Science Series #10: Clinical Trials
What are clinical trials?
Clinical trials are types of interventional research studies, conducted in order to test new emerging or already approved treatments to evaluate their effects on health outcomes. These are conducted on a group of participants, who are assigned to one or more health related interventions such as drugs, behavioral treatments and surgical procedures. A trial is done when there is valid reasoning behind supporting new treatments that may improve patient care and safety.
Some clinical trials may compare a new medical approach to a pre-existing one, or to a placebo that contains no active ingredients, or to participant groups that have not received any intervention, in order to access the possible effects of the new drug or treatment. This is done by measuring certain outcomes set by the researchers that prove the efficacy of the newly tested treatment.
Clinical trials are designed as they expand the current medical knowledge about a certain disease or behavior, and can lead to promising results in finding new preventative treatments to serious illnesses. In addition, these can also reveal mechanisms of prevention and information about diagnosis of diseases that were not previously known, and are important to reveal any possible side effects of newly developed drugs.
(Source: World Health Organization, U.S. Food and Drug Administration, National Comprehensive Cancer Network, ClinicalTrials.gov)
Process prior to conducting clinical trials
Prior to clinical trials, the novel treatments are assessed in preclinical research, which is not done on humans and assess the drug’s safety and toxicity, or in other words, to determine if it causes serious harm. This can be done either in-vitro, meaning in laboratories through the use of cell studies, or in-vivo meaning on animals. Following the success of the preclinical trials, a request must be approved in order to begin the next phase of clinical trials on humans, to determine the treatment’s efficiency and safety of use.
Before beginning the clinical trial, in the USA, drug developers must submit an Investigational New Drug (IND) application to the Food and Drug Administration (FDA). In this application, drug developers disclose information such as the animal study data and toxicity, manufacturing information, clinical protocols, data from prior research and information about the investigators. In the European Union (EU), upon the success of preclinical trials, researchers must submit a Clinical Trial Application (CTA) to the Competent Health Authority and an Ethics Committee in the specific country in order to proceed with clinical trials. Phase I trials must be registered in European EudraCT database after the application is approved. A clinical trial is conducted under compliance with the Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP) regulations. Both of these regulations ensure ethical and scientific standards that guide the researchers on designing and reporting trials with human participants, while additionally ensuring the rights, safety and wellbeing of the participants.
(Source: U.S. Food and Drug Administration, European Medicines Agency, European Federation of Pharmaceutical Industries and Associations)
What are the different phases of clinical trials?
There are 3 clinical phases described for the approval of new drugs, these are:
Tests new drugs for the first time on a limited group of participants, usually ranging from 15-30 patients, and is conducted for several months. Researchers give the participants low doses of the treatment and monitor for potential side effects. This allows the researcher to access the treatment’s safety and determine the safe dosage.
After ensuring the safety of the new drug in phase I, the group of participants in the clinical trial is expanded to about 100 subjects to monitor adverse side effects and to access the drug’s effectiveness. This phase can last up to two years.
The clinical trial is then done on a large population in various geographical locations, ranging from 300 to 3,000 participants. Researchers confirm the drug’s effectiveness, monitor side effects, compare it to available drugs, and collect information about the safety of use. During this phase, researchers compare the side effects of each drug in order to determine which one is better. Most of these trials are randomized to ensure that there are no individual differences that may influence the results. This phase is usually done right before a treatment is approved and the trial can take around one to four years to complete.
When the new drug is proven to be more effective or safer than the current treatment, a New Drug Application (NDA) is submitted to the FDA for their review. If approved, the new treatment can become a standard of care. If the FDA does not approve, they might request additional information or to conduct more trials. The FDA may also place the trial on clinical hold if it exposed the participants to health risks, if the information disclosed about the trials were misleading for the participants, or if the investigational new drug application does not provide enough information about the potential risks
(Source: U.S. Food and Drug Administration, World Health Organization, U.S. Food and Drug Administration, American Cancer Society)
What happens after the drug is approved?
Drug approval regulations vary based on the country. Each country has its own regulatory entity that approves and follows supplementary guidelines after the completion and success of clinical trials. The most recognized entities worldwide are the Food and Drug Administration and the European Medicines Agency.
After the FDA has approved the new treatment and the drug has been licensed, further testing is conducted on a wide population for a longer period of time. This is often known as the post-marketing surveillance trial, or phase IV. It provides the researchers with information about the drug’s risks, benefits and best use. In addition, they may access the patient’s quality of life or the drug’s cost effectiveness.
In the EU, the EMA’s Committee for Medical Products for Human Use (CHMP) assesses the new medicine in order to seek single authorization. The assessments are based on scientific criteria in addition to the clinical study reports and the application dossiers to determine the efficacy, safety, and quality of the product as established by the EU legislation guidelines. After the drug is approved, phase IV trials begin, which include studies that were not considered necessary for the previous phases, yet enhance the optimization of the drug’s use.
(Source: U.S. Food and Drug Administration, y, European Medicines Agency, European Federation of Pharmaceutical Industries and Associations)
Participating in Clinical Trials
Clinical trials are conducted based on a protocol set by the researchers. This protocol is set to answer specific research questions and ensure the health of the participants. The protocol includes the reason behind conducting the study, who is eligible to participate, the number of participants and the schedules of the tests, the length of the study, how the drugs will be given, what information will be disclosed about the participants, and how the data will be used and analyzed.
Participants are protected based on an Informed Consent Form (ICF), which provides the participants with information about the clinical study, including the possible health risks and benefits. Participants may withdraw from the study at any time, even if the study is not yet completed.
Committees such as the research ethics committees or institutional review board make sure the clinical trial is ethical, the welfare of the participants is maintained, and the research risks are minimized to a reasonable amount compared to the anticipated benefits.
Participating in clinical trials is important as it leads to expanding the existing medical knowledge and establishing new beneficial treatments that work better than the current ones available. In many ways, despite the potential risks, participating in clinical trials play an essential role in progressing against illnesses, and hopefully to reach novel cures
(Source: U.S. Food and Drug Administration, ClinicalTrials.gov)
Current Clinical Trials Statistics
As of March 2021, there are currently 369,133 clinical studies being conducted through the 50 states of the US and in 219 countries. Out of the total trials currently under study, 78% are interventional studies, including drug intervention behavioral studies, surgical procedures, or studies conducted on certain medical devices. The remaining 22% are observational studies. There are currently 3,540 trials in early phase I, 45,981 studies in phase I, 65,004 in phase II, 38,518 in phase III, and 27,865 studies in phase IV. The major topics currently under clinical trials are communicable diseases, infection, and vascular diseases. One type of cancer that is extensively studied is Adenocarcinoma, with a total of 8,558 clinical trials being conducted to date. Adenocarcinoma is a type of cancer, which begins in the mucous glands and expands to the lungs, colon, and even the breasts. Additionally, 82 studies have been conducted or are still active trials that are focused on breast cancer lymphedema, meaning the swelling tissue caused by breast cancer. There are several studies looking for intervention and surgical treatments. There are also 304 studies currently being conducted about breast cancer immunotherapy, with 6 studies in early phase I, 165 studies in phase I, 155 in phase II, and 12 in phase III.
Our work in Clinical Trials
JCWO is developing a low cost and potentially safe and effective personalized immunotherapy for breast cancer, named ConvitVax, combining autologous tumor cells with BCG, and low concentrations of formalin. Preclinical studies and a human pilot experience have shown that this vaccine effectively reduces tumor growth, evidenced by extensive tumor elimination. Additionally, this immunotherapy has exhibited a safe profile with minimal side effects.
ConvitVax is approved by the Food and Drugs Administration (FDA) with IND #18487 to initiate a phase I clinical study in stage IV breast cancer female patients. Additionally, the Danish BCG vaccine producer of strain 1331, AJ Vaccines A/S, approved the clinical protocol to conduct the trial using ConvitVax with their BCG vaccine.
Currently, JCWO is building international alliances to execute trials and advance in the development of this therapy, benefiting underprivileged patients in developing countries. For more information on this work, visit JCWO’s press room and learn more about the Cancer Immunotherapy program.