Intermediate-Size Patient Populations INDs: What Are They, When Should They Be Used, and Who May Apply for Them?” Richard Klein, Former Director, FDA Patient Liaison Program Office of Health and Constituent Affairs Food and Drug Administration Marjorie A. Speers, Ph.D. Executive Director, WCG Foundation

Expanded Access Goes by Many Names Treatment Acces Named Patient Program Special Access Programme Compassionate Use Single Patient IND Pre-launch Access Pre-approval Access

What is Expanded Access? Use of an investigational drug or biologic, outside of a clinical trial, to treat a patient with a serious disease or condition who does not have comparable or satisfactory alternative therapies to treat the disease or condition. – Intent is clearly treatment Contrast with investigational drug in a clinical trial where the primary intent is research – systematic collection of data with the intent to analyze it to learn about the drug

Why Expanded Access? Not all patients can wait for approved drugs No effective therapy for condition Exhausted approved options Intolerant of approved products Ineligible or otherwise unable to participate in trials Expanded access allows access to unapproved/investigational drugs that might potentially provide benefit, when company is willing to provide, and ethical protections are in place (IRB/informed consent)

Two Categories of Access Based on Urgency Emergency • Non-emergency Three Tiers of Access Based on Size of Group Individual or single patient IND Intermediate Size Population Treatment IND

IND or protocol? “Access IND” has a new and distinct IND number “Access protocol” is added as supplement to an existing IND

Requirements shared by all Expanded Access Programs 21 CFR 312.305 Serious or immediately life threatening illness or condition No comparable or satisfactory alternative therapy Potential benefit justifies the potential risks of the treatment, and those risks are not unreasonable in the context of the disease or condition being treated Providing drug will not interfere with or compromise development for the expanded access use

Intermediate-size patient populations INDs 21 CFR 312.315 Allow an investigational drug to be used for the treatment of a patient population smaller than that typical of a treatment IND or treatment protocol (~100) Sponsor may apply if they foresee likelihood of multiple individual patients seeking access FDA may ask a sponsor to consolidate expanded access under this section when the agency has received a significant number of requests for individual patient expanded access to an investigational drug for the same use FDA reviews IND annual report to determine whether it is appropriate for the expanded access to continue under Intermediate-size patient IND

Intermediate-size patient population INDs Tend to be underutilized In 2016, only 54 intermediate-size INDs approved by CDER and CBER compared to 1,021 single patient INDs for drugs

When to consider USING an intermediate-size Patient population IND Drug being developed: Patients may not be able to participate in the trial because they have a different disease or stage of disease than the one being studied or otherwise do not meet the enrollment criteria, because enrollment in the trial is closed, or because the trial site is not geographically accessible Multiple patients who are unable to participate in the trial requesting the drug for expanded access use Drug not being developed: The drug is not being developed, for example, because the disease or condition is so rare that the sponsor is unable to recruit patients for a clinical trial – appropriate for any number beyond a single patient Drug is approved, but unavailable The drug is an approved drug product that is no longer marketed for safety reasons or is unavailable through marketing due to failure to meet the conditions of the approved application, or The drug contains the same active moiety as an approved drug product that is unavailable through marketing due to failure to meet the conditions of the approved application

When to consider USING AN intermediate-size Patient population IND Drug Shortage: Multiple single patient uses involving an approved product that is not available because there is a shortage of the product, where an alternate, but unapproved supply might be available. This might be, for example, a foreign version produced in a facility not registered under the New Drug Application (NDA) For Risk Evaluation and Mitigation Strategy (REMS): Situations where the REMS may restrict use of approved products outside the approved indication, though patients with other conditions might potentially benefit from access to the product Intermediate-size patient population expanded access is intended to accommodate population sizes smaller than the large populations typical of treatment INDs or protocols, but there is no set regulatory limitation on the number of patients.

When to consider USING an intermediate-size Patient Population IND When a physician or product manufacturer anticipates that there will be multiple (e.g., five or more) requests and there is basic safety information, an intermediate-size patient population IND application should be considered What is considered basic safety information will depend on the specific circumstances of the therapeutic use For example, there might be phase 2 or 3 data available, or in the case of children, there are safety data from the use of the investigational products in adults More confidence in the safety of the product is important because with an intermediate-size patient population IND, patients who are unknown at the time that the IND is granted will be enrolled in the treatment use This contrasts with a single patient IND where the decision to grant the expanded access use includes medical history details specific to an individual patient

When to consider USING an intermediate-size Patient Population IND An intermediate-size patient population IND may be appropriate when a number of patients are enrolled in separate individual patient INDs for the same drug and indication FDA or the commercial sponsor may suggest creating an intermediate- size patient population IND Adding patients to an intermediate-size patient population IND can reduce paperwork and simplify IRB review. In such cases, any number beyond one patient might be reasonable. When a growing number of eligible patients might benefit from treatment access under an intermediate-size patient population IND and safety information is accumulated, FDA may suggest transition from intermediate-size patient population IND to a treatment IND.

CRITERIA FOR an intermediate-size Patient population IND FDA determines that: There is enough evidence that the drug is safe at the dose and duration proposed for expanded access use to justify a clinical trial of the drug in the approximate number of patients expected to receive the drug under expanded access; and There is at least preliminary clinical evidence of effectiveness of the drug, or of a plausible pharmacologic effect of the drug to make expanded access use a reasonable therapeutic option in the anticipated patient population

Who can serve as a sponsor for an intermediate-size Patient Population IND A product manufacturer A physician An investigator A private entity (that has a licensed physician on board to serve as sponsor) Hospital Academic institution Patient advocacy organization Sometimes FDA or drug manufacturer will suggest to the physician or investigator that an intermediate size IND would be appropriate and should be sought from FDA The suggestion could also come from the IRB, investigator, patient group, etc.

Why seek an intermediate-size Patient Population IND Less paperwork for everyone – physician, drug manufacturer, and FDA when use of the investigational agent is made available to multiple patients under expanded access Once the intermediate-size patient population IND is in place, patients can be treated faster because no additional FDA or IRB paperwork necessary to include additional patients under the IND New patients can simply be added to the IND maintained by the physician/sponsor

IRB responsibilities A convened full-board IRB must review and approve the protocol using the criteria described in 21 CFR 56.111 FDA’s new full board review waiver only applies to single patient INDs Recognizing that the purpose is a treatment use, the IRB should interpret the criteria appropriately for the treatment use Consider whether the safety information is reasonable in relationship to the anticipated benefit from the proposed treatment plan. That risks are minimized to the extent possible in the proposed treatment plan Receive documentation from FDA that includes the IND number and any comments about the treatment use (e.g., patient safety monitoring requirements) Determine that there are adequate provisions for ensuring the safety of the patients including adequate monitoring (timing and type of tests/exams, etc.) and appropriate plans for collecting and reporting the data 

Patient Consent - important function of the IRB - The IRB should review and approve an informed consent document and process that is appropriate to a treatment use and that it will be documented Given the compassionate nature of the request and FDA’s involvement, consent documents should meet the requirements listed in 21 CFR 50.25, using plain language that is specifically aimed at “patients” who expect direct benefit, as opposed to “subjects” who may not expect direct benefit If some or all patients are not able to give informed consent, procedures to obtain appropriate permissions should be approved by the IRB

Submission to FDA A cover sheet (Form FDA 1571) meeting the requirements of 312.23(a); (The 3926 short form is only for individual patient IND, and not applicable for intermediate-size patient population INDs) The rationale for the intended use of the drug, including a list of available therapeutic options that would ordinarily be tried before resorting to the investigational drug or an explanation of why the use of the investigational drug is preferable to the use of available therapeutic options; The criteria for patient selection; The method of administration of the drug, dose, and duration of therapy; A description of the facility where the drug will be manufactured; Chemistry, manufacturing, and controls information (usually referenced from commercial IND) adequate to ensure the proper identification, quality, purity, and strength of the investigational drug;

Submission to FDA Pharmacology and toxicology information adequate to conclude that the drug is reasonably safe at the dose and duration proposed for expanded access use; A description of clinical procedures, laboratory tests, or other monitoring necessary to evaluate the effects of the drug and minimize its risks. The submission must state whether the drug is being developed or is not being developed and describe the patient population to be treated. If the drug is not being actively developed, the IND sponsor must explain why the drug cannot currently be developed for the expanded access use and under what circumstances the drug could be developed. If the drug is being studied in a clinical trial, the IND sponsor must explain why the patients to be treated cannot be enrolled in the clinical trial and under what circumstances the sponsor would conduct a clinical trial in these patients.

For Additional Information https://www.fda.gov/downloads/drugs/guidances/ucm351261.p df

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Contact For more information about this webinar, contact: Marjorie Speers mspeers@wcgfoundation.org 404.386.8982 Richard Klein rklein123@aol.com FDA CDER Division of Drug Information (DDI): 855.543.3784 or 301.796.3400 Office of Health and Constituent Affairs: 301.796.8460

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