Clinical trials have led to the development of many new medicines, medical and diagnostic devices, and procedures for the prevention of diseases in recent decades. Scientists and doctors use them to study newly developed medical interventions to evaluate how well they work and their safety.
Their importance, not just to the medical community, but also to patients themselves, is therefore clear. However, nothing in life, including participating in clinical trials, is 100% risk free, but we will see that in clinical trials a lot is done to minimize the risks. This article will look at how risks in clinical trials are managed, and levels of oversight that exist to ensure that:
- risks are minimized as much as is humanly possible, and
- A clinical trial must present some real medical value to patients before it can be approved, and
- If any safety issues are detected once a trial has started, all possible steps are taken to protect patients.
Safety procedures at the planning and design stage
The organizers of a clinical trial are required by law to explain to you fully the purpose of a trial, the background to the treatment being studied, all the procedures involved during the trial, and all potential risks and benefits to you, before you can be enrolled on the trial. This is known as the informed consent process, and it involves a form - the informed consent form (ICF) - and possibly other educational tools (e.g., videos), that inform you of all the relevant information for your trial, as well as the appropriate time with a doctor to go through any questions you may have. An informed consent form must be signed by you before you can start on the trial, to confirm that you fully understand the process and any risks involved.
Clinical trial protocol
So that the results of clinical trials can be used as scientific proof that new medicines are safe and effective, clinical trials are run in a very careful, controlled, and closely monitored way. For example, all trials must follow a detailed plan, known as a protocol. A clinical trial protocol describes how a trial will be conducted, and contains information about the goals of the trial, who is eligible to take part, what safety measures will be taken to protect participants, details about what tests, procedures and treatments will be carried out, and how long the trial will last.
Clinical trial protocols are always designed based on the results of preliminary safety and efficacy studies that can tell researchers if there are any potential risks in particular to look out for in a trial, and what they are likely to be. The results of these studies - carried out on human cells or in animal models - are then used to build safety checks and considerations into the design of the trial itself. For example, certain types of patients with other illnesses or conditions, or who are on certain types of medications that put them at extra risk may be excluded from the trial.
As well as carefully controlling what kinds of patients can join a trial, many checks are carried out at frequent and regular intervals during the trial itself, to look for any signs of possible safety issues. For example, during a trial, blood and other specimen samples are taken from patients at regular intervals and analyzed for any kind of abnormality that would suggest the possibility of harm to the patient. As well as analysis of blood and specimen (e.g., urine) samples, other tests are performed regularly to monitor patients’ wellbeing during trials, such as electrocardiograms, or ECGs - to check heart health - physical examinations, vital signs checks (heart rate and blood pressure) and reports from patients of any adverse effects they are experiencing. These assessments are also important to check that the medication or procedure is actually working. If a test medication or procedure is found not to be having any beneficial effect during a trial, a trial may still be stopped, regardless of there being any safety issues or not, as there would no longer be enough benefit to patients to justify the potential risk of being on the trial.
Levels of safety review: groups involved
On top of the described safety procedures that are part of the planning and conduct of the trial, there are also a number of different levels of oversight that exist throughout the planning and conduct stages of a trial to ensure these safety procedures are being carried out correctly at all times. Each of these levels of oversight has the authority to halt or require modifications to the procedures of a trial if it feels any aspect of the trial is posing an unreasonable, or unjustifiable level of risk to patients.
Internal disease team
In brain tumor studies, for example, each site will have a group of brain tumor specialist physicians that will review a clinical trial’s protocol and other safety documents (including ICF) before starting, and only then approve a study if they feel everything possible has been done to protect patients’ safety.
In cancer trials, the main coordinating center will also review all trial documents to evaluate whether the benefits of the trial justify the potential risks, whether patients’ safety is adequately protected, whether the study is even feasible at the site, and whether it presents some real value to patients, before giving approval for the trial to go ahead. If approved, the study then moves on to the next level of oversight, the Institutional Review Board (IRB).
Institutional Review Board (IRB)
An Institutional Review Board is a group of doctors, nurses, chaplains, social workers, lawyers and patients established to protect the rights and welfare of patients in clinical trials. IRBs are responsible for checking that a trial is well designed, legal, ethical, does not involve unneeded risks, and includes a safety plan for patients. All clinical trials must be reviewed and approved by an IRB before they can begin, and IRBs have the authority to disapprove or require modifications to, as well as approve clinical trials.
Three of the main safety review activities performed by the IRB are the initial protocol review, the reviewing of interim data reports, and carrying out audits.
Initial protocol review
The IRB’s initial review of a clinical trial protocol is guided by international and national ethics standards, which means that before approving any trial, an IRB will look at the protocol to check that:
- Any risks associated with the trial are minimized as much as possible
- Any risks are reasonable and justified by the benefits of the trial to patient
- The trial has an adequate and documented Informed Consent process to ensure that all the risks and potential discomforts as well as benefits are clearly described to patients beforehand.
- The trial includes an appropriate plan and schedule to regularly monitor data being collected during the trial for any signs of potential safety issues
- The privacy and confidentiality of patients will be protected, and their data kept confidential.
- There are safeguarding measures in place to protect any patients who are likely to be vulnerable to coercion or undue influence - e.g., children, disadvantaged individuals, mentally disabled people.
Interim data reports
After the trial starts, researchers must also submit to the IRB any analyses of the data being collected that suggest either an increased level of risk, for example more frequent or severe than expected side effects, or a decrease in the level of benefit to the patient, for example a lower effectiveness than expected of the treatment being tested. After examining the reports, the IRB can take action to terminate the trial, pause it until issues are investigated further and the risk level is confirmed as safe enough to continue, or allow it to continue if it feels the risk is acceptable based on the benefits to the patients.
IRBs also have the authority to request an audit of a clinical trial if they have any concerns about the conduct of the trial or about the process of obtaining informed consent. An audit will involve a thorough check of all study-related documentation (including the protocols and informed consent process) and data to ensure the trial is being carried out ethically, is being fully documented, and is complying with all relevant institutional, state and federal safety and quality requirements.
Food and Drug Administration (FDA)
The FDA is a federal agency that is also responsible for overseeing clinical trials, to make sure they are designed, conducted, analyzed and reported in accordance with federal law and international standards. If a new drug is being tested in a clinical trial, before it can be given to patients in a clinical trial, the developers must also submit an application to the FDA for approval, called an Investigational New Drug (IND) application. An IND must include all the evidence collected in preliminary testing that suggests the drug could be effective and safe, details on how the drug is manufactured, information about the Drs working on the trial, and a copy of the clinical trial protocol.
The FDA is also authorized to carry out audits of clinical trials, to check that all procedures are being followed and documented correctly. Audits can be announced, or unannounced, and can be in response to a particular complaint or simply routine inspections. For this reason, it is in a clinical trial site’s best interests to be always “inspection-ready”, i.e. ensure that all required documentation is continuously correct and up to date, and that trials are always being conducted in line with all safety guidelines. If the FDA finds any safety issues during an inspection, they are authorized to terminate the trial, or pause it until improvements are made.
Data Safety and Monitoring Board (DSMB)
An additional level of oversight on clinical trials that looks out for any signs of safety issues is the Data Safety and Monitoring Board (DSMB). A DSMB is an independent group of clinical experts that review data being gathered from the clinical trial to assess the safety of the participants and the efficacy of the treatment being studied. Based on their assessments, a DSMB can make recommendations on the continuation, modification, or termination of a clinical trial.
Safety Reporting to the IRB and FDA
Organizers of clinical trials - known as sponsors - must regularly update both the IRB and the FDA on any suspected side effects, or medical issues, experienced by patients on a clinical trial. As well as scheduled, regular reports on safety issues, any serious issues that result in a patient being hospitalized or dying must be reported immediately to the IRB and FDA. Sponsors must notify the FDA within 15 days of serious issues, or within 7 days of life-threatening or fatal issues. Reports of serious, and life-threatening issues must be sent to IRBs within similarly short timelines, and reports of fatal events must be reported to IRBs within 24 hours.
Early termination of a clinical trial
The FDA and IRBs have the authority to terminate a clinical trial, and the doctors in charge of a trial can stop any new patients from joining a trial, if they have reasons to believe that there is no longer any justification for exposing patients to the risks of being in a trial. Examples of reasons why the FDA or an IRB might terminate a trial early include:
- Safety - for example severe and unexpected adverse events (potential side effects to the drug) - that mean the risks to patients are too great to continue.
- Efficacy - if the drug is not working sufficiently well, it is no longer possible to justify exposing patients to the risk of being in the trial. Similarly, if a drug is working much better than the treatment it is being compared to, it would no longer be ethical to deny patients from receiving it, and therefore the trial may be stopped so all patients can receive it.
- Serious issues were found during an audit, e.g., lack of compliance with safety guidelines that mean the trial is not being conducted safely.
- If misconduct has been found, e.g., fabrication or falsification of data
There are inherent risks in clinical trials, as part of their objective is to understand more clearly the safety of new treatments. However, researchers will already have an idea of the potential risks beforehand, and clinical trials are very carefully planned and closely monitored in order to minimize risks to patients. On top of this there are several levels of expert oversight whose responsibility it is to ensure that clinical trials are being planned and carried out safely and meeting all safety requirements, as well as closely monitor a trial during its conduct to look out for any signs of safety issues. These levels of oversight all have the authority to terminate a trial early or pause it until changes or further investigations are made, if they feel that it may be unsafe for patients to continue. For these reasons, as well as the benefits of potentially receiving a promising new treatment months or even years before it becomes widely available, it is highly recommended that if you are considering participating in a clinical trial, you should discuss it further with your physician to understand the potential risks and benefits.