What are Clinical Trial Phases?

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Clinical trials to test new cancer treatments involve a series of steps, called phases. If a new treatment is successful in one phase, it will proceed to further testing in the next phase.

Understanding Cancer Research Study Design and How to Evaluate Results

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Approved by the Cancer.Net Editorial Board, 04/2018

Doctors and scientists conduct research studies to find better ways to prevent and treat cancer. Depending on the questions they want to answer, researchers can design these studies in different ways. No study design is perfect. Each has strengths and drawbacks. It is important to understand a study’s design. By doing this, you can understand the results to know if they apply to your situation.

In cancer research, there are 2 main types of research studies:

  • Experimental studies. This type of study provides an intervention, such as a new treatment. The intervention is given to a group of people. Then, researchers compare their results to those of another group that does not receive the intervention. This other group is known as the control group. The researchers choose who does and does not receive the intervention either randomly or through a selection process. Experimental studies help researchers learn more about how cancer starts or spreads. These studies can also test new imaging techniques and explore quality of life issues.
  • Observational studies. This type of study involves observing groups of people in a natural setting and looking at a specific result. A result may include whether 1 group of people has more cancer diagnoses than another group. In these studies, the researchers cannot control the intervention, such as a person’s weight or whether they took vitamin supplements. These studies are often described as epidemiologic. Epidemiology involves studying how different risks cause or spread a disease in a community.

Types of experimental studies

Experimental studies are more reliable than observational studies. This is because the volunteers are placed in the intervention or control group by chance. This reduces the likelihood that the assumptions or preferences of the researchers or volunteers will change the study results. Such assumptions or preferences are called bias.

This type of study also helps researchers to better find and control other factors, such as age, sex, and weight. These factors can affect the results of the study.

Researchers may also consider certain factors when choosing people to enroll in an experimental study. They could be based on type of cancer, stage of the disease, or whether the cancer has spread.

One of the most common types of experimental studies is the clinical trial. This is a research study that tests a medical intervention in people. Clinical trials test:

  • The effectiveness or safety of a new drug or combination of drugs
  • A new approach to radiation therapy or surgery
  • A new treatment or way to prevent cancer
  • Ways to lower the risk of cancer coming back

Doctors and researchers conduct clinical research in segments called phases. Each phase of a clinical trial provides different answers about the new treatment. For instance, it can show the dose, safety, and efficacy of the treatment. The efficacy is how well the treatment works. There are 4 phases of clinical trials.

In a clinical trial, volunteers are usually selected by chance to either be in the treatment or control group. Researchers can prevent bias in a clinical trial by keeping volunteers and/or themselves from knowing how the volunteers are grouped. This is a process known as “blinding.”

Types of experimental studies include:

  • Double-blind randomized trial. Most scientists believe this type of clinical trial will produce the best evidence in a study. Neither the volunteers nor the researchers know who belongs to a treatment or control group until the study ends.
  • Single-blind randomized trial. In this type of trial, the volunteers do not know whether they belong to a treatment or control group. But the researchers know.
  • Open/unblinded trial. Both volunteers and researchers know who belongs to each test group in this type of study. This occurs when it is not possible to use blinding. For instance, the study could compare a surgical treatment to a drug.

Types of observational studies

In observational studies, researchers have less control over the study volunteers. This means that certain factors could affect the results. These studies, however, are useful in providing initial evidence that can help guide future research.

Types of observational studies include:

  • Case-control studies. These types of studies compare 2 groups of people. For instance, they could compare those who have cancer (the case) and those who do not (the control). Researchers may look for lifestyle or genetic differences between the 2 groups. By doing this, they hope to find out why 1 group has a disease and the other group does not. These studies are conducted retrospectively. That is, they are researching what has already happened.
  • Cohort studies. These studies are prospective, which means that researchers study the event as it occurs. They monitor a group of people for a long time and track something. For example, they could track any new cancer diagnoses. This type of study can assess whether certain nutrients or actions can prevent cancer. This approach can also find cancer risk factors. For instance, cohort studies have looked at whether postmenopausal hormone replacement therapy increases the risk of breast cancer.
  • Case reports and case series. These studies are detailed descriptions of a patient’s medical history. The individual patient descriptions are called case reports. If many patients receive a similar treatment, the case reports may be combined into a case series. The results of case series studies are descriptions of patients’ histories within a specific group. As such, they should not be used to determine treatment options.
  • Cross-sectional studies. These studies examine how diseases interact with other factors within a specific group at a point in time. But because these studies only measure interactions at a single point in time, they cannot prove that something causes cancer.

Types of review articles

A large number of cancer research studies are published every year. Given this, it is challenging for doctors, as well as interested patients and caregivers, to keep up with the latest advances. Research studies published in journals are constantly shaping and reshaping the scientific understanding of that subject. No single study provides the final word on a topic, type of cancer, or treatment. As a result, review articles, which evaluate and summarize the findings of all published research on a certain topic, are extremely helpful.

Types of review articles include:

  • Systematic reviews. These articles summarize the best available research on a specific topic. Researchers use an organized method to locate, gather, and evaluate a number of research studies on a particular topic. By combining the findings of a number of studies, researchers are able to draw more reliable conclusions.
  • Meta-analyses. These studies combine data from several research studies on the same topic. By combining these data, a meta-analysis can find trends that are hard to see in smaller studies. But if the single studies were poorly designed, the results of the meta-analysis may not be useful.

Evaluating research studies

Here are some tips for finding out the quality of a research study:

  • Find out if the journal uses a peer-review process. Results from a study are more reliable if they are peer-reviewed. This means that researchers who are not a part of the study have looked over and approved the design and methods.
  • Look at the length of the study and the number of people involved. A study is more useful and credible if the same results occur in many people across a long time. Studies of rare types of cancer or cancers with a poor chance of getting better are an exception to this rule. This is because there are a small number of patients to study. Also, when looking at the length of the study, it may be suitable for some clinical trials to be shorter. For instance, cancer prevention trials are often much longer than treatment clinical trials. This is because it usually takes longer to figure out if a prevention strategy is working compared to a treatment.
  • Consider the phase of the study when learning about new treatments. Phase I and II clinical trials usually tell you more about the safety of a treatment and less about how well it works. These studies tend to have a smaller number of patients compared to phase III clinical trials.  Phase III clinical trials compare a new treatment with the standard of care. “Standard of care” means the best treatments known. Doctors consider phase III clinical trials to be the most reliable.
  • Find out if the study supports or contradicts current research. New results are exciting, but other researchers must validate the results before the medical field accepts them as fact. Review articles like systematic reviews are of special interest. They review and draw conclusions across all of the published research on a specific topic.
  • Watch out for conclusions that overstate or oversimplify the results. Each study is a small piece of the research puzzle. Medical practice rarely changes because of the results of a single study.

Questions to ask your health care team

Always talk to your health care team about what you find in an abstract or study. If you have reviewed a study that suggests a different approach to cancer treatment, do not stop or change your treatment. First talk with your health care team about how the study relates to your treatment plan.

Consider asking your health care team the following questions:

  • I recently heard about a study that used a new treatment. Is this treatment related to my type and stage of cancer?
  • What type of journals should I read to learn more about my type of cancer?
  • Should I consider being a part of a clinical trial?
  • What clinical trials are open to me?
  • Where can I learn more about clinical trials?

Drug Discovery and Development

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Approved by the Cancer.Net Editorial Board, 08/2018

Doctors and scientists are always looking for better ways to care for people with cancer. To do this, they create and study new drugs. They also look for new ways to use drugs that are already available.

A drug goes from being an idea in the lab to something that a doctor prescribes. To do this, it must go through a long development and approval process. During this process, researchers make sure the drug is safe for people to take and effectively treats cancer. This process often takes many years and significant resources. But the actual amount of time and money needed depends on the drug.

There are 3 main steps in finding and developing a new drug:

  • Preclinical research, which is when the drug is found and first tested
  • Clinical research, which is when the drug is tested in people
  • Post-clinical research, which takes place after the drug is approved

Drug discovery and initial testing

The discovery of new cancer drugs can happen in different ways:

Accidental discovery. In the early 1940s, an explosion exposed sailors to poisonous mustard gas. Doctors found that these sailors had low white blood cell counts. So they began using nitrogen mustard, or mechlorethamine (Mustargen) to treat Hodgkin lymphoma. This is a cancer of the lymphatic system involving the white blood cells. Nitrogen mustard is still a cancer treatment used today. But accidental discoveries such as this are rare.

Testing plants, fungi, and animals. Paclitaxel (Taxol) treats several types of cancer. This was first found in the bark of the Pacific yew tree. More recently, a primitive animal called a sea sponge was used to create the drug eribulin (Halaven). The National Cancer Institute (NCI) has samples of thousands of plants, marine organisms, bacteria, and fungi. These are collected from around the world in the hopes of finding new cancer treatments.

Studying the biology of cancer cells. Most cancer researchers start by comparing both the genes found in DNA and growth patterns of cancer cells to healthy cells. This identifies important steps in the cancer growth process that a drug could fix.

For example, researchers learned that about 20% of all breast cancers have an abnormal amount of a certain protein. It is called HER2 and controls the growth and spread of cancer cells. Five drugs were created to target HER2: trastuzumab (Herceptin), lapatinib (Tykerb), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), and neratinib (Nerlynx). Now, a person with breast cancer has the tumor tested to check for HER2. It will show if these drugs can treat the cancer. Learn more about these targeted treatments.

Understanding the chemical structure of a drug target. Scientists may use computers to mimic how a potential drug interacts with its target. This is similar to fitting 2 puzzle pieces together. Researchers can then make chemical compounds that interact with the specific drug target.

After drugs are created, researchers test them on human tumor cells in the lab. They see if the drugs stop the growth of cancer cells. Next, they test the drug in animals to find out if it is still effective at treating cancer. Researchers test the drug in 2 or more animal species. They learn how the body uses the new drug. They also learn what side effects the drug may cause and what dose of the drug to test in people.

Drug developers and sponsors

The U.S. Food and Drug Administration (FDA) does not develop or test drugs. Instead, medical research universities, government agencies such as the NCI, and drug companies find and test new drugs. The sponsor is the group that develops a drug. It does the research needed for the FDA to approve the drug.

Biosimilars

Drug developers are creating different types of biologic medicines to treat cancer. One kind of biologic medicine is called biosimilars.

Biosimilars are a variation of drugs already approved by the FDA. They offer a growing number of new treatment options for people. They also often cost less than similar drugs.

The FDA requires a biosimilar drug to be compared with an existing one. The existing drug is called a reference drug. The biosimilar must be highly similar in structure and function and have no large differences compared to the reference drug.

Biosimilars have to meet a strict approval process by the FDA to make sure it is a safe and effective treatment option. Talk with your health care team to find out if biosimilars could be a part of your treatment plan.

Clinical research

Before new drugs are tested in people, the sponsor must submit an Investigational New Drug (IND) application to the FDA. The IND provides information about past and future research plans, such as:

  • Preclinical studies done in the lab and in animals
  • Plans for clinical trials in people
  • How the new drug is made

The FDA approves potential drugs for testing in people under certain conditions:

  • The research shows that the drug is likely to work and be safe.
  • The proposed clinical trials must be designed correctly.
  • The drug can be made the same way every time.

Clinical trials are research studies involving volunteers. They are used to find out if a new drug is safe, effective, and better than the standard treatments. Each phase involves a larger number of people than the previous phase. It also provides more detail about the new drug’s safety and effectiveness.

Clinical trials may involve hundreds or thousands of people. They usually take years to complete. But sometimes, if a small clinical trial shows very promising results, the process may be sped up.

Early phases of clinical trials focus on safety, dosing, and how the body processes the drug. Later phases center on how well the drug works. Learn more about clinical trials.

Clinical review and FDA approval

If the clinical trials are successful, the drug sponsor submits a New Drug Application (NDA) to the FDA. The NDA requests approval for the drug to be prescribed by doctors. The request includes:

  • Results from the preclinical and clinical studies.
  • Details about how the drug will be made and labeled.
  • The drug’s possible side effects and any interactions with food or other drugs.

The FDA may approve the drug if the evidence shows it is effective and safe for use. No drug is completely safe or free from side effects. But a drug is approved if there are more benefits than risks.

After FDA approval

A drug is ready for the market when it receives FDA approval. This means it can be prescribed by doctors and sold to people. But the FDA may require that the sponsor conduct more clinical trials. These are called phase IV clinical trials.

Phase IV clinical trials look for other possible side effects or confirm the benefits of the treatment. They may study the drug in different doses, new combinations, or in different schedules. They may also study the treatment in new groups of people, such as older adults or children. Or they may assess the drug’s long-term effects.

Some drug makers may conduct their own phase IV clinical trials. They may do more research to get FDA approval to use the drug in a new way, such as for another type of cancer.

The FDA also monitors the safety of drugs currently on the market. They do this to make sure that drug makers report any new or serious side effects. The FDA may withdraw a drug from the market if new research shows it is not safe or effective.

Understanding Clinical Trials

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It’s Pancreatic Cancer Clinical Trial Awareness Month, and this short video from the National Pancreas Foundation gives a great overview of what clinical trials are, how they are conducted, and why they are important for patients with diseases like pancreatic cancer. It provides a thorough overview of study design, eligibility criteria, informed consent, safeguards, different phases of clinical trials, and the potential benefits and potential risks of participation. Find out more about cancer clinical trials HERE.

 

Understanding the Phases of Clinical Trials

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Phases of clinical trials explainedClinical trials typically are conducted through a sequence of phases, each successive stage building upon the last. Each of these phases is designed to address a specific set of questions and having knowledge of each phase is essential in understanding what is currently known about an experimental therapy. There are benefits and drawbacks associated with moving a treatment into each specific phase.

The clinical trial is only conducted when researchers have reason to believe that a new treatment or test could significantly improve patient care. Before these trials are carried out, the treatment or test is first evaluated in preclinical research.

Preclinical Trials: Before Testing in Humans

Preclinical trials assess the features of the proposed solution through cellular research and experiments with tissue and animal models. The goal of the preclinical trials is to ensure that the solution is safe to use before testing it in humans during clinical trials.

After this preclinical research, a series of clinical trials are then conducted. These trials assess whether the test or treatment is safe and effective in human patients. These clinical trials are conducted in five phases, which will be explained below using the example of an experimental drug.

Phase 0: Small Doses in Humans

Phase 0 trials mark the first clinical trials done in humans. The goal of this phase is to learn a drug is processed by the body and what effects it can have. These trials recruit about 10-15 people who are given a minuscule dose of the drug. The purpose of this phase is to facilitate the drug approval process. Researchers can assess several factors in this stage, like whether the drug reaches the target site, how cells respond to the drug, and how the patient tolerates the dose.

What sets phase 0 trials apart from the latter phases is that it is very unlikely that the participant will see any benefit. These low dosages administered during this phase allow the researchers to evaluate the drug’s effectiveness while minimizing risk in the patients. This step allows scientists to recognize flaws in essential steps like drug absorption early, rather than having to address this years down the road in later phase trials.

Phase 0 studies are not always used, being that they would not be helpful for some drugs. This stage is not required for the testing of a new treatment.

Phase I: Evaluating Safety

Trials in phase I aim to identify which doses of a drug yield the least side effects. The drug is tested in groups of 15-30 patients in this stage, with doctors giving them the drug in various doses. The first few patients are given a very low dose and if they show negligible side effects, the next participants receive a higher dosage. This is repeated until the researchers find the quantity of the drug that is likely to be effective while producing an acceptable amount of side effects.

These trials do not use placebos and are typically considered to have the most potential risk. Though patients may see some benefits from the drug in phase I, the primary goal of this stage is to test the drug’s safety in humans. If the drug is found to be safe, it is then tested in a phase II clinical trial.

Phase II: Testing the Drug’s Effectiveness

Phase II trials aim to further validate the treatment’s safety, often narrowing the participant cohort to those with a specific condition. Phase II trials recruit more participants than phase I trials, with about 25-100 participants typically involved. These patients are given the optimal dose identified in the phase I trial and are closely observed to see if the proposed treatment is effective. Participants in phase II trials typically all receive the same dose, but some studies randomly assign participants to receive different doses or routes of administration. No placebos are used in phase II clinical trials.

Phase III: Comparing to Current Treatments

The phase III trials aim to compare a new drug to the standard-of-care drug, or the current drug used to treat a condition. These experiments compare the side effects and efficacies of each drug to determine which is best for the patient. Phase III trials typically involve several hundred patients.

These trials are often randomized, meaning that the participants are randomly assigned to receive either the experimental drug or the standard-of-care drug. This randomization is important in ensuring that the participants are alike in each group, therefore any differences in outcomes can be attributed to the treatments, not the group composition.

Phase III trials are typically conducted in various locations throughout a country or even internationally. These studies are also longer than phase I and II trials in duration. Placebos can be used in phase III trials, but they are never used alone if there is also a standard-of-care treatment available for the patients. These trials are terminated if the side effects of the experimental drug are becoming too severe or if one group is performing significantly better than the other. The phase III clinical trial is often required for the FDA to approve the use of a new drug.

New Drug Application (NDA)

When an experimental drug outperforms the standard-of-care in a phase III trial, an NDA is submitted to the FDA for approval in the U.S. The FDA reviews the results from the trials and decides whether the drug is worthy of approval for use in patients. If approved, this new treatment often becomes the new standard-of-care. The FDA can also deem that further research is needed to show that the drug’s benefits outweigh its risks and request that more studies be conducted.

Phase IV: Large-Scale Studies After Approval

These trials aim to test new drugs that the FDA has approved. The drug is evaluated in hundreds or thousands of patients, allowing for more information regarding short-term and long-term side effects to be obtained. These trials may uncover rare side effects that are only seen in large groups of people. Physicians are also able to learn from phase IV trials by seeing how a drug works in concert with other medications. These trials can look at other aspects of the drug as well, such as cost-effectiveness and its effect on quality of life.

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(Source: docwirenews.com)