Managing Access To Drugs Prior To Approval And Launch

By Simon Estcourt

Consider the following scenarios. You’ve got an oncology drug in the pipeline that’s showing great promise. Results from your clinical trials are making news, and your company is flooded with calls from physicians and desperately ill patients requesting access to the drug prior to final approval.

In Europe, your drug for an orphan disease has secured centralized EMEA (European Medicines Agency) approval, but it will be months before the drug is available in all EU countries — too long of a wait for critically ill patients.

For patients who are terminally or seriously ill, have exhausted all available therapies, and cannot enter a clinical trial, access to an investigational drug/biologic outside the trial setting or prior to launch can represent a new treatment option.

Recognizing this situation, governments around the world have established regulations that allow patients with unmet medical needs to gain access to drugs prior to their approval for general marketing. Through these access management programs, pharmaceutical and biotechnology companies can provide access to drugs in their pipeline to patients with serious or life-threatening conditions of all types, including cancer, infectious diseases, as well as rare diseases.

Outside the United States, such programs also enable patients to access drugs approved in other countries but not yet in their home country. In the EU, these programs allow patients to access drugs in the time period between centralized EMEA approval and launch in their home country. (See sidebar on page 32, “Enabling Access,” for an overview of global programs.) These access programs can be leveraged around the world in a number of ways and for a number of circumstances when companies face demand for drugs prior to approval or launch. In this article, we describe the use of these programs in two very different circumstances — but with one overarching objective — helping patients who have run out of therapeutic options.

Extraordinary Results, Extraordinary Demand
Gerry Kennealey, M.D., was VP of oncology clinical research at AstraZeneca when he led the team that developed the expanded access program for Iressa in 2001 (Dr. Kennealey is not representing the view of AstraZeneca nor his current employer, Cephalon). Iressa is an oral agent with little toxicity that in clinical trials showed activity in patients with nonsmall cell lung cancer. About 75% of all lung cancers fall into the nonsmall cell category. Clinical trials revealed dramatic results in about 10% of patients.

Favorable tolerability and unprecedented responses in 10% of the patients in Phase 1 trials were first reported at the National Cancer Institute-European Organisation for Research and Treatment of Cancer-American Association Cancer Research (NCI-EORTC-AACR) meeting in 1998. This generated a substantial amount of publicity. Employees at AstraZeneca received literally hundreds of phone calls from physicians, patients, and family members requesting access to Iressa outside of the clinical trial setting.

“The reason AstraZeneca established the expanded access program was the very early results from the drug,” recalls Dr. Kennealey. “This was a drug that was expected to slow the growth of cancer, and what surprised us and astonished key opinion leaders was that it actually shrank tumors. We knew we were dealing with something that had a meaningful benefit for patients. Additionally, we knew the drug was reasonably safe and had a much more benign toxicity profile compared to chemotherapy agents currently used to treat this disease.”

As with any expanded access initiative, a number of factors were carefully considered prior to implementing the program for Iressa. “The best way to get a drug to patients who need it is to get the drug on the market,” noted Dr. Kennealey. “We wanted to make sure that an expanded access program would not interfere with studies that we had to get done to get the drug on the market.”
Different internal teams were responsible for the registration studies and the expanded access program. While the expanded access program was ongoing, yet another team remained focused on getting the drug to market.

When considering expanded access, companies must make certain there is enough supply of the drug to complete registration studies and support the access program in parallel. Another consideration is the resources needed to establish and run the program; included in this are processes for handling and vetting requests, the mechanisms to review physicians requesting the drug, and procedures to handle adverse event reporting.

It is also critical that a company clearly define which patients are to be included in an expanded access program. In the case of Iressa, the drug was believed to act by influencing a tumor marker — a marker that was not only present in lung cancer, but in other types of cancers. At the time, the company had data for only nonsmall cell lung cancer.

“We felt that if we opened up the access program beyond lung cancer, it could lead to chaos,” recalls Dr. Kennealey. “We decided that the drug would be made available only to patients whose nonsmall cell lung tumors had failed to respond to chemotherapy or patients who were unable to tolerate chemotherapy. We ultimately enrolled over 20,000 patients in the global program. No exceptions were made on the basis of persistence, political position, or country of origin — that was something we had as a policy, and I’m very proud to say that we adhered to it throughout the program.”

Close contact with the FDA helped to ensure success. As this was the first expanded access program undertaken at the company, FDA involvement and counsel was critical, including input on the consent form to ensure it was understandable to patients.
Another important factor was proper vetting of physicians; they had to be oncologists or hematologists or be able to demonstrate expertise in the use of potentially toxic cancer treatments. Through this program, a large group of physicians outside those directly involved in the trial were able to gain access to an experimental drug that might help their patients.

“There are thousands of medical oncologists in this country,” notes Dr. Kennealey, “and when you do a trial you involve maybe 50 of them.”

The program ended 90 days after the drug was approved. The company felt that this time frame would be sufficient for physicians to know the drug was approved and to make arrangement to get the drug commercially.

Trial data showed that Iressa provided benefit to about 10% of patients. Extrapolating this to the number of patients receiving Iressa via expanded access, perhaps 2,000 patients who had run out of therapeutic options were helped by the program.

“I was in practice for a decade, in the industry since 1987, and have been involved in getting drugs to market for breast cancer and prostate cancer,” reflects Dr. Kennealey. “But to be able to have a direct impact on such a large number of patients for something that really made a difference was very gratifying for me.”

A Unique Drug, A Unique Need
The grim prospects for long-term survival in acute myeloid leukemia (AML) strongly motivated EpiCept to provide patients a route of access in advance of the commercial introduction of its drug, Ceplene, the first approved immunotherapy for remission maintenance and prevention of relapse in adult AML patients in first remission. AML is an orphan disease with about 16,000 to 18,000 new patients diagnosed each year worldwide.

EpiCept has made Ceplene available on a named patient basis in Europe and in dozens of other geographies, including Latin America, Asia/Pacific, Australia, Israel, and Canada. (See sidebar on page 32, “Enabling Access,” for a description of programs outside the United States.)

“Ceplene is a unique drug that fulfills an unmet medical need in a highly lethal disease,” describes Jack Talley, president and CEO of EpiCept. “It has been approved in the EU, but regulatory constraints and decentralized reimbursement processes can delay actual launches in individual countries for more than a year. As a result of this time lag and the fact that there is no other therapy that can prevent relapse in AML patients, we felt there was a need to make it available to patients prior to commercial launch.”

The processes and regulations governing named patient programs in Europe are well-established and facilitate timely availability of a drug in advance of a commercial launch.

EpiCept is also making Ceplene available via named patient programs in countries where applications for approval are being prepared and in countries where approval won’t be sought.

“Even for big companies where it’s not really cost-effective to pursue the regulatory approval of an orphan drug, it makes sense to consider a named patient program in lieu of a full-blown regulatory approval in a fairly small territory,” advises Talley.

Beyond the medical need addressed by Ceplene, a key factor in deciding to offer the drug in advance of launch, in advance of approval, or in lieu of approval was the fact that the drug had earned EU approval. In doing so, the company had fully developed a package insert with comprehensive prescribing information that had undergone a substantial and sophisticated review by a regulatory body.

The successful development and implementation of the global program required involvement and coordination of many disciplines within EpiCept, including representatives from medical affairs, pharmaceutical development, regulatory, supply chain, business development, and finance. The cross-functional team was responsible for ensuring that the clinical criteria for patient participation were established, physician educational materials were defined, drug supply was adequate to support the program, and enrollment in any ongoing clinical trials would not be affected.

An important decision for the company was whether or not to allow use of Ceplene beyond AML. “There’s no doubt that this is an intellectually intriguing compound,” comments Talley. “It effectively works to scavenge minimal residual disease in patients in remission, and so it might be helpful in other hematologic diseases as well. We wrestled internally with how broad we should make this program, but felt at the end of the day the responsible decision was to limit it to AML and not venture into other diseases where we had not proven, to our satisfaction as well as the EMEA’s, safety and efficacy.”

In order to navigate the regulatory and logistical pathways to provide access in more than 100 countries and remain in compliance with all authorities, EpiCept chose to partner with Idis, a specialist in the development and management of these drug access programs, rather than rely on internal resources. Establishing and managing these programs requires specialized knowledge that didn’t reside at EpiCept. Partnering with Idis also allowed EpiCept’s functional teams to stay focused on preparing for upcoming commercial launches and approvals.

Once the decision was made to offer Ceplene on a named patient basis, establishment of the program required about 10 weeks. Initiation of the program in the EU was timed to coincide with the date the drug was ready from a manufacturing standpoint and had complete and final EMEA approval and sign-off.

Meeting Global Demand For Access
Greater transparency of drug development pipelines, intense media coverage of trial results, and fingertip access to information about investigational drugs via websites and blogs have created a more educated and empowered population of patients. But, for patients with life-threatening illnesses, waiting for license approval or commercial launch of an innovative new drug may come too late. Access management strategies such as expanded access and named patient programs represent a practical solution, as they enable well-regulated, well-controlled access to potential new treatment options for patients who have exhausted all alternatives.

As shown in the examples provided, these programs can be used by companies of all sizes, from large to emerging, for sizable patient populations and rare diseases, for patients in the United States and around the world. No matter what their structure, these programs share an important goal — to help patients with unmet medical needs.

About The Author
Simon Estcourt is global business development director at Idis, a company that develops and implements access strategies in partnership with pharmaceutical and biotech companies.

Enabling Access

For Patients In The United States
Since 1987, the FDA has had rules in place that allow patient access to investigational drugs under certain circumstances, even though the safety and effectiveness of the drug have not been fully established. These rules were recently clarified by the FDA, and new types of access for treatment use were added to ensure “broad and equitable access to investigational drugs for treatment.”

The regulations also define the different types of mechanisms that are available, including:

• l Access for individual patients under a single-patient IND (investigational new drug; also known as an emergency IND)
• l Access for small to intermediate groups of patients
• l Access for larger groups of patients, which is called a treatment IND or treatment protocol

Single-patient INDs
A single-patient IND is a request from a physician to the FDA that an individual patient be allowed access to an investigational drug on an emergency or compassionate use basis.

Intermediate-size Patient Populations
When the FDA receives a significant number of requests (~10 to 100) for individual patient access to an investigational drug for the same use, the agency may ask the trial sponsor to consolidate these requests, creating an intermediate-size group.

Treatment INDs And Treatment Protocols
Treatment INDs and treatment protocols provide large numbers of patients who would not otherwise qualify for clinical trials access to investigational drugs.

A treatment protocol is a formal addendum to a company’s active IND, submitted to the FDA by the drug company sponsoring the trial, defining the criteria for access to the treatment that is under investigation. In order for a patient to access a drug under a treatment protocol, their physician must be qualified to participate as an investigator. Once this qualification process is complete, any patient who meets the entrance criteria for the treatment protocol can be enrolled by the physician.

A treatment IND, also submitted to the FDA by a drug company, is effectively the same process as a treatment protocol except that the company submits a new IND with the treatment protocol within it for the purpose of treating patients. An example in which a treatment IND may be preferred to a treatment protocol is when a company has been studying a second indication for a drug and ultimately intends to out-license this indication to a partner for further development and commercialization. In this case, the new IND is kept separate from other submissions and can be easily transferred to the new sponsor.

While the new FDA rules clarify the types of access that are available, there remains flexibility as to exactly how and when these programs can be applied. Ultimately, the choice to offer expanded access — or not — is left up to the drug developer. FDA regulations do not force companies to offer access to their investigational drugs. When considering this option, however, companies must undertake a thorough evaluation of important questions such as when to offer access and for which patients.

For Patients Outside The United States
Outside the United States, these access programs are known by a variety of names, including “named patient programs” (NPPs – in which physicians can request access to drugs on behalf of individual “named” patients), “named patient supply,” and “temporary authorization for use.” These programs are similar to U.S.-based EAPs (expanded access programs) in that they facilitate access to investigational drugs for individual patients or groups of patients with unmet medical needs. These programs also allow access, in specific circumstances, to drugs that are approved in other countries but not yet approved in a patient’s home country.

The 30 countries comprising the EU — which fall under the jurisdiction of the European Medicines Agency (EMEA) — each have their own nationalized regulations regarding the access to unlicensed medications for individual patients and patient groups. In the EU, named patient programs also allow patients to access drugs in the time period between centralized EMEA approval and launch in their home countries, which can range from one year to 18 months. Regulations differ widely among countries due to differences in national medical practices, resources available, product funding, hospital structures, and national insurance systems.

Countries outside the United States and Europe also offer these programs. Canada’s “Special Access Programme” provides access to nonmarketed drugs to practitioners treating patients with serious or life-threatening illnesses when conventional therapies have failed, are unsuitable, or are unavailable. Similarly, in Australia, patients can access experimental drugs via the “Special Access Scheme.” In Japan, government sanctioned “Named Patient Access” allows access to drugs with an expectation that the drug be approved in the exporting country.