Supplementing clinical development with a managed access program and post-trial access

Good news travels fast, especially when positive clinical trial data sparks demand for access to an investigational drug from physicians and their patients who are unable to participate in a clinical trial or who have participated in a trial, but need ongoing treatment ahead of commercialization. This can be for a variety of reasons, such as:

• A patient does not have access to a clinical study site
• A patient does not qualify for a clinical trial
• Enrollment has closed to new patients
• The trial has completed, and there remains a gap between trial completion and commercialization.

While the primary pathway for patient access to new drugs is through the standard course of development, approval and commercialization, a Managed Access Program (MAP) can enable early access to patients when the following criteria have been met:

• The drug is intended to treat a serious medical condition
• No satisfactory approved treatment alternative is available
• The MAP will not disrupt ongoing or planned clinical trials
• The primary objective of the MAP is to provide treatment, not collection of data for regulatory submissions
• The likely benefits to the patient outweigh the potential risks

The term “Managed Access Program” encompasses a variety of regulatory approaches globally, including Expanded Access Program (EAP), Early Access Program (EAP), Named Patient Program (NPP), and Compassionate Use Program (CUP). Common to all of these mechanisms is the primary objective to provide treatment to patients with unmet medical needs.

MAPs can be implemented on a patient-by-patient basis, or in some countries for a group of patients. MAPs address the “access gap” that exists at any time during a drug’s lifecycle when there is a difference between the level of patient access and patient demand for a drug. This gap is more pronounced the greater the unmet medical need.

When a company establishes a MAP, it is usually to meet one or more of the following objectives:

• To provide lifesaving treatment to patients who can’t wait for commercialization in their country
• To make a drug in clinical development available to patients who are unable to participate in a clinical trial
• To make a treatment available to study participants after the completion of a study but before it becomes commercially available
• To make an approved drug available to patients with a different unapproved therapeutic indication
• To make a treatment that has been approved in one country available in a country where it has not yet been approved or where approval is not expected.
• To make a treatment available when commercialization is unlikely even though the drug benefits a small population with, for example, a rare disease
• To make a drug available after development or commercialization in a specific market if it has been terminated, but current patients still need treatment

MAP Benefits to the Company

In addition to the primary ethical objective of providing access to patients in need, run effectively, MAPs can offer many additional advantages to a pharmaceutical company, including the following:

• Generates valuable information from pre-approval use in clinical practice
• Might uncover patient sub-types not represented in clinical trial
• Might help identify patients who can, instead, be referred to a clinical trial
• Provides a treatment option to fill the gap between clinical research and commercial supply
• Enhances the company’s reputation and corporate social responsibility (CSR)

PATIENT PARTICIPATION IN A MAP

As a drug progresses through clinical development and subsequent commercialization, various events can trigger patient demand for the drug. For instance, an investigator may present positive clinical data at a scientific conference. Or, the media might be especially interested in the drug because it is first-in-class with a novel mechanism of action, improved safety profile, or the treatment represents a new option for an underserved population such as patients with a rare disease. As positive news propagates through traditional and social media, it can generate an empowered, vocal patient population seeking — if not demanding — early access.

Figure 1 shows a representative pattern of MAP participation. In this case, a large biotechnology company with a diverse pipeline of specialty and orphan drugs had a product in development for an oncology indication. The company experienced a high level of demand from physicians and patients who were aware of the published clinical trial data. The drug represented a major advance over existing therapies that were currently available. Some treatments were even being used off-label, all with limited efficacy and significant side effects. The company put a MAP in place to address the large number of requests for access to the drug.

As shown in Figure 1, the number of patients gaining access to the drug via the MAP grew steadily, and continued to climb during the period leading up to various country approvals. Once approved by both FDA and EMA, new participation in the program tapered off as commercial supply became available May through to August 2021. In July 2021 the company decided to broaden access to incorporate patients exiting clinical trials (which we can refer to as ‘Post Trial Access’ (PTA)) in order to close out a number of ongoing studies as per protocol, but also to continue access to those patients who were benefiting from treatment. The addition of the PTA patients caused a spike in supply in September 2021. The MAP and PTA combined ultimately delivered product to more than 100 physicians and their 150 patients in 10 countries.

Figure 1. New Patients Entering MAP

^{Source: Clinigen, 2022} 

PLANNING AND pREPARATION

MAP planning and preparation should begin six to twelve months before anticipated demand but should be considered much earlier in the product lifecycle. Developing and implementing a Managed Access Program requires coordination of many stakeholders across the company, including, but not limited to, clinical operations, medical affairs, regulatory affairs, pharmacovigilance, and supply chain/logistics. A cross-functional team can ensure that:

• Criteria for participation and exclusion are established
• Drug supply is adequate to support the program
• Physician educational materials are available
• Data on adverse events will be captured
• Enrollment in clinical trials is not compromised as this remains the gold standard access route for unapproved treatments
• Regulatory approvals are obtained where needed

Determining whether or not to charge for the drug in a MAP can be a complicated decision that should be addressed on a country-by-country basis. The decision whether to provide free access or to charge for the drug depends on a number of factors, including the following:

• The program’s objectives
• The company’s ability to fund the program
• The feasibility of charging, as permitted by economic factors and regulations in specific countries
• The cost and projected price of the drug
• The availability of treatment alternatives
• The company’s position regarding compassionate use

Historically, MAPs begin at the end of the Phase III clinical program or when a drug has been approved in at least one market. However, with the number of products being fast-tracked through various regulatory mechanisms, companies have started to require alternative access solutions sooner in the product lifecycle, in some cases as early as Phase II. Early initiation is more common with rare and orphan diseases where treatments are unavailable, and development pipelines are limited.

If a MAP will be running while registration trials are ongoing, it is essential to define the scope of the populations(s) and indication(s) for the MAP. Clear and logical inclusion criteria support responsible review and approval of early patient access requests and identification of those who are suitable for enrolment into a clinical trial as the priority. A MAP running in parallel with registration trials are usually limited to patients who fall outside the clinical trial's enrolment criteria or patients who cannot gain access to a trial site. Later in the development process, broadening the criteria for inclusion into the MAP can be considered.

tRANSITIONING STUDY PARTICIPANTS

Withdrawing a drug from study participants who are benefiting from an investigational treatment or not making the treatment available to study subjects who received the placebo can be ethically objectionable. Regulatory authorities can require a study sponsor to make the study drug available to participants after the study is over and until it can be obtained commercially.

One option is to offer study patients participation in an open-label extension study (OLE). OLEs typically continue to monitor patients and collect data similar in nature and frequency to that collected for registration studies, even though that data might have very limited value to the study sponsor. OLE is sometimes requested as a commitment or conditional to Marketing Authorisation approval by the Competent Authorities.

Anecdotally, Post Trial Access Programs (PTAs) offer a much more economical and efficient solution. Generally, PTAs collect only safety data, require little, if any, site monitoring, and there are no requirements to pay physicians or sites for participation, although in the US in particular, this decision will be dependent upon the amount of data collected and activity required to administer the treatment.
Transitioning study participants from a registration study to a PTA is appropriate when the rationale includes:

• Treatment, rather than collection of data, is the primary focus
• The company wants to provide continuing access to treatment for patients who benefited from the treatment during a clinical trial or were in the placebo arm
• The company wants a cost-effective and efficient alternative to an OLE study while maintaining ethical supply to patients
• The company no longer wishes to develop and commercialize the product, even though physicians and a subset of patients have identified a treatment benefit

PROVISION FOR pOST-TRIAL ACCESS (PTA)

A major industry trend: The growing cost of clinical research across all sized pharmaceutical and biotech companies are causing companies to take a closer look at the value of running expensive long-term open-label extensions or roll over studies when the sole purpose is to provide treatment. Often all data required for approval submission may have already been collected.

It would seem logical that PTA would be ideal for this scenario, however, a small number of health authorities are not supportive of using early access only for post-trial patients. Instead, they hold the view that patients should have access to the treatment regardless of whether they participated in the clinical trial and this is reflected in their country specific guidance.

Companies looking at post-trial access should keep this in mind, especially in countries where a formal submission is required. A careful analysis of country regulations should always be considered when embarking on a PTA program.

cONCLUSION

MAPs offer a range of solutions for addressing the needs of patients who cannot obtain medicines within a clinical trial or through commercial channels. In our current world of early awareness through global communication and social media, it is essential to anticipate the timing and quantity of possible patient demand that will parallel clinical trials in the development process. Physicians, patients and advocacy groups can apply significant pressure on a company to provide access to their treatments in development. Managed Access Programs should be considered an integral part of every product strategy. Preparing for this demand well in advance will ensure the implementation of a successful MAP. It goes without saying that it is important that companies conduct proper planning and that early discussions with authorities are critical to ensure continued treatment outside of CT.

PTAs can offer a great way to fill the gap between study completion and local commercialization. It is important to have a thorough analysis of each product and countries regulations when considering PTA as not all countries will allow this type of access. PTA should be considered an integral part of every research and development to ensure PTA is an established option at study closure or completion. Early contemplation of PTA can provide cost effective and efficient end of study treatment options.

AUTHOR

Dan Wasserstrom is Senior Director of Global Business Development at Clinigen Group. Contact him at dan.wasserstrom@clinigengroup.com.