Overview

Since NCATS Toolkit was first launched, the power of the patient voice in the therapy development process has continued to grow thanks to trailblazing patient group leaders. Patient group leaders, like yourself, continue to find new paths to involvement. Furthermore, in most cases, patient group involvement is essential to all stakeholders, including academic researchers, startup research companies, the larger pharmaceutical industry, and the U.S. Food and Drug Administration (FDA).

Opportunities for your group to become involved are highlighted in each of the subsequent sections of NCATS Toolkit. However, some of the benefits of a collective patient voice are summarized here, along with multiple resources for those who would like to learn even more about the growing involvement of patients in the therapy development process. Though there is no one-size-fits-all approach to the development of therapies, the involvement of your group can establish that the development process is patient centered from the earliest stages to the last. 

If you are not involved in a patient group, finding or forming a group may be an important first step, so NCATS Toolkit also includes several resources that can help you take that step.

Finding a Group

If you are not currently involved in a patient group and wish to be involved in the therapy development process, you first want to find any patient groups already involved in advancing research for your disease, whether they are disease-specific or larger umbrella organizations. Competition for patients is of particular concern for rare diseases, because the patient population may be very small. Having one united patient group fosters collaborations and prevents fracturing within your rare disease community, allows for the pooling of resources, reduces duplication of efforts, and avoids sources of competition.

• If you locate a group, their mission statement can help you determine whether the group is supporting or driving therapy development for your disease. 
  • If yes, contact the group either by email or phone to find ways you can become involved.
  • If not, they may be interested in expanding their mission to include therapy development, especially with someone willing to lead the way.
  • If the group is not interested in supporting therapy research, you may consider forming a group that solely focuses on supporting therapy development while still working with the established group to avoid duplicating efforts or splitting the patient population. 
• If the group is an umbrella organization, you may be able to form a subgroup and work within their established system. Alternatively, you may need to form a separate group, but again continue to work with the larger umbrella group whenever possible.
• If a patient group does not exist for your disease, you may wish to consider establishing one.

Biorepository

A biorepository or biobank is fundamentally a library that stores and manages biosamples, also known as biospecimens, for use in research. Your group can lead the effort to establish a biorepository for your disease(s).

• A biorepository can accelerate the development of new therapies by providing researchers with biosamples to:
  • Improve understanding of the underlying disease process.
  • Examine gene expression at different ages, disease stages, or tissue types.
  • Predict toxicity of potential treatment in tissue samples.
  • Identify and clarify biomarkers.
  • Aid in the selection of preclinical cellular and/or animal models.
• Biosamples may include:
  • Tissue
  • Blood
  • Saliva
  • Plasma
  • Purified DNA
  • Urine
• Donors to the biorepository may include:
  • Patients.
  • Siblings who do not have the disease.
  • Parents or other close relatives, depending on disease family pattern.
• Timing of the collection of samples will depend on the disease, samples being collected, and end goal of biorepository. 
  • During patient lifetime:
    • During surgical procedures or tests.
    • At the time a patient joins biobank. 
    • Specific times throughout the course of disease.
  • At time of patient’s death:
    • Although possibly a very sensitive topic while a patient, especially when the patient is a child living with a currently fatal disease, you may wish to educate patients (if old enough) or parents about providing samples to the biobank before the end stage of disease so arrangements can be made ahead of time. 
• Donor (patient) information, such as data about their medical condition and demographic characteristics, is usually collected along with samples.
  • Often collected in conjunction with a natural history study.
    • Determining Patients’ Needs: Natural History Study, also in NCATS Toolkit Discovery, provides more information about this type of patient registry. 
  • Personal Identifying Information (PII) should be protected through de-identification coding of samples and donor data.
• Informed consent processes should be in place for donors.
• Current best practices should be used to collect, maintain, and share the highest quality biosamples.
• Long term financial burden of maintaining biorepository should be considered prior to beginning the process.
• Researchers applying for use of specimens from biorepository should have Institutional Review Board (IRB ) approval for their research study.
• Prior to developing a biorepository, make sure one does not already exist for your disease(s).
• Check with the NIH Institute or Center (IC) most closely aligned with your disease to determine whether there are any grant opportunities or programs to start a biorepository.
• Learn more about biorepositories using the following resource:
  • The National Cancer Institute (NCI) Best Practices for Biospecimen Resources (2016) outlines the state of biosample research practices and principles that can be used by laboratories to develop research procedures. Organizations can use this document to evaluate and better understand biosample resource practices. 

Cell and Animal Models

A disease model is an animal or cell which displays all or some of the disease processes that are observed in the actual human. 

• Studying disease models aids understanding of how the disease develops and testing potential treatment approaches.
• Preclinical studies in animal or cell models demonstrating the safety and efficacy of a potential treatment must be submitted to the FDA prior to being granted approval for trials in humans.
• Cell and animal models include:
  • Primary or patient-derived immortalized cell lines.
  • Patient-derived induced pluripotent stem cell (iPSCs).
  • Organoids, which are tiny, self-organized, three-dimensional tissue cultures that are derived from stem cells. Such cultures can be crafted to replicate much of the complexity of an organ, or to express selected aspects of it like producing only certain types of cells.
  • Yeast.
  • Slime mold.
  • Roundworm.
  • Fruit fly.
  • Zebra fish.
  • Frog.
  • Mouse. 
  • Rat.
  • Rabbit.
  • Pig.
  • Other mammals.
• Animal Model Qualification Program provides information about the steps to have an animal model qualified by the FDA for preclinical studies.

Overview

Your patient group can help accelerate the discovery stage of therapy development for your disease by working with patients, scientists, and industry partners to develop translational research tools. Translational research and development is the process of turning observations from the laboratory, clinic, and patient community into therapies that improve the health of the patients. Translational research tools are needed to bridge the gap from understanding the disease process to identifying therapeutic targets and testing potential therapies in preparation for clinical research in humans. These tools include biological assays (bioassays), biomarkers, cell and animal models, and biorepositories.

Bioassays

In the context of medical research, a biological assay (bioassay) is a procedure that allows a biological process to be quantified.  Bioassays are important in the development of drugs and many biologics.

• In early therapy development, bioassays help determine which potential compounds have a higher likelihood of being an effective treatment.
• Bioassays can be cell-free (or biochemical) or cell-based procedures.
• High-throughput assays (also called high-throughput screenings) utilize advanced technology to miniaturize and automate the bioassay so that large libraries of potential therapies can be screened very quickly. For example, the National Center for Advancing Translational Sciences (NCATS) qHTS can screen more than a million compounds a day.
• Bioassay procedures usually include applying a set of reagents. A reagent is a substance or compound added to a system to cause a chemical reaction or added to test whether a reaction occurs. 
• The set of reagents used in a bioassay produces a detectable signal that can quantify the target biological activity. Signals that can be measured quantitatively include:
  • Absorbance
  • Fluorescence
  • Luminescence
  • Radioactivity
• Required qualities of bioassays include:  
  • Reproducibility
  • Reliability
  • Robust
  • Biologically relevant
• Knowing the biological pathway underlying your disease can help researchers develop a more comprehensive bioassay.
• Researcher(s) developing bioassays for your disease may benefit from knowing about NCATS Assay Guidance Manual, a free, best-practices online resource that is devoted to the successful development of robust, early-stage therapy discovery assays.

Biomarkers

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Biological markers (biomarkers) are characteristics that can be objectively measured and used as an indicator of normal biological processes, disease processes, or pharmacologic responses to a therapy. Biomarkers are important for the development of drugs, biologics, and certain medical devices.

• Biomarkers are a subcategory of medical signs and can be detected through different tests and procedures. Examples of biomarkers include:
  • Blood pressure and body temperature (physiological biomarkers).
  • LDL cholesterol level and red blood cell count (molecular biomarkers).
  • Tumor detected by contrast MRI or bone fracture detected by X-ray (imaging biomarkers).
• Biomarkers can also be categorized by what they measure. The biomarkers that are important to the therapy development process include:
  • Susceptibility/risk biomarkers
    • Associated with an  increased or decreased chance of developing a disease or medical condition.
    • Identifies patients who do not yet clinically have the disease, which is important when the treatment will be most effective prior to development of symptoms.
  • Diagnostic biomarkers
    • Confirms or establishes diagnosis.
    • Selects patient population for clinical trials.
  • Monitoring biomarker
    • Detects the change in degree or extent of disease.
    • Indicates toxicity or assesses safety.
    • Provides evidence of exposure.
  • Prognostic biomarker
    • Identifies the likelihood of a clinical event, disease recurrence, or progression in patients diagnosed with the disease.
    • Enriches clinical trials with patients who have a higher likelihood of experiencing an event and therefore increase statistical power.
  • Predictive biomarker
    • Indicates the likely benefit to the patient from the treatment, compared with their condition at baseline. 
    • Classifies patients into responders and non-responders for the therapeutic agent using companion diagnostics (a test or assay that detects a predictive biomarker).
    • Enriches later phases of clinical trials with patients more likely to respond to the therapeutic agent.
    • Is usually specific to a therapeutic agent.
    • Does not guarantee benefit, but rather excludes patients who are most likely not to benefit.
  • Pharmacodynamic (response) biomarker
    • Shows biological response related to a therapy or environmental exposure.
    • May act as a surrogate clinical endpoint (also known as efficacy response biomarker) in a clinical trial when validated. For a biomarker to be validated, it: 
      • Must be solid scientific evidence that a biomarker consistently and accurately predicts a clinical outcome, either a benefit or harm.
      • Is important if survival or recurrence is the clinical outcome endpoint.
    • Validated surrogate clinical endpoint biomarkers may
      • Provide early evidence about the safety and efficacy of a therapy.
      • Reduce the risk of harm to subjects; the early data provided by biomarkers can allow researchers the opportunity to stop administration of a therapy potentially harmful to subjects before the associated clinical data would be available.
      • Provide useful information for patient management, for example, whether to continue treatment or to adjust dose.
      • Allow researchers to design smaller, more efficient studies, reducing the number of subjects exposed to a given experimental therapy.
      • Speed the overall therapy development process, allowing effective treatments to reach their target patient populations sooner.
    • Until validated, a biomarker can still be considered by the U.S. Food and Drug Administration (FDA) in the marketing review process of the potential therapy as “reasonably likely surrogate endpoint” or “candidate surrogate endpoint.”
  • Safety biomarker
    • Monitors adverse effects of the therapy.
• CDER Biomarker Qualification Program (2018) provides more information about biomarkers and their use in clinical trials, as well as steps to have a biomarker qualified by the FDA. 
  • Qualification means the biomarker has undergone a formal regulatory process to ensure that the FDA can rely on it to have a specific interpretation and application in therapy development and marketing review process, within the stated context of use.
• Other resources include:
  • BEST (Biomarkers, EndpointS, and other Tools) Resource (2018) is a glossary that clarifies definitions of different types of biomarkers and clinical assessments. This glossary describes the roles of biomarkers in research and therapy development and was developed by the FDA-NIH Biomarker Working Group
  • Developing and Validating Biomarkers (2016) is a video presentation from a Global Genes Rare Advocacy Summit that outlines the role of patient advocacy organizations in the development of biomarkers. The 1 hour presentation:
    • Defines biomarkers and different types.
    • Discusses how they can be used in research.
    • Includes specific examples of the use of biomarkers in accelerating diagnosis and treatment of rare diseases.

Overview

U.S. Food and Drug Administration Advisory Committee (FDA Ad Comm) meetings are open to the public. You and your patient community can take part in these meetings by submitting oral or written testimony or attending as an audience member. Your comments may include advising the FDA about benefits or risks of an investigational therapy or discussing the impact of living with your disease.

Providing Testimony

As mentioned previously, FDA Ad Comm meetings provide 2 ways for members of the public, including patients, patient advocates, caregivers, and medical professionals involved in the care of patients, to provide information to the Committee to be considered during their discussions and recommendations to the FDA. Both are highly valued and can be a way for your patient community’s voice to be heard at a critical time in the regulatory decision making process. 

• Written testimony: Copies of all written testimony are distributed to the members of the committee prior to the meeting. 
  • One of the advantages of written testimony is the provided information can be referenced repeatedly by the committee members. 
  • Written testimony can be submitted by those who:
    • Cannot attend the meeting.
    • Plan on attending the meeting.
    • Will be also presenting oral testimony.
    • Are from outside the United States.
  • The meeting announcement in the Federal Register will include the details required to submit written testimony, including
    • The FDA staff receiving the submissions.
    • The deadline for submissions to be included in the meeting.
    • Email address, mailing address, and FAX number for submission. 
• Oral testimony: The impact of your patient community’s voice speaking directly to committee members, as well as the FDA staff attending the meeting, can be powerful.
  • One of the advantages of oral testimony is allowing the committee members to put faces to the patients, families, and clinicians affected by the final decision of the FDA.
  • To during the open public hearing, interested persons need to contact the designated FDA staff by the deadline in the Federal Register announcement. Contact should include:
    • Name and contact information of the person wishing to provide testimony.
      • If representing a group, then the spokesperson’s name and contact information, name of group, population represented by group, and mission statement of group.
    • A brief statement or outline of the general nature of the evidence or arguments the person wishes to present.
    • The approximate amount of time requested to make your presentation (usual allotment is between 5 to 10 minutes, but is dependent on the number of presentations and the information being presented).
  • A confirmation will be sent to individuals indicating that their testimony will be among those included during the Open Public Hearing. 
    • Allotted time for an individual’s oral testimony is usually included in the confirmation.
    • In rare instances where public demand is high, the FDA may opt to implement a lottery and randomly select from among the requests to speak.
    • To allow more speakers, individuals with similar evidence or arguments may be asked to group their presentation into one.
    • FDA may decline a request to speak at an Open Public Hearing if the person wishes to address a matter that is unrelated to the advisory committee’s work. 
  • After acceptance, if the presenter would like to use slides or videos during their presentation, they should inform the designated FDA staff to determine the best format to be used.
    • All videos or slides should be sent at least a week prior to the FDA Ad Comm so that playability can be ensured and corrected if there are any technical issues.
    • Due to software security concerns, videos or slides will not be accepted on a thumb drive the day of the FDA Ad Comm meeting.
  • When arriving on the day of the FDA Ad Comm meeting, designated speakers should identify themselves to FDA staff members and provide the staff with any handouts or other materials for distribution to committee members, and be included in the meeting’s permanent record.
    • A table will be made available near the registration desk for any printed materials you wish to make available to those attending the meeting.
  • Designated speakers will be assigned a number to establish order of speakers.
  • Special seating is usually reserved for registered speakers from the public.
  • Those who speak are encouraged to disclose any financial relationships they may have with the topic of the meeting or with the sponsors or competitors of the therapies under discussion.
  • After a person has made their statement, the FDA Ad Comm members may ask the person questions.
  • The Open Public Hearing most often is held the hour after the lunch break. 
  • For more details, you may wish to review the FDA Guidance: The Open Public Hearing at FDA Advisory Committee Meetings
  • The FDA also provides a more public friendly version of the Guidance, which summarizes steps to becoming a designated speaker and some tips for speaking: Guidelines for Speakers at the Open Public Hearing of an FDA Advisory Committee Meeting
• Testimony content: 
  • Clinical trial participants (and their guardians, if the child is a minor) and physicians involved in the clinical trial should consult the agreement signed with the Sponsor of the therapy clinical trial prior to providing written or oral testimony. 
    • In some cases, there may be limitations on what can be shared.
    • The FDA Ad Comm meeting does not nullify the signed agreement.
  • Limit the amount of general statistics and data that is provided. 
    • For example, in most cases the committee members will already be aware of how many people have the disease.
    • Depending on the concerns of the particular therapy, you or a member of your Scientific/Medical Advisory Board may wish to present data that you wish to be considered in the decision in either written or oral testimony rather than being presented by multiple members of your patient community.
  • Encourage members of your patient community and associated clinicians to share their direct experience with the symptoms being targeted by the current therapy. For example, discuss the impact of: 
    • Targeted symptom(s) on quality of life and daily living, including not only patients, but also family and friends.
    • Current treatment option(s). For example the current treatment option:
      • May not be effective for most.
      • Is difficult to administer.
      • Has multiple or serious adverse effects.
    • The potential of the investigational therapy to improve quality of life and daily living.
  • Share specific, personal experiences that demonstrate the impact of symptom(s), disease, and/or an investigational therapy rather than general statements. 
  • Describe the hopes and dreams of the patient community and how this medical treatment may be a step towards realizing those dreams. 
  • Consider grouping individual oral testimonies that are similar together and be presented by 1 speaker
    • The FDA Ad Comm may make this request if there are many speakers wishing to provide oral testimony.
    • Grouping similar testimonies allows more time for different aspects or perspectives to be presented.
    • One person speaking for multiple patients or families can actually have a greater impact, then each individual presenting a similar story. 
    • The spokesperson can name the other patients/families or state how many patients/families they are representing.
    • Each person or family can still provide written testimony.

Members of an FDA Ad Comm

An FDA Ad Comm ordinarily consists of 10 to 15 fixed or “standing” members including the chairperson. Members are selected because they possess expertise specific to the committee’s function. Most committees will also have a consumer representative and an industry representative. FDA Patient Representatives and expert consultants are often added as temporary voting members.

• Scientific members: 
  • Physician-scientists whose specialties or research involves the kinds of therapies being reviewed, including: 
    • Statisticians
    • Epidemiologists
    • Medical faculty
    • Chemists
    • Biologists
    • Engineers
    • Nutritionists
    • Toxicologists
    • Experts in preclinical (animal) studies
  • As core members of FDA Ad Comms, responsibilities will not be limited to a single disease or a specific therapy of interest. However members of your Scientific/Medical Advisory Board may be interested in learning more about the opportunity:
    •  Applying for Membership on FDA Advisory Committees
• Industry representatives:
  • Address global concerns for industry, not their specific employer.
  • Are not the industry Sponsor for the therapy being reviewed.
  • May or may not have the ability to vote, depending on the specific committee.
• Consumer representatives:
  • Offer broad knowledge of consumer rights and needs.
  • Have an affiliation with and/or active participation in consumer or community-based organizations.
  • Consumer representatives are core members and therefore are not focused on a single disease or specifictherapy. However, the FDA does provide more information about applying to be a consumer representative if you or someone you know is interested:
    • Consumer Representatives on FDA Advisory Committees
• FDA Patient Representatives:
  • FDA Patient Representatives are recruited and then specially trained to participate as temporary voting members for FDA Ad Comm meetings and to provide input earlier in the regulatory therapy development and review process by engaging directly with Division review staff. 
  • They are appointed as Special Government Employees (temporary employees) to provide direct input to agency staff as they share valuable insight on their experiences with various diseases, conditions, and devices while gaining access to confidential information.
  • Qualifications include:
    • Personal experience with the disease either as a patient or primary caregiver.
    • Ability to be objective while representing the concerns of others in their communities.
    • Willingness and ability to communicate in public their views and perspectives.
    • Knowledge about most treatment options and research for the areas of experience they are representing.
    • Impartiality with minimal to no financial conflicts of interest or ethical issues for self or close family members, for example, a financial interest, such as stock, in companies that may be affected by FDA decisions.
  • FDA Patient Representatives are added to the FDA Ad Comm panel for a meeting when a therapy concerns their disease or a disease within their area of expertise.
  • Due to the required training, you or a member of your patient community cannot apply to be a Patient Representative for an already scheduled or soon to be scheduled FDA Ad Comm meeting for a therapy for your disorder. 
  • The FDA provides more information about FDA Patient Representatives including how to apply.
    • About the FDA Patient Representative Program
    • How to Apply to the FDA Patient Representative Program
• Consultants: Scientists or medical personnel whose expertise is not represented by the fixed voting membership may be added to an FDA Ad Comm.
  • World experts on the topic being discussed are often added as temporary voting members.
  • These experts are present only for special meetings.
  • Members of your Scientific/Medical Advisory Board may meet the qualifications to be a consultant if there is no conflict of interest.