Clinical Studies Definition and Types
Clinical studies are intended to add to medical knowledge and most often involve human volunteers as participants. Clinical studies can either be observational studies or experimental studies (also referred to as interventional studies).
In an observational study, investigators assess health outcomes in groups of participants over time which may last for years or even decades. Researchers observe the effect of a specific variable as it occurs naturally, without making any attempt to intervene.
In a clinical trial, participants receive specific interventions which may be medical products, such as drugs or devices; procedures; or changes to participants’ behavior, such as diet. Participants are randomly assigned to the control and experimental group. By comparing the impact of the intervention to those who did not receive the intervention, researchers can observe and measure the effects of the intervention. Clinical trials help researchers discover new treatments for diseases and develop new ways to prevent and detect those diseases.
Stakeholders in a Clinical Research
Stakeholders in clinical research have the responsibility to ensure that the principles of the International Conference on Harmonization Good Clinical Practice (ICH-GCP) are complied with. The key stakeholders are the Institutional Review Board, investigator, and sponsor. Other stakeholders are the regulatory authorities such as the Food and Drug Administration, contract research organization (CRO), trial sites, auditor, clinical research coordinator (CRC)/clinical research associate (CRA), data and safety monitoring board, and study participants.
Sponsor, Contract Research Organization, and Investigator
The sponsor is responsible for the initiation, management, and if applicable, the financing of a clinical trial. A sponsor may transfer any or all of its trial-related duties and functions to a Contract Research Organization (CRO) but should ensure continuous oversight of activities done by the CRO. The ultimate responsibility for maintaining the quality of the conduct of the study and trial data resides with the sponsor.
A CRO is an organization contracted by the sponsor to perform the sponsor’s trial-related duties and functions, depending on the agreement made by both parties. Duties and functions that may be delegated by the sponsor include, but are not limited to, trial design, trial management, data handling, record-keeping, investigator selection, notification to the regulatory authority, supply of investigational product, monitoring, audit, and preparation of clinical study report.
Pharmalytics Corporation is an accredited Contract Research Organization in the Philippines established in 2014. We have already conducted clinical studies from preclinical studies to phase 1 to 4 clinical trials.
Food and Drug Administration and Institutional Review Board
Before a clinical trial can begin, researchers perform laboratory tests and studies on animals to test a potential therapy’s safety. Animals receive high doses of the new therapy and are carefully observed and monitored for side effects over a specified period of time. After the study period, pathologists examine the organs for signs of drug toxicity. This drug safety testing in animals is carried out under national and international policies and regulations. A clinical trial on human participants shall gain authorization from the Food and Drug Administration (FDA) for conduct in the Philippines through the process of approval as stated in DOH AO 2020-0010 entitled, Regulations on the Conduct of Clinical Trials for Investigational Products.
In addition to FDA oversight, all clinical trials must be approved and monitored by an Institutional Review Board (IRB) to make sure the risks are as low as possible and are worth any potential benefits. An IRB is an independent committee of qualified individuals who collectively have the experience in reviewing and evaluating the science, medical aspects, and ethics of the proposed trial. The IRB ensures that the rights, safety, and well-being of trial participants are protected.
General Considerations in the Conduct of Clinical Studies in Human Participants
The ethical conduct of clinical studies and the protection of participants stated in ICH E6-Good Clinical Practice have their origins in the Declaration of Helsinki. The design of trials should optimize the knowledge to be gained from the study without imposing unnecessary risks to study participants.
Before initiating a clinical study, sufficient data should be collected to ensure that the treatment is acceptably safe for research in human participants. Procedures for identification, monitoring, and reporting of safety concerns should be specified in the protocol.
Phase 1 studies are the initial introduction of an investigational drug into humans. Participants usually comprise a small group of healthy volunteers who are closely monitored, ideally in a hospital setting. Phase 1 studies are typically conducted as “open-label” studies that are not randomized, blinded, or controlled.
Dose escalation schemes are employed to examine the short-term toxicity and define the maximum tolerated dose. Side effects are monitored as dosage increases. The long-term toxicity, however, is not yet identified at this point of the investigation.
Phase 1 studies also determine the pharmacokinetics of the drug in humans. Drug concentrations are measured by obtaining blood samples at specified time intervals and collecting urine or other body fluids or tissues. Assessment of pharmacodynamics is done through the measurement of laboratory tests, noninvasive tests, vital signs, and other clinical assessments. The pharmacokinetic and pharmacodynamic data give researchers an idea of the dose range for efficacy testing in later, phase 2 trials.
One of the projects of the Anti-Dengue Drug Development program is a Phase 1 safety and dose-escalation trial conducted by Pharmalytics Corporation which administered a fixed-dose combination capsule of select herbal plants. After the establishment of the safety and tolerability of the drug, the study proceeded to the phase 2/3 trial which aims to determine the safety and efficacy of the drug in the treatment of dengue without warning signs.
Phase 2 clinical trials occur once the initial safety of the study drug has been confirmed in Phase 1 trials. Phase 2 trials are performed on larger groups of participants (up to a few hundred) with the disease or condition under study to assess how well the treatment works, as well as to continue assessments on safety and toxicity in Phase 1 studies. A key focus of Phase 2 studies is determining the optimal dose of a drug candidate in order to determine how best to administer the drug to maximize possible benefits while minimizing risks.
Most phase 2 studies are randomized and are often double-blind. Randomization means that participants are assigned randomly to receive either the experimental treatment or a placebo (treatment or substance with no therapeutic value). Those who receive the placebo are called the control group. Meanwhile, double-blinding means that treatment allocation is not known to both participant and physician.
Since larger numbers of participants receive treatment in phase 2 studies than in phase I studies, there is a greater chance to observe and compile adverse effect/adverse drug reaction information.
Phase 3 clinical trials are large confirmatory studies meant to establish the treatment’s safety and efficacy in order to gain regulatory approval for a precisely defined indication. Evidence from phase III studies that strongly support the proposed indication will generally lead to the adoption of therapy.
Phase 3 study designs are mostly randomized and double-blinded. Sample sizes usually range from hundreds to thousands to have a high probability of ruling out the possibility of ineffective therapies and to estimate the treatment effect with high statistical precision. Since phase 3 employs a larger sample size, there is a better opportunity to detect rare serious toxicities.
Once safety and efficacy are demonstrated, the sponsor can submit a New Drug Application (NDA), which contains all of the data and information gathered at every phase of the trial, as well as other information required by the applicable regulatory authority. The NDA is submitted to the FDA for consideration for marketing approval.
Phase 4 clinical trials are post-marketing trials that take place after the FDA has issued regulatory approval for use of the treatment. Guidelines on revised post-marketing surveillance requirements are detailed in FDA Circular No. 2021-020.
A treatment’s effectiveness and safety are monitored in large, diverse populations. This way, rare but serious adverse effects that cannot be assessed in smaller phase 3 studies can be evaluated.
It is important to distinguish between the efficacy and the effectiveness of an intervention. Efficacy is defined by how the intervention performs in ideal and controlled conditions, such as in phase 1 to 3 clinical trials, as opposed to effectiveness which refers to how well an intervention works in real-world conditions. While phase 3 trials focus on efficacy by demonstrating the treatment benefit of prevention through some surrogate biomarker of the disease, phase IV trials focus on effectiveness by using the clinically relevant outcome in a population-based sample of individuals who receive the adopted treatment. Since populations are not homogenous in their characteristics and individual behavior affects the efficacy of treatment, postmarketing trials also seek to evaluate these factors.
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