By Tiia Pelkonen & Chiara Facciotto
(In Finnish / suomeksi)
The survival of ovarian cancer patients has improved only modestly in the past decades – still less than 50% of the patients are alive in five years. However, new therapies are now emerging from basic research and clinical trials into patient care. To have some insight on the clinical trials part of a drug’s journey to the clinic, we interviewed MD Johanna Hynninen, a specialist in gynecologic oncology at the Turku University Hospital, Finland. We discuss here the basics of clinical trials, what are their limitations, and how they can benefit the patients.
What is a clinical trial and how does it work?
A drug has to go through several phases of research and clinical development before it can be approved for use in patients. In drug development, only 1 out of 10,000 preliminary compounds is approved for clinical use after approximately 10 years of research and trials. Clinical trials are divided into three main phases before approval:
- Phase 1 trials study the safety of a compound, its dosage, and side effects in humans.
- Phase 2 trials study whether the drug has the desired effect on the disease and gather further safety information on a larger number of people (100-300).
- Phase 3 trials confirm the efficacy of the drug on larger numbers of patients (1000-3000), compare its performance to other treatments, and collect further information on its safety and side effects.
After approval, information is still collected from the use of the drug (reported side effects etc.) and used to modify the dosage or safety information if needed (Phase 4). It is always important to report any possible side effects, as some are so rare that they are only discovered once the drug is in wide-spread use.
Before a drug can go on to a clinical trial, it has already some data on safety, pharmacodynamics (what effect the drug has on the body) and pharmacokinetics (what effect the body has on the drug) from cell and animal studies. These studies provide preliminary data on the dosage and how often you can take the drug (more about clinical trials in wikipedia).
In Phase 1 trials, the drug is only tested to see if the human body can tolerate it, not whether it has any effect on the disease. Usually in Phase 1, drugs are tested on healthy volunteers, but cancer research is different, since cancer drugs cannot be given to healthy people. Cancer drugs in Phase 1 trials are tested on patients who receive no more benefit from regular treatments and are willing to try something else, even though there is no guarantee that it will help either. In Turku Central Hospital, there are currently a couple of Phase 3 trials in ovarian cancer. This means that in addition to the standard treatment, the participating patients receive either a new trial drug (for example immunotherapy or PARP inhibitors) or a placebo.
Who designs and carries out clinical trials?
Most clinical trials are designed by pharma companies when they have a compound that they want to test and sell. The companies usually contact associations, such as the Nordic Society of Gynecologic Oncology, and the members of these associations discuss together whether this trial is something they would like to have. If the members agree, then hospitals in the association countries are asked to participate. Nowadays almost all clinical trials are large international collaborations with several hospitals. Especially in the case of rare diseases, it is important to include many sites to recruit enough patients.
Once a hospital decides to take part in a certain trial, the doctors will identify those patients who would be suitable for the trial, explain what the trial is about, and ask the patient to sign the informed consent document. After this, pathology slides, meaning the samples used to diagnose the tumor, are often sent to the study organization for central review, to check the diagnosis and to confirm that the patient can be enrolled in the trial.
How do you make sure a drug is safe?
There are many tests to follow up the dosage and amount of the drug in the blood, and to measure whether it is causing damage to the liver or kidneys, for example. Patients are also monitored closely. They fill in forms and write down how they feel and what kind of side effects they are experiencing.
How serious a side effect can be to still be considered ‘tolerable’ depends on how effective the drug is and what it is trying to cure. For young patients who can be cured of cancer, it’s probably fine to stay six months in bed due to side effects. But if the drug only extends life by a few months, it should also be quite well tolerated. For patients with advanced cancer, quality of life and the opportunity to spend time with their family are usually more important.
What are the limitations of clinical trials?
Phase 1 and 2 trials naturally have risks because the compounds are new and there is no certainty that they will not harm anyone. During Phase 3 the drug should already be safe.
Patients may also have high expectations that the drug will cure them, but they might be receiving the placebo. And if they are receiving the trial drug, they may suffer side effects possibly without any benefit. That is why it is important that patients are well informed when they consider participating in a trial.
Participating in a trial may also mean that you have to travel more often to the hospital if you live far away. But participation is always voluntary: nobody has to participate if they don’t want to, and it doesn’t affect their patient-doctor relationship. However, most patients who are asked want to participate.
It’s very rare to have any drug trials for children or pregnant women, but it’s important to have different age groups represented. Younger and more fit patients participate more often in clinical trials, so in the elderly, children or pregnant women the drug may have more or different side effects. If a drug is approved for adults, it’s not trivial to then approve it for children. So in some cases, a drug simply isn’t approved for children because it is too difficult to study whether it’s safe for them.
What are the benefits of participating in clinical trials for the patients?
For the patients, participating in a trial means they are monitored a bit more, have more blood tests and CT (computed tomography) scans taken, and the study nurses and doctors see them very often.
Participating in a trial may also be the only way for a patient to receive new medications that are already on the market but not sold for their disease or disease stage. For example, nowadays PARP inhibitors are being used with success in relapsed ovarian cancer, but there are already some very promising results indicating that they would improve treatment outcome also if used in the first, primary occurrence of the cancer. However, for most ovarian cancer patients currently the only way to receive PARP inhibitors during the first occurrence of the disease is when she participates in a trial.
If you are a patient looking to participate in a trial, please ask the physician treating you for advice. Information on registered clinical trials conducted around the world can be found from the clinicaltrials.gov website.
The expert interviewed for this post is Johanna Hynninen, MD PhD, a senior consultant and specialist in gynecologic oncology at the Department of Obstetrics and Gynecology, Turku University Hospital, Finland, and a member of the HERCULES research consortium.