Post-Trial Access to Treatment: How Expanded Access May Offer A Strategic Solution

Within the development process of each drug, it is essential to realize that when clinical studies end, it affects not only the patients who volunteer to participate in a Clinical Trial but also the pharmaceutical company, and thus companies must plan ahead for the implications of Clinical Trial closure or completion from multiple angles.

“Post-Trial Access” (PTA) refers to the provision of a product, either investigational treatment or comparator, to Clinical Trial participants following trial completion. Post-trial access may involve open-label trial extension studies, long-term extension studies, rollover clinical studies, separate protocols, or protocol amendments.

All phases of clinical research are highly regulated; however, the regulations for continuing to treat a patient after a Clinical Trial ends (post-trial) are unclear or nonexistent.

The lack of firm guidance and over-arching frameworks for PTA creates a need for equitable solutions for all stakeholders involved. Ongoing pressure from patients over the entire course of their journey has exposed a need to adequately consider the provision of a drug for continued treatment of those who have participated in a Clinical Trial, while also engaging in a proactive and patient-friendly manner[1].

Consequently, companies are increasingly looking for other access pathways to continue with the provision of treatment while also trying to explore new opportunities to collect treatment-related data to inform regulatory decision-making.

Declaration of Helsinki Post-Trial Access

Historically, drug companies have relied on international ethical frameworks such as the Declaration of Helsinki, the ICH Good Clinical Practices, and other international guidelines such as CIOMS10 and UNESCO’s Universal Declaration on Bioethics and Human Rights because there are not many country-specific regulations.

The Good Clinical Practice (GCP) Guidelines describe the responsibilities and expectations of those involved in the conduct of Clinical Trials. Unfortunately, the GCP guidelines do not describe any responsibilities for continuing treatment after a trial.

However, paragraph 34 of the Declaration of Helsinki draws focus to post-trial responsibilities.

“In advance of a clinical trial, sponsors, researchers, and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.”

The Council for International Organizations of Medical Sciences (CIOMS), in collaboration with the World Health Organization (WHO), states in its International Ethical Guidelines for Biomedical Research Involving Human Subjects that companies should consider the following:

“Whether, when, and how any products or interventions proven by the research to be safe and effective will be made available to subjects after they have completed their participation in the research, and whether they will be expected to pay for them…”

These two ethical frameworks provided some guidance concerning the topic but left many questions unanswered.

CIOMS revisions and FDA, EMA on Post-Trial Access

In 2016, CIOMS released a revised version of its Ethical Guidelines for Biomedical Research.

Among other suggestions, the draft guideline recommends that researchers and sponsors must make provision for:

• Providing continued access to study interventions that have demonstrated significant benefits; and
• Consulting with other relevant stakeholders, if any, to determine everyone’s responsibilities and the conditions under which participants will receive continued access to an investigational drug that has demonstrated significant benefit in the study.

The CIOMS revisions also gave examples of valid reasons for ending Post-Trial Access(PTA), such as a pre-determined period for treatment provision or the local availability of other treatment options (approved drugs or other clinical research). Upfront communication before a trial commencement was also suggested.

With these revisions, it is clear that the ideals of the Declaration of Helsinki have shaped current practice, mostly stipulating that access is to be provided after the research to investigational interventions that have demonstrated significant benefit.

In the U.S., the topic has also gained recent traction. As a result, the FDA is actively encouraging drug developers to consider Expanded Access (EA) as this could be very appropriate in many case-specific situations. It stated that:

“If the purpose is primarily to provide the drug to patients who continue to need it, an EA program may be used for either moderately sized populations (intermediate EA) or large size populations (treatment EA), often when most studies in support of approval have been completed.”

“EA is generally available when clinical trial results show that the drug is effective in the studied population. However, sometimes drugs that have not shown benefit across the overall study population may still be providing benefit for individual patients.”

The latter statement resonates with the Declaration of Helsinki but also advocates a clear role for Expanded Access.

In Europe, Clinical Trial sponsors are required to describe PTA for trial participants with respect to the local regulations. Other countries, such as Brazil, also require PTA commitments from the drug developer before a trial starts.

However, a lack of clarity still makes it challenging for drug companies to interpret some of the regulatory and ethical guidance available to them.

• Firstly, neither the Declaration of Helsinki nor CIOMS define how one determines whether an intervention or drug is “beneficial”, and under what circumstances responsibilities for stakeholders emerge.
• Secondly, both frameworks do not address how the safety (risk) of an investigational drug should be evaluated and considered.
• Finally, it is unclear what specific responsibility(ies) apply to each stakeholder with regard to PTA and how long those responsibilities last.

Open-label extension studies, Long-Term extension studies Post-Trial Access, Treatment Arms, Rollover studies Clinical Trials, and Phase 4 studies

Many country-specific regulations, including the U.S., do not explicitly address Post-Trial Access (PTA). As a result, PTA is often managed in open-label (OLE), long-term/extension (LTE) studies, treatment arms of Clinical Trials, and more recently, Expanded Access Programs which have become the preferred choice.

Patients who are benefiting from treatment may be enrolled in a study extension such as an open-label extension study or long-term extension study. OLE and LTE studies are often conducted to assess the long-term safety and tolerability of an investigational new drug.

The purpose of a clinical study’s treatment arm is solely for patient treatment done in a research setting but without patients receiving a placebo. This is similarly the case when rollover clinical studies are considered.

If the intent is to gather more additional rigorous information in support of the application, which requires fundamental research hypotheses – OLE and LTE studies, a Clinical Trial arm or roll-over studies have proven to be more useful.

Expanded Access could be the appropriate mechanism for patient treatment purposes if the objective is to provide the drug for treatment only.

After approval, a Phase 4 study is referred to as post-marketing surveillance and as the name suggests, is conducted after the drug is already approved and available to the general public.

To understand the nuances between various pathways that are currently used, we summarized an overview in the following table:

Comparison table between Open-Label Extension Study, Post-Trial Access (Under EA), and Phase IV Study

Post-Trial Access through Expanded Access

Over the past several years, the increasing popularity of Expanded Access has moved beyond its treatment-only focus within emergency use towards helping larger groups of patients. In addition, Expanded Access Programs (EAP) have had no-to-minimal data collection requirements other than pharmacovigilance. More recently, Real-World Data collection within Expanded Access has become part of a new strategic imperative for drug developers and has increased focus on data collection opportunities outside the realms of an interventional research study.

Although the use of Expanded Access for Post-Trial Access (PTA) is gaining traction, it remains fairly underutilized. Typically, an EAP is designed to run alongside different phases of Trials to manage more than PTA and is designed for patients who:

• Are not able to access a Clinical Trial site or ineligible for trial
• Have completed trial participation or trial has ended
• Have shown benefit from treatment with a trial drug

Post-trial access for a potential patient may be conducted through Expanded Access when a trial has been closed (For reasons other than safety reasons):

• The patient has shown benefit from treatment
• There is a potential negative consequence if the patient stops treatment

Considerations for drug developers

Inevitably Clinical Trials remain the most important part of the development and registration of innovative products, as they enable the collection of robust safety and efficacy data on investigational products to support regulatory approval.

Before choosing the pathway for Post-Trial Access (PTA) considerations, here are some recommendations summarized for drug developers:

• Describe PTA provision in all the Clinical Trial Protocols
• Communicate clearly the PTA policy on their company website
• Develop patient-friendly communications for PTA policy and seek patient input
• Write a separate section in the related patient informed consent forms (ICF), so that patients are fully aware prior to agreeing to participate in a research study
• Provide upfront disclosure to regulatory authorities and ethical committees about the company’s PTA plans, prior to protocol development and patient enrollment

Explore the treatment-related data collection opportunities

Other areas that need some preparation as well include:

• Understanding patient-specific factors, e.g. duration of treatment
• Moment of treatment cycle and longer-term supply considerations
• Potential patient benefit derived from a product vs. other available treatments (including Clinical Trials) – not on a group level but on a per-patient basis
• Additional labeling requirements as well as other document amendments that may be necessary to satisfy the transition

It is important to realize that each PTA claim will vary depending on a number of context-specific factors. PTA is not valid when the investigational treatment does not provide benefit over standard treatment. Furthermore, patients who advocate for early termination of a trial to obtain access need to be checked for compliance reasons.

Post-Trial Access Decision Tree

Conclusion

The Declaration of Helsinki provides a very high-level idea of what is needed for Post-Trial considerations. Although some revisions and new suggestions from regulatory authorities have been made, it remains challenging to understand how to develop a clinical development strategy while carefully taking into consideration the needs of patients when Clinical Trials end.

Despite this, companies have an important duty and moral obligation to help those who take part in drug development. Companies need to treat participants with respect by acknowledging the importance of their contribution to clinical research and promoting dignity throughout trials, especially when they end.

Companies should aim to develop policies that provide reassurance to Clinical Trial participants that the end of the Clinical Trial does not necessarily mean an end to treatment. Pharmaceutical companies need to embrace these developments by further increasing their understanding of how to plan for and execute their Post-Trial Access needs, and whether Expanded Access may offer strategic solutions.

Please contact us if you have additional questions