Protecting participants

One of our core responsibilities to those taking part in our trials is to make sure that we protect them from any unnecessary risks. Throughout the research process, we continuously review, and make judgements on whether the potential benefits of a new medicine continue to outweigh the risk of side effects.

In addition to compliance with all relevant laws, we have strict internal procedures for managing safety issues during clinical trials and ensuring we act in the best interests of participants.

How do you know a new compound is safe enough to be tested in humans for the first time?

Data gathered from our pre-clinical research, including animal research and testing in vitro, forms the basis of our assessment of whether a new compound is safe enough to be tested in people for the first time.

We have formal committees that evaluate our pre-clinical research to decide whether we should proceed to clinical trials. They must judge whether the potential benefits of a new compound outweigh its likely side effects. There is no established formula for deciding what level of risk is acceptable – it will depend on how the new medicine will be used and the disease it is intended to treat. For example, in treating life-threatening diseases such as cancer, potentially serious side effects may be judged acceptable because of the potential benefits the medicine offers in saving or extending life. The committees will also decide on the appropriate dose – ie how much of the new compound can be safely given to trial participants. The committees are chaired by the Chief Medical Officer and include experts in toxicology, pharmacology, patient safety, clinical and regulatory affairs.

All trials must be approved by external national or local ethics committees. They review our data and make an independent decision on whether a compound is safe enough to be tested in people. They also review the trial protocol, and assess the suitability of the investigators, facilities, and informed consent process. An ethics committee is made up of medical professionals and non-medical members.

We do not conduct clinical trials in countries where there are no appropriately staffed, independent ethics committees. In most countries our data are also reviewed by the local regulatory authority which must give approval for a new trial to begin.

How do you make sure that patients understand the possible risks of taking part in a trial?

Patients and volunteers must give their informed consent before they participate in a clinical trial. During the informed consent process, participants are given information about the purpose of the trial and how it will be conducted. They are informed what the potential benefits and likely risks of the new medicine may be, including any specific risks identified during pre-clinical research. It is also explained that they could potentially receive a comparator drug or placebo rather than the new treatment and the likelihood for that. It is made clear that they can withdraw from the trial at any time without giving a reason and without impact for their future care. This information is summarised in a written information leaflet.

Information is made available in a language that the participant is able to read and understand, and throughout the informed consent process there are opportunities for the participants to ask questions.

In some countries literacy levels differ, and some participants in our trials may not be able to read or write. In these situations, the written information is read and explained to the subjects before signing. An independent witness must be present throughout the whole process and must confirm that the participant has received and understood all the information they need to give their informed consent. The witness must also sign and date the consent form.

Consent forms include a lot of information, most of which is required by law. We need to balance the need for detail with the necessity to provide clear information that can be easily understood by participants. If forms are too complex or detailed it may be difficult for people to identify the key points and understand the potential risks and benefits. We work on an ongoing basis with regulatory authorities and our trade associations to improve the consent forms.

The consent form must be signed by the participant and by the physician providing the information before we begin the trial. Consent forms also include information on data privacy and confidentiality. The informed consent process is included in our monitoring and auditing of clinical trials.

Do children ever take part in your trials? How do you obtain their consent?

Some of our medicines, such as asthma therapies, are designed to treat children as well as adults. Sometimes a child can receive a reduced adult dose of a medicine, adjusted according to body weight, but in many other ways, children are not miniatures of grown-ups. Normally, every medicine must be studied separately in children to ensure factors that vary according to age, such as liver and kidney functions, are accounted for in establishing the right dose.

In a number of regions, including the US and Europe, paediatric studies are now mandatory if a new medicine has potential for use in children/ adolescents.

When minors (under the legal age of consent) participate in a clinical trial, we obtain consent from their parents or legal guardians. The trial process is also explained to the minor directly if possible. The amount of information given will vary according to the age of the minor. We work with experienced child healthcare professionals to ensure that the information provided for the minor, and for the parents or legal guardians who give the informed consent, is appropriate to the age of the minor. If the minor is able to write, their written assent is sought, as well as the consent of their parents.

How do you identify safety issues during a trial and what steps do you take to prevent them?

Patient safety is a core focus of all our clinical trials, and safety information is collected and evaluated continuously throughout our studies.

On a day-to-day basis, the doctors and investigators responsible for running the trial are responsible for identifying and reporting safety issues, in line with our established trial protocol.

We also work to ensure that steps are taken from the outset to reduce risks for participants.

  • In Phase I trials, we start off with very low doses of the new compound in healthy volunteers to establish whether it can be tolerated. Doses are then increased to allow us to determine a dose or a range of doses that may show appropriate safety and efficacy for the treatment of patients.
  • Trial participants are asked to identify any potential side-effects.
  • Clinical trials involve additional measurements, such as blood tests and blood pressure monitoring, which may not be part of standard clinical care, to assess the effects of treatment.
  • For some studies, in addition to our own internal resources, we also use independent external safety data monitoring boards to further strengthen the safety evaluation process.

Potential side effects and safety issues that we identify during a trial are known as adverse events. It is important to note that not all adverse events will be related to the medicine being tested.

We report all serious adverse events to Health Authorities and the independent Ethics Committees who approved the trial and notify investigators and participants, as appropriate.

If serious adverse events are identified during a trial there are a number of steps that can be taken to address them. These include:

  • Increased safety monitoring of trial participants.
  • In the most extreme cases we may stop the trial entirely or for certain subgroups.

Why do you perform placebo-controlled trials?

Placebo-controlled clinical trials can be necessary to establish the efficacy of medicines under investigation. Sometimes, just the act of giving a patient a pill results in some benefit to the patient - the so-called ‘placebo effect’. We do placebo-controlled trials to show that the medicine we are giving patients has a benefit over and above that of giving a placebo. The placebo control can also help us in assessing the side effects observed with the new treatment. Placebo-controlled trials can form an important part of the assessment by both product manufacturers and regulatory authorities when considering the overall benefit / risk profile of a product. In some cases, regulatory authorities may require placebo-controlled trials.

Different types of placebo-controlled trials are used to evaluate the safety and efficacy of medicines. As part of our informed consent process, participants are told that they may receive a placebo during the trial. An increasingly common type of placebo-controlled trial is the 'add-on' trial, where a new treatment, or a placebo, is administered in addition to the patient’s standard current therapy. This enables us to compare the effectiveness of a new treatment with placebo whilst at the same time allowing participants in the trial to continue to receive their standard therapy. For example, in the design of a trial for a new cancer therapy, we may have all patients in the trial receive standard chemotherapy. Patients would then receive either the new treatment or a placebo in addition to the standard therapy. In this way, we can evaluate whether the new therapy provides value to patients over and above the standard therapy.

Whilst such ‘add-on’ placebo-controlled trials are widely used, in some situations a new treatment may need to be evaluated directly and not when added to a patient’s standard therapy. This could be the case, for example, where a patients existing medication ‘masks’ the effect of a new therapy (see below).

Patient safety is always a core priority

For example, in a trial setting, the existing medication that asthma sufferers use may ‘mask’ the effect of a new therapy, and this effect may last for some time after the patient comes off their treatment. In this situation, a patient may be willing to forego their treatment for a short period during the trial in order that the effectiveness of the new therapy can be accurately assessed. We always gain informed consent from the patient first and ensuring their safety is paramount. When this type of placebo controlled trial is used, a number of safeguards are put in place. These include enrolling patients with milder forms of asthma and the allowance for the use of ‘rescue’ or ‘escape’ medications when study participants feel their asthma symptoms require it. These safeguards are in addition to the provision of 24 hour contact numbers and instructions for what to do in the unlikely event of an emergency.

If patients benefit from a medicine during a trial, do you continue to provide the treatment once the trial is finished?

We recognise that situations may exist where continued provision of non-approved clinical study drug to patients is both appropriate and necessary following the completion of a clinical study.

Factors we take into account include the severity of the disease being treated, the local availability of alternative treatments, the development stage of the new medicine, the individual patient response to the medicine, and the overall benefit/risk profile of the medicine based on completed and ongoing studies. If a decision is made to continue to provide a clinical study drug after the original study is completed, we will ensure that appropriate oversight measures are in place, such as dispensing treatment in the context of a clinical study or a compassionate use programme.

Once we have provided a clinical study drug to patients after completion of the clinical study, we will continue to do so until either the drug is licensed in that country, or it is determined that the benefit/risk profile does not support continued development of the drug, or the national health authority has deemed the drug not approvable. In all of these scenarios, we will work with investigators on the proper transition of patients to alternative therapies if possible.

For our clinical trials with nationally-approved AstraZeneca medicines, we do not typically provide continued treatment after the completion of a clinical study. Approved medicines are usually available to patients through their government, national healthcare programme, or insurers. However, in exceptional circumstances, where our medicines are not accessible to patients, we may provide them.

In general, we address the issue of post-study provision of clinical study drug in pre-study agreements, the clinical study protocol, and within the patient informed consent.

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AstraZeneca is committed to making information about our clinical trial activities publicly available.

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