Tips for Success

• Discuss with the Sponsor how you can contribute during the meeting.
• Be prepared to present analyzed patient data from patient registries, natural history studies, and patient preference studies, and discuss how this data informed or supports required elements of the IND application.
  • Making Data Talk: A Workbook by the National Cancer Institute (2011) is a workbook describing how to communicate public health data to the public, policy makers, and the press. Although written for a researcher/scientist familiar with statistical analysis, the definitions and tips within the workbook can help you understand the analysis of your own data and learn about the best way to communicate the information to others. 
• Contact the FDA Patient Affairs , available at +1-301-796-8460, to understand the type of information or specific presentation formats that may be most helpful from the FDA’s perspective.
• Reach out to other group leaders who have recently been involved in pre-IND meetings for investigational therapies being developed for their disease.
• During the meeting, listen for ways you can help the Sponsor overcome any uncovered obstacles or missing information that may delay the submission of the IND application.
• Schedule a follow-up meeting with the Sponsor to debrief the information learned in the meeting and to discuss next steps to move forward. 

Overview

Talk to the Sponsor about participating in their early meetings with the U.S. Food and Drug Administration (FDA). In most circumstances, before an Industry Sponsor can administer an investigational therapy to humans, they must submit an Investigational New Drug (IND) Application to request authorization from FDA to transport or distribute the investigational therapy across state lines. The Sponsor may request pre-IND meetings with FDA to request feedback on their development program. FDA regulators are increasingly interested in having patients and patient advocates participate in these early discussions. However, it is up to the Industry Sponsor to invite patient groups to participate because the FDA cannot invite patients or patient advocates directly. 

• The biologics license application (BLA) is similar to the IND application and is used by Sponsors for investigational biologics. Pre-BLA meetings with the FDA have similar goals as pre-IND. 
• The FDA approval of medical devices prior to marketing the device is very dependent on the classification of the device and is not addressed specifically in this section. To learn more about the medical device marketing approval process, you may wish to reference FDA: How to Study and Market Your Device , which is written for small business and industry Sponsors, and FDA: The Device Development Process , which is written for patients.

Securing an Invitation

FDA regulators are increasingly interested in having patients and patient group representatives participate in these early discussions, but the Sponsor is the one who will invite you to a pre-IND meeting. It is your job to make certain the Sponsor is aware of the benefits of your participation. Studies are often designed with hard data and statistical measures in mind, but this approach may not produce results that the patients and caregivers find valuable. Your participation in pre-IND meeting can ensure the FDA that the study objectives are designed with the needs of the patient community in mind.  

Participation by your group representatives in initial meetings between the Sponsor and the FDA can reduce therapy time to market by:

• Ensuring that studies are designed to provide useful information.
• Enhancing the understanding of data proposed to be gathered by clinical trial.
• Providing a platform for the patient voice.
• Creating or further growing a relationship between your group and the FDA.
• Minimizing clinical holds on therapy development (an order issued by FDA to delay or suspend an ongoing trial/investigation).

Prepare for the Meeting

Pre-IND meetings are the most productive when they are focused on specific issues, like regulatory requirements, previous studies, IND application requirements, and so on. Therefore prior to the meeting, it is important that you:

• Identify the purpose and goal of the meeting from the Sponsor’s point of view.
• Become familiar with the information provided to the FDA by the Sponsor in the meeting packet.
• Understand the role of the FDA:
  • Review Working with Regulators: A Focus on the FDA (2015) is a resource developed by the Cancer Support Community to provide patient groups with information about working with the FDA. The resource contains information about the role of the FDA, the relationship between the FDA and patient groups, and new initiatives that allow patients to have better access to therapies.
  • Be aware that the FDA does not conduct medical research or regulate the practice of medicine. 
  • Reach out to the FDA Patient Affairs , available at +1-301-796-8460. The FDA Patient Affairs Staff can help you understand more about pre-IND meetings and how your participation may be helpful.
• Know what is included in an IND application (specific to therapies classified as drugs):
  • Chemical composition of the drug being studied in the clinical trial.
  • Studies performed in animal or cell models supporting safety and the potential benefits of the investigational treatment.
  • Methods to assure safety, including range of possible doses.
  • Recommendations for size and scope of clinical trials.
  • Controls, i.e. what the investigational therapy will be compared to.
  • Study endpoints throughout the different phases of the clinical trial process.
  • Multiple designated points of interaction between the FDA and the Sponsor during the clinical trial process to assure that every clinical trial is addressed in detail, the development program is well designed, and to establish safety profile and determine efficacy.
  • To learn more about the comparable application process for biologics, you may reference FDA: Biologics License Applications (BLA) Process (CBER) .
• Learn about Target Product Profile (TPP) and how it may be used in a pre-IND meeting.
  • The TPP is a template that summarizes the information that a Sponsor hopes to include in the drug (biologic or device) label after FDA approval. In other words, it is beginning the therapy development process with the goals in mind. 
  • A TPP is filled out by the Sponsor of the investigational therapy and submitted to the FDA, often with the pre-IND packet. It is however not a required document.
  • A TPP has been found to increase constructive discussions with the FDA in the pre-IND meeting and throughout the clinical trial process.
  • A TPP helps focus a Sponsor’s therapy development team and FDA review staff on the therapy development goals in terms of labeling. 
  • A TPP can help address issues early on in the therapy development process thereby preventing late stage failures and decreasing the total time involved with treatment development.  
  • The final version of the TPP will be similar to the annotated draft labeling submitted with a New Drug Application (NDA) or BLA.
  • The U.S. Department of Health and Human Services (HHS) provides an example of a TPP: Target Product Profile
  • The Center for Biologics Evaluation and Research (CBER) Office of Cellular, Tissue and Gene Therapies (OCTGT) webpage for industry education also has a 15 minute webinar on The Target Product Profile .
• Recognize the difference between 505(b)(1) and 505(b)(2) New Drug Applications (NDA) and how they affect the IND for investigational drugs (similar standards apply to biologics and medical devices).
  • 505(b)(1) application is for new drugs that have not previously been studied. It requires the Sponsor to conduct all necessary safety and efficacy studies. The IND application of a 505(b)(1) must contain a report that includes the results of the pre-clinical trial studies performed in cell and/or animal models.
  • 505(b)(2) is for new drugs containing previously approved active ingredients. This allows the Sponsor to submit an IND (and later a New Drug Application) which uses some of the safety and efficacy information on the active ingredient from studies not conducted by or for the applicant. The 505(b)(2) can be a less expensive and faster route of approval compared with the 505(b)(1) process. Examples of investigational drugs that may be eligible for 505(b)(2) include:
    • A new dosage form that is faster acting.
    • A combination drug using 2 active ingredients in a novel way.
    • A drug delivery mechanism that patients or doctors prefer over previous versions (for example, a pill form of a drug previously only available in liquid form).
    • A new use of a drug that already has FDA approval to treat a different disease or symptom.

Clinical Outcome Assessments

Clinical outcome assessments (COAs) include any assessment that may be influenced by human choices, judgment, or motivation. Since many rare diseases do not have clear biomarkers that can measure the effectiveness and benefits of a therapy, choosing or developing the right COA tool can mean the difference between achieving FDA approval and denial. Providing Sponsors with information from registries, natural history studies, and patient preference studies can ensure the COA that is developed or chosen measures benefits reliably and reflects the desires of the patient population. 

• There are 4 types of COAs:
  • Patient-reported outcomes (PRO) are used when the benefit of interest can only be observed or felt by the patient, for example symptom severity or effect on overall feelings of well being. 
  • Clinician-reported outcomes (ClinRO) are used when the benefit of interest can be observed by a clinician and requires clinical interpretation or judgement.
  • Observer-reported outcomes (ObsRO) are used when the benefit of interest can only be observed outside the clinical setting and the patient is not able to self-report.
  • Performance outcomes (PerfO) are used if the benefit of interest requires observation of a patient’s function while performing a set of defined tasks in the clinical setting.
• Clinical studies may use a combination of COAs and may also use clinical biomarkers.
• Sponsors may use or modify established COAs or develop new ones.
• The FDA Clinical Outcome Assessment (COA) Qualification Program works with requesters to develop well defined and reliable COAs that integrate the patient voice into therapy development with endpoints that are meaningful to patients and responsive to treatment.
• Timing of different COAs usage may be determined in part by natural history studies.
• Some of the assessment time points may be able to be performed remotely, while others may need to be performed at participating centers. The burden of travel experienced by the target participant population may influence these decisions.
• Learn more about COAs using the following resources:
  • Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (2009) is an FDA Guidance for Industry that reviews methods used by the Food and Drug Administration to evaluate PRO instruments for claims in labeling of the therapy. 
  • Clinical Outcome Assessment Compendium (updated periodically) is part of FDA’s efforts to foster patient-focused therapy development. The Compendium is a table that describes available COAs and how they can be used in clinical trials. This table can be used to identify if there is a COA available for clinical trials for a specific condition.
  • The Science of Clinical Outcome Assessment (COA) in Medical Product Development – An Intensive Online Educational Series   (2018 launch) is an online course offered by the University of Maryland School of Pharmacy to introduce COA fundamentals for those working in the area of therapy development. Learning goals include understanding the different types of clinical outcome measures and their appropriate use. You will also learn how to apply the principles of the FDA Roadmap to Patient-Focused Outcome Measurement and COA Framework to assess measurement strategies.
  • Amyotrophic Lateral Sclerosis (ALS): Developing Drugs for Treatment Guidance for Industry (2019) is an FDA Guidance for Industry that although specific to ALS, includes information about COAs that is applicable to many rare diseases.

Participant Eligibility

When designing clinical trials, the Sponsor’s goal is to target the correct population so that the effectiveness and safety of the new therapy can be properly assessed. Your group can help the Sponsor understand factors that may need to be considered when defining participant eligibility by drawing on natural history studies, availability of diagnostic criteria, and the knowledge only people living with the disease may have.

• Current diagnostic criteria: 
  • A clinical diagnosis is a diagnosis based on patient-reported and clinician-observed signs and symptoms. 
    • Usually this means there is not a specific test that can be performed to establish or confirm a diagnosis. 
    • Depending on the disease, this type of diagnosis can make it difficult to define a clear patient population to be involved in the clinical study.
    • Established consensus diagnostic guidelines can be invaluable for diseases with a clinical diagnosis, especially when multiple sites are going to be involved in the study.
    • A Center of Excellence Network can provide medical providers experienced in making the clinical diagnosis.
  • Even when there is a diagnostic test for the disease, participant eligibility may be limited if most clinicians forego the test due to cost or other barriers. But these barriers do not have to stop the clinical trial.
    • You may suggest the clinical study include the diagnostic test as part of the initial process for joining the study.  
    • If cost is the limiting factor, your group may be able to partner with a larger group or a philanthropic organization which can fund a program to offer diagnostic testing for free or at a reduced cost to those meeting clinical criteria.
    • If the diagnostic test is available at a limited number of medical centers, helping those with eligible clinical criteria arrange travel to 1 of these centers may be a feasible option.  
    • If, however, the diagnostic test poses unnecessary medical risk to patients, it may be most helpful to support the establishment of clear clinical diagnostic guidelines.
• Comorbid medical conditions:
  • You can provide valuable information on comorbidities that researchers may not understand or expect. 
  • If subpopulations of the disease have very different comorbid diseases or conditions, study results may be very difficult to analyze. You may suggest the Sponsor considers:
    • Including only 1 subpopulation in the initial studies, preferably the subpopulation with no comorbidities or comorbidities least likely to affect the clinical outcome measures.
    • Clearly identifying the subpopulations at the beginning of the study and then separating the data by the different subpopulations during analysis.
• Target symptom:
  • Many clinical trials are focused on a single symptom or a cluster of symptoms but the severity of the symptoms and even the presence of a specific symptom may vary across the patient population. 
  • The number and severity of disease symptoms may also affect a patient’s willingness to participate in a clinical trial, especially if the targeted symptom is not considered a high burden by the patient. 
• Target stage of disease:
  • Sponsors may need to understand if the symptom(s) being targeted by their investigational therapy is only present or more likely to progress at specific stages of the disease.
  • Disease stage may affect a patient’s willingness to participate in a clinical trial, especially if the treatment is novel or poses significant risks.

Study Protocols

The general design of a study, or the study protocols, can make all the difference when recruiting participants, retaining participants, and collecting meaningful data. Your participation can ensure that clinical trials are designed to be patient-friendly and will provide inclusive data that foregrounds patient concerns. Design elements and types  include:

• Therapy delivery method:
  • Different therapy delivery methods may each have benefits and drawbacks that can affect whether a patient population will even participate in a study. 
  • For example, intravenous (IV) therapy administration gives dependable and reproducible effects and the dose can be adjusted immediately, which seems to make it ideal for clinical trials. However, if the majority of the patient population consists of children, then a different route might be preferable. 
• Frequency and duration of therapy delivery:
  • Since you know the patient population well, you can help the Sponsor balance the requirements of treatment frequency and duration of delivery with the patients’ perceived burden of the symptom(s) being treated.
  • The frequency a person must have a treatment can affect their compliance with the clinical trial protocol. For example, due to factors that the Sponsor may not be aware of, the burden of taking a pill multiple times a day 2 hours before or after a meal may make compliance very difficult.
  • The duration of the therapy delivery can also affect compliance, especially in combination with frequency. For example, a therapy that must be delivered slowly over a 6 hour period by IV administration may greatly decrease participant participation unless the frequency is once a week, or possibly monthly.
  • The more burdensome the symptom(s) being treated are perceived by a patient, the more likely a patient will accept higher treatment frequency and longer duration of the therapy administration.
• Comorbidities: 
  • Sponsors may not be aware of comorbidities that may affect the clinical design. For example, if researchers are designing their clinical trial to require fasting blood work, they may need to redesign the protocol if low blood sugar is a common comorbidity. 
• Historical controls: 
  • A historical control is an evaluation technique that is used in place of a control group when it would be inappropriate to give a placebo. 
  • It essentially compares previous data, like older clinical trials, to new data. 
  • However, historical control data can be inaccurate or subject to biases, especially when the data was generated before patient input was actively sought by the research community. 
  • Your input and the data from natural history studies can help correct these biases, which will generate more accurate and useful data. 
• Add-on design:
  • Add-on design is a protocol that gives the therapy being  being studied while currently available treatment is continued. 
  • The control group in this type of design will continue receiving current clinical care and a placebo.
  • This type of design may increase patient participation, especially when stopping current treatment might lead to disease progression or an increase in severity of symptoms.
  • Add-on design may not always be possible. For example, the therapy being studied and the current treatment may be predicted to interact negatively or the combination may increase the risk of adverse effects. 
• Time-to-event trials:
  • Time-to-event trials can use the attainment of a clinically meaningful worsening of the disease as a primary endpoint. For example, for a disease that progresses to respiratory problems, requiring mechanical ventilation can be a primary endpoint. 
  • Increased time to reach the event demonstrated in participants in the experimental trial can support the ability of the therapeutic approach to slow the progression of the disease.
  • Participants can be transitioned to open-label extension upon reaching the event.
• Open-label extension:
  • This is a new, separate clinical study that may be available to participants after they have completed an experimental randomized study.  
  • It only includes participants from “parent” experimental studies testing the same therapy.
  • The goal is to gather more long term data on safety and efficacy. Data from this study type is also included in the New Drug Application (NDA) required for the U.S. Food and Drug Administration (FDA) marketing review process.
  • All participants in an open-label extension study receive the therapy, even participants who were previously in the control group. 
  • The availability of an open-label extension study is presented in the informed consent of the original study, but the participant can wait until the end of the study to decide if they wish to participate.
  • Since the researchers of the original study need to remain blind to the control and experimental group assignments until after data analysis, it may be necessary to have a  new study coordinator who is not involved in the original study provide information to the participants that may affect their decision to join the open-label extension. 
    • For example, if a person in the placebo group had positive clinical outcome measures, it may not be in their best interest to begin the investigational therapy.
  • Timing the start of the open-label extension study must be executed so that treatment doses are not missed.
  • Eligibility for continuation into the open-label extension must also be clearly established.
  • Results of these studies may be biased since participants are self-selected and more likely to have seen positive clinical outcome measures and few, if any, adverse effects if they were in the experimental group.

Overview

Your patient group can draw from your patient registries, natural history databases, patient preference studies, and clinical site networks to help industry partners (Sponsors) design clinical trials in terms of subject and site selection, patient-reported outcome and other clinical outcome measures, and study procedures that will be well tolerated by the patients and capture meaningful data. When you and your patient group are involved in clinical trial design, you may improve recruitment, retention, endpoint selection, and study completion.

Patient Group Assessment by Industry

Knowing the criteria Industry uses to assess your group can help you maximize and articulate your expertise and assets.  

• The vision, mission, and goals:
  • Ensure that your group’s  vision, mission, and goals are clearly stated in all materials and  demonstrate that your vision, mission, and goals are at the center of your activities and are reasonable in respect to your budget. 
  • Your goals and objectives are summarized in your vision and mission statements. 
  • A vision statement concentrates on the future; what is your ultimate goal?  The vision statement should be clearly written and engaging, but at the same time it should also express realistic desires and give a clear timeline. A vision statement guides later decision-making. 
  • A mission statement is about the present; it outlines your current goals and the processes you have in place to meet those objectives. What is the purpose of your organization, who does your organization serve, and what is its primary focus? This statement should avoid the use of generic endpoints (e.g., our goal is to lower therapy prices) and should instead be as specific as possible (e.g., our goal is to provide support for the Orphan Drug Act by broadening public knowledge of Wilson’s Disease). 
• Operations:
  • Group operations are evaluated in several places to ensure that the group is sophisticated enough to demonstrate a measurable impact. 
  • Specifically, it is important to have scientific and medical community members involved either directly or as advisers.
  • Your outreach methods to partner with other groups, researchers, and Centers of Excellence will also be evaluated. 
  • Check your ratings with the Better Business Bureau and Charity Navigator and take the necessary steps to correct any inaccuracies. 
• Budget:
  • The amount of your income is less important than the diversity of sources and fundraising capacity. 
  • The ways in which you use your resources is also relevant; most of your budget should be going towards operations and activities instead of overhead. 
• Communications:
  • Groups are also evaluated on the effectiveness of their communication system, including their social media presence, publications, and outreach activities. 
  • The impact of informal publications (e.g., blogs, press releases) and formal publications (e.g., white papers) is also considered.

Site Selection

Your participation in choosing the site(s) for the clinical study can help mitigate patient risk and attract participants, as well as providing useful knowledge of day-to-day living and general practicalities to researchers. Geographic and travel information is vital to the site selection process. Researchers may also be unaware of certain travel barriers (motion sickness, frequent bathroom breaks) or issues of accessibility (no accessible transit available) that will affect your patient participation. 

• An established Center of Excellence Network can simplify the site selection process. 
• If a Network has not been established, you may wish to suggest the Sponsor consider:
  • Areas where the target population lives and normally travels.
  • Barriers travel may present.
  • Special accommodations that may be needed at participating sites.
• If the clinical study will involve long stays at a distant site, it may be helpful to make the Sponsor aware of how this may affect an individual or their family, and therefore also affect patient participation and retention in the study. For example, 
  • It may be difficult for the patient’s partner, parents, or other family caregivers to maintain their jobs.
  • If the family has children who are not participating in the study, the children’s daily care or school attendance may be affected.
  • The participant or their family may be far from their support network. 
  • Financial burden may increase if the participants medical insurance provider may not be willing to cover medical costs that occur outside the study protocol because the site is out of network.