The Ins and Outs of EAPs

Wayne M. Dankner, MD, is a senior medical director of North American Medical Services, and Hua Dupré, MD, PhD, is a director of project management and operations, for Parexel International.

For a patient who is running out of hope, waiting for a drug to be approved can be interminable. Even on the fast track, a review can take six months or longer. Some patients with life-threatening diseases cannot afford to wait. In response, many countries have developed expanded access programs (EAPs) that give patients with no other viable alternative access to medically important drugs before they are commercialized.

The benefit of expanded access is clear. In fact, much of the groundwork for FDA's current policy regarding EAPs was driven by the AIDS community and its vocal demand for access to experimental treatments in the 1980s and early 1990s. Regulatory agencies such as FDA also stand to gain, because an EAP can generate additional safety data on the new product. But what about pharmaceutical companies? What is the benefit to them?

This article outlines the benefits of EAPs, describes how programs are structured in the United States and abroad, examines several regulatory issues associated with EAPs, and highlights the management and logistical issues that should be taken into account when considering implementing them.

The Upside

For pharmaceutical companies, EAPs create several advantages, including:

• public good will

• expanded safety data across a more clinically and ethnically diverse population than often encountered in clinical trials

• opportunity for larger groups of physicians to gain experience with both the benefits and adverse events associated with the drug

• pre-approval exposure to hundreds or thousands of practicing physicians

• the potential to develop valuable clinical experience that may support additional labeling and/or product-related publications and communications.

Those benefits—and in some countries, the possibility of generating revenue—can make it well worth a sponsor's while to consider EAPs for certain products.

Making the drug available on a global scale can multiply those benefits across a wider marketplace, but the process can be challenging because of differences in regulations and philosophy from one country to the next, particularly in Europe. A thorough understanding of those variations can facilitate a successful global EAP. Such insight is especially important given that the programs are conducted under regulatory review.

Making the Case

EAPs—sometimes called compassionate use programs—have been most commonly used in oncology and HIV/AIDS, although their application is expanding into such areas as neuropathy, hepatitis B, sepsis, and coagulopathy (a disease affecting blood coagulation).

Pharmaceutical companies should consider EAPs when they are developing a new product for a life-threatening illness or disorder that leads to major disability and when there are patients who have exhausted alternative therapies in that particular therapeutic category. However, the decision must be weighed carefully. Regulatory agencies are particularly sensitive to demonstration of patient need. Programs that the agencies perceive to have marketing value only will not be approved.

EAPs are usually established during Phase III of development, between pivotal trials for approval and receipt of marketing authorization. At that point, the sponsor has accumulated sufficient safety and efficacy information to permit use of the new drug in a minimally controlled outpatient setting.

Patient entry criteria for EAPs need not be as strict as they are for clinical trials but should match the indications in the proposed drug label. Patients who participate in an EAP often have not been eligible for a Phase III trial because of co-morbidity, disease stage, or concomitant medication use—or simply because they reside in countries where no clinical trial is available. In the United States, where EAPs are administered primarily through an FDA–designated Treatment Investigational New Drug (IND), a clinician must still determine patient eligibility, but the inclusion/exclusion criteria are more open.

How They Differ

In certain countries, particularly the United States, an EAP is similar to a standard Phase IIIb trial: both are conducted according to a specific protocol and require Institutional Review Board (IRB) oversight and informed consent from patients. The major difference between an EAP and a standard Phase IIIb clinical trial is that no efficacy data are collected. Data collection for an EAP is usually limited to demographic and safety information and involves far fewer case report forms (CRFs). Data monitoring can be done remotely instead of performing on-site visits for source data verification.

In other countries, EAPs can be administered through open-label Phase III trials, cohort patient programs, or named-patient programs. In those capacities, it is the pharmaceutical company's primary role to supply the drug, and it is the physician's responsibility (and decision) to enroll patients.

Unlike a standard clinical trial, an EAP involves an unknown number of patients and sites—which can make it a challenge to plan for adequate production of drug supply, especially before the product has been fully commercialized. Inadequate supply in the face of high demand could adversely affect the good will the company hopes to generate.

Another potentially significant area of difference is medication cost. In Phase III trials, the sponsor provides the medication. In certain types of EAPs, in countries such as France or the United Kingdom (but not typically in the United States), the treatment cost may be covered by a national or private insurance system, and the manufacturer has the option to charge a fee for the drug. Charging payers for the product enables the company to recover some manufacturing, research, development, and handling costs, particularly in the case of new biotechnology products.

Varying Regulations

In the United States, FDA has allowed expanded access to new products since the late 1980s. Current US regulations provide for three types of EAPs:

• Emergency Use IND in life-threatening situations before approval by an IRB (most often applied for by the treating physician)

• Compassionate Use IND requested by a practitioner to provide access for a single patient under an existing or new protocol

• Treatment IND protocol added to an existing IND application by the pharma sponsor to cover an unspecified number of patients to be treated by physicians who follow the protocol.

The Treatment IND offers the greatest opportunity for companies and regulatory agencies to collect data, but the route has potential pitfalls, most notably, the chance that a serious adverse event which may not be related to the drug itself could jeopardize approval.

Most pharma sponsors and US contract research organizations are accustomed to FDA guidelines. Outside the United States, the options become a little more complex. In European Union member states, Council Directive 65/65/EEC (later amended by 89/341/EEC) governs the compassionate use of medicinal products and allows EU member states to make unapproved innovative drugs available to patients outside of clinical trials.

Two main types of programs may be used in Europe, depending on the applicable national regulations:

• Compassionate use on a named-patient basis, involving individual patients. Although in most cases, these programs are set up by the pharma sponsor, the request of using the new drug is from the treating physician on an individual patient basis, and the sponsor functions primarily to ensure drug distribution.

• Compassionate use involving a large number of patients (cohort program).

In certain countries such as France, pharma sponsors can apply for a temporary authorization that needs to be renewed every year. The procedure does not require a physician prescription. All patients who meet the criteria can receive the treatment, and the cost is covered by the insurance system.

Country by Country

Denmark, Finland, France, Greece, Luxembourg, the Netherlands, Sweden, and the United Kingdom all have programs both for a cohort of patients and for individual named patients. Other European countries have only named-patient programs. In many, expanded access for a larger group of patients requires a Phase IIIb clinical trial or safety study—a more complex and time-consuming route than a Treatment IND.

In determining the geopolitical scope of an EAP, pharma companies must balance the potential costs with the potential benefits of exposure, good will, and enhanced data. Differences in regulations and medical practice from one country to the next will affect each of those factors. Ultimately, where the EAPs will be offered is a decision that companies must make based on disease prevalence and future market availability of the drug in that country.

All regulatory agencies require some type of safety reporting for EAPs. A cohort-basis program usually gives the sponsor the greatest degree of control over the program's conduct and provides access to safety data collected by participant physicians. Under most countries' named-patient programs, the pharma company will not receive safety data directly from the treating physician. In the United Kingdom, physicians report adverse events (AEs) to the Medicines Control Agency (MCA), but the sponsor may not learn of them for several months, possibly even a year, therefore missing the opportunity to gather more information when an event occurs.

In other countries, including Germany, however, a Phase IIIb approach may often be preferable to a named-patient program because of conflicting ethical and legal issues that affect compassionate use of non-approved drugs. Such conflicts, on the one hand, can lead to advocacy for access of non-approved drugs for those who would benefit most, but at the same time, they can increase the potential liability for sponsors and individual physicians for providing non-approved medications.

Thus, strict adherence to international guidelines such as the Declaration of Helsinki, International Conference on Harmonization (ICH), and Good Clinical Practice (GCP) are critical for named-patient programs. Yet because those same guidelines are in effect for Phase IIIb studies, sponsors may gain more control over the conduct of the study through the Phase IIIb approach. However, companies must weigh the advantages gained through greater control—such as improved screening of eligible patients and better collection of patient demographic and safety data—against the cost of more restrictive entry criteria, which requires heavy administrative and logistic supports.

Cost recovery is another strategic issue that companies must consider when determining what type of EAPS to pursue and in which countries. If a company decides to charge for the product to offset the cost of the EAP, that price remains the reference point for further price negotiations with regulatory bodies and health insurance systems when the drug goes to market. In all cases, an experienced contract service provider can help sponsors make cost/benefit decisions and, in turn, execute a successful EAP.

Centralized Management

Generally, EAPs involve physicians who may not be experienced clinical researchers and are not monitored by on-site clinical research associates (CRAs). In light of those realities, sponsors must carefully design case report form data collection procedures to ensure complete, accurate, and timely safety reporting.

For Treatment INDs and named-patient or cohort programs, a centralized coordination center usually is the most efficient, cost-effective approach to EAP management. Global EAP programs usually require centralized coordination both in the United States and in Europe to cover all of the appropriate time zones. A coordination center in Asia may be added if the program covers that area, too. Since EAPs involve physicians who may use the local language, sponsors may want to consider staffing centers with multilingual personnel.

A properly staffed center can perform clinical monitoring and document management—functions that otherwise would be carried out by CRAs or at the home office. The staff can also screen, enroll, and initiate sites; help physicians gain access to the program; and review inclusion and exemption requests. The coordination center can function as a facility for drug distribution and re-supply, as well as for safety reporting and safety event management. The center can also collect CRFs and collate regulatory documents, essentially acting as the central conduit for all critical information that needs to be transmitted into the sponsor's larger database. (See "EAP Process Flow," page 67.)

Collecting EAP data can be challenging. Although US physicians must sign Form 1572 recognizing their regulatory obligations, they are not compensated for their efforts, as is true in most countries. So it is not unusual to receive incomplete CRFs. A simple, well-designed CRF and a monitoring/follow-up process can help increase the likelihood that physicians will provide complete information. Still, an experienced central center staff is necessary to provide all-important query follow-up, as the coordination center is often the sponsor's only link with physicians.

Because participant sites may not be familiar with terminology, completion of AE forms often requires multiple queries to ensure that the appropriate information is collected. Coordination center staff should be trained to conduct appropriate safety follow-up and refer all AEs to the sponsor's designated safety group.

Finally, a coordination center can support the pharmaceutical company's communication strategy by providing a harmonized voice and a consistent message to both physician and patient communities. At the same time that it must seek uniformity, a global EAP center must have the experience, knowledge, and flexibility to understand local variability within the program and work within the boundaries of local regulations.

The Advantages

Global EAPs offer pharmaceutical companies several strategic advantages, including a wider market in which to showcase their new drug and its benefits, and an opportunity to familiarize physicians with the product before marketing approval. Pharma sponsors may also generate considerable public good will by making the new therapy available to a patient community that is in desperate need of treatment alternatives. In addition, a global EAP also provides companies with an opportunity to expand the safety database and clinical experience of a drug in an ethnically and geographically diverse population.

Successful EAPs require careful preplanning, including an objective estimation of the potential number of patients, the costs, and a projection of production and distribution requirements. The diversity of the regulatory environment across Europe and other regions of the world adds yet another level of complexity to the planning process. None of those barriers is insurmountable, and the benefits are often well worth the effort.