Clinical trials test new methods of diagnosing, treating or preventing health conditions. The goal of a clinical trial is to determine whether a medical or behavioural intervention is both safe and effective. A clinical trial involves research using volunteers and its purposes is to add to medical knowledge.
In a clinical trial, participants receive specific interventions according to the research plan or protocol created by the sponsor. A variety of interventions are evaluated through clinical trials, including: medications, medication combinations, new uses for existing medications, vaccines, medical devices and behavioural changes, like diet.
Clinical trials may compare a new medical approach to either a standard one that is already available and in use, to a placebo that contains no active ingredients, or to no intervention at all. Some clinical trials compare interventions, that are already available, against each other to see which is best.
When a new product or approach is being studied, it is not usually known whether it will be helpful, harmful, or no different than available alternatives.
The investigators first study the product or approach in the lab and in animal trials to determine safety and efficacy. Once they have met certain standards of safety in these early stages, they move onto different phases of the trial where they start testing the product or approach in people. They first assess the safety of the intervention by observing and measuring the responses of the participants.
In later phases, they look at the effectiveness of the intervention by measuring it against certain outcomes. For example, investigators may give a drug or treatment to participants who have high blood pressure to see whether their blood pressure decreases.
It is important to remember, however, that no treatment is completely safe for everyone but a clinical trial helps make sure that the treatment is safe and effective for the vast majority of people. Without clinical trials we would have no medications or agents to fight illness or to prevent illness in our population.
Clinical trials can take place in many locations, including hospitals, universities, doctors’ offices, and community clinics. The location depends on who is conducting the trial and what is being tested.
Usually, trials are run at clinical research sites. Clinical studies can be sponsored, or funded, by pharmaceutical companies, academic medical centres, universities, voluntary groups, government agencies and a variety of other organisations.
Every clinical trial is led by a principal investigator, often a medical doctor. Clinical trials also have a research team that may include doctors, nurses, social workers, and other health care professionals.
Everyone benefits from clinical trials. New medications and developments in the medical and health fields could not be found if it were not for clinical trials. Any medication that we take today, including something as basic as Panado, has come from clinical trials, and even science about lifestyle choices has been investigated using clinical trials.
Clinical trials have standards outlining who can participate. These standards are called eligibility criteria and are listed in the trial protocol. Some clinical trials seek participants who have the illnesses or conditions that will be studied, while some are looking for healthy participants, and others are limited to a set group of people who are asked by researchers to enrol.
The factors that allow someone to participate in a clinical trial are called inclusion criteria, and the factors that prevent someone from participating are called exclusion criteria. They are based on characteristics such as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions.
The length of a clinical trial varies, depending on what is being studied. Participants are told how long the study will last before they enrol.
This depends on the trial and the risks involved. However, in most instances participants will simply be reimbursed for any costs required to participate. They often also receive free high-quality medical care for the duration of the trial.
No treatment, even ‘natural’ treatments, are guaranteed to be completely safe for everyone even after clinical trials have been performed. The medications we take every day all have side effects and risks.
A clinical trial is designed, however, to make sure that the benefits of the treatment, vaccine or drug outweigh the possible risks for the majority of people.
In the early phases of the trial (Phases 0, 1 and 2) the focus is predominantly on the correct dose and the safety of the drug or treatment. From Phase 3 onwards, common side effects are more or less established, and the main question is then about how effective the treatment or drug is, although safety monitoring continues, even after registration of the new medication.
In South Africa, the following regulatory bodies have to approve the clinical research before any trial can commence:
• Research Ethics Committee – This committee is independent of the sponsor and the clinical investigators. These committees are usually affiliated with a university scientist e.g. specialist, and also someone from the community e.g. pastors, lawyers and traditional healers.
• South African Health Products Regulatory Authority (SAHPRA) – This is an entity of the National Department of Health, created by the South African Government to ensure that the health and well-being of people and animals is prioritised. SAHPRA is tasked with regulating (monitoring, evaluating, investigating, inspecting and registering) all health products. This includes clinical trials, complementary medicines and medical devices.
Other regulatory approvals are also required, for example from the Department of Health and the hospital or clinic involved in the trial.
Internationally, there are also research networks that provide oversight to trials taking place all over the world and all clinical trials are conducted in accordance with World Health Organisation regulations.
Additional safety factors for participants are that:
• Independent data safety monitoring boards (DSMB) monitor trial results and side-effects throughout the process, and will pause or halt the trial if they have any concerns regarding the safety of participants.
• The clinicians who take part in and run the trial also put the interests of the participants first. They work independently and are not dictated to by the sponsors of the trial. As local doctors who are part of the local communities, they really do have the participant’s best interests as their primary focus.
• All trial participants complete an informed consent form, which details exactly what the trial involves and any potential risks. All participants will therefore have all the aspects of the trial explained to them, and have all their questions answered in advance. Informed consent is only valid if the person fully understands what is required, and has voluntarily confirmed their willingness to participate.
• All participants have the option of withdrawing from a trial at any time.
Clinical trials used in drug development are described by a phase once they are ready to test in people. These phases are pre-defined and provide structure to the process.
Phase 0 of a clinical trial generally involves fewer than 15 participants, and in this phase a very small dose is usually given to exclude that the medicine or treatment causes harm.
Phase 1 normally has between 20 and 80 participants, who are all in good health. In this phase the dosing is tested, to establish the highest dose tolerable to people.
In Phase 2 there are several hundreds of participants. In this phase the safety of the medication or treatment continues to be evaluated, and commonly some people with underlying conditions are now involved, to again establish safety.
In Phase 3 there are commonly a few thousand participants. The aim of this phase is to evaluate the effectiveness of the medication or treatment being tested, with safety having been mainly established in phases 0-2. Side effects are monitored. The medication or treatment will be tested in the healthy population, as well as in those with underlying conditions and comorbidities.
Phase 4 trials occur after the drugs have been approved for use by the public. These trials look at long term safety data.
No one is ever forced or coerced to participate. It is a decision every individual makes for him or herself. It is voluntary. People that are considering participating will be provided with comprehensive information about the clinical trial. If they choose to participate in the trial, they will sign a voluntary informed consent form. Voluntary informed consent is the cornerstone of health research ethics.
Voluntary informed consent is a procedure through which a competent volunteer, after having received and understood all the research-related information, can voluntarily provide his or her willingness to participate in a clinical trial. He or she is provided with information about the trial, its aims, benefits, and potential risks. Only after signing a voluntary informed consent form can a participant take part in the trial.
The Clinical HIV Research Unit (CHRU) ensures that all the ethical and legal requirements for voluntary informed consent for clinical research participation are fulfilled. It also adheres to the South African Guidelines for Good Practice in the Conduct of Clinical Trials with Human Participants in South Africa.
Research sites across the world have community advisory boards (CABs). A CAB is an independent body and acts as a watch dog to ensure that studies proceed properly and trial participants’ concerns are accommodated and their rights are protected. Members of a CAB reflect a diverse mix of experiences, profiles and skills, and have cultural insight into the communities participating in the clinical trials. They are volunteers who are trained on good clinical practice. They educate people about clinical trials and about studies taking place at the research site, and they advocate for participants, give feedback on cultural and religious sensitivities and raise community concerns.
The research team, made up of doctors, nurses, social workers and other health care professionals also put the interests of trial participants first. They work independently and are not dictated to by the sponsors of the trial. As local doctors who are part of the local communities, they really do have the participant’s best interests as their primary focus.
Clinical trials are designed to improve the science of medicine. They are not designed to put people at risk. Everything about a trial is made clear to a participant before they sign the voluntary informed consent form:
• What is required from them
• How long they will be involved in the study
• How often they need to go to the research site
• The tests and procedures involved in assessing their health and response to the study
Participants can withdraw from a study at any time. The informed consent process includes counselling which makes it clear that someone can withdraw at any time. The only thing the participant must do is inform the principal investigator of the study that she or he is withdrawing. They do not need to provide a reason.
When a participant enrols for the trial, they are given a card with the names of their healthcare team at the research site, and their contact information. If a participant develops any symptoms or feels unwell in any way, they need to contact the healthcare providers immediately and discuss their symptoms. The healthcare provider may decide that they want to see the patient to assess them, in which case they will be assisted with transport, or, they may refer the patient to a healthcare facility.
Data safety monitoring boards monitor the safety of a clinical trial at regular intervals. Should there be a signal that there is an increase in side effects, they will halt the trial while they investigate the issues and start-up the trial once they are satisfied with all safety aspects.
When a participant alerts the study team to a symptom or side-effect and the scientists respond quickly, it shows that the safety protocols are working and that the safety measures are in place.
The purpose of a vaccine/prevention clinical trial is to determine the efficacy (whether it works) and safety of an investigational vaccine for the prevention of a particular disease e.g. COVID-19.
In a vaccination clinical trial, the vaccine is given to volunteers who are monitored to see if they become unwell, or contract the illness being vaccinated against. This informs researchers as to whether the vaccine is safe and effective.
All vaccines available today have been tested in clinical trials. Vaccines against smallpox, measles and polio were all developed in clinical trials.
Vaccines are designed to develop antibodies to a disease. When someone is injected with a vaccine, their body produces an immune response to the disease in the same way it would following exposure to that disease but the person doesn’t get sick. If the person comes in contact with the disease in the future, the body is able to make an immune response fast enough to prevent the person developing the disease or developing a severe case of the disease.
The active ingredients of a vaccine are made from viruses or bacteria (also called ‘antigens’). They challenge the immune system to fight the disease and create antibodies. Vaccines contain tiny quantities of active ingredients – just a few micrograms (millionths of a gram) per vaccine. To give some idea of how small these quantities are, one paracetamol tablet contains 500 milligrams of the drug, which is several thousand times more than the quantity of the active ingredients you would find in most vaccines. Hundreds of thousands of individual vaccines can be made from a single teaspoon of active ingredients.
Compared to the number of viruses and bacteria in the environment that our bodies have to deal with every day, the amount of active ingredients in a vaccine is very small.
In addition to the active ingredients in a vaccine, vaccines may also contain either a small amount of preservative or a small amount of an antibiotic to act as a preservative. Some vaccines may also contain a small amount of an aluminium salt, which helps produce a better immune response. Aluminium is one of the most common metals found in nature and is present in air, food, and water, and the amount of aluminium contained in vaccines is similar to that found in a litre of infant formula.
At the moment many people’s lives are on hold as we wait to be able to return to ‘normal’. The COVID-19 virus is not going anywhere, with second waves of infection being seen across the globe. It is therefore imperative that we find a way to prevent the virus, particularly in our most vulnerable populations. This would allow people to return to work and to go about their lives again as normal. Prevention of infection in our vulnerable populations is the only way of safely and responsibly returning to ‘normal’ and finding a vaccine is the best and most effective way of preventing spread and disease for those most at risk.
Drugs don’t necessarily work similarly across different populations. Africa has different needs and concerns compared to many other regions of the world. For example, we have had issues with Ebola, and our HIV and TB incidences are very high. It is therefore important that we test drugs on people here to ensure that they work as well for us as they do for other populations.
Over 16000 people have died of COVID-19 since March in South Africa. This includes the elderly, diabetics, people with hypertension, overweight people and others. We have a responsibility to protect vulnerable people whose immune systems and general health may not be as strong as ours to fight the coronavirus. We have also lost many health workers who cannot avoid COVID-19 exposure and we also need to do everything we can to protect them.
Studies for new medications, vaccines, regimens and devices should always be done in countries that will use them. We know that there are genetic differences between people in different parts of the world, and the only way to know if there will be differences in side effects and effectiveness, is to do the trials in all relevant populations. Trials are therefore conducted all over the world.
Previous research studies have shown that the African population has had relatively unique responses to certain drugs and vaccines.
For example, the flu vaccine from 2009 was very effective in European and North American populations, but not in Africa. Another example is the antiretroviral drug Nevirapine, which had very serious side effects in African women with high CD4 counts. Scientists would not have known this had the clinical trials not also been conducted in Africa. Clinical trials provide very controlled structures within which new interventions can be checked for side effects.
As an additional incentive, participating in clinical trials gives us the opportunity to get first access to medications that could prove to be life-saving. This avoids delays waiting for drugs to be fully registered and then marketed.
South Africa has benefitted hugely in the past from being involved in clinical research, in that access to expensive medications that would otherwise have been inaccessible to most of the population were made available to those who needed them most through clinical trials.
In terms of a COVID-19 vaccine, the pandemic affects all countries, and all countries have vulnerable populations that need to be protected. If South Africans don’t come together to ensure that a vaccine is safe for our people, we won’t be giving the vulnerable in our communities the protection they need.
There is currently no vaccine against the coronavirus. There have been stories in the media that have been found to be false, or at the very least entirely unsubstantiated.
There is a fake news story doing the rounds concerning the oral polio vaccine. It was recently announced that wild type polio has been eliminated from Africa, which is a wonderful achievement. However, in areas with very low polio vaccination coverage with low levels of herd immunity, mutations can occur and lead to vaccine derived polio. These outbreaks occur from time to time, but the numbers are very small compared to the cases prevented by polio vaccine.
You can read more here: https://www.who.int/westernpacific/news/q-a-detail/what-is-vaccine-derived-polio.
The Bill and Melinda Gates foundation donate significantly towards many programmes.
It is also worth noting that, generally, websites that make outrageous claims and are trying to sell you something on their page, are often sources of fake news.
Researchers who conduct the study are required to follow strict rules to keep participants as safe as possible. Although side effects can occur in any clinical trial, the study is designed to minimise the risk and participants are monitored very closely.
Large trials have data safety monitoring boards to monitor the safety of the trial at regular intervals. If there is any sign at any stage that there is an unacceptable rate of side effects, or that the severity of side effects is high, the trial will be paused. Upon pausing the trial they will stop recruiting new participants, and investigate the causes of concern. They look at the safety issues and the side effects, and if they establish that the problems were completely unrelated or of such minor significance as to be tolerated, the trial is restarted. This should not be seen as something going wrong with the trial, but rather as the safety procedures being effective.
