Critical Considerations for Expanded Access Programs

14 May 2024

Expanded access programs (EAP) provide critical pathways to investigational drugs or devices to patients who are ineligible for randomised controlled trials (RCTs). RCTs are focused on determining the safety and efficacy of an investigational drug or device. Yet, due to their rigid structure, certain patients end up being excluded from participation. EAPs, rather, are designed to treat patients with life-threatening conditions who could benefit from an investigational drug or device but are ineligible for clinical trials.1

RCTs often incorporate strict and inflexible inclusion and exclusion criteria, which makes it difficult for certain patient populations to participate in trials. Moreover, they are extremely expensive, which might make developers reluctant to invest in novel products and establish additional sites, further limiting patient access. In addition, investigational drugs and devices are facing increasing delays to market due to progressively more complex pricing and reimbursement negotiations brought on by greater demands for real-world evidence and post-market data from regulators and payers.

To fill the widening gaps in treatment caused by these delays and restrictions, sponsors are investing more resources into EAPs. At the same time, patients and physicians have become more aware of EAPs. As a consequence, developers have been pressured to implement them earlier in the development pipeline.2 Traditionally,

EAPs have been implemented after Phase III trials, while the investigational product is awaiting approval and adoption by a payer. Now, EAPs are being used after Phase II trials as the demand for access to potentially life-saving treatments has grown.

For the purpose of this discussion, we will discuss the different types of EAPs, how they benefit patients and sponsors, and what logistical, technical, and regulatory concerns sponsors must consider as demand continues to increase and they begin to use them more frequently.

Categories of EAPs

EAPs are categorised by their size.2,3 Specifically, they can be:

Established for a single individual in need of treatment, which are filed by the patient’s physician. These EAPs are administered and approved on a case-by-case basis, depending on the individual patient’s needs. Often called “Compassionate Use Programs”, they can be applied at times of urgent need, such as when a patient is terminal, when treatment is needed before a written application can be submitted. These EAPs can be submitted electronically or over the phone in lieu of a written submission.
Applied to two to 100 patients, which are considered intermediate in size because they are smaller than a typical Investigational New Drug (IND) or protocol. Intermediate-sized EAPs are requested when patients cannot access a product in the marketplace because it was either not approved or there is a shortage of the product.
Applied to more than 100 patients, which are considered to be in widespread use. The investigational product must be under development for marketing.

Benefits of EAPs to patients

The main purpose of EAPs is to provide life-saving treatments to patients who do not have access to them through clinical trials.4 This “access gap” can develop for several reasons, all of which can be resolved using an EAP:

EAPs can close the gap that occurs after an investigational drug or device is approved, but before it is released to market. Typically, eligible patients who participate in clinical trials receive treatment during the trial. Yet, after the trial is over, these patients lose access to the product until it reaches the marketplace, a process that can take months or even years.5 Oftentimes, there is no acceptable alternative during this period and these patients begin to demand access to the product earlier.6 An EAP can close this gap by providing a patient with access to the product until it reaches the market and is adopted by a payer.
EAPs can fill the void that develops when an investigational product is not approved in all markets, when a product’s commercialisation is discontinued in a particular market, or when approval may be staggered, such as when patients in one region receive access before patients in another. For patients who do not have access to approved products simply because of where they live, EAPs can give them a source of treatment.
EAPs can grant patients access to products that are still in clinical development if the patient in question is not eligible for or cannot access its trials.
EAPs can give patients access to medications that were not approved, but that, in clinical trials, showed a benefit to a subpopulation to which they belong.

Benefits of EAPs to sponsors

Using EAPs earlier in development can also benefit sponsors in several ways:

Since EAPs are customised and carried out on an individual basis, physicians have the opportunity to collect early real-world data (RWD) on patients’ responses to the treatment. Collecting RWD earlier in the development process can strengthen a sponsor’s case for adoption, as it provides payers with more evidence of a product’s cost-effectiveness. These data can also inform strategic decision-making at the portfolio level by demonstrating which products in a sponsor’ pipeline show the greatest potential in the marketplace.
If EAPs are in place during the gap between approval and commercialization, a sponsor can more easily demonstrate the benefits of their product to patients and physicians earlier, increasing commercial demand for the product and making it easier to transfer patients to a commercial supply.

Operational and technical considerations

There are several logistical questions sponsors must address to ensure the proper and smooth administration of EAPs. They include:

Setting mutually exclusive inclusion/exclusion criteria for RCTs and EAPs

Sponsors must set mutually exclusive enrolment criteria for EAPs and RCTs to ensure that they do not compete for patients. Patients will almost always find EAPs more attractive than RCTs because RCTs are generally not individualised, and they are not designed to treat patients, which means a patient may be placed in a placebo group or in a less effective treatment arm.

Setting mutually exclusive enrolment criteria guarantees that patients who are eligible for an RCT cannot enrol in an EAP instead.7 These enrolment criteria must be communicated to all physicians so they know which route to recommend to their patients.

In addition, sponsors must determine inclusion and exclusion criteria for their EAPs and RCTs early and objectively because EAPs cannot interfere with a RCT that is in progress, or else they could damage a sponsor’s development pipeline. Specifically, while EAPs may resolve short-term health issues in certain patients by providing them with the proper medical therapy, they cannot preclude the completion of a RCT.7

If an EAP shared inclusion criteria with an ongoing RCT, it could attract patients away from the RCT, and sponsors would be incentivised to pull money from the operation of RCTs and put it towards EAPs. Ironically, this would reduce the likelihood that the RCT will finish and that the investigational product would ultimately reach the market, all the more reason why it is critical to have mutually inclusive/exclusive criteria in place at the outset.

Setting financial expectations

When a physician requests an EAP from the FDA, the developer of the investigational product has the option to request that the patient cover the direct costs of the product. For intermediate-sized and widespread use EAPs, a sponsor can request that the patients be charged for monitoring and reporting as well.8

However, when a sponsor charges the patient, they reveal the price of the medication, which is usually less than the market price, and this can hinder commercialisation efforts. Most sponsors ultimately choose to pay for the EAP themselves due to pressure from patients whose insurance will not pay.8 Sponsors must address these considerations on a case-by-case before they decide whether or not to fund EAPs.

Meeting operational and technical needs

Due to the regulatory environment surrounding an EAP, a sponsor must start planning at least six to 12 months prior to the anticipated demand for the investigational product. In this time, a sponsor must establish a cross-functional team to prepare all stakeholders for the program.

Not only must the sponsor establish inclusion and exclusion criteria for the program, but also, it must create educational material for physicians who might not be familiar with the product or how EAPs work. The developer must also supply these physicians with an adequate supply of the product.

It is important to remember that due to the nature of EAPs, administering the protocol may be more risky than administering an RCT protocol, so the sponsor must ensure that a risk monitoring protocol is in place. Finally, the sponsor must start and maintain enrolment, making sure that anyone who is eligible for an RCT is directed to the appropriate RCT study.

Meeting regulatory demands

Since the FDA’s priority is safety, for them to approve a physician’s request for an EAP, the physician must demonstrate that the benefits of using an investigational drug or device on his or her patients outweighs the potential risks.4 However, even if a physician meets the FDA’s requirements, the FDA cannot legally compel the sponsor to provide its product for an EAP; the sponsor can turn down the FDA’s request for an EAP if it is unable to pay for or provide the necessary supply.4

If a sponsor chooses to comply with the FDA’s request, the investigator or sponsor must submit its protocol for regulatory approval to guarantee that the FDA guidelines are met. More specifically, they must submit an IND or amend an existing IND to include plans for an EAP. This IND must discuss the risks and benefits associated with running the EAP, include proof that the sponsor has obtained institutional review board approval, and ensure that the sponsor will report adverse events and outcomes.

Conclusion

As demand for early access to life-saving medical products increases, sponsors will have to integrate EAPs into the development pipeline earlier and at a greater frequency. EAPs operate differently than RCTs, and therefore EAP-specific expertise is needed to meet this demand.

With EAPs, sponsors can reach patients who previously were ineligible for their clinical trials, demonstrate value where it could not be seen before, and increase the strength of their portfolio overall.

References:

1. FDA. FAQ: ClinicalTrials.gov - What is “Expanded Access”? FAQ: ClinicalTrials.gov Questions, 2009.

2. Rabourn, J. Expanded Access in the United States; exploring its current and future role in clinical drug development. Clinical Trials Arena, 2015.

3. FDA. Expanded Access Categories for Drugs (Including Biologics). Public Health Focus, 2016.

4. FDA. Expanded Access (Compassionate Use). Public Health Focus, 2016.

5. Makower, J et al. FDA Impact on US Medical Technology Innovation. Medical Device Manufacturers Association, 2010.

6. Estcourt, S. Integrating Managed Access Programs: Global Considerations. Applied Clinical Trials, 2014.

7. Rabourn, J. Expanded Access yet to reach Watershed moment, says expert. Clinical Trials Arena, 2016.

8. Darrow, et. al.