Overview

The development of new therapies for any disease can be loosely categorized into different stages, with the final goal of a therapy being approved by the U.S. Food and Drug Administration (FDA) for marketing. Because the stages—and the components within each stage—are not necessarily linear, you may find that your patient group already has completed some of the important pieces in the process or that some of the pieces may not be necessary for your disease. Understanding the whole process can help you develop an overall plan of the best approach for your group to engage in the therapy development process. 

From a patient group perspective, the stages to develop new therapies may be organized into: 

• Discovery or developing a therapeutic approach.
• Preparing for clinical trials, including preclinical studies.
• Clinical trials. 
• FDA review and marketing approval.
• Postmarket approval.

After FDA Market Approval

After a therapy receives approval from the FDA, there are still opportunities for your group to support the process, including collecting data to continue monitoring its safety and effectiveness and ensuring the new treatment is available as an option to all patients. 

• Postmarket surveillance: The FDA has processes and programs in place to provide further monitoring of approved therapies. In some cases, the FDA will require a Phase 4 clinical trial as part of the marketing approval, or the Sponsor will include a Phase 4 clinical trial or other monitoring program, such as a long-term natural history study, as part of the NDA.
  • Phase 4 clinical trials: Postmarket studies are conducted after a therapy has received FDA marketing approval to provide additional information including the treatment or drug’s risks, benefits, and best use. 
• NCATS Toolkit provides information about ways your group can support postmarket surveillance and other key areas in After FDA Approval. Other key areas after FDA marketing approval include:
  • Ensuring patients are correctly and quickly diagnosed, so the new therapy is available to them.
  • Updating or developing clinical care guidelines.
  • Working with medical insurance providers to reimburse patients for the newly approved therapy.

Preparation for Clinical Trials

Testing a therapy candidate in preclinical studies is usually the next step. But if a therapy appears to be both safe and effective in the initial studies, there are actually several other elements that need to be in place prior to moving to clinical trials in humans. In addition to helping fund preclinical studies, your group can choose to be involved in these key areas as a therapy moves forward towards clinical trials. 

• Preclinical studies: In most cases, the FDA requires preclinical laboratory studies in disease cell lines and animal models prior to beginning any therapy studies in humans .
  • When a potential therapy is a drug or biologic, it will be tested in unaffected and disease cell lines and animal models. Preclinical studies are needed to: 
    • Initially demonstrate that the therapy will not cause serious harm.
    • Establish toxicity levels.
    • Determine dosage level to achieve treatment
  • Medical devices may also have to complete preclinical studies to establish biocompatibility and safety depending on several factors. For example:
    • If the medical device will be inserted into the human body (an implant), potential toxicity and ability to cause mutations must be ruled out. 
    • If the medical device is made of a new material, the new material must go through a series of tests to determine its safety. 
  • The FDA requires researchers to use good laboratory practices, defined in therapy development regulations, for preclinical laboratory studies.
    • The FDA Guidance for Industry: Good Laboratory Practices Questions and Answers (2007) provides more information.
• Special FDA designations: The FDA has several designations and approaches to speed the development and approval of effective and safe therapy for rare and serious diseases that have unmet medical needs or no effective treatment. The FDA provides several resources to help you become familiar with the special statuses, including:
  • Developing Products for Rare Diseases & Conditions
  • Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review .
• Approval to move to clinical trials: When preclinical studies support the safety and potential therapeutic potential of a new therapy, the Sponsor will submit an Investigational New Drug (IND) Application. The FDA will review the IND and if approved the therapy will move forward to human clinical trials. 
  • Approximately half of the candidate therapy that start preclinical studies will make it to clinical trials.
• NCATS Toolkit provides more information on preclinical studies and the IND, including other key areas your group can support the process in Prepare for Clinical Trials. Other key elements that may occur during preparation for clinical trials include:
  • Establishing a network of clinical centers.
  • Using data from patient registries, natural histories, and patient preference studies, as well as your own knowledge of your patient community, to inform the design of the clinical trial protocol and the informed consent process.
  • Engaging with the FDA.

Tips to Learn More

• FDA has several resources that can help you learn more about the therapy development process. Although not specific to patient groups, the information is provided in an easy to understand manner:
  • How Does FDA Approve a Drug? provides a quick overview of the drug approval process in an animated 2 minute video. 
  • The Drug Development Process provides a basic overview of the approval process for drugs from discovery to postmarketing studies. The process is very similar for biologics. Each phase of the process has links to subsequent pages of more information. 
  • The Device Development Process provides a similar overview for medical devices.  
  • The Center for Drug Evaluation and Research (CDER)  Learn Training and Education offers educational and information modules about human drug regulation and activities through podcasts, education courses, and videos. 
    • Drug Approval: Bringing a New Drug to the Market , is a fictional case study navigating the drug approval process from conducting nonclinical testing and clinical trials to submitting a new drug application to FDA. It is in the form of an easy-to-read Fact Sheet. 
• Global Genes , a nonprofit with the mission of connecting, empowering, and inspiring the rare disease community, provides several resources focused on the therapy development process.
  • Drug Development Roadmap (2015) includes a glossary of terms and a brief description of each of the stages of the therapy development process from the patient group perspective. 
  • From Molecules To Medicine: How Are New Drugs & Therapies Developed? (2018) goes into greater detail about each of the stages as well as provides insight on how your patient group can become involved in the process. 
  • The 10 Things You Need to Pursue Research For Your Disease: What Are the Options for Research and Why is it so Hard? (2015) is a 1-hour video presentation given by Brad Margus, who is both a parent of two children with a rare disease and a founder of a nonprofit patient group for that disease. Brad did not start out with a strong background in science and presents his advice for navigating the process of research for rare diseases in an empowering and practical manner. 
• European Patients’ Academy  is a website focused on education and training to increase the ability of patients to understand and contribute to medical research and development. This site includes online courses, webinars, and a searchable toolbox with over 3,000 resources.

FDA Review and Approval

After completion of the first 3 phases of clinical trials, the Sponsor analyzes the data. If the data shows that the therapy is effective and safe, the company submits a New Drug Application (NDA) to the FDA. Your group may wish to become a member of the FDA Advisory Committee if one is needed during the review process. 

• An NDA will contain: 
  •  Data from all the preclinical and Phase 1, 2 and 3 studies, plus analyses of that data. 
  • Information about how the therapy is produced. 
• Review of an NDA can take up to 1 year. The FDA:
  • Establishes that the data demonstrates  that the therapy is both safe and effective.
  • Weighs the benefits and potential risks of the therapy. 
  • Decides what information should be included in the package insert to instruct doctors about how to use the therapy and for which patients. 
  • Ensures that the therapy will be manufactured to the highest quality.
• If the data cannot be clearly interpreted to grant approval or disapproval, the FDA may decide to have an FDA Advisory Committee review the evidence in a public meeting to gain additional perspectives to include in their decision making process. 
  •  NCATS Toolkit provides more information on FDA Advisory Committees in  Clinical Trials and FDA Review: Participate in the FDA Advisory Committee Meetings.
•  If the therapy is approved, then manufacturing on a large scale begins and the drug can be sold to patients outside of clinical and research studies.

Clinical Trials

Clinical trials refer to the research stage in which potential therapy is tested and monitored in humans. There are 3 stages of clinical trials required before a therapy can be approved and marketed (sold) for use outside a research or clinical study. In addition to supporting clinical trial recruitment and engaging with the FDA, you or others in your patient community may be interested in becoming a member of one of the boards involved in review and monitoring of clinical trials.

• Institutional Review Boards (IRBs) and Data Safety and Monitoring Boards (DSMBs) both play important, though different, roles in reviewing and monitoring each phase of a clinical trial. 
  • NCATS Toolkit provides more information about IRB and DSMB in Clinical Trials and FDA Review: Serve on Boards to Review and Monitor Clinical Trials.
• Phase 1: The therapy is tested in a very small group of  healthy volunteers (or sometimes patients) to confirm it is safe to use in humans, as well as to determine the therapeutic dosage. This phase usually lasts a few months. 
  • According to the FDA, about 70% of therapies move on to Phase 2.
• Phase 2: The therapies is tested in a small group of patients (up to several hundred) to determine whether it is effective and whether there are side effects. This phase can last anywhere from several months to 2 years.
  • According to the FDA, only 33% of therapies move on to Phase 3.  
  • Many therapies fail in Phase 2 because they are found to be ineffective or produce unpredicted safety issues or serious side effects. 
• Phase 3: The therapy is tested in a larger group of patients (from a few hundred to several thousand) to continue to gather data on the effectiveness, as well as to monitor for adverse reactions. This phase usually lasts 1 to 4 years. 
  • Phase 3 Trials also have a high rate of failure. According to the FDA, only 25% to 30% will receive FDA marketing approval. 
• Rare diseases: When a disease is rare, certain allowances during the clinical trial process may be allowed by the FDA. For example, the number of patients required for a specific clinical trial phase will usually be much lower than required for a more common disease.
• NCATS Toolkit provides more information on clinical trials, including other key areas your group can support the process in Clinical Trials and FDA Review.

Tips for Success

• Utilize information from natural history studies and patient preference studies to inform an investigational therapy’s Sponsor about any predictable concerns of the study design or eligibility criteria that can be directly addressed in the informed consent.
• Start educational outreach about the informed consent process to your disease community before the clinical trial is ready to begin accepting participants.
• Work with the Sponsor to develop a Frequently Asked Questions document that is relevant to the target participant population.  
• Offer resources developed for your members to the Sponsor to help with their outreach efforts.

Research versus Clinical Care

Although there is a clear distinction between a research clinical setting and clinical care, the distinction becomes more complicated when the research is taking place in a clinical care setting. Since many rare disease clinical trials take place in a clinical setting, it is important for you to understand what this means and how it may affect the informed consent process, including the return of test results. 

• Research clinical trial setting:
  • Protects participants from harm. 
  • Focuses on understanding the effectiveness and safety of investigational therapy.
  • May not directly benefit participants, but instead benefit future patients.
  • May limit the return of an individual’s results. 
  • Requires Institutional Review Board (IRB) approval to return a result that may be potentially medically relevant to a participant, but falls outside the original scope of the approved clinical study protocol. 
  • It is the participant’s responsibility to follow-up on disclosed results with their own medical provider, including having the result verified by a clinical laboratory.
  • Is not the same as health care provided by a personal medical care provider.
  • Gathers and assesses certain measures or clinical outcomes at specific times.
  • Publishes results, although participants are not identified individually.
  • Does not enter a participant’s data into their individual medical records.
• Clinical care setting, no research involved:
  • Provides care that is in the best interest of the patient.
  • Addresses the needs of individual patients.
  • Makes real-time decisions about health care plans, including trying different treatments.
  • Uses treatments and therapies known to be safe and effective.
  • Maintains confidentiality of medical records.
  • Records health care in a patient’s individual medical records.
  • Permits patients to access all test results and information included in the medical records.
• Research in a clinical care setting:
  • Provides the investigational therapy as part of participants’ health care.
  • May provide the investigational therapy as an addition to current treatment rather than replacing current treatment.
  • Follows protocols of a research study and the therapy may not directly benefit the participant.
  • Gathers and assesses certain measures and clinical outcomes at specific times.
  • Enters data from measures and clinical outcomes as part of participant’s medical records.
  • Permits patient to access all test results and information included in the medical records.
  • May require IRB approval to return results of potential medical significance that fall outside the original scope of approved study protocol. The result will be verified in a clinical lab prior to being disclosed and the clinicians involved in the study will provide next-step guidance  
  • Publishes results, although participants are not identified individually.
  • Researcher may be part of the clinical team. 
  • Needs very clear informed consent to distinguish what is research and what is part of clinical care.
• You can learn more about the differences between research, clinical care, different research settings, and the return of potentially medically significant results in the following resources.
  • FDA: Clinical Research Versus Medical Treatment
  • 2013 published article: Return of results: ethical and legal distinctions between research and clinical care

Overview

Informed consent allows clinical trial participants to understand what will happen during a clinical study, including the possible risks and whether participants will receive their personal results. Your patient group can provide input during the development of informed consent documents and help clinical trial participants better prepare for the consent process.

Outreach

Helping potential participants understand their rights prior to beginning the informed consent process can help mitigate any concerns that may jeopardize participation. It can be helpful to provide information about the informed consent process before a clinical trial is ready to recruit. Your knowledge of the informed consent process together with your knowledge of your disease community can help you determine the best approach to ensure the process reaches its goal of informed consent. 

• Provide general information about clinical trials and informed consent on your website.
• Explain possible future benefits of studies that may not provide immediate benefit to participants, for example what the study hopes to discover, mitigate, or develop.
• Hold a webinar about informed consent and make it available to those who can’t attend. 
• Bring in speakers at an upcoming conference who can talk about the informed consent process.
• Develop InfoGraphs or pamphlets that can be downloaded from your website or mailed to members who may not have easy internet access.
• Post links to relevant information, events, or webinars provided by large umbrella organizations like NORD, Global Genes, and FasterCures.