Australia: Clinical drug trials – what could possibly go wrong?

Last Updated: 7 March 2016
Article by Anna Feros

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.

Clinical trials

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.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on

Click to Login as an existing user or Register so you can print this article.

Some comments from our readers…
“The articles are extremely timely and highly applicable”
“I often find critical information not available elsewhere”
“As in-house counsel, Mondaq’s service is of great value”

Up-coming Events Search
Font Size:
Mondaq on Twitter
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
Email Address
Company Name
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
United States
Worldwide Updates
Check to state you have read and
agree to our Terms and Conditions

Terms & Conditions and Privacy Statement (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

Use of

You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these terms & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.


Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use or performance of information available from this server.

The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.


Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.

Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

If you do not want us to provide your name and email address you may opt out by clicking here .

If you do not wish to receive any future announcements of products and services offered by Mondaq by clicking here .

Information Collection and Use

We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to with “no disclosure” in the subject heading

Mondaq News Alerts

In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.


A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

Log Files

We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.


This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

Surveys & Contests

From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.


If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.


This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to

Correcting/Updating Personal Information

If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to

Notification of Changes

If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

How to contact Mondaq

You can contact us with comments or queries at

If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at and we will use commercially reasonable efforts to determine and correct the problem promptly.