Table of Contents:

1. Clinical Research Basics

What Is Clinical Research?

Why Is Clinical Research Important?

Ethical Considerations in Clinical Research

2. The Phases of Clinical Trials

Phase I Clinical Trials

Phase II Clinical Trials

Phase III Clinical Trials

Phase IV Clinical Trials

3. How Are Clinical Trials Designed?

Randomized Controlled Trials (RCTs)

Blind and Double-Blind Studies

Placebo Effect and Control Groups

4. Clinical Trial Recruitment

Patient Recruitment Strategies

The Informed Consent Process

Participant Eligibility Criteria

5. Data Collection Methods

6. Statistical Analysis in Clinical Trials

7. Data Monitoring Committees

8. Getting To Know Regulatory Compliance

FDA Regulations for Clinical Trials

Ethical Review Boards (IRBs)

Good Clinical Practice (GCP)

9. Clinical Trial Phases and Disease Areas

Clinical Trials in Oncology

Clinical Trials for Infectious Diseases

Clinical Trials in Neurology

10. Future Trends in Clinical Research

AI and Machine Learning in Clinical Trials

Patient-Centric Clinical Research

Virtual Clinical Trials

Clinical Research Basics

The most significant advances in medicine often come from clinical research, a process in which new drugs, treatments, and therapies are tested in the laboratory, sometimes on animals and then on humans. Clinical research looks at people's health and illnesses, and it's at the heart of every advance that helps heal those with health issues.

What Is Clinical Research?

Clinical research is the comprehensive study of the effectiveness and safety of new drugs, medical devices, medical techniques, tools, diagnostic tests, and technologies. It involves volunteers and differs from lab research in that it usually involves people who assist with the testing as test subjects.

There are two kinds of clinical research:

1. Clinical trials, also known as interventional studies, examine the effectiveness and safety of procedures, tools, or medications.
2. Observational studies look at patterns in medical data or biological samples.

Clinical research studies generally look at people of all ages, health statuses, ethnicities, races, genders, and cultural backgrounds. Researchers do this to ensure that clinicians and scientists gather enough information to understand how procedures or treatments work. Volunteers are always screened to make sure they're qualified and meet requirements to keep them safe during the trials.

Why Is Clinical Research Important?

Clinical research is vital because it helps scientists and researchers develop new strategies, treatments, medications, and tools to help treat or prevent disease. Essentially, clinical research helps expand medical knowledge and improve overall patient care. This can be the difference between making advances in medicine or merely maintaining the status quo.

Avoiding Mad Science: Ethical Considerations in Clinical Research

In a clinical research setting, ethics are paramount to protecting the rights, autonomy, and well-being of all participants. Researchers must prioritize the health and safety of all people involved in trials.

Within clinical research, it is understood that researchers must aim to maximize benefits but not do so at the expense of the participants' comfort or well-being. Individuals need to have continued autonomy, which includes the right to determine if and when they will participate in research.

There are a few formal documents that contain ethical frameworks that clinical researchers should abide by. These ethical frameworks can be found at the following links:

1. The Nuremberg Code. This code was ratified after the end of World War II and is a direct response to the clinical trials performed by Nazi scientists. It serves as an international standard for ethics in clinical research.
2. The U.S. Common Rule. This U.S.-based ethical guideline protects patients in clinical trials within the United States.
3. The Belmont Report. The Belmont Report was designed by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research and is specifically for use in biomedical research cases.
4. The Declaration of Helsinki. This declaration was brought forward by the World Medical Association and addresses new and evolving ethical concerns internationally.

It is important to note that there have been ethical violations of patient rights in the past, which is why ethics are taken so seriously today. Here are some examples of those cases:

The Tuskegee Syphilis Study

The Tuskegee Syphilis Study was performed at the Tuskegee Institute in 1932. At that time, Black men were recruited to participate in the trial, exploring how syphilis is transmitted from one person to the other. What they did not know was that there was no known treatment for syphilis at the start of the study. Additionally, they were not given complete informed consent. They were misled to believe that they were being treated for "bad blood."

In 1947, penicillin became the standard treatment for syphilis, but study participants were not offered the treatment to cure the disease, and research on the untreated subjects continued for decades.

Plutonium Trials

Also known as the human plutonium injection experiments, these experiments took place beginning in 1945 and continued through 1947. During the study, a total of 18 people were injected with plutonium long before the effects of radiation were understood. After injection, most participants lived only 11.7 years. At the time of injection, though, those who received the most significant doses (94.2 mg of Pu-239) were terminally ill, so the results could be skewed.

It's unclear if the participants knew they had been injected. Today, this would be considered an unethical study.

MK-ULTRA

The name of the CIA's "mind control" study, MK-Ultra, was a top-secret program that used a number of experiments to try to control others. The test subjects sometimes volunteered freely, but others were coerced or had no informed consent.

MK-Ultra involved hypnosis, radiation, electroshock therapy, and a litany of drugs and chemicals, including lysergic acid diethylamide (LSD). The CIA tested on a variety of subjects, including American soldiers, the mentally impaired, and prisoners.

Willowbrook Hepatitis Experimentation

In what is now considered one of the worst violations of ethics during human clinical trials, the Willowbrook hepatitis experiments involved a school for children with special needs: Willowbrook State School in Staten Island, New York. During the experiment, which started in 1956 and lasted for 14 years, researchers intentionally infected children with hepatitis. The goal was to study how viral infection developed, and the researchers had gamma globulin injections ready to help protect against hepatitis infection.

Despite parental consent, it has been argued that the parents didn't really have a clear understanding that the children would be intentionally infected and, because of a waiting list to get into the school, they may have been coerced into allowing the experimentation in exchange for access to boarding.

Order in the Court: The Phases of Clinical Trials

Clinical trials have four phases. Participants in Phase I trials are at the beginning of the trials, while those participating in Phase IV trials are part of Food and Drug Administration (FDA)- approved product or treatment testing.

Phase I Clinical Trials

Phase I clinical trials look at a new drug or treatment. Researchers start by identifying the correct dosing of a drug, for example, as well as what they can do to minimize side effects or unwanted complications.

Phase II Clinical Trials

Phase II clinical trials take place after treatments or drugs pass Phase I. At this time, the dosing of medications (as an example) will be fine-tuned. Researchers look closely at the safety implications of using new drugs or medications.

Phase III Clinical Trials

Phase III clinical trials involve comparing new treatments to older, dated treatments. The goal is to be sure that any new methods are an improvement on past options for patients.

Phase IV Clinical Trials

Phase IV clinical trials are only performed after the U.S. Food and Drug Administration (FDA) approves a new drug or improved medication. At that time, the test product was ready to be used among patients and trial participants. Usually, there must be hundreds or thousands of tests on unique individuals before a new product will go to market. Doing this many tests helps make sure that nothing harmful makes it to market on a larger scale.

How Are Clinical Trials Designed?

Clinical trials have to be planned and executed carefully for their own integrity and to protect the rights and safety of the patients and test participants. These tests are designed with clearly defined hypotheses or test questions and objectives.

Researchers are careful to choose only the best-suited patient population for the research, helping to ensure that the test results will be accurate and relevant to those who may benefit from the research in the future. For example, depending on the goals of the study, testing a diabetic drug on those with diabetes may make more sense than testing on a patient population that has not been diagnosed.

There are several kinds of clinical trials. Three of them include:

• Randomized controlled trials (RCTs)
• Blinding and double-blind studies
• Placebo effect and control groups

It's important to know the difference between these types of trials. Each one has its own benefits and downsides for researchers.

Randomized Controlled Trials (RCTs)

The first kind of trial to learn about is the randomized controlled trial (RCT). An RCT assesses the safety and effectiveness of a drug, treatment, or therapy.

To perform this type of trial, it's necessary for participants to be assigned to various groups. Two primary groups include a placebo group (the group that receives no treatment) and the treatment group. It's also possible to have other groups involved, such as:

• Those receiving no treatment
• Those receiving standardized treatments

Keep in mind that these groups are ordinarily randomized. Researchers don't always know who is in them, depending on other factors, such as whether the study is blind or double-blind.

Blind and Double-Blind Studies

Blind studies are studies that withhold information about the treatment from participants. For example, in a single-blind study, participants may not know if they're being given a new medication, taking a placebo, or receiving their standard treatment. However, researchers will still be aware of that case.

In double-blind studies, neither the participants nor the researchers know who is or is not getting a new treatment, therapy, or drug. Double-blind studies are considered to be incredibly valuable because there is no way for researchers to have conscious or subconscious biases during the tests. Additionally, the subjects of the tests don't know if they have or have not been made part of a specific group, which helps prevent the results from being influenced in any way.

Did It Really Work? Remember the Placebo Effect and Control Groups

The core of all research studies that are either blind or double-blind includes one important group: The control group.

A control group is essential because it helps determine the true effects of the trial product or substance. Those in the group are given a simple placebo drug or treatment. That means that they actually don't receive the new treatment or drug at all. Instead, they're either kept on their usual treatments or given nothing at all.

A good example of this is the idea of "sugar pills." Pills that contain no active ingredients can be made to look just like pills with active ingredients, but those in the control group will get the so-called "sugar pill" rather than the treatment.

This helps offset the possibility of a placebo effect, an effect in which treatment seems to work even though nothing about the patient's care has actually changed. Using a control group helps eliminate that placebo effect and establish a baseline for the study.

Clinical Trial Recruitment

Recruiting patients is among the most important parts of clinical trials. Today, recruitment is normally done through recruitment campaigns. However, once the trial is designed and ready to go, there are some other options for getting patients into it.

Patient Recruitment Strategies

Researchers can employ several different patient recruitment strategies. For example, they may look through electronic medical records (EMRs) to identify patients with the desired qualifications. They may also speak with local physicians to see if they know of any patients who would fit the study's guidelines.

In cases where finding patients is difficult, a full recruitment campaign is also possible. In that case, the researchers determine their target demographics, which will include information such as age, location, and gender, before launching a campaign. That campaign might take place within a hospital system, be distributed among primary care offices, or even occur on TV or social media in some cases.

Informed Consent Process

The informed consent process has three primary features that need to be met for it to protect patients and ensure they have the information they need to make good decisions about their health and participate in a clinical trial:

1. All the necessary information should be disclosed to patients during the trial so they can decide whether to participate.
2. Researchers and healthcare providers should talk to patients to be sure they understand what has been disclosed.
3. The researchers and involved medical teams should ensure that all patients understand that being in the trial is completely voluntary.

The law requires informed consent to be obtained. This includes communicating the role of the subjects and the risks and potential rewards of a study.

Participant Eligibility Criteria

"Participant eligibility criteria" include any requirements that people must meet in order to be involved in a clinical research study. These criteria are in place to make sure that all participants are similar to one another in the ways that matter for the study. Eligibility may be based on factors such as:

• The individuals' general health
• Previous treatments or therapies
• The stage of a disease the person is living with
• Age
• Gender

For the purposes of clinical research, it is possible to have both eligibility and ineligibility criteria. These can also be called inclusion or exclusion criteria.

Inclusion criteria determine who can be included in a study, and exclusion criteria make someone ineligible for a study. For example, someone with diabetes may not be eligible for a study involving high doses of steroid medications, as steroid medications can increase blood sugar levels and could lead to dangerously high blood sugar levels.

Not Just the Facts: Data Collection and Analysis

In clinical trials, data is normally collected from the source. That means that the data comes directly from the patient and provider performing tests. For instance, if a patient has their blood drawn, the labwork is regarded as the first point of contact with new data. And the data is collected from that point.

It's very important for medical researchers to collect data from legitimate sources of original data, such as:

• Automated instruments used to perform tests
• Imaging
• Copies or transcriptions that have been certified and verified as legitimate copies
• Questionnaires
• Pharmacy records
• Laboratory notes
• Hospital records
• Participant diaries

Every trial should have a data management plan that describes where source data will come from and how it will be collected.

Data Collection Methods

There are several ways to collect data for clinical trials. Some include:

1. Interviews and focus groups
2. Recorded data from EEGs, ECGs, CTs, MRIs, and other scans or tests
3. Phone records
4. Medical records, including office and clinic charts
5. Surveys
6. Questionnaires

It is of the utmost importance that any data collected is accurate. The validity of data can greatly influence the outcome of a study, so it's necessary for researchers to avoid using any data that can't be verified. For example, hearsay about a side effect wouldn't be good data, but digital health records showing the side effects of a medication would be.

It's also necessary for researchers and others involved in the trial to maintain good written and electronic records in compliance with any and all regulations. If parts of the research protocol have to be changed, having records of everything that has been done (and to whom) matters.

Improper data collection can lead to serious problems including (but not limited to):

• The inability to answer the research questions
• Misleading results
• Harm to animal or human subjects
• The inability to validate or repeat the study
• Wasted resources

If data collection methods are not controlled, errors are the most common issue. From violations of protocol to problems with fraud or misconduct, poor data collection can lead to significant concerns that can be difficult to correct without stopping a study and throwing out its results.

Statistical Analysis in Clinical Trials

In clinical trials, statistical analyses are normally performed at the end of the study. The researchers record data at specified check-in times and save it for analysis when the study concludes.

Once the study is over, or when a specific interval of time is reached, the current data is analyzed and compared to the original hypotheses. Scientists and researchers use the data to come up with conclusions based on their findings.

Data Monitoring Committees

Clinical trial data monitoring committees are responsible for working with investigators and sponsors. They monitor clinical trials to assess their safety and conduct, assessing the risks and benefits of the trials while also making recommendations about how to help protect those who have chosen to participate.

The Clinical Trials Transformation Initiative makes recommendations to help those involved in clinical trials work well together with the data monitoring committees to achieve the best outcomes for all people involved in trials.

Data monitoring committees have an important role. In 1967, DMCs were introduced to provide additional oversight. Rather than allowing researchers and scientists already working on a trial to determine when it should end or if it should be altered, the DMC steps in as an independent group of scientists not involved in the trial. Since this group doesn't have as much of a bias, it is able to clearly define when trials should end, when there is enough evidence and data to stop performing a trial, when a trial could cause harm, etc.

Getting To Know Regulatory Compliance

One important aspect of clinical trials is adhering to regulatory guidelines. Regulatory compliance isn't a single set of rules but encompasses many different practices and sets of guidelines.

FDA Regulations for Clinical Trials

FDA regulations state exactly how human subjects are to be protected during clinical trials and provide details about how clinical trials must be performed.

This list includes links to all the FDA regulations that govern both circumstances:

• Electronic Records; Electronic Signatures (21 CFR Part 11)
• Premarket Approval of Medical Devices (21 CFR Part 814)
• Regulatory Hearing Before the Food and Drug Administration (21 CFR Part 16)
• Investigational Device Exemptions (21 CFR Part 812)
• Protection of Human Subjects (Informed Consent) (21 CFR Part 50)
• Applications for FDA Approval of a Biologic License (21 CFR Part 601)
• New Animal Drug Applications (21 CFR Part 514)
• Financial Disclosure by Clinical Investigators (21 CFR Part 54)
• New Animal Drugs for Investigational Use (21 CFR Part 511)
• Institutional Review Boards (21 CFR Part 56)
• Bioavailability and Bioequivalence Requirements (21 CFR Part 320)
• Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58)
• Applications for FDA Approval to Market a New Drug (21 CFR Part 314)
• Investigational New Drug Application (21 CFR Part 312)

Ethical Review Boards (IRBs)

Ethical review boards consist of individuals who oversee and maintain the rights of human research subjects who are part of specific institutions' trials. Called Institutional Review Boards, these administrative bodies play an important role in reviewing research that includes human participants.

The IRB isn't responsible for every aspect of a clinical trial, but it is responsible for determining if a trial will protect the privacy, welfare, and rights of the participants. The IRB has several types of authority, including the authority to:

• Approve research activities
• Require modifications to research activities
• Disapprove/reject research
• Monitor research as needed

Each facility's IRB must consist of at least five people. They must come from varied backgrounds to ensure that they adequately review the legal, scientific, institutional, and social implications of research projects. There are also additional rules about who can be on an IRB panel. For instance, at least one member should not be a scientist, and another should not be affiliated with the research institution.

Good Clinical Practice (GCP)

Good clinical practice refers to the practices mandated by the U.S. Food and Drug Administration to ensure the integrity of clinical data and to protect the safety, rights, and welfare of the humans involved in the studies.

The FDA's website provides general information about clinical investigators, activities that involve targeted groups of people, institutional review boards (IRBs), and other regulations. Additional details can be found on the U.S. Food and Drug Administration's Good Clinical Practice page.

Clinical Trial Phases and Disease Areas

One important thing to keep in mind about clinical trials is that they are performed in phases. For example, pre-clinical studies, also called laboratory studies, take place first to ensure that a new treatment or drug is likely to be effective and safe. Pre-clinical studies can involve cell or animal studies.

Following this stage, new drugs have to be approved via an investigational new drug (IND) application. The research from the previous phase is reviewed by the U.S. Food and Drug Administration, and researchers decide whether to approve the clinical trial or deny it based on the information provided about risks, how the treatment is done, and other factors.

From there, the process goes through several more phases, including:

• Phase 0 trials
• Phase I trials
• Phase II trials
• Phase III trials
• Phase IV trials
  

Several areas of preclinical and clinical research exist. These include oncology, gastroenterology, cardiology, hematology, veterinary medicine, dermatology, neurology, gene therapy, medical devices, and many more. Let’s look at a few of them.

Clinical Trials in Oncology

Clinical trials in oncology explore how to improve the quality of life of those who live with cancer.  These trials are particularly important for people who take cancer-treating medications and experience side effects from those medications or therapies.

Clinical trials for oncology look at drugs that help with nausea or depression. They can also look at drugs to help with pain or better treatment of different kinds of cancer.

Clinical Trials for Infectious Diseases

Clinical trials for infectious diseases are some of the riskiest trials. They investigate diseases related to pathogens, bacteria, viruses, parasites, and/or fungi. These trials are sometimes performed post-infection, but they can also take place with ongoing infections. For instance, there are medication trials for AIDS medications, allergy medications, and viral illnesses such as bronchitis or coronaviruses.

Studies usually examine the long-term impacts of infectious diseases (such as the COVID-19 pandemic). This study, for example, examines the long-term clinical effects.

Clinical Trials in Neurology

Clinical trials in neurology look at how medications and treatments interact with the brain and nervous system. Clinical trials may look at treatments for conditions such as:

• Epilepsy
• Headaches
• Memory disorders and diseases
• Alzheimer's disease
• Movement disorders, including Huntington's disease and Parkinson's disease
• Autonomic disorders such as REM sleep disorder
• Neuroimmunology conditions such as multiple sclerosis

Clinical research may also be performed to help treat neuromuscular conditions, those in need of stroke and neurocritical care, neuro-oncology cases, and pediatric groups.

What's Next? Future Trends in Clinical Research

There are changes coming to clinical research and trials. These include real differences created by the implementation of AI and machine learning, which can speed up analysis and help build better trial protocols. Patient-centric clinical research is also becoming more common, as are virtual clinical trials that don't require much, if any, interaction with a doctor.

Healing or Repairs? AI and Machine Learning in Clinical Trials

The implementation of AI and machine learning in clinical trials may well create opportunities for expediting research and analysis. Artificial intelligence is currently in a phase of "enthusiastic development," and in the future, it may be harnessed to help analyze data and keep workflows running smoothly during trials.

Presently, though, there are challenges that complicate using AI in this context. Most of these challenges are ethical in nature: Simply put, there is not enough regulatory guidance to fully implement AI or other machine learning software.

However, as the probability of success with AI increases, it becomes more likely that it will be used in medical and research software to help reduce the burden of clinical trials and speed up both regulatory approval and research, respectively.

The Doctor Will See You Now: Patient-Centric Clinical Research

What is a patient-centric approach in clinical research? It's an approach that focuses on patient feedback. For example, during a typical trial, the data that is most often collected comes from blood work, testing, and other statistical resources. However, those trials don't always consider how the patient feels or what their families think.

Those two factors must be considered because the way people feel about their treatments or what they're going through matters. For instance, a treatment may have a 100% success rate, but if it leaves someone with a disability and causes emotional distress, researchers would have to ask if that is the right treatment.

Patient-centric clinical research examines not only what patients need but also what researchers can do to make the trial more convenient for them.

Around 85% of clinical trials don't hit their goals for recruitment, and the average drop-out rate is around 30%. While it's impossible to prevent all drop-out cases due to the volunteer requirements, carefully considering what patients need and how you can make a trial more convenient for those who are participating can help.

Note that patient-centric approaches do work, and the numbers prove it. One study determined that new medications developed via a patient-centric approach had an 87% chance of launching. When a patient-centric approach wasn't taken, the likelihood of the drug being released dropped to 68%.

Key ways that a clinical trial can be more patient-centric include:

• Working with patient advocacy programs and organizations to see what patients need or want during a trial
• Talking to patients to assess what their personal needs are during a trial
• Thinking about recruitment strategies and answering any and all questions potential volunteers may have
• Accepting ongoing feedback during a trial
• Designing protocols that protect patients' wants and needs throughout the trial

Getting Proper Bed Rest: Virtual Clinical Trials

Virtual clinical trials are relatively new, but they harness internet access and the simplicity of not having to attend sessions in person (at least, not regularly). Using mobile apps, remote monitoring devices, and social engagement platforms allows some types of trials to run even when the subjects don't live nearby or can't be seen in person.

Digital health technologies make the biggest difference in these trials. For instance, a trial on diabetes may require all patients to wear digital blood sugar tracking devices. The information collected by the devices would be submitted over the Internet, allowing the patients to avoid regularly coming into a testing facility.

Virtual clinical trials do face some challenges, though. Privacy concerns often arise, and other issues, such as poor digital training or a lack of access to the internet, can also create issues for patients and the clinical team. However, in cases where the subjects are able to complete their tests, researchers can gain much-needed information from the digital technology they wear or use to report back their test results.

Privacy concerns are legitimate, which is why we at Studypages launched our secure, HIPAA-compliant, web-based messaging feature for effective clinical research communication. This new feature ensures richer communication and easy accessibility between study teams and participants, all with top-notch data privacy, security, and compliance.

Clinical research is an important part of creating new treatments and bettering the treatments and therapies that already exist. Without clinical research and trials, little would be done to advance the medical field. Fortunately, with volunteers, it is possible to make strides in medicine so more people can benefit from new findings.

For more information about clinical trials or ways to get involved as a volunteer, contact Studypages.