Introduction to Clinical Trials

What are Clinical Trials?

Clinical trials are research studies that are conducted in humans (healthy participants or patients with a specific health issue) in order to study and test new medical treatments, such as drugs, vaccines, medical devices (e.g. spinal cord stimulators), medical procedures, clinical strategies and diagnostic tests. Clinical trials may also be conducted to study new combinations of treatments, or to compare treatments, or to study an already available treatment for a new use (e.g. to trial a drug currently used for depression in patients with chronic pain).

This article will focus on clinical trials for new drugs or medical devices. It will provide an overview of what comes before clinical trials, the stages / phases of clinical trials, the regulatory, ethical and safety requirements, who is involved in clinical trials, what is involved and what happens after a trial is complete.

What Comes Before Clinical Trials?

Basic Research → Therapeutic Discovery → Preclinical Research

Experiments performed in the laboratory are known as “basic research”. The goal of basic medical research is to improve our understanding of normal human biology and diseases, and ultimately to discover and develop new treatments or technologies to improve health.   Before newly discovered (potential) treatments can even be considered for testing in humans, however, they will have to undergo more intense laboratory testing and preclinical research. Potential drugs will undergo several stages of experimentation in vitro (in test tubes) to study their chemical properties. Potential treatments that have favourable chemistry and the potential to improve health (therapeutic potential) may then be studied in cells and/or tissues grown in the laboratory in order to study their biological effects, especially toxicity, and to establish a safe dosing plan for further experimentation. If they pass this stage, they may then be tested in in vivo (in animals) in order to study the effects in whole living systems and to get a better idea of effective, safe dosing in humans. If the potential treatment appears to have therapeutic potential in animals (or healthy/diseased human cells/tissues/organs), appears to be safe and the risk of side effects appears to be low and minor, it may eventually progress to the first phase of clinical trials.

The discovery process and preclinical research can take up to 6 years

Phases of Clinical Trials

Once the safety and potential effectiveness of the treatment has been supported by preclinical studies and approved for human research, it will undergo a series of carefully designed clinical trials. Clinical trials are staged into “phases”. The following table provides a summary of the phases of clinical trials. Many clinical trials begin at Phase 1.

Phase Nature Participants Purpose(s)
0 Exploratory / Pilot Study 10 – 15
  • A small study (pilot) to test how the human body responds to a very small (subtherapeutic) dose of a drug.
  •  To explore diagnostic tests or mechanisms of action of drugs or devices (exploratory study).
I Safety 20 – 100
  • The first stage of testing effective doses in humans (healthy humans and/or patients) to establish the safe, therapeutic dose rage and identify any side effects.
II Proof of Concept 100’s
  • To assess the effectiveness of the treatment and further investigate its safety.
III Regulatory Proof 100’s – 1000’s
  • To confirm the clinical benefit and safety risks of the treatment for the intended health condition.
  • To compare the new treatment to another treatment, usually something already on the market, or to non-interventional standard care (e.g. physical therapy).
IV Post-Market / Surveillance Large populations
  • Marketing and safety surveillance of the now approved treatment to monitor its effectiveness, safety and long-term effects in the general population.
  • To compare the approved treatment to a wide range of established treatments and confirm where it is best used.

It usually takes around 10 to 15 years for a new drug to pass through clinical trials and receive market approval.

Clinical Trial Design Terminology

Controlled? Placebo? Blinded? Randomized? Crossover?

If you’ve ever looked up clinical trials or applied for one, you may have come across these terms. So, what exactly do they mean?

Controlled

A controlled study is one in which there is some form of “neutral” comparator. To have something to compare the treatment to makes for a much more powerful study with meaningful results. In clinical trials that involve patients and healthy participants, the healthy group is the control group. If it is unethical to include healthy controls, the control group may consist of patients who either don’t receive anything, or who only receive standard non-interventional care, or who receive a standard form of treatment such as a commonly prescribed medication or physical therapy, or who receive a placebo.

Placebo

A placebo is an inactive control that looks identical to the study treatment. For example, a sugar pill or an injection of saline. The point of a placebo is to determine if the effects of the study treatment are related to the actual biological/chemical properties of the treatment, versus the psychological effects – the “placebo effect”. A person who receives a placebo or an active treatment may experience effects (whether good or bad) simply because they believe they are receiving something that will improve their condition or may give them side effects. These effects are psychological and proven to be real, but they are not related to the actual treatment mechanisms and they usually wear off relatively quickly.

A placebo is a very powerful comparator, although not always appropriate and may be considered ethically questionable. For example, a placebo for a surgical study is called a “sham”, whereby a fake surgery is performed. The use of sham surgery is highly controversial and rarely performed in humans.

Blinded

A controlled trial will usually be “blinded”. Naturally, placebo-controlled trials are always blinded. This means that participants are unaware of which treatment they receive until the study is complete. A study is double-blinded if the study investigator(s) are also unaware of which treatment the participants receive. Blinding ensures that the outcomes are not biased by participants’ or investigators’ preconceptions – that is, what they think the outcome will be if they know which treatment they are receiving. For example, a person who receives a new treatment versus an already available or a standard treatment may think that they will experience more side effects or better results.

Randomized

Randomization is the process of randomly allocating participants to treatment / control / comparison groups (also known as “treatment arms”). This is generally performed by a computer program. Randomization ensures that the process of selection is unbiased, that the groups are balanced and therefore more comparable, and that participants have an equal chance of receiving the treatment or control / placebo / comparison treatment.

Crossover

A clinical trial in which participants receive either the treatment or the control / comparator only is known as a “parallel” study. A crossover study is one in which participants get to experience both or multiple treatment arms. The crossover process usually involves a washout period, during which participants cease treatment (or control / comparator) for a certain amount of time in order to “wash away” any residual effects before beginning the next arm of the trial. This type of clinical trial is generally much longer than a parallel clinical trial. The main advantage is that participants become their own controls. This minimises a large source of variation in the data that is associated with comparing treatment vs control/comparator between different people.

Regulation, Ethics & Safety

Clinical trials are heavily regulated and must be conducted in accordance with standard ethical guidelines, codes of conduct and national laws. This is to ensure participant safety, protection of human rights and privacy, good clinical practice, responsible research conduct, and quality data collection.

For clinical trials involving a new treatment, an application must first be sent to the national regulatory authority – i.e. the Therapeutic Goods Administration (TGA) in Australia, or the Food and Drug Administration (FDA) in the USA.

All clinical trials, whether for new or established treatments, must be approved by an institutional review board (IRB) or a human research ethics committee (HREC; as in Australia). The board or committee consists of doctors, researchers and members of the community. They will review and discuss the study protocol and all other study documents and forms to ensure that the proposed study is ethical, that the rights and welfare of the participants will be protected, and that the potential risks are minimised and reasonable when weighed against the potential benefits of the study. Once approved, the IRB / HREC will continue to monitor the trial.

The safety of the participants always comes first!

A clinical trial may be terminated if there are serious safety concerns, or in the event of futility (i.e. there appears to be no benefit associated with the treatment and/or the final results are unlikely to be of any significance – basically, it would be a waste of time and resources to continue the trial). On the other hand, a trial may be terminated in the event of overwhelming benefit (i.e. the results so far indicate a substantial statistically significant benefit associated with the treatment), in which case regulatory approval and market-release may be achieved much sooner than normal.

Who is Involved in Clinical Trials?

Investigators – Doctors

Clinical trials are conducted by doctors, usually specialists. The lead doctor is known as the principal investigator and any other involved investigative doctors are known as sub-investigators. Qualified clinical research staff may also perform the roles of a sub-investigator. The investigator(s) will supervise or perform the treatment and perform study visits / follow-up consultations. The principal investigator is responsible for ensuring good clinical practice, that the trial is run according to the protocol and safely and that participants receive the appropriate care.

Clinical Trial Coordinators

These are qualified clinical researchers (i.e. research nurses or researchers with a biomedical degree or similar who have clinical experience). They are usually the main point of contact for participants and are present at the majority of study visits. They are involved in recruiting participants and providing them important information about the trial before enrolment and throughout the trial, organising appointments and medical tests, monitoring participants, and data collection. They may also administer treatment and take blood if qualified and designated to do so by the principal investigator.

Other Health Professionals

Various other health professionals may be involved in clinical trials, whether actively involved in the study or as external support. Examples include:

  • General practitioners or specialist physicians – may inform their patients about appropriate clinical trials, provide advice on clinical trial participation, support their patients during a clinical trial;
  • Allied health practitioners (i.e. psychologists, physiotherapists);
  • Pathology and medical imaging staff (radiologists);
  • Pharmacists;
  • Company engineers who perform routine programming / maintenance for medical devices.

Sponsor

Clinical trials may be industry sponsored, non-industry sponsored or investigator-initiated. The sponsor may be a government agency, a pharmaceutical, biotechnology or medical device company, a charity, research organisation, hospital, university or an individual.

Monitors / Clinical Research Associates

These are people contracted or employed by the sponsor tasked with overseeing the trial to ensure that it is conducted and reported in accordance with regulatory requirements. They perform site initiation visits, inspections and data and safety monitoring, amongst other tasks.

What is Involved?

Participant Recruitment

Recruitment of clinical trial participants may be conducted in several ways, for example:

  • In collaboration with doctors who may inform potentially suitable patients and refer them to a trial site;
  • Advertisements in newspapers, radio, bulletin boards, posters, flyers, social media, etc;
  • Community information sessions or events;
  • Contacting past participants or people who have registered their interest to participate in clinical trials and have joined a research database.

People who find clinical trials online may be directed to a survey that is designed to briefly assess their suitability to participate. Others may be pre-screened via telephone. The full screening process is conducted at the trial site.

Screening

To be eligible to participate in a clinical trial, potential participants must attend the site for a screening visit. They must meet set “inclusion criteria” and not meet any “exclusion criteria”. These often-strict selection criteria are put in place for safety purposes and to minimise variation in the study group(s) that might influence the results. Clinical trials in later phases may have less strict selection criteria.

Eligibility criteria may include:

  • Age;
  • Sex;
  • Health condition;
  • Symptom presentation;
  • Duration of illness or symptoms;
  • Other medical history;
  • Treatment history.

Common exclusion criteria include:

  • High BMI;
  • High blood pressure;
  • Comorbid conditions (e.g. diabetes);
  • Use of excluded medications;
  • Pregnant or breast-feeding mothers;
  • Inability to undergo certain procedures or tests;
  • Living too far away from the trial site.

Potential participants will be asked to complete questionnaires designed to assess their health status or health condition and determine whether the study is suitable for them. They may also need to undergo a physical examination and medical tests (i.e. blood tests, X-rays, MRI) in order to determine their eligibility.

In the event that a person is found not to be eligible for the study, they will be told promptly and may then be asked if they would like to remain on the site’s research database where they may be contacted about potentially suitable trials in the future.

Consent & Enrolment

Before an eligible person can be enrolled into a clinical trial, they must first meet with the investigator to discuss the trial and give “informed consent”. This begins at the screening visit. Informed consent is a legal and ethical requirement and is described below.

At the screening visit, the investigator and coordinator will provide important information on the clinical trial in the form of a study brochure or information sheet and will answer any questions or concerns. They should ensure that the potential participant has an adequate understanding of the trial, its purpose, the procedures, the risks and potential benefits of participation, and their requirements and rights as a participant. The study information may be taken home and discussed with others (family, friends, doctors). If the person decides to participate in the trial, they will need to return to the site to meet with the investigator and sign the consent document. This document is not a contract, it represents an agreement to participate in the trial and an understanding of what it will involve. Participants may withdraw their consent and leave the trial at any time.

Important points to consider:

  • Informed consent is more than just the signing of a document and pre-enrolment discussion, it is an ongoing process;
  • Participants should feel free to ask as many questions as they need to before and after signing the consent document and during the study;
  • If there are any changes to the study, participants will be informed and may be asked to re-consent before continuing the trial;
  • Many patients have the misconception that participating in a clinical trial will improve their condition. It must be made clear that this is not guaranteed;
  • Patients with debilitating conditions, cognitive impairments, limited literacy skills, non-English speakers, the elderly, and so forth, should be accompanied by a family member/carer. Modified strategies and more time and effort may be required in order to adequately complete the informed consent process.

Baseline Visit / Receiving Treatment

Eligible participants who provide informed consent will be booked in for a baseline visit. At this visit, the participant will meet with the investigator and coordinator where they can continue to discuss the trial. The participant will be asked to complete sponsor study documents, medical information forms and questionnaires to assess health, symptoms, etc. The participant may also be required to undergo a physical examination and medical tests, such as blood tests, X-rays, MRI, etc. The information collected as this visit forms the baseline data. Participants may also receive a diary to take home in which they should record information such as any side effects, medication changes and health condition changes, should they occur.

Following the collection of baseline data, the participant will receive the trial treatment. This may be in the form of pills to be taken as directed, an injection that is performed at the site or that is self-administered at home, or an external medical device that is worn by the patient. The investigator/coordinator (and/or a company engineer for medical device trials) will educate the participant on how to take or use the treatment.

For Implantable Device Trials:

If the treatment is a surgically implanted device, the coordinator will arrange the procedure booking. The procedure will take place at a designated hospital and will be performed by the investigator. Usually, the participant will need to return to the trial site shortly after to have their device set up by the engineer/programmer.

In the case of a neuromodulation device trial (i.e. spinal cord stimulator) the participant will be required to trial the device for around a week, during which they will complete a diary to record the effects of trial device. The trial device is partially implanted – the stimulating leads are implanted whereas the pulse generator is worn externally. After the trial, the device is completely removed and the diary is assessed to determine if the device provided clinically significant benefits to the participant. If the trial was a success, the participant will be booked in for their implant procedure, during which the entire device is surgically implanted. Usually about a week later, the patient will return to the site to have their device activated by the engineer/programmer, who will adjust and optimise the device program parameters.

Follow-Up Visits

Participants will be required to attend regular, scheduled follow-up study visits. The number of visits and length of time between visits depends on the treatment and the trial design. During these visits, more data will be collected in the form of questionnaires, and perhaps physical examination and/or blood tests and/or medical imaging. Medical device trials may require extra time or visits for device programming.

Adverse Events / Side Effects

Whilst clinical trials are carefully designed, staged and controlled in order to minimise the risks associated with testing new treatments, adverse events are not uncommon. Even medications already on the market are often associated the side effects. Adverse events include side effects or reactions to the study treatment, any events or illnesses that occur during the trial, even if it is uncertain whether they are or are not related to the study treatment, worsening of a health condition, and so forth.

Just as any prescribing doctor and pharmacist will advise patients of the potential side effects before taking medications, investigators and clinical staff should ensure that potential participants are aware of the potential risks associated with the clinical trial.

If any adverse event occurs, participants should notify the clinical staff and schedule a visit as soon as possible, even if they’ve already sought medical help elsewhere. The adverse event will be thoroughly documented and the investigator and clinical staff will follow the event until it is resolved. If the participant decides to withdraw from the trial, the investigator will continue to see them, providing the necessary medical care in order to resolve the adverse event. On the other hand, the investigator may decide to withdraw the participant if there is serious concern. All adverse events will be reported to the sponsor and the relevant authority and appropriate safety measures will be taken.

What Happens Next?

Once all participant visits have been completed and the trial has been closed, all study information and data are collected, compiled, analysed and interpreted. This can take quite some time, depending on the size and complexity of the trial. Eventually, a final study report is produced. The study may also be published in a scientific journal. These should be made available to the participants.

Further trials (phases) may then be conducted. If a treatment successfully passes clinical trial testing in terms of effectiveness and safety, as reviewed by the relevant authorities, the treatment will receive approval and can then be released to the market.

All new treatments will undergo post-market monitoring / surveillance (phase IV). Further phase IV clinical trials may be conducted in order to compare a treatment to established treatments, or to investigate its use in other conditions.

Where to Find Clinical Trials:

 

Written By Dr Danielle Santarelli

References & Resources

  1. Australian Clinical Trials: https://www.australianclinicaltrials.gov.au
  2. gov (NIH: U.S. National Library of Medicine): https://clinicaltrials.gov
  3. Therapeutic Goods Administration (TGA: Australian Government Department of Health): https://www.tga.gov.au
  4. “About Clinical Trials” Patients at Heart (AbbVie; Canada): https://www.patientsatheart.com/clinical-trials
  5. “Clinical Trials” Medicines Australia: https://medicinesaustralia.com.au/policy/clinical-trials
  6. “Clinical Trials” MedlinePlus (NIH: U.S. National Library of Medicine): https://medlineplus.gov/clinicaltrials.html
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January 17th, 2018|