Safeguarding Subjects
October 2007
Dr. Tim Mant, senior medical adviser at Guy’s Drug Research Unit for Quintiles, explains the importance of protecting volunteer safety in early clinical trials.
It is without question that society needs more safe and effective drugs for a number of conditions; and the proper development of these drugs requires a considerable investment of both time and money. Unfortunately, pre-clinical testing does not tell researchers everything about a therapeutic. Therefore, it is a necessary and critical step in the drug development process to test the drug in humans, and for ethical, medical and practical reasons, these studies often are reliant upon healthy volunteers. Ensuring their safety is one of the most important tasks that we, as an industry, are charged with.
From tolerability, to time course of absorption, distribution, metabolism and excretion, there’s a whole range of critical data that can come only from testing a new drug candidate in volunteers. This has been a common research practice for decades and, by and large, the track record with regard to safety is remarkable, both in the U.K. and elsewhere.
Before a new drug candidate is ever administered to humans, the pre-clinical work must be scrutinized by investigators, regulators and, in some cases, ethics committees, so that they can gain a solid understanding of the science behind the drug. It’s also a good practice to think about the worst-case scenario so that you can design the study so the trial is low-risk. With healthy volunteers, the risk must be minimal—or else it’s not ethical to do the study.
Exercise Caution
The clinical research industry’s approach to early-phase clinical trials has become slightly more conservative in the past year, a reasonable reaction following the TGN1412 incident, in which healthy volunteers who were given the novel monoclonal antibody experienced severe adverse events. For the most part, there’s more focus on dose staggering and the way in which the pre-clinical data is evaluated. The scrutiny is higher for molecules defined as “high risk” by the MHRA. In the U.K., investigators can receive an evaluation from an expert advisory group (EAG) as part of the regulatory submission process. Since monoclonal antibodies have such a specific target, you should be able to predict what may happen. So the contribution of the EAG is really to help raise the right questions in the early stages to ensure that the drug is safe and investigated correctly in humans. This will help to fully protect volunteers and patients in the future, whilst avoiding unnecessary delay, that’s the way to go.
Choose Wisely
It is important to screen the volunteers very carefully. Beyond standard informed consent, a full medical history and mental examination must be part of the screening process. Obviously, simple things like age and weight may affect how the drug will be handled by the body.
To help differentiate drug effects we’re looking for a very homogeneous group of people and reduce “normal” variability. We look also at kidney function, liver function and bone marrow function, and we’ll run an ECG to make sure the heart rhythm is normal. The entire process is to ensure that the volunteers are fit, healthy people when they enter the study, so that if there is a slight change, we’ll be able to pick it up immediately. In the U.K., we’re lucky because we have a very good system of general family practitioners, in which patients are registered with their family doctor. A trial unit can contact the family doctor—provided they’ve obtained informed consent from the volunteer to do so—and confirm the medical history that the volunteer has submitted.
Train Well
Perhaps the most important aspect of ensuring safety is the quality of the staff of the clinical trials unit itself. You’re only as strong as your weakest link in this type of research. A common practice is to perform a full safety assessment between doses so investigators can decide if it’s reasonable to continue with the planned next dose or not. Naturally, continuous monitoring of the volunteers—and knowing how to interpret any change—is a critical function of the unit’s staff. One mistake by any of member of the team can have a detrimental effect on that drug’s development or more importantly increase the risk to the trial participants and future patients.
At Quintiles, our clinical research staff members are trained rigorously, and our aim is to make the training and procedures as user-friendly for the staff as possible. We continually emphasize how important it is to do things accurately and safely; otherwise, you could do people harm. Our approach to safety is a bit like the airline industry in that we have good procedures, good staff and good systems with plenty of checks and balances. There is continuous assessment of performance with feedback from trial participants, staff and sponsors. Having properly trained staff members who can identify problems early is fundamental to ensuring the safety of healthy clinical trial volunteers.
Whilst the sponsor, CRO, Regulatory Authority and Ethics Committee all have an integral part in ensuring safety, it is the Investigator who is the person primarily responsible for the safety and welfare of the trial participants.
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