Your Clinical Trial Journey: Understanding the Clinical Trial Landscape
As you embark on your clinical trial journey, you may be asking:
- What happens before the drug gets tested in humans?
- What is a clinical trial?
- How come some clinical trials have few participants and some have hundreds or thousands?
What happens before the drug gets tested in humans?
Collectively, the main reason for the performance of clinical trials is to confirm to regulators (the Federal Drug Administration -FDA- in the United States) that a treatment is both effective toward a condition or disease and safe for human consumption. Before clinical trials in humans happen, a potential drug candidate goes through a rigorous process. The discovery process of a drug molecule includes a great deal of work that needs to happen in the laboratory before it can even encounter a human being. Libraries of compounds are put through a screening process, called high-throughput screening (HTP). This mechanical process searches for molecules (drug compounds) that:
- modify (change) an identified target (such as a specific type of tumor cell) and
- are less likely to modify a related target (such as a healthy cell).
Only a few molecules pass this screening process. Molecules that do pass the screening phase then enter into preclinical trials. Lab technicians perform a variety of tests that answer questions about the safety of the compound as well as to identify what the recommended starting dose should be if the drug compound should make it into human clinical trials. Lab technicians also study the drug’s toxicity levels and effects on the body. Most likely, this phase of research is performed in animals and can take many years to complete. In order for the FDA to approve the drug for clinical human research, there must exist sufficient evidence from the process thus far (discovery, development and preclinical research), as well as evidence of thoughtful plans for prospective clinical trials. When this information is compiled, the drug developers apply to the FDA for what is called an Investigational Drug Application (IND). This application process is legally required before the drug candidate can be tested on or in humans. Once the FDA approves the IND application, the compound can then be tested in human beings. The process from discovery to IND acceptance typically takes three to six years. It is only after the successful execution of clinical trials that a drug candidate can be approved for human use by the FDA.
What is a clinical trial?
In order to be considered a clinical trial, a variety of requirements must be met. First, to be considered a clinical trial, the National Institutes of Health (NIH) require studies to include at least one or more human volunteers (or participants). Also, a study is required to have a documented and approved study protocol. Approval must be made by an Institutional Regulatory Board (IRB) and the FDA. And IRB is a group of doctors, community members, and researchers who approve and monitor clinical trials to ensure the study’s ethics, integrity, and patient safety are maintained.
There are a variety of clinical trial types and reasons to be performed. Here is a list from the FDA:
“Treatment Research generally involves an intervention such as medication, psychotherapy, new devices, or new approaches to surgery or radiation therapy.
Prevention Research looks for better ways to prevent disorders from developing or returning. Different kinds of prevention research may study medicines, vitamins, vaccines, minerals, or lifestyle changes.
Diagnostic Research refers to the practice of looking for better ways to identify a particular disorder or condition.
Screening Research aims to find the best ways to detect certain disorders or health conditions.
Quality of Life Research explores ways to improve comfort and the quality of life for individuals with a chronic illness.
Genetic studies aim to improve the prediction of disorders by identifying and understanding how genes and illnesses may be related. Research in this area may explore ways in which a person’s genes make him or her more or less likely to develop a disorder. This may lead to development of tailor-made treatments based on a patient’s genetic make-up.
Epidemiological studies seek to identify the patterns, causes, and control of disorders in groups of people. “
Clinical trials are categorized as being either observational or interventional. The goal of an observational clinical study, also known as an epidemiological study, is to find out if there is a relationship between a known factor (such as smoking) and a specifically known outcome (such as lung cancer). The researcher does this by analyzing data from a pool of selected participants. There is no change to a treatment plan of study participants. The participant is not interfered with however questionnaires may be requested to complete.
The observational study may either be prospective, looking into the future to watch for outcomes; or retrospective, looking at historical data to identify risk or protection factors for a specified condition. For example, a researcher performs a retrospective, observational study from the years 1950-1990 to determine the risk and protection factors that exist for lung cancer. An intervention may be required during an observational study however the intervention will only be included as part of standard of care and will never be an investigational drug.
The goal of an interventional clinical trial is to demonstrate successfully that a treatment method is effective and safe for human consumption. In addition to IRB and FDA study protocol approval, the researchers must also have an IRB approved, study-specific, informed consent form. The study team should also have a thorough consenting process for which a study volunteer can ask any and all questions before signing the informed consent form. A participant is never forced to sign a consent form and may take as long as one wishes to make a decision (pending the study-specific timelines). Once a consent is signed by the participant, the study procedures may begin. The research team is not allowed to perform any study-specific procedures prior to the study volunteer signing the consent form.
Interventional trials will include select tests to confirm the participant meets study-enrollment requirements and continues to maintain study eligibility. During the trial, the study patient is given a placebo or treatment and testing will continue throughout the study to ensure patient safety and study integrity. Any side effects, called adverse events, are collected by the study team. Patient safety is closely and consistently monitored throughout the patient’s study participation. A close-out visit will always occur when a patient voluntarily leaves a study or when eligibility is no longer met.
How come some clinical trials have few participants and some have hundreds or thousands?
Whether a study is observational or interventional, it will be classified as one of the five phases of clinical trials. Trial phases I-III are required by the FDA to be successfully completed in order for a drug sponsor company to apply to have the drug sold and marketed in the US. There are four types of marketing applications that can be filed with the FDA:
- New Drug Application (NDA)
- Abbreviated New Drug Application (aNDA) for generic drugs
- Biologics Licensing Agreement (BLA)
- Over-the-Counter (OTC)
Phase 0 clinical trials are rare and not required by the FDA. If a phase 0 study is carried out, it must be included in addition to the required phases of clinical research. A phase 0 clinical trial involves giving approximately 10 people (healthy or not) a less-than-therapeutic level of drug to test for the safety of the treatment. A phase 0 clinical trial would not replace a clinical trial but would occur in addition to the phase I, II, and III studies that are required by the FDA in order to apply for drug approval. Most often though, especially since there is no benefit to participating in a phase 0 study, sponsors will begin clinical trials in phase I.
Phase I clinical trials are designed to test the safety and tolerability of the drug in the human body and are categorized as either phase Ia, a single ascending dose trial, or phase 1b, a multiple ascending dose trial. Since phase I trials are first-in-human studies, they are commonly performed in a clinical setting where volunteers can be observed round-the-clock. Phase I clinical trials are typically short in duration and small in quantity (less than 100 volunteers). After completing the informed consent form, the volunteers (healthy or with the condition being tested) are given a pre-determined dose of the drug and observed for a specified period of time. Several escalating doses are tested in a scheduled sequence until the pre-determined safety threshold is reached.
Phase II clinical trials include a larger pool of participants, anywhere from 100 to 300 volunteers, as researchers need to collect more data about how effective the drug is, or isn’t, in addition to further testing the drug’s safety and side effects in a larger number of humans. Phase II studies have the lowest success rate of all the phases, only about 31% made it from phase II to phase III.
Phase III clinical trials are larger than the phase II counterpart and include hundreds to thousands of volunteers. This phase of research tests the drug candidate against an approved standard of care treatment while still collecting safety data and monitoring all adverse events. Typically, there will be two phase III studies performed, possibly running simultaneously, and in-progress during the drug sponsor’s marketing application process. Having clinical trials run during the application process allows patients who are having success with the drug to continue to receive treatment until the drug becomes available on the market.
(Image source: BIO report, PDF link)
Phase IV studies occur after a drug is approved for commercial sale in the United States by the FDA. Phase IV studies are also referred to as post-market research. “Not all Phase IV studies are post-marketing surveillance (PMS) studies but every PMS study is a phase IV study.” The aim of phase IV research is to collect safety and efficacy data from the real-world population. These studies may be required by the FDA or be a part of a sponsor company’s competitive strategy. Whether regulatory or sponsor-funded, it is at least two years long and will collect the largest breadth of clinical safety data from a wide range of patient situations.
It can take an average of six to eight years to complete the entire clinical research phase for a drug, from the drug’s first phase I trial through to the end of the pivotal phase III trials. This taken into consideration with the drug discovery process comes out to be about nine to fourteen years for a drug to go from discovery to market.
As your clinical trial journey begins, information may seem daunting, overwhelming, or foreign. Be sure to access trustworthy resources as you learn more about the beneficial process of drug discovery.
Written by Amy Rochford
Amy is a data analyst and self-described jack-of-all-trades at TrialScout. Amy is a transplant who moved to Buffalo three years ago, bringing experience from multiple industries including clinical trial operations, physician office management, and travel and tourism management. Amy’s time is consumed by her husband, two young boys, two dogs, and many foster dogs.