The Ideal Managed Access / Compassionate Use Legislation
Numerous voices in the recent past phrased concerns about the complexity of the legal framework for Compassionate Use / Managed Access in the EU1,2,3. While authorities are aware of the situation4, and initiatives are on the way, this appears not to be a priority. Instead, we as pharmaceutical industry feel the need for change and harmonization.
We see that some member states have a clear regulation; others have no regulation. At this point, patients across EU cannot consistently benefit from the idea of compassionate use. A clear regulatory landscape for Pharma Companies (acting as or sponsors) is missing to allow providing such products under a standardized legal framework. For details regarding the experienced pain, we particularly refer to our recent publication1.
We, the author group, are Qualified Persons, concerned with the release of managed access medication. Our point of view is driven by GMP legislation; thus, we feel a broad overlap with the interests of our medical colleagues:
We want to make unauthorized medicinal products available to patients that are suffering from life-threatening, long-lasting or seriously debilitating illnesses, which cannot be treated satisfactorily with any currently authorised medicine5.
Consider this paradigm be the basis for all conclusions drawn in this publication, even when not repeated.
Thus, we also want to make sure that we are compliant with legal requirements. Moreover, we want to achieve the best possible assurance for efficacy, safety, and quality of the unapproved products used in Managed Access Programs in line with their stage of development.
The solution is further harmonization of the fragmented regulatory landscape concerning Managed Access / Compassionate Use. In this paper, we want to propose the elements of an Ideal Managed Access Legislation from an Industry perspective. We want to combine the proven elements and best practices existing in the different member states into one new proposal.
In the end, we want to achieve a revision of the Compassionate Use regulation given in Regulation 726/2004, Article 836.
Encouraged by the recently completed harmonization on the legislation for Clinical Trials achieved with the applicability of the CTR7 as of 31-Jan-2022, we want to call on to our legislators now to take care also of Managed Access / Compassionate Use.
While we are primarily focussed on the EU, we suggest, that this could be of value also for PIC/S. We should note that all these concepts are already available in some members of PIC/S.
What should be regulated?
This publication will describe an industry view on what aspects of Managed Access should be regulated EU wide, defining
- Accepted Compassionate Use / Managed Access types;
- Interaction with authorities;
- Documentation that should be submitted to authorities;
- End of the program;
- Manufacturing and Quality standards;
- Some general Legal Framework aspects.
Managed Access Concepts
Regulation 726/2004, article 83, specifies the concept of compassionate use.
This is a good start, thus, there are other widely established concepts across EU member states that we suggest to legally define EU wide. The list of generally accepted Access types should be:
- Compassionate Use
- Post-Trial Access
- Named Patient Access
What are the differences?
Compassionate use describes a program for a group of patients, suffering from life-threatening, long-lasting or seriously debilitating illnesses, which cannot be treated satisfactorily with any currently authorised medicine. Pharma companies provide unapproved products under this concept. Typically, this requires approval of local Health authorities.
Post-Trial Access shall be a Compassionate Use Program building on existing and approved Clinical Trials. It should provide the option to transition study participants straight into a follow-up program that ensures that patients stay on life-saving treatments.
Currently we could supply trial medication past the end of trial if the protocol allows doing so. Thus, for multiple trials and countries, this comes with a regulatory and logistical complexity that creates highly artificial efforts. In addition, if the protocol does not foresee an open label extension that allows patients to stay on treatment, Post-Trial Access would solve the problem.
With the concept of Post-Trial Access, as an alternative to the program for a group of patients, regulators could provide additional support for the pharmaceutical industry. Finally, a patient's prospect of continued supply could speed up enrolment and thereby shorten development timelines.
Named Patient Access is an option to treat single patients. In contrast to a program, the responsibility is solely with the medical doctor, whereas the Pharma Company would 'only' supply medication based on a specific request of the physician.
The 'only' indicates the difficulties arising from this concept not being consistently allowed or officially regulated in all member states. We as QPs are facing particular difficulties when requested to release and confirm compliance for the use of a product batch in such context. What is supposed to be considered to certify medication for a Named Patient Access?
We would appreciate a harmonized regulatory framework in which release concepts are reflected to define the minimum requirements to clarify certification/confirmation requirements for the QP.
All three concepts should be defined in the Regulation (EC) 726/2004. Named Patient Access and Post-Trial Access should therefore be added as an amendment.
Health Authority Interaction
All Managed Access Scenarios should require a specific interaction with the pertinent Health Authority. Please see our proposal below:
Compassionate Use Program for a group of patients
- There should be a formalized submission by the Pharma Company (see below for submission requirements) to a Health Authority8.
- The program should be formally approved (or non-objection confirmed)
- There has already been an approval for the Clinical Trials - or several ongoing Clinical Trials - that are to be continued under such concept.
- Accordingly, the Health Authority interaction should be significantly easier than for a program for a group of patients.
- We imagine a simple request mechanism where we refer to the study outcome and confirm a positive Risk-Benefit Ratio.
- Accordingly, the approval mechanism should be simple as well - to allow patients to remain on treatment
- Since Clinical Trials are approved centrally, imagine the benefits of doing so for a Post-Trial Access Program. The first step must be to have Post-Trial Access be allowed in all member states as per EU law.
Named Patient Case
- The common concept of the Doctor's privilege allows the use of unauthorized products. Thus, there is a great variety in approaches in member states regarding the submission and approval for named patient access. We would expect a formalized notification by the Health Care Professional to a Health Authority or Ethics Committee. We do not expect a formal approval, thus, evidence of receipt or at least the submission are helpful. Looking at the variety of different processes at member state authorities at this point in time, we tend to leave it to the member state to decide, which authorities are appropriate. To start with, the concept should be permitted in all member states by regulation.
Submission Documentation Requirements
The different scope of the three proposed access types, should be adequately accompanied by submission packages in line with the number of patients exposed and the corresponding potential risks of administering an unapproved product to patients.
Compassionate Use Program
- For a Compassionate Use Program, the submission should contain comprehensive Chemistry, Manufacturing and Controls (CMC) data. This can be achieved with an IMPD-type document, or more easily with a cross-reference to a Clinical Trial in the EU or a cross-reference to a submitted MAA. It should also be possible to submit an IND or a CMC dossier from another MRA country.
- We propose the following documents, as evidence that these products fulfil basic Quality and GMP expectations, to be obligatory components of such a submission:
- Manufacturing and Import Authorization (MIA) /GMP certificate of the importer/manufacturer,
- QP declaration,
- Product Label9.
- Medical information: For an unapproved medicinal product, a clear focus should be on medical information: This should include e.g.
- Description of the medical condition,
- Assessment that no other treatment options exist,
- Risk-benefit assessment,
- Patient inclusion criteria,
- Treatment plan,
- IB/Draft SmPC,
- Informed consent,
- Qualification requirements for Health Care Professionals (HCPs).
- The concept of Post-Trial Access builds on existing Clinical Trials.
- The submission requirements should accordingly be limited to a cross-reference to the existing trials in exchange to other CMC and Medical information, with one exception:
- The core of this submission should be the justification to continue treatment via an updated risk-benefit assessment taking into account the new study results10.
- Note: Our expectation is that in a Post-Trial Access scenario, no substantial CMC changes occur in comparison to the trial that the application refers to.
- Named Patient Access
- Typically, submission requirements for a Named Patient Access are lower (if they exist at all).
- Still, the documentation should contain the following:
- Identification of the product(s): This sounds self-explanatory, thus, as these documents are typically not compiled by the Pharma Company, you would today be quite pleased if the product name, strength, and dosage form are provided correctly. An easy way to include a more precise product information, though indirect, would be by adding a crossreference letter to a clinical study.
- There should be a formalized requirement that Named Patient Access medication is manufactured according to GMP and released under a MIA, and that systems need to be in place that assure the Quality of the unapproved product. However, we do not expect the submission package to include a MIA or a QP declaration.
- Medical information of such a submission should include:
- Justification of Treatment,
- Treatment plan,
- A Statement that the HCP is solely responsible for the treatment of this patient.
For different reasons, it can take a significant amount of time between when a patient is identified to be eligible for a Managed Access until he actually gets treated. An important factor are authority approval timelines. We recently observed that official approval timelines within EU member states vary between 1 and 60 days with upwards excursions1.
Such period should be harmonized and limited to account for the high medical need. Accordingly, we propose the following approval periods
- Compassionate Use Program for a group of patients: maximum 30 days
- Post-Trial Access: maximum 30 days
- Named Patient Access: No approval should be required
As stated above, and as a visionary outlook, we are drawing a mental picture where the landscape for Managed Access Legislation is completely harmonized within the EU and we apply centrally through an electronic portal.
Amendments to CMC Documentation
Information that we submitted might need to be amended whenever there are substantial changes. This applies to Compassionate Use as well and should be stated by our envisioned new legislation. The existing guidance for Clinical Trials could be referred to.
End of Program
Commercial availability marks an endpoint as per Regulation 726/2004.
Interestingly, this requirement was translated into national legislation in different ways, so that the endpoint condition could either be the
• Marketing Authorization Approval,
• Commercial Availability,
Commercial Availability might differ significantly between member states.
Note: commercial availability refers to a specific member state.
Availability in one member state should have no impact on the continuation of Managed Access in another country.
For some countries, reimbursement arrangements take years to be in place. Only with reimbursement, medication can be assumed not only as "commercially available", but also "practically available" to patients.
We do by no means intend to question the member states sovereignty on Pricing and Market Access. Thus, the logical conclusion would be to generally allow the continuation of all three Managed Access concepts until Reimbursement is achieved. Note: Several member states allow to do Compassionate Use Programs in an unapproved indication, in other countries it is specifically forbidden. We tend to leave it to the law makers discretion how to decide here, but we expect a harmonized approach within the EU.
Period of validity of an approval
Many national Managed Access concepts limit the approvals to a certain period of time or a certain amount of drug product. We understand that authorities have an interest to limit the duration due to the implications of using an unapproved product. On the other hand, it is in the self-interest of the Pharma Company to finish Managed Access and to achieve Marketing Authorization approval as quickly as possible11.
A compromise would be, to limit the validity to one year, and establish a simplified - e.g., one page - reapplication process.
Another interesting question: What happens, if we do not reach a reimbursement agreement in a certain country? Logically, it should be allowed to continue treatment under Compassionate Use.
The Free-of-charge paradigm
Compassionate Use Medication should be free of charge from a moral and ethical standpoint and in the sense of the meaning "compassionate".
In particular, Compassionate Use medication should be free of charge prior to Marketing Authorization Approval.
Some member states extend the concept of Compassionate use after Marketing Authorization approval and commercialization.
Other countries instead, explicitly prohibit the dispensing of commercial medicinal products free of charge.
In contrast to the above, in several member states, specific reimbursement options for compassionate use exist that are independent of a general reimbursement agreement after commercialization. This facilitates access to medication for patients in urgent need, and member states may certainly do so.
There should be a general agreement across industry that the concept of Compassionate Use is not meant to create additional revenue streams. On the other hand, there might be situations where a company might find it financially unreasonable or difficult, e.g., for a start-up company, to perform a compassionate use program.
It might be difficult to find a compromise here. Our proposal is:
Compassionate Use Medication should by default be free of charge and remain so until reimbursement agreements are reached. If additional reimbursement concepts exist for compassionate use on a national level, they benefit patients and industry and should be used.
Development product may be supplied under a compassionate use label until commercial product is available. Commercial products may be used in their national make-up. If they are given away freeof charge, we propose an additional label "For Compassionate Use only!".
A new Compassionate Use legislation should also include harmonized labelling requirements for Compassionate Use, Named Patient Access, and Post-Trial Access. The important elements are:
- Basic requirements, similar to CTR Annex VI, should be defined;
- English is the preferential language to be used in a hospital setting;
- For home administration, booklets should be the labelling of choice. They should contain languages rather than countries, as there is no predefined country list.
Local special regulations, e.g., adding a program code that is communicated via the program approval to the pharma company, should be avoided by all means. Such a requirement means that the labelling will not start until after program approval. Such regulations illustrate a complete disregard for industry supply logistics. We do certainly not assume the intent to delay or prevent treatment, thus, such a requirement might mean preventing treatment in many situations where compassionate use is typically applied. This again illustrates the urgent need for revising and harmonizing the Compassionate Use regulatory landscape.
As QPs, it is our job to assure product quality and GMP compliance for the products that go into Managed Access programs. However, we believe that this should be a prerequisite for every legally defined Access mechanism. Accordingly, we believe that the manufacture and import of Managed Access medication should occur under a MIA covering Managed Access / Compassionate Use and the requirement for certification by a QP should be stated in the law.
There needs to be a Quality System in place to assure compliance, e.g.:
- The respective Managed Access Mechanism must be approved;
- Each batch must be certified by a QP for this certain access mechanism;
- Products have to match the information submitted to and approved by the authorities;
- In addition to QP release, there must be a second release step to assign the released stock to a certain patient.
Distribution and Import
To enable fast access to medication, distribution of medication under an approved Managed Access concept should not require additional licenses for involved wholesalers, pharmacies, or HCPs. The new legislation should make provisions to allow distribution directly to HCPs when they are not associated with hospital pharmacies. Import should happen under a MIA and involve QP Release.
In some countries (e.g., Bulgaria, Ireland, Iceland, and Latvia1,12) compassionate use is based on importation via a wholesaler and we acknowledge the conflicting requirements and interests:
The authors see the existence of a MIA and QP release as the basis to assure compliance to GMP and the necessary quality of a medicinal product. Some legislations put this obligation on the wholesaler who has to e.g., retrieve a certificate of release (Bulgaria12).
Of course, a wholesale license is needed in addition to a MIA to allow distribution of medicinal products.
Requiring both, a MIA for the import and a wholesale license for the distribution, might be the possible compromise between the different approaches. This discussion also shows how difficult it may be to navigate between the pitfalls of our current Compassionate Use legislation.
Pharmacovigilance and Complaints
There must be systems in place to report and monitoring complaints and safety signals.
Compassionate use programs are published by the competent authorities and any form of advertisement should not be allowed. The concept of the "unsolicited request" from Health Care Providers should remain.
In cases where an MAA was not granted this should not imply that Compassionate Use programs are to be stopped. Accordingly, if a company decides to withdraw an MAA due to not reaching a reimbursement agreement, we suggest that a continuation of Compassionate Use Programs should be allowed.
Concepts out of scope
We want to make three known concepts of Managed Access to be included under the Compassionate Use umbrella and legally defined for the EU as a whole: The Program for a group of patients, Post-Trial Access, And Named Patient Access.
We do not want to touch other existing Managed Access concepts that in some member states might be closely related to Compassionate Use. These concepts may remain legally defined in national legislation; thus, we did not want to propose them to be included in the EU's harmonized Compassionate Use framework. Such concepts are therefor out of scope of this publication, e.g.:
- Off-label use - prescribing a product to a patient in an unapproved indication is in general legally possible in all member states. Thus, we do not see it as Managed Access. Testing a medicinal product in a new indication should be done in clinical trials.
- Import of a product approved in another country by a public pharmacy based on a prescription. This is possible in many countries. In some countries, this is labelled Compassionate Use. The authors appreciate the value of the concept: It allows single patients access to medication that is already approved in another country, often the US, while the product is not yet approved in the EU. Thus, we do not see it as a desirable concept to organize compassionate use.
- Managed Access Concepts that involve Compounding or Pharmacy operations, are considered out of scope as well. o Reimbursement and Market Access arrangements.
This publication defines the cornerstones of what the author group considers the ideal of a future harmonized EU legislation. We do not have answers to all questions thus, we know that this already would be a big step forward. Accordingly, we want to herewith request EU legislators to initiate the revision of the current legislation defined in regulation 726/2004, Article 83.
And we want to make it clear that we believe that this call for harmonization is urgent!
About the Authors
The ECA IMP Group Task Force Compassionate Use:
Andreas Schwinn, Birgit Becker, Constantinos Kousoulos, Kerstin Thaele, Karoliina Nurminen, Lucia Dalvit, Pam Turner, Eveline Reininger, Scott Smith, Renate Steurer, Sara Taglialatela, Tine Wentzel Bekker
1 GMP Journal 22.11.2021: https://www.gmp-journal.com/current-articles/details/compassionate-use-and-other-managed-access-concepts.html
2 JAMA Health Forum 15.04.2022: https://jamanetwork.com/journals/jama-health-forum/fullarticle/2791197
3 Regulatory Rapporteur, Sep 2020 (members only): https://www.topra.org/TOPRA/TOPRA_Member/REGRAP/Public/Regulatory_Rapporteur_Issue_Detail_Public.aspx?IssueID=533884&ID=57221
4 HMA – Timely Access Group, 01/2020:
5 As per the purpose of Compassionate use defined by the EMA under
6 REGULATION (EC) No 726/2004 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.
7 REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC.
8 We do not want to be too bold and request a centralized submission and approval within the EU, knowing that it took twenty years to achieve this for Clinical Trials from Clinical Trial Directive 2001/20/EC to CTR 536/2014 becoming applicable on 31_Jan-2022.
9 If the proposed new legislation would provide an EU wide definition of such label text, the requirement of this to be filed could be reconsidered. National peculiarities, like adding the program number from that is provided with the approval must be eliminated. CTR, Annex VI requirements are a good start, thus, do not fully match. It would also be beneficial, if a general acceptance would exist, that an English label text is sufficient for a hospital setting.
10 As a vision, we imagine Post-Trial Access being an amendment to the respective Clinical Trials – thus, for the moment we settle for it being a legitimate EU wide concept.
11 Please be aware that there are also access concepts in EU member states where products are used for years without the potential MA holder even aiming for approval. We want to note, that we do not consider this as Compassionate Use and outside the scope of this publication.
12 Regulatory Requirements for Managed Access in Europe, collected by the Managed Access Taskforce of the EQPA, https://www.qp-association.eu/download_imp%2FCompassionate-Use-Landscape-Jan2021.xlsx