Understand The R&D Process

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.

Discovery of Therapeutic Approach

The search for a therapy, whether a drug, biologic, or medical device, begins when a disease or clinical condition does not have an effective treatment currently available. Finding a therapeutic approach relies on research that provides an understanding of the disease process. Although not as costly as preclinical studies and clinical trials, this stage is considered a high risk financially because it may take many years and capital to find a target and subsequently a candidate therapy that will make it through all the clinical trials and be approved for market. This stage also has the greatest potential for failures and often requires researchers to go back to either identifying a new target or candidate therapy. 

  • Identifying a target: Using knowledge about the disease, researchers develop a hypothesis that inhibiting or activating a specific target involved in the disease process will be able to change the course of the disease in a positive way. There is no set way to find a potential target beyond an educated guess. 
    • A target can be a gene, RNA, protein, biological pathway, physiological response, virus, or bacteria. 
    • A target must have the potential to be affected by a therapy in a measurable way. For example, the interaction between a target and a drug or biologic must cause a biological response that can be measured both in a test tube or cell culture (in vitro) and in a living organism (in vivo). A target medical device interaction must also be measurable. 
    • A target goes through multiple levels of validation to make sure that, if it is affected in the hypothesized way, the result will indeed be therapeutic. 
  • Determining therapy type: After identifying a target, researchers will need to determine the type of therapy that will be able to affect the target. The term “therapy”, as used in NCATS Toolkit, includes:
    • Drugs and medications: Conventionally, drugs are synthesized pharmaceutical molecules or compounds intended to treat or cure a disease. However since the FDA includes biologics in their definition of drugs, a more accurate term for this type of therapy is small molecule drug.
      • Small molecule drugs are currently still the most common therapy that is developed. 
      • Examples include: acetaminophen, ibuprofen, metformin, gabapentin, and amoxicillin. 
    • Biologics: Also called biopharmaceuticals, biologics are derived from biological sources. 
      • Biologics include a wide range of therapies such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. 
      • Most biologics developed as a therapy are complex mixtures that are not easily identified or characterized. 
      • Examples include: insulin, Botox (onabotulinumtoxina), Humira (adalimumab), and Rituxan (rituximab).
    • Medical devices: In contrast to drugs and biologics, many complex devices involve a number of components that, together, form a system. 
      • Medical devices may be intended to diagnose, cure, treat, or mitigate disease. 
      • The definition of medical device is wide, and examples can range from adhesive bandages and tongue depressors to implanted cardiac and neurological devices, stair-walking wheelchairs, robotic surgical systems, and magnetic resonance imaging (MRI) devices.
  • Finding a potential therapy: In the best-case scenario, when focused on drug or biologic development, several potential therapies are identified that have the desired effect. Further testing and screening then narrows the field to several lead candidates for intensive testing before industry or researchers proceed to preclinical studies. 
    • Typically, researchers discover new drugs that can affect a validated disease target through: 
      • Screening many molecular compounds and biologics to find ones that have the potential produce the desired effect when interacting with the target.
        • Prior to screening, researchers develop biological assays (bioassays) that can measure compound-target interactions.
        • When possible the bioassay is adapted to high throughput screening (HTS). 
          • HTS automates and miniaturizes the bioassay using robotics, data processing, and sensitive detectors. 
          • HTS can quickly perform millions of assays to determine the therapeutic-like properties of large libraries of compounds.
        • NCATS Toolkit provides more information and resources to learn more about bioassays in Discovery: Understand Discovery Research Tools.
      • Designing a therapy to create the desired effect. 
      • Repurposing existing treatments that have unanticipated effects and are found to affect the target “accidentally.”
      • Using new technologies, such as those that provide new ways to target therapies to specific sites within the body or to manipulate genetic material.
    • Lead therapies are tested further to ensure their effect is reproducible in other assays or in vitro systems. Identified therapies are also compared to determine which may work best. Further considerations include:
      • Absorption, distribution, metabolism, and excretion properties. In other words, how a body processes the therapy (pharmacokinetics).
      • Impact on other functions within the body (pharmacodynamics).
      • Potential toxicity or side effects.
      • Dose-response curves.
      • Method of administration, for example, whether it is taken in pill form, injected, or inhaled and whether this administration will work for the patient population.
      • Interactions with other drugs and treatments, especially those used by the patient population.
      • Differing effects on different groups of people, such as by age, gender, race, or ethnicity.
      • Ability to be produced and manufactured.
  • NCATS Toolkit provides more information on the Discovery stage of therapy development including key areas your group can support the process. Key areas include:
    • Collecting patient data.
    • Facilitating scientific collaboration. 
    • Funding research.

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.
  • 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:
  • 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:

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. 
  • 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.

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. 
  •  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.

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.

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:
  • 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.
  • 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.

Resources

Preparation for Clinical Trials 
Developing Products for Rare Diseases & Conditions U. S. Food and Drug Administration (FDA) (link)
Tips to Learn More
How Does FDA Approve a Drug U.S. Food and Drug Administration (FDA) (link)
The Drug Development Process U.S. Food and Drug Administration (FDA) (link)
The Device Development Process U.S. Food and Drug Administration (FDA) (link)
CDER Learn Training and Education U.S. Food and Drug Administration (FDA) (link)
Drug Approval: Bringing a New Drug to the Market U.S. Food and Drug Administration (FDA) (link)
European Patients' Academy European Patients' Academy on Therapeutic Innovation (link)

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.

The search for a therapy, whether a drug, biologic, or medical device, begins when a disease or clinical condition does not have an effective treatment currently available. Finding a therapeutic approach relies on research that provides an understanding of the disease process. Although not as costly as preclinical studies and clinical trials, this stage is considered a high risk financially because it may take many years and capital to find a target and subsequently a candidate therapy that will make it through all the clinical trials and be approved for market. This stage also has the greatest potential for failures and often requires researchers to go back to either identifying a new target or candidate therapy. 

  • Identifying a target: Using knowledge about the disease, researchers develop a hypothesis that inhibiting or activating a specific target involved in the disease process will be able to change the course of the disease in a positive way. There is no set way to find a potential target beyond an educated guess. 
    • A target can be a gene, RNA, protein, biological pathway, physiological response, virus, or bacteria. 
    • A target must have the potential to be affected by a therapy in a measurable way. For example, the interaction between a target and a drug or biologic must cause a biological response that can be measured both in a test tube or cell culture (in vitro) and in a living organism (in vivo). A target medical device interaction must also be measurable. 
    • A target goes through multiple levels of validation to make sure that, if it is affected in the hypothesized way, the result will indeed be therapeutic. 
  • Determining therapy type: After identifying a target, researchers will need to determine the type of therapy that will be able to affect the target. The term “therapy”, as used in NCATS Toolkit, includes:
    • Drugs and medications: Conventionally, drugs are synthesized pharmaceutical molecules or compounds intended to treat or cure a disease. However since the FDA includes biologics in their definition of drugs, a more accurate term for this type of therapy is small molecule drug.
      • Small molecule drugs are currently still the most common therapy that is developed. 
      • Examples include: acetaminophen, ibuprofen, metformin, gabapentin, and amoxicillin. 
    • Biologics: Also called biopharmaceuticals, biologics are derived from biological sources. 
      • Biologics include a wide range of therapies such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. 
      • Most biologics developed as a therapy are complex mixtures that are not easily identified or characterized. 
      • Examples include: insulin, Botox (onabotulinumtoxina), Humira (adalimumab), and Rituxan (rituximab).
    • Medical devices: In contrast to drugs and biologics, many complex devices involve a number of components that, together, form a system. 
      • Medical devices may be intended to diagnose, cure, treat, or mitigate disease. 
      • The definition of medical device is wide, and examples can range from adhesive bandages and tongue depressors to implanted cardiac and neurological devices, stair-walking wheelchairs, robotic surgical systems, and magnetic resonance imaging (MRI) devices.
  • Finding a potential therapy: In the best-case scenario, when focused on drug or biologic development, several potential therapies are identified that have the desired effect. Further testing and screening then narrows the field to several lead candidates for intensive testing before industry or researchers proceed to preclinical studies. 
    • Typically, researchers discover new drugs that can affect a validated disease target through: 
      • Screening many molecular compounds and biologics to find ones that have the potential produce the desired effect when interacting with the target.
        • Prior to screening, researchers develop biological assays (bioassays) that can measure compound-target interactions.
        • When possible the bioassay is adapted to high throughput screening (HTS). 
          • HTS automates and miniaturizes the bioassay using robotics, data processing, and sensitive detectors. 
          • HTS can quickly perform millions of assays to determine the therapeutic-like properties of large libraries of compounds.
        • NCATS Toolkit provides more information and resources to learn more about bioassays in Discovery: Understand Discovery Research Tools.
      • Designing a therapy to create the desired effect. 
      • Repurposing existing treatments that have unanticipated effects and are found to affect the target “accidentally.”
      • Using new technologies, such as those that provide new ways to target therapies to specific sites within the body or to manipulate genetic material.
    • Lead therapies are tested further to ensure their effect is reproducible in other assays or in vitro systems. Identified therapies are also compared to determine which may work best. Further considerations include:
      • Absorption, distribution, metabolism, and excretion properties. In other words, how a body processes the therapy (pharmacokinetics).
      • Impact on other functions within the body (pharmacodynamics).
      • Potential toxicity or side effects.
      • Dose-response curves.
      • Method of administration, for example, whether it is taken in pill form, injected, or inhaled and whether this administration will work for the patient population.
      • Interactions with other drugs and treatments, especially those used by the patient population.
      • Differing effects on different groups of people, such as by age, gender, race, or ethnicity.
      • Ability to be produced and manufactured.
  • NCATS Toolkit provides more information on the Discovery stage of therapy development including key areas your group can support the process. Key areas include:
    • Collecting patient data.
    • Facilitating scientific collaboration. 
    • Funding research.

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.
  • 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:
  • 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:

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. 
  • 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.

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. 
  •  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.

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.

  • 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:
  • 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.
  • 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.

Resources

Preparation for Clinical Trials 
Developing Products for Rare Diseases & Conditions U. S. Food and Drug Administration (FDA) (link)
Tips to Learn More
How Does FDA Approve a Drug U.S. Food and Drug Administration (FDA) (link)
The Drug Development Process U.S. Food and Drug Administration (FDA) (link)
The Device Development Process U.S. Food and Drug Administration (FDA) (link)
CDER Learn Training and Education U.S. Food and Drug Administration (FDA) (link)
Drug Approval: Bringing a New Drug to the Market U.S. Food and Drug Administration (FDA) (link)
European Patients' Academy European Patients' Academy on Therapeutic Innovation (link)