By Maria Kempshall

Greater transparency of drug development pipelines, increased media coverage of healthcare issues, and fingertip access to information about investigational drugs via websites and blogs have created a more educated and empowered population of patients.

The heightened awareness of drugs in development brings with it an increase in demand from patients, their physicians, and advocacy groups worldwide for access to these potentially promising medications despite their preapproval status.

Governments worldwide have created provisions for granting access to investigational drugs for patients who have exhausted all alternative treatment options and do not match clinical trial entry criteria. Often grouped under the labels of compassionate use, expanded access, or named patient supply, these processes allow companies to provide patients with access to their drugs while the drugs are still in the preapproval or pre-launch phase. Regulations governing such access define access criteria, data collection, promotion, and control of drug distribution.

OPTIONS FOR PROVIDING PREAPPROVAL ACCESS
In 1987, the FDA formally put in place regulations to improve patient access to investigational drugs. These expanded access program (EAP) regulations focused on drugs that would address existing therapeutic gaps, including cases in which therapies were not available and those in which patients were unresponsive or not adequately treated with currently marketed drugs.

An updated rule governing expanded access in the United States was published by the FDA in August 2009. The rule clarifies existing regulations and adds new types of expanded access for treatment use. The rule enables expanded access to investigational drugs to individual patients, including in the case of emergencies, to intermediate-size patient populations and to larger populations under a treatment protocol or treatment investigational new drug (IND) application.

The rule provides criteria that must be met to authorize the expanded access use, the requirements for expanded access submissions, and safeguards to protect patients and preserve the ability to develop meaningful data about treatment use.

MEETING DEMAND FROM OUTSIDE THE UNITED STATES
Named patient programs enable physicians, on behalf of their patients, to access medicines approved or nearing approval in other countries before marketing approval has been granted in their home country. Through these programs, individual patients outside the United States can potentially access, via their physician, drugs approved or in late-stage clinical trials in other countries for an unmet medical need. Named patient programs allow U.S.-based companies to provide patients outside the United States with access to drugs they have in late-stage clinical trials or those drugs approved in the United States but not in the home country of the patient.

The 30 member states of the European Union, for example (all of whom nominally come under the jurisdiction of the European Medicines Agency [EMEA]), each has its own nationalized regulations regarding the access to unlicensed medications for compassionate use programs (both for individual patients and cohorts). Named patient programs also allow patients to access drugs in the time period between EMEA approval and launch in their home countries.

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.

INTEGRATING CLINICAL TRIALS AND EXPANDED ACCESS
Expanded access programs can be established while a clinical trial is ongoing, but careful coordination and timing are needed in order to avoid compromising recruitment for the trial. Companies should remain mindful of the impact that any expanded access program may have on patient accrual to clinical trials. Through an expanded access program, patients can be assured of receiving the drug, not a placebo or control treatment, a factor that may make them reluctant to join a clinical trial. Expanded access programs can be used effectively, however, in concert with clinical trials with minimal impact on accrual because these programs provide access to patients in geographies where there may be no clinical trial in progress.

When run in conjunction with a clinical trial, expanded access programs also make the investigational drug available to patients who cannot enter a clinical trial due to their demographic restrictions, such as age or medical factors resulting in exclusion. Detailed screening criteria are used to evaluate patient requests within the context of an expanded access program. This screening process can also be used to assess patients based on the clinical trial entrance criteria and forward those patients who meet these criteria to the sponsor or their CRO for inclusion in the trial.

COMMUNICATING AVAILABILITY
While the humanitarian motivation for providing preapproval access is to respond to the needs of desperately ill patients, what cannot be ignored is the fact that offering access to drugs still in development creates increased visibility for these drugs on a prelaunch basis and initiates early physician and pharmacist engagement. The possibility of a head start in gaining market acceptance for a drug as key physicians become familiar with the product prior to launch can be attractive to companies that choose to participate in these programs.

Although the structure of any expanded access program naturally yields market benefits, promotion of investigational drugs is not allowed. In addition, misuse of these programs, whether intentional or unintentional, in order to secure an even more significant marketplace advantage can subject a company to penalties.

As a result, companies providing access to investigational drugs must exercise caution when publicizing such programs. Companies can provide information regarding preapproval access to physicians at medical conferences, for example, but cannot solicit interest from target physicians, advocacy groups, or patients, nor can the company use their sales force to promote such programs.

NAVIGATING REGULATORY COMPLEXITY
Requests for drugs within the context of a named patient program can originate from any country. As such, the coordination of these programs is complicated by regulations that vary from country to country. Furthermore, because they involve export of drugs out of the United States (in accordance with the FDA guidance document released in July 2007), named patient programs operate under different rules than those governing U.S.-based EAPs (expanded access programs).

Once a drug has left the United States, it leaves FDA jurisdiction and enters that of the nation (or nations) to which it is being exported. Most countries legally allow for named patient access as a means of providing medications to patients when local alternatives are either unavailable or inappropriate.

The structure of programs within each country can vary widely due to differences in medical practices, resources, funding, and national insurance systems. Some member states allow both named patient and cohort programs, while others allow only named patient programs. In some countries, approval for compassionate use must be provided by a competent authority; in others, an import certificate may be all that is needed. Country-specific regulations also define requirements for payment, liability, adverse event reporting, and whether a drug must be licensed elsewhere before it can be offered via such programs.

PLANNING FOR A NAMED PATIENT PROGRAM
When considering a named patient program to address global demand, know that planning should be early — with the program in place at least several months prior to expected marketing authorization. If the program is in place too early, the company might not have an adequate supply of drug available to meet the named patient demand. If the program is started too late, there may not be sufficient use of the program. In cases where demand for the drug is extremely high, however, starting the program within just a few months of expected authorization is warranted.

The planning phase of a named patient program includes preparation of documents and, if needed, establishment of a contract with a named patient program specialist; development of information for physicians and pharmacists regarding dosing, administration, and restrictions; and establishment of treatment criteria to insure proper selection of patients. If the drug is approved in another country prior to the start of the named patient program, the package insert should be included in the physician and pharmacist information.

As part of a global market access strategy, named patient programs are typically put in place at any stage post phase II and can run in parallel with phase III trials until commercial launch. Named patient programs can be utilized to provide patient access at a number of stages throughout a product’s life cycle:

• during Phase III, to patients with an unmet medical need who do not meet the clinical trial’s inclusion criteria
• bridging the gap between the end of Phase III and receipt of marketing authorization
• alongside the staggered global launch while following approval and reimbursement is being sought across countries worldwide.

INTEGRATING CLINICAL TRIALS AND NAMED PATIENT PROGRAMS
Named patient programs can be established while the drug’s clinical trial is on-going but careful coordination and timing are needed in order to avoid compromising recruitment for the trial. Named patient programs are generally put in place while the drug is in Phase III trials, after a general safety profile has been established. These programs can provide additional “real life” risk/benefit evaluation of drugs in a wider population outside of a controlled clinical trial setting.

When run in conjunction with a clinical trial, named patient programs make the investigational drug available to patients who cannot enter a clinical trial due to either their geographic location, demographic restrictions such as age, or medical factors resulting in exclusion. Detailed screening criteria are used to evaluate patient requests within the context of a named patient program. This screening process can also be used to assess patients based on the clinical trial entrance criteria and forward patients who meet these criteria to the sponsor or their CRO for inclusion in the trial.

Expanded access and named patient programs can provide months and perhaps years of treatment for patients with unmet medical needs when all other therapeutic options have failed or no other options are available. The benefits of these programs are best realized when a company incorporates planning for such programs early in a drug’s clinical development stages and includes all relevant stakeholders in the process. Although some companies prefer to manage their programs in-house, others prefer to partner with a program specialist who is often better equipped to manage worldwide logistical and regulatory complexities. Regardless of the approach, these programs are essential for meeting global demand for prelaunch medicines.

About the Author
Maria Kempshall is head of regulatory affairs and quality assurance at Idis. Prior to joining Idis, Maria implemented quality management systems on a variety of scales from large pharmaceutical companies through to small start-up companies. As a lead auditor, she has gained experience of quality systems outside of the medical industry, which has given her a broad perspective of quality assurance and its application.