Simon Estcourt

For some patients who do not meet the clinical trial enrollment criteria or live outside the region where a clinical trial is being performed, access to a medicine outside the clinical trial setting can represent a new, and in many cases, lifesaving treatment option. Similarly, many drugs commonly available in the United States may have limited availability in foreign markets. Hence, clinicians in these countries are forced to seek untraditional routes to obtain medicines for their patients in need. When such demand arises, implementation of a Managed Access Program (MAP) enables a company to provide treatment options for these patients while not competing with ongoing trials.  

While the primary pathway for patient access is through the standard course of drug development, approval, and commercialization, MAPs can generally be considered as an option for enabling early access when the following criteria have been met: 					

The primary intent of the MAP is to provide treatment, not assess safety or efficacy 

This is a serious or life threatening disease or condition (based on clinician's medical judgment)

There are no comparable or satisfactory treatment alternatives available

The MAP will not interfere with ongoing clinical trials 

The presumed benefit outweighs presumed risk in the context of the disease or condition

Managed access encompasses a variety of regulatory approaches globally including Expanded Access Program, Named Patient Program, Autorisations Temporaires d'Utilisation patient or cohort programs, and Compassionate Use Program. Common to all is the primary objective to provide treatment to patients with unmet medical needs. MAPs can be implemented on a per-patient basis or for a group of patients. This may be desirable in a variety of situations including: 					

Medicines that are still in clinical development and may offer a chance for effective treatment, but cannot be accessed through a clinical trial

To continue treatment between the end of a clinical trial and commercial availability for patients who had been enrolled in the trial

For medicines that are approved in one country, but not another

For medicines for which commercial launches are staggered or delayed or may not ever happen in a particular geography 

Where medicines may never be approved, but still offer value for a very small population 

When a medicine is being discontinued from development or commercialization in a specific market or region, but ongoing patients still need treatment

As a drug progresses through clinical development and subsequent commercialization, a number of situations can trigger demand for access from patients. Strong positive clinical data presented at a conference may be the subject of media coverage; the drug may be first in class or offer a novel mechanism of action, an improved delivery mechanism or safety profile, or represent a new treatment option for an underserved population, such as in the case of rare diseases. Such demand is typically amplified through social media channels, resulting in an empowered, vocal patient population seeking early access.  

Figure 2 shows a representative pattern of patient demand leading up to FDA and EMA approval that was addressed via a recent MAP. In this situation, a large biotechnology company with a diverse pipeline of specialty and orphan drugs had a product in development for an oncology indication. While awaiting US and EU approvals, the company experienced a high level of demand from physicians and patients, which had been generated by heightened awareness of published clinical trial data. The drug represented a major advancement over existing therapies that were currently being used off-label with limited efficacy and significant side effects.  

The company put a MAP in place to address this demand. The company chose to partner with a MAP expert so that its internal team focused on US/EU registration activities, approvals and commercial launches. 

As shown in Figure 2, the number of patients gaining access to the drug via the MAP grew steadily prior to FDA approval, and continued to climb during the period leading up to EMA approval. Once approved by EMA, new demand through the program tapered off as commercial supply became available. The MAP ultimately delivered product to more than 1,300 patients in 43 countries. Over 950 physicians participated in the program, expanding the real-life experience with the drug among healthcare providers.  

Historically, implementation of a MAP has been initiated at the end of the Phase III clinical program or when a drug has been approved in at least one market. Recently, companies have begun MAPs earlier—in some cases as early as Phase II—driven by strong early data and anticipated patient demand. This is particularly apparent in the rare and orphan disease space where treatments have never been available and drug pipelines are limited.  

Planning for a MAP should begin six-to-12 months in advance of anticipated demand to allow time for preparation and program development. Consultation with regulatory authorities for approval of the program, and creation of educational information for physicians and pharmacists regarding dosing, administration and restrictions must all be considered in the planning process. 

Developing and implementing a MAP also requires the involvement and coordination of many disciplines across the company including clinical operations, medical and regulatory affairs, and supply chain/logistics. A cross-functional team is critical to ensure the clinical criteria for patient participation are established, physician educational materials are available, the supply of drug is adequate to support the program, a mechanism is in place to capture all adverse events, and that enrollment in any ongoing clinical trials is not compromised.  

Another consideration to make is whether to charge for the drug as part of the MAP. Determining whether or not to charge for the drug in a MAP can be a complicated decision, which should be addressed on a country-by-country basis before the outset of the program. The decision to provide free access or charge depends on the sponsor's ability to fund a program; the regulations in specific countries; objectives; price; availability of treatment alternatives; and if there is a position on compassionate use.  

A company needs to evaluate all of the assumptions and known factors in order to land on the optimal strategy. However, this strategy should allow for flexibility in response to the market dynamics and differences throughout different regions of the world. 

If a MAP will be running while registration trials are ongoing, it is important to define the scope of the indication for the MAP and clearly delineate which patients will be included. Companies must define inclusion criteria proactively and objectively to ensure proper selection of patients and identify those who could be moved into the clinical trial population. These criteria must be consistently communicated to all participating physicians. A program run in parallel with a Phase II trial requires more stringency, usually limiting the program to those patients who fall outside the enrollment criteria for the trial, or for patients who cannot gain access to a trial site. Later in the development process, broadening of the criteria for inclusion into the MAP can be considered.  

There are situations in which regulatory authorities require that a trial sponsor continue to make a drug available to trial participants after the study is over until it can be obtained commercially. They recognize the ethical dilemma of withdrawing a drug from trial patients who may be benefiting from an investigational treatment, or not making the treatment available to study subjects who may have received placebo in the clinical trial.  

Extending access for study participants via a traditional open-label extension study is one option, but an open-label extension study can add significant costs and require internal resources. Typically, these extension studies continue to monitor patients and collect data similar in nature and frequency to that collected for registration studies, although the return on investment may be limited, based on self-selection and the relatively small number of patients rolling onto the open-label extension study. Compared to open-label extension studies, MAPs generally offer a more economical solution, with less extensive site monitoring, as well as lower investigator fees to participate, depending on the amount of data collected.  

Transitioning trial patients from a registration study to a MAP is appropriate when the key rationale includes: 					

Provision of treatment as the primary focus

Interest in continuing access to treatment for patients who demonstrated benefit on therapy during the trial 

Providing a more cost effective and efficient alternative to an open-label extension study 

Rigorous data collection is not a primary requirement

The additional clinical data collected in an open-label extension study would be of limited scientific value  

The company no longer wishes to develop a product, yet physicians and patients have identified a treatment benefit.

Despite the marketing approval of a medicine, access may continue to be delayed for patients in need for a variety of reasons. In these situations, MAPs can provide timely access to much needed medicines. 

Figure 3 illustrates the delay in access to treatment that patients in Europe may experience even though a drug has been approved via the centralized procedure. Each year the European Federation of Pharmaceutical Industries and Associations publishes the Patients W.A.I.T. Indicator (Patients Waiting to Access Innovative Medicines). These data represent 66 new medicines available in 2011 that were approved by the EMA during the years 2008 to 2010.  

As depicted in the graph, in 19 European countries (excluding the UK), the average elapsed or "wait" time between the date of EMA market authorization and the "accessibility date" (i.e., the date of completion of pricing/reimbursement procedures) varied from 116 to 848 days. The sometimes substantial lag between approval and commercial availability is often the result of national pricing and reimbursement negotiations and a growing trend toward the use of health technology assessments, in addition to national, regional, or local variations. 

For each country the blue bar represents the percentage of medicines with a valid EMA marketing authorization during the previous three years, which were "available" commercially in 2011.  

While clinical trials and MAPs both provide patients with controlled and compliant access to investigational drugs, their approach to doing so is quite different. For example, in a clinical trial setting, regulations take a "top-down" approach in that there is a protocol, stringent rules, and guidelines from which there can be no, or minimal, deviation. With a MAP, the rules and regulations can be described as "bottom-up," i.e., unique to each country or circumstance. Frequently, collection of safety data on the patients receiving drug is the only requirement, making a MAP significantly less costly than a clinical trial. Despite the different approaches, MAPs can work synergistically with clinical trials, addressing the needs of patients who do not fit within the typical clinical framework. Sometimes via a MAP, patients are identified who more appropriately should be treated within a clinical trial, and they are referred into that setting, thereby helping to increase enrollment into registration studies. 

In addition to the primary objective of providing access to patients in need, MAPs offer a number of additional benefits which include: 									

Providing treatment without requiring significant supporting infrastructure to be in place in countries where commercial launch is not initially planned or will be delayed

Pre-approval use among early adopting clinicians can provide real world information pre-launch that can be used to ensure easier adoption at commercial launch

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