Post-trial access to treatment: How managed access programs could be a solution

Abstract

The rising cost of clinical development, coupled with the ethical obligation to ensure that patients exiting a clinical trial are able to remain on active treatment if necessary, has led some pharmaceutical and bio-pharmaceutical companies to review their trial protocols and consider alternative options. The traditional open-label extension or phase IV trial is appropriate in some instances, as is a post-trial supply program using the legislation available for unlicensed medicines in the many countries around the world. This article looks at some of the key considerations and how many companies are adopting different supply models.

Introduction

The Good Clinical Practice Guidelines ¹ describe the responsibilities and expectations of those involved in the conduct of clinical trials. However, these guidelines do not describe any responsibilities for continuing treatment after the trial. Other international ethical guidelines such as the Declaration of Helsinki ² do exist, which do include the right to post-trial access.

There is, however, a lack of firm guidance for post-trial access,^3,4 which is fuelling questions from patients and manufacturers regarding the treatment options for patients after clinical trials, particularly in rare diseases and oncology, where treatment is typically expensive and may be in short supply.

In many cases, it is clearly written into the trial protocol what the supply route will be following the closure of the trial. However, this may not always be the case, and this important component of trial protocol can often lack clarity.

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. (Article 34, Declaration of Helsinki 2013)

So what actually happens in practice and how are companies preparing for potential demand once a trial completes prior to the medicine becoming commercially available for the patient in their own country? This scenario needs to be carefully planned for—in the protocol ideally—regardless of the trial endpoint being positive or negative. For some investigators and patients, a treatment benefit for an individual patient may mean that they need to remain on the drug beyond the closure of the study.

Current practice

During the last 2–3 years, the author has seen a notable increase in the number of pharmaceutical and biotech companies exploring options for post-trial supply or managed access programs (MAPs). Interest in post-trial MAPs has increased, and the author has observed a shift in how companies manage their post-trial supply obligations. Herein is outlined how this area is evolving and the key considerations that need to be made by companies and physicians.

One option that is commonly pursued in order to provide an unlicensed investigational drug until marketing approval is to enroll patients that are benefiting from treatment into a study extension such as an open-label extension (OLE) study or long-term extension (LTE) study. The other alternative is a MAP, depending on the regulatory mechanisms available in each country and the need/desire to collect further data. For example, in the experience of the author, the Agence nationale de sécurité du médicament et des produits de santé (ANSM) in France have stated that the Temporary Authorisation for Use (ATU) route is not designed for post-trial access. Other country-specific regulations need to be investigated early on in discussions about a post-trial program, as the mechanism could be different to the more traditional named patient or group/cohort option for an unlicensed treatment. Many competent authorities, in developed countries at least, are reviewing their existing legislation for unlicensed supply which will often include specific mechanisms for post-trial supply, but this is not always the case. Regulations for unlicensed supply have recently been updated in Italy (Ministerial Decree 7th September 2017 (D.M. 07/09/2017)—entered into force on 2 December 2017 and replacing Ministerial Decree 8th May 2003 (D.M. 08/05/2003)—defines the therapeutic use of medicinal products undergoing clinical experimentation (compassionate use). Within this decree, it is expressly stated that ex-clinical patients can be included in the program, that is, those had previously benefited from a treatment in the framework of a concluded clinical trial.), and it is fair to say that regulations evolve continuously and the detail on this subject alone is beyond the scope of this article.

Challenges for companies

For many companies, post-trial access via a MAP will be a new area, where the legislation and regulations for supply differ significantly from those under which clinical trials operate. This lack of knowledge can create uncertainty within an organization where the primary concerns are obviously maintaining a smooth uninterrupted supply to the right patients and supporting the investigators through the process of accessing treatment via a different supply route. Companies will naturally be fiercely protective of their reputation and will not want to cause any unnecessary stress or inconvenience to the patient or investigator. Patients’ lives and well-being are the priorities, and it is incumbent on pharmaceutical companies to put patient need above other considerations. In many cases, the drug being used in clinical trials will be both of high cost and potentially in limited supply prior to commercial availability. Education and alignment internally are critical steps in the planning phase, as well as the broader considerations required in the supply chain. Companies will also need to consider long-term supply implications, particularly if marketing authorization will not be pursued in that particular country. Many companies have a policy for supply of unlicensed medicines that includes post-trial provision, and where available policy documents should be adhered to. It would be the recommendation of this author that companies without a current policy should consider developing one, as full transparency between the company, physician, and patient from the outset is of paramount importance to avoid any surprises at a later date.

Communication

Following on from challenges, clear and timely communication to sites and investigators regarding the provision and processes for post-trial supply are critical. If a MAP is being used to provide treatment after the study, the responsibilities of the investigator will change significantly versus the previous supply route via the clinical study. Depending on the regulatory and importation processes in each country, the investigator may have to seek approval from the competent authority for each individual request they submit. This part of the process is one of the reasons many companies seek to partner with a specialist vendor, who can guide and support the company and physician through this transition process.

Clinical trials versus MAPs

One of the fundamental differences between clinical trials and MAPs is their primary objective. Clinical trials are rightly the gold standard for proving safety and efficacy and should always be the priority route, if available, for a patient who could benefit. MAPs are for providing access to treatment primarily. While invaluable real-world data can be collected via a MAP, this would be supplemental to the validated data collected through a clinical trial. Clinical trials are also sponsor driven, and companies go to great lengths to ensure that investigators are supported throughout the duration of the study. MAPs are much more driven by the physician, where companies (or appointed specialist vendors) respond reactively to the physician’s request for access. Finally, while some monitoring is required during a MAP, this is generally minimal unlike the intensive monitoring necessary for a clinical trial. Appreciating these key differences between these two routes to access unlicensed medicine is crucial and links in with the above points on communication and alignment internally before proceeding with a post-trial access program.

Costs

Finally, it is always worth considering costs. While direct comparisons between OLE studies and MAPs vary considerably, depending on the scope and objectives of each, in this author’s experience MAPs are significantly less expensive. One recent example quoted to the author in non-small cell lung cancer was $3300/patient in a MAP versus $25,000 for a clinical study. While this example is at the extreme end of the scale, it is not uncommon for a MAP to be three to five times less expensive per patient than a comparable OLE study and it is often the number of sites that drives up the cost for OLE/LTE studies, particularly in decentralized treatments like in lung cancer.

Conclusion

Patient access to medicines across the lifecycle from Phase I testing through to discontinuation follows a typical pattern. The number of patients gaining access grows as the trial process moves forward and continues to increase following the first and subsequent launches. Actual patient demand for medicines that address unmet medical needs often exceeds the level of access that is typically delivered. This scenario is no more apparent than in the post-trial phase, where in larger pivotal studies patient numbers are ramping up along with awareness from physicians around the world. The need for companies to be prepared is key and should ideally be reflected clearly in the trial protocol where provisions for supply once a study closes should be clear to all stakeholders.