For Drugs and Biologics: Intermediate-size Patient Populations and Widespread Treatment

For Drugs and Biologics: Intermediate-size Patient Populations and Widespread Treatment2018-10-04T15:43:54+00:00

For Drugs and Biologics: Intermediate-size Patient Populations and Widespread Treatment

Expanded access to investigational drugs and biologics through FDA is not limited to individual patients. Under appropriate circumstances, FDA offers additional pathways to provide access to investigational (unapproved) products for multiple patients. Products available through these pathways typically have undergone sufficient clinical study to provide confidence that the product will provide some level of benefit and is unlikely to cause harm or injury.

As with single patient access, there is no government requirement for product manufacturers to provide multiple patient access and, therefore, no obligation on the part of the company to do so.

For drugs and biologics, the FDA offers the following pathways for multiple patient access:

  • Intermediate-size Patient Population Expanded Access. Access to an investigational drug (including a biologic) for use by more than one patient, but generally fewer patients than 100, is treated under a typical expanded access IND or a protocol submitted under an existing IND. The investigational product may but need not be under development for marketing. Unless FDA notifies the sponsor that treatment may begin earlier, there is a 30-day waiting period before treatment may begin. This expanded access option is available to the treating physician, product manufacturer, or other entity that serves as the sponsor.

Another option is for the product manufacturer to submit a protocol to an existing IND. The investigational product may but need not be under development for marketing. There is no 30-day waiting period before treatment with the investigational product may begin, but the protocol must be received by FDA and have IRB approval before treatment may begin. This option is available only to the product manufacturer.

  • Expanded Access for Widespread Treatment. Access for widespread treatment use in larger patient populations, is available through a new treatment IND or by adding a separate new protocol to an existing IND filed with FDA. This pathway is available only to the product manufacturer and can only be used when the investigational product is under active development for marketing approval.

Intermediate-size Patient Population Expanded Access IND and Protocol

The intermediate-size patient population expanded access use should be considered when there is an expectation that there will be multiple single patient uses. This pathway may be used when a product is in ongoing development or when a product is not under active development. Obtaining a new intermediate-size patient population IND or modifying an existing IND minimizes the burden on physicians, product manufacturers, IRBs, and FDA while getting the investigational product to desperately ill patients more quickly.

Despite these advantages, intermediate-size patient population expanded access is underutilized. FDA reports that it received 47 requests for intermediate-size patient population INDs in 2017, and 45 were allowed to proceed (approved). The same year, FDA received 1,151 requests for single patient INDs, and 1,143 were allowed to proceed.

Requesting intermediate-size patient population INDs

A product manufacturer, a physician, an investigator, or a private entity—such as an advocacy organization—acting in the role of a sponsor, may submit a request for an intermediate-size patient population IND to FDA. In some cases, FDA notices that multiple single patient expanded access requests have been made and allowed to proceed, and will suggest to the product manufacturer, the physician, or investigator (that is, the individual who is acting in the role of the sponsor) to seek an intermediate-size use. In other cases, the product manufacturer receives multiple requests for single patient expanded access INDs from an individual physician and recommends to the physician to seek an intermediate-size patient population IND.

In a health care setting, such as a hospital or an academic institution, where a physician or medical department (e.g., pediatrics or oncology) plans to treat multiple patients with an investigational product, the hospital or physician may make a request to FDA for an intermediate-size patient population IND. If a physician is working with other physicians within his or her institution or at other institutions, the physician may make a request to FDA for an intermediate-size patient population IND. In this circumstance, the physician makes the request to FDA as the sponsor, and other physicians join as sub-investigators.

Simply, different types of individuals (or entities) may serve as the sponsor and request an intermediate-size patient population IND. Further, the suggestion to pursue such a request may come from FDA, the product manufacturer, the physician/investigator, or even another entity. 

When to consider initiating an intermediate-size patient population IND 

  • In place of multiple single patient uses involving an investigational product that is not available because the product is not being developed for marketing purposes or cannot meet the conditions for approval.
  • When use is likely or may be predicted by a number of patients with a shared indication who may benefit from access to the investigational product.
  • 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.
  • To provide broader access to a promising therapeutic product under the auspices of an advocacy organization, as long as a physician associated with the organization files the application and takes responsibility to ensure proper administration and monitoring. This is especially useful in circumstances where a therapeutic product may offer benefit to patients with rare disease who are unable to participate in clinical trials.
  • To allow access to treatment with an approved drug or biologic or a related product that is not available through marketing channels because it is no longer marketed. This expanded access pathway may also be used in the case of a drug shortage if an unapproved source of the drug, such as a foreign manufacturer, is available, provided the drug and the patient meet the general criteria for expanded access as and the criteria specific to use in an intermediate-size patient population. The intermediate-size patient population IND is the appropriate pathway in this situation, even if the number of patients exceeds 100, since the treatment IND is applicable only for drugs or biologics being actively developed for marketing approval.

There could be other situations that could be appropriate for an intermediate-size patient population use; the most common are listed above.

When to seek an intermediate-size patient population IND

 When a physician or product manufacturer anticipates that there will be at least several 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 use. For example, there might be phase 2 or 3 data available, or in the case of children, there might be safety data from the use of the investigational products in adults. More confidence in the safety of the product is preferred because with an intermediate-size patient population IND, patients who are unknown at the time 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.

Applying for an intermediate-size patient population IND

The individual who takes on responsibility for the intermediate-size patient population IND submits a protocol following the instructions for FDA Form 1571. This individual may be a product manufacturer, a physician, an investigator, or a private entity, such as a patient advocacy group. It’s important to note that Form 1571 is intended as an application for a new IND, including commercial INDs. Not every field is applicable to expanded access use.

Similar to FDA Form 3926 used for the individual patient IND, information to be submitted includes the name and address of the sponsor, name of the product, intended indication, parameters for patient eligibility, a proposed treatment plan, the type of expanded access being requested (e.g., intermediate-size patient population), the investigator’s brochure, information about the institution, and the chemistry, manufacturing, and controls (CMC) information pertaining to the investigational product.

Because only the manufacturer usually has the required CMC information, a letter of authorization (LOA) from the manufacturer should be included to provide relevant identifying information, such as the sponsor’s relevant application (e.g., IND) number. This allows FDA to cross-reference the CMC data from the original IND. The company will provide the LOA when they agree to provide product for treatment use.

Like Form 3926, Form 1571 requires a certification that treatment will not begin until IRB review and approval is secured.

In addition to the Form 1571, a Form 1572 must be completed for each physician/investigator who will administer treatment under the intermediate-size expanded access IND. If a commercial sponsor is filing the IND, they will usually collect Form 1572 from each physician who signs up to administer the drug to patients outside the clinical trial under the IND, and submit them to FDA under the IND.

Simplified Instructions on how to fill out Forms 1571 and 1572 can be found at How to Complete Form FDA 1571 and Form FDA 1572. More specific directions for filling out Form 1571 are available at Instructions for Filling out Form FDA 1571.

Unless FDA notifies the sponsor that treatment may begin earlier, there is a 30-day waiting period when an IND is submitted to FDA to allow safety review of the product data and details of the intended use. FDA will usually respond sooner than the full 30 days. 

IRB review and considerations 

A convened IRB must review and approve the protocol using the criteria described in 21 CFR 56.111. Recognizing that the purpose is a treatment use, the IRB should interpret the criteria appropriately and should:

  • Consider whether the safety information is reasonable in relationship to the anticipated benefit from the proposed treatment plan.
  • Ensure 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.
  • Receive documentation that FDA has made its determinations regarding safety and effectiveness and has given clearance for the use (evidenced by issuance of an IND number).
  • Review the protocol and determine that it makes adequate provision 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.
  • Approve an informed consent process that is appropriate to a treatment use and ensure 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 benefit. If some or all patients are not able to give informed consent, procedures to obtain appropriate permissions should be approved by the IRB.

Intermediate-size Patient Population Expanded Access Protocol

Access to an investigational drug (including a biologic) for use by multiple patients may also be submitted as a protocol under an existing IND by the commercial sponsor. The investigational product may or may not be under development for marketing. There is no 30-day waiting period before treatment with the investigational product may begin under an existing IND, but the protocol must be submitted and received by FDA and have IRB approval before treatment may begin.

FDA regulations describing the requirements for intermediate-size patient populations can be found under 21 CFR 312.315.

Widespread Use Under a Treatment IND or Protocol

Access for widespread treatment use in larger patient populations may be accomplished through a treatment IND. This pathway can only be used when the investigational product is under active development for marketing approval, and only the commercial sponsor can apply for the treatment IND.

Generally, the treatment IND is used when treatment access is intended for about 100 or more patients. Some treatment INDs have provided pre-approval treatment access to unapproved drugs to tens of thousands of patients.

FDA also allows the commercial sponsor to file a separate treatment protocol under their existing IND. As with the treatment IND, the investigational product must be under development for marketing. Unlike other access protocols submitted to existing INDs, however, there is a 30-day waiting period before treatment may begin, unless FDA notifies the sponsor that treatment may begin earlier.

Submission requirements 

The expanded access submission must include:

  • A cover sheet (Form FDA 1571).
  • 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 or, for an individual patient, a description of the patient’s disease or condition, including recent medical history and previous treatments of the disease or condition.
  • 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 adequate to ensure the proper identification, quality, purity, and strength of the investigational drug.
  • Pharmacology and toxicology information adequate to conclude that the drug is reasonably safe at the dose and duration proposed for expanded access use (ordinarily, information that would be adequate to permit clinical testing of the drug in a population of the size expected to be treated).
  • A description of clinical procedures, laboratory tests, or other monitoring necessary to evaluate the effects of the drug and minimize its risks.

The expanded access submission and its mailing cover must be plainly marked “EXPANDED ACCESS SUBMISSION.” If the expanded access submission is for a treatment IND or treatment protocol, the applicable box on Form FDA 1571 must be checked.

Criteria for FDA Approval

 To grant approval, FDA must determine that:

  • The patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition; and
  • The potential patient benefit justifies the potential risks of the treatment use, and those potential risks are not unreasonable in the context of the disease or condition to be treated; and
  • Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use; and
  • The drug is being investigated in a controlled clinical trial under an IND designed to support a marketing application for the expanded access use, or all clinical trials of the drug have been completed; and
  • The sponsor is actively pursuing marketing approval of the drug for the expanded access use with due diligence; and
  • When the expanded access use is for a serious disease or condition, there is sufficient clinical evidence of safety and effectiveness to support the expanded access use. Such evidence would ordinarily consist of data from phase 3 trials, but could consist of compelling data from completed phase 2 trials; or
  • When the expanded access use is for an immediately life-threatening disease or condition, the available scientific evidence, taken as a whole, provides a reasonable basis to conclude that the investigational drug may be effective for the expanded access use and would not expose patients to an unreasonable and significant risk of illness or injury. This evidence would ordinarily consist of clinical data from phase 3 or phase 2 trials, but could be based on more preliminary clinical evidence.

Reporting and Other Responsibilities

For all FDA expanded access to drugs and biologics, physicians (sponsor/investigators) are responsible for the following:

  • Reporting adverse drug events to FDA and the commercial sponsor.
  • Ensuring that the informed consent requirements are met.
  • Ensuring that IRB review of the expanded access use is obtained.
  • Maintaining accurate case histories and drug disposition records for a period of 2 years.
  • Submitting IND safety reports and annual reports (when the IND or protocol continues for 1 year or longer) to FDA.

Additional Resources

From Clinical Research Pathways

FDA Expanded Access