarding the fact that the participants were dosed almost simultaneously, and five of the participants continued to be dosed the next morning following the hospitalisation of the first participant (who ultimately died) but they were not informed of this fact to allow them to reconsider their continued participation in the clinical trial. In addition, Bial and Biotrial did not notify the relevant authorities until four days after the first serious adverse reaction, which some may consider to be slow. However, GCP and the current European clinical trials directive (as well as the forthcoming replacement EU regulation) are clear about the timing of the notice that the sponsor must provide to the regulatory authorities, and Bial's notice timing falls within the maximum legislated time period for expedited reporting. These periods are the same as those set out in GCP guidelines as adopted by the TGA in Australia.
Where to from here?
In the wake of the events in France, calls have been made for Bial to release further pre-clinical and clinical trial documentation to allow third parties to review the data (particularly, the animal testing data). Bial has so far refused, citing trade secrets. This is further fuelling the long-running intense debate within the industry about clinical data transparency. In addition, Janssen (a unit of Johnson & Johnson) has suspended its Phase II clinical trial of a similar drug until investigations have concluded.
Both Bial and Biotrial have maintained their positions that they complied fully with all applicable regulations, guidelines and processes. The full investigative report by the French authorities is due at the end of March, and should be very interesting as it is expected to disclose further relevant information, such as the actual dosing schedule and whether the deceased participant had an unknown predisposition that may have played a role in his reaction. It should also disclose whether the pre-clinical data was considered sufficiently before moving into human clinical trials.
In the meantime, observations made so far may lead to possible consultation and legislative review in France (and the EU) including in relation to potentially shorter reporting timeframes for serious adverse events, whether even more information should be provided to participants at different stages of a clinical trial and when specific events arise during a trial, and re-examination of dosing regimes. The results of such a review will also have global ramifications for all clinical trial regulatory regimes including Australia's as most jurisdictions aim to harmonise drug regulation at all levels.
This article is intended to provide commentary and general information. It should not be relied upon as legal advice. Formal legal advice should be sought in particular transactions or on matters of interest arising from this article. Authors listed may not be admitted in all states and territories