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What Are the Types of Research?

Research is necessary to discover life-changing new treatments – and eventually a cure – for Rett syndrome. There’s Basic Research, Translational Research, Neuro-habilitation Research, and Clinical Research. Here, we define each type of research, and explain what each contributes to the goal of creating a cure.

Basic Research

Basic research investigates the life processes involved in health and disease. It’s usually performed in a laboratory using cells or animal models. This type of research may not apply directly to a treatment, but such investigations are essential to generate new ideas for therapeutic development down the line.

Translational Research

Translational research, also called “bench to bedside” research, tests something that came from basic research for its use in improving health outcomes. Like basic research, translational studies are typically performed in the lab using a model. The goal of translational studies is to produce a new treatment. Hopefully, the new treatment will prove safe and effective enough in an experimental setting to be tested in a clinical trial.

Neuro-habilitation Research

Neuro-habilitation research searches for ways to re-train the brain through cognitive, speech, occupational, and physical therapies. This type of research may involve animal studies or human participants. Rehabilitation professionals carefully supervise the research in a clinical setting. The data collected in neuro-habilitation research helps in the design of new treatment protocols that are based on science rather than isolated cases.

Clinical Research

Clinical research investigates health and disease in humans. One type of study that falls in this category is a clinical trial. This type of research requires human participants. It often takes place in a clinic setting, and a clinical team always oversees it. Surveys and neuro-habitational studies are other types of clinical research.

Clinical studies can be broken down into two categories: Observational Trials and Interventional Trials.

In an observational trial, researchers monitor participants’ health, collecting data on their disease symptoms and progression over time.

In an interventional trial, researchers study a participant’s response to a therapy. This therapy could be a drug, surgery, vitamin, exercise, or some other means of influencing disease processes. You can see the current list of interventional trials in myRett Trial Finder by searching by study type and selecting “Interventional.”

The time, money, and energy required of the families who choose to participate may vary by the individual clinical study. However, the goal of all clinical research is the same: to improve the quality of life for patients by advancing our understanding of a disease and its treatment.

Learn more about Rettsyndrome.org’s current and previous investment in the research mentioned above. (https://www.rettsyndrome.org/research/our-research/funded-research/).

How Are New Therapies Developed?

The development of any new drug or therapy for Rett syndrome or any disorder must follow a scientifically rigorous and well-regulated path.  This path is designed to make sure that any new therapy is safe and effective when it is made available to the public. The therapy development path is divided into five stages.

The development of a new therapy for Rett syndrome or any disorder must follow the path that regulatory bodies (such as the U.S. Food and Drug Administration (FDA) or European Medicines Agency) have established. This path helps to assure that any new therapy is safe and effective when it is made available to the public. The therapy development path is divided into five stages. Because of the challenges involved in developing a new therapy, the overall path takes 10-25 years to complete.

Stage 1: Discovery and Development (5-10 years)

The development of a therapy begins in the lab as a basic research discovery. Scientists work for several months to years to generate these discoveries. In this stage, scientists identify new ways to modify a disease process or new disease-fighting technologies. They may identify a new drug, often by testing a library of 100,000+ compounds.

When they find a new treatment approach that looks promising in a first set of experiments, researchers gather more information to develop it. They get this information by performing experiments designed to answer questions about the new therapy, including:

  • How does it react with the body?
  • Are there any side effects?
  • What is the best dose to use?
  • Can the new treatment be modified to improve its potential to reach the desired outcomes?
  • What is the best way to give the new treatment (such as by mouth or injection)?
  • How does the new treatment compare to other treatment approaches to address patients’ health needs?

All these questions must be answered before a new treatment can be developed further. A large number of different experiments are required, which is why this stage of drug development is often one of the longest.

Researchers perform all tests in this stage of drug development in cell culture or animal models. They review all the data they collect. This review gives researchers the information they need to determine whether or not to continue developing the new treatment.

Stage 2: Preclinical Research (3-5 years)

If a new therapy shows promising results in Stage 1, it moves on to the preclinical research stage (Stage 2). Preclinical research carefully tests the new drug or approach for potential to cause severe sickness, injury, or death in cell culture and animal models. This stage follows the regulatory agency mandated requirements (https://www.fda.gov/patients/drug-development-process/step-2-preclinical-research). As in Stage 1, many different kinds of experiments are involved. The results of these experiments are carefully reviewed to determine if the new drug or approach is safe enough to test in humans.

Stage 3: Clinical Research (6-7 years)

If the sponsors leading the investigation of a new treatment or approach decide it looks safe and promising in preclinical testing and should be developed further, researchers design experiments to test it in humans. These clinical research designs define:

  • Who qualifies as a participant?
  • How many people will be involved?
  • How long the study will last?
  • How bias in the research will be limited?
  • What data will be collected?
  • How the data will be analyzed?

These trials are necessary to determine if the treatment produces the desired outcome in the human body. To protect human participants as much as possible, the new treatment sponsor must apply to the regulatory authorities for permission to conduct clinical research. In their application, the treatment sponsors must provide basic information about the new treatment (like how it is made), information about study investigators, the data obtained from preclinical testing, and all the details of their clinical research design.

A new treatment can only enter the clinical trial stage if regulatory authorities approve this application. The success of participant recruitment, the length of time participants need to be monitored, and how clear the results are all factors that affect the duration of the clinical research state.

Stage 4: Drug Review (1-2 years)

If the results from pre-clinical and clinical trials indicate that a new treatment approach is safe and effective, the sponsor can apply to the regulatory agency for permission to market it. During this drug review stage, regulatory authorities study all information collected about the new therapy. They then decide whether to approve, reject, or request additional data. If approved, the sponsor develops prescribing information with instructions for using the new treatment, and the treatment enters the market.       

Stage 5: Post-Market Safety Monitoring (months to years after approval)

Regulatory agencies continue to monitor the outcomes of patients being treated with a new therapy after its approval. As more people receive the new treatment, more data becomes available. This data may reveal new information about the therapy since it is impossible to find out everything during the therapy development process. Continued safety monitoring enables the prescribing information for a therapy to be changed if needed to protect patients.

Clinical Trial Phases

Before any new treatment reaches the market, it must be tested in a series of interventional clinical trial phases to determine if it is safe and effective. Each phase must answer a different question about the new therapy. As such, each follows a different study design.

Phase I: Is It Safe for Humans?

A Phase I clinical trial tests a potential new treatment in people for the first time, sometimes called “first-in-human studies.” The primary goal of this testing is to determine if the treatment is safe in humans. This phase can also help identify a safe dose in humans.

Only a few volunteers (usually 10-100) are needed in this phase. The volunteers may be healthy “controls” (people without Rett syndrome) or may be individuals with Rett syndrome. A Phase I trial typically achieves its goal in months.

In addition to gathering information about the safety of a new treatment, a Phase I trial may also reveal:

  • Any side effects
  • The optimal treatment dose for humans
  • The best way to give the treatment such as by mouth or injection

About 70% of treatment approaches tested in Phase I clinical trials advance to Phase II.

Phase II: Is It Safe and Effective for the Target Disease?

The goal of a Phase II trial is to find out if the new therapy safely and effectively treats its target disease. These trials require more participants, and these participants must have the disease that the new therapy is intended to treat. Phase II trials also take longer than Phase I Clinical Trials to complete — usually months to years.

Sometimes Phase II trials assign participants into two groups by chance. One group receives the new experimental treatment. The other (the “control” group) receives either the standard of care intervention (whatever treatment is typically recommended for the disease) or a placebo (a substance that looks like the experimental treatment but is inactive).

Because no treatments currently exist for Rett syndrome, the “control” group in a Rett syndrome clinical trial would likely receive a placebo. Often, neither the participants nor the researchers know which treatment group an individual participant is in. This helps minimize bias in measuring a patient’s treatment outcomes.

If Phase II trials demonstrate that the new treatment is safe and effective at treating disease in the relatively small number of patients treated, the regulatory agency will allow Phase III testing to proceed.

Around 33% of new treatment approaches tested in Phase II trials meet the criteria to move on to Phase III.

Phase III: Can Phase II Findings Be Confirmed?

Phase III trials aim to confirm or disprove the findings made in Phase II. They generally require more participants who have the disease the new therapy is intended to treat than Phase II trials do. That may be around 100 participants for a rare disease but can be thousands of participants for common conditions. This phase can often last several years and take place at several different medical centers.

Phase III trials usually randomly assign participants into either a “control” or “experimental” group. If a Phase III trial confirms the results of Phase I and Phase II trials for safety and efficacy, it can be considered for approval. During this approval process, regulatory agencies review the hundreds of pages of data collected on the new therapy. That review can take up to 12 months. Once approved, the new treatment is sent to pharmacies and may be prescribed to those who would benefit from it.

Approximately 25-30% of drug tests in Phase III move to regulatory approval. If approved, the new therapy can be brought to market and prescribed for use.

Phase IV: Does It Perform as Expected in the “Real World”?

Studies of a new treatment continue after it enters the market. The goal of these Phase IV clinical trials is to assess the new treatment’s performance in the “real world.” This is important because prior to its approval, the new treatment was only examined in a study setting. Many of the variables that are present in the lab or clinic are removed. These “real world” studies will reveal any long-term side effects and may detect any potential for the new therapy to treat other diseases.

What to Expect: Your Rights & Protections

Choosing to participate in a clinical trial is a big decision for your family. We want to help you understand your rights and protections as a research volunteer. Many regulations and safety measures are in place to ensure your loved one’s health and safety and minimize risks.

Clinical trials and the treatments that come out of them do not happen without volunteers. For rare diseases such as Rett syndrome, finding enough participants can be a significant barrier to a clinical trial’s success.

Although risks are always involved in clinical trial participation, regulatory authorities are responsible for making sure that these experiments are performed in the safest way possible. An Institutional Review Board (IRB), a group of doctors, scientists, and lay people who are not affiliated with the study, oversees many of these safety measures. The IRB reviews a study’s design and informed consent document. The informed consent is a form that all clinical trial participants must be given that outlines their rights, any risks involved in participation, and what to expect during the clinical trial.

The IRB must approve the study design and informed consent document before a clinical trial can begin. The IRB also monitors the study while it is ongoing to make sure the strict protocol detailed in the study’s design are followed. The group’s goal during the entire process is to protect the welfare of all study participants.

Before you join a study in any phase as a participant, you will meet with the researchers conducting the trial to discuss relevant aspects of the study and go over the informed consent form. Specifically, each study will vary in terms of who can participate, how many participants are needed, what tests will be used, how long the study will last, and how the data will be analyzed. It will also vary in terms of the time, money, and energy required of you and your family if you choose to participate. You should ask as many questions of the researchers conducting the trial to get the information you need to decide whether participation is right for you and your family. Carefully consider what questions to ask (https://www.rettsyndrome.org/wp-content/uploads/RSO_StartTheConversation_7.7.20.pdf) before participating in a clinical trial includes a list of questions to carefully consider.

After the data is collected from the study, the clinical trial team analyzes it to identify the key findings. The team uses these findings to determine what to do next with the therapy. The next step could be the next phase of clinical trials if the data look promising, and the regulatory agency agrees. However, if the therapy does not meet set safety and/or efficacy standards, no further investigation will be performed.

As a participant, you may be curious about the study results. The researchers conducting the trial may provide these results to you, or you may search for published results online. Depending on the protocol, participants may find out if they received a placebo or the experimental treatment. They may also be allowed to continue in the later clinical trial phases if they so desire.

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