Opinion Article | Open Access | Published 9th December 2021
Compassionate Use and other Managed Access concepts – Requirement Landscape across Europe from a QP's Perspective
Andreas Schwinn, Constantinos Kousoulos, Birgit Becker, Kerstin Thaele, Eveline Reininger, Karen Joosen, Karoliina Nurminen, Loretta Dougan, Louise Grundberg, Lucia Dalvit, Maria Krook, Pam Turner, Peter Mayne, Raffaele Misul, Renate Steurer, Sara Taglialatela, Scott Smith, Srikanth Sunkari, Tine Wentzel Bekker | Cite this article | Download this PDF Paper
Compassionate Use and related Managed Access concepts, to the authors of this publication, are the embodiment of patient centricity. This is where your release decision as a QP can be directly related to a specific patient's fate. You might be presented with a real patient's medical records (certainly anonymized) describing not only a disease, but, a tragic life story. Your release decision as a QP can make the difference to this patient.
As per Regulation 726/2004, Article 83 , Compassionate Use means to make unapproved medicinal products available to a group of patients that are suffering from a life-threatening, chronically or seriously debilitating disease, that otherwise cannot be adequately treated. The product shall be subject to an MAA or in Clinical Trials.
The legal basis for Compassionate Use is an EC regulation, and accordingly, the expectation should be that this is directly legally applicable in each member state. Surprisingly, beyond the legal basis in 726/2004, the regulations in each member state have little in common.
Actually, those national legal requirements show an immense variety and contradicting qualities. It is also not particularly helpful, that many of them are available only in the local language. This makes the Compassionate Use regulatory landscape quite difficult to work with. This is particularly difficult for Qualified Persons, per Annex 16 dedicated to "certifying … compliance with the … requirements of the … destination country" and, by definition, personally liable for such compliance. The intent is to follow those requirements when releasing Compassionate Use medication to European patients, patients who have the highest possible need to receive such medication, although the requirements to release against are far from transparent. There is definitely no guidance document out there, few helpful publications and not many subject matter experts.
In this situation, the IMP Working Group of the EQPA decided to sponsor a task force, to prepare a summary document of QP release requirements for Compassionate Use medication. This group of 15-20 QPs from several European companies with some noteworthy effort compiled such release requirements. A summary of those efforts was presented during the QP Forum on 25-Nov-2020, and the first Version of the QP Release Requirement Summary was published in Feb 2021 on the EQPA webpageⁱⁱⁱ.
One of the first observations of the taskforce was the numerous names of concepts that are similar, but not identical to Compassionate Use as defined above. To account for the differences in definitions, the task force decided to use the term "Managed Access" as a generic bracket to address all such concepts and use Compassionate Use when addressing a program for a group of patients.
A summary of the rather complex nomenclature is provided in Table 1: Nomenclature of Compassionate Use / Managed Access concepts.
The first two names in Table 1, Compassionate Use and Named Patient Use, define two generic concepts. Compassionate Use is for a group of patients defined by a life-threatening type of disease, thus those patients are not pre-defined at the time, when such a Compassionate Use Program is initiated. Compassionate Use Programs are typically applied for by the Pharma Company.
In contrast to that, Named Patient Use is indeed for specific patients, whose anonymized details (Initials, sex, date of birth) are part of the documents submitted to authorities upon application. The treating physician will typically do the application (if one is required).
Table 1: Nomenclature of Compassionate Use / Managed Access concepts
The requirement summary as of today compiles 40 Managed Access concepts from 28 EU/EEA countries plus the UK. This list is meant as a living document with more concepts to be added in the future.
The execution of the different Managed Access programs requires an existing regulatory compliance and quality management system, which ensures that the other obligations besides the QP-responsibilities are fulfilled. These obligations are outside the scope of a QP. Nevertheless, a QP cannot certify the medicinal products for use, if the other prerequisites are not fulfilled.
Given the very specific and different legal / regulatory approaches on a country level, it is very important that other departments address their responsibilities as diligently as the QP, since the QP must rely on a systematic approach for compliance with all requirements.
It is recommended to perform regular self-inspection of this specific part of the regulatory compliance and quality management system.
The framework of this supply of medication is very different from other supply options (marketed products, Investigational medicinal products). Therefore, without additional special measures, there is a serious risk that compliance issues may occur.
Changes in the legal and regulatory environment, which are likely to happen on a country specific rather than a pan-European basis, have also to be monitored and implemented within the Quality Management System as appropriate. This will necessitate close cooperation with country affiliates or other experts.
The following questions need to be addressed by the regulatory compliance / quality management system:
the decision of a Pharma Company to conduct such a program (if applicable),
that a medical professional decided to treat a certain patient under his responsibility and addressed a formal request to the pharma company,
the decision of the Pharma Company to support treatment of such a patient
that a medical condition is life-threatening, seriously debilitating or chronic,
that such condition cannot be treated with an authorized product or in a clinical trial,
that there is a positive risk-benefit ratio for the treatment of a certain patient,
that such treatment is covered in a contract between the respective medical professional and the pharma company,
that patients undergo an Informed Consent procedure that is adequate for a non-approved product,
that such treatment is covered by some kind of protocol (as applicable for the specific setting),
that the treatment of each patient is in line with the respective submissions and/or approvals, where applicable,
that the chosen mode of access is in line with other regulatory requirements, e.g. concerning the distribution pathway, or to provide medication free of charge ,
that a risk management and pharmacovigilance system is in place and adequate for such treatment options,
that any reporting requirements (e.g. safety information, changes to submitted information, termination of program) are fulfilled as required by regulations,
that applicable data protection regulations are observed.
A two-step release process (following the concept in the IMP-release process) can be a potential way to safeguard, that all requirements are met, before the medication is send out for use:
Certification of the medicinal product by the QP
Confirmation that all other requirements for the specific Managed Access programs are fulfilled (e.g. – Filing, Submit to HA, Ethics committee, verify approvals).
This step is similar to the “sponsor release” for IMPs but takes into account the specific requirements of the Managed Access regulation in the applicable country(s).
A checklist approach depending on the Managed Access type might be of help, to facilitate the execution of this step.
To make you familiar with the regulatory framework for Managed Access we will ask – and answer - questions, that we found useful to characterize the different concepts. Graphical Representations are based on the above-mentioned Requirement Summary on the EQPA homepage3. When we refer to countries, we mean EU, EEA, and UK.
Do you need a specific MIA to release Managed Access Medication?
In most countries the manufacturing authorization granted for IMPs covers manufacturing and release activities for medicinal products provided as Managed Access. There is no special authorization required to apply for.
However, special requirements are defined in some countries:
Latvia’s regulation (§94.2 of Cabinet Regulation No. 416) defines a special license to apply for.
In Denmark Managed Access must be stated in the MIA for Human Medicinal Products instead of the MIA for Human Investigational Medicinal Products.
In the UK, the Manufacturer's "Specials" license is required for manufacturing/release of unlicensed medicinal products for Named Patient Use. For the Early Access to Medicines program we are aware of “Specials” or IMP license being agreed by MHRA and, given the status of these programs, we would expect a full commercial license also to be accepted.
Whereas in Ireland and Iceland import is conducted based on a wholesaler distribution license instead of a MIA.
Furthermore, local Health Authorities may have their own interpretation of the national regulation, e.g. expectation of German local district governments differ, some expect formal notification about extending IMP release activities to Managed Access release activities and others formalize the extended scope in the clarification section of the IMP manufacturing/import authorization.
Is QP release required?
Article 5 of Directive 2001/83/EC excludes individual patient supplies from the provisions of the Directive and Article 83 of Regulation 726/2004 also excludes compassionate supply from commercial supply provisions of the Directive. Furthermore, both the Regulation and Directive give individual Member States the responsibility for regulating these supplies, something that they do inconsistently, as described elsewhere in this paper. There is no European-wide harmonized requirement for QP release of these products. And, because not all countries require CMC data to be filed, a “standard” Certification requiring a check against the requirements of the marketing authorization or clinical trial application is not actually possible.
However, the survey found that most Member States either require, or are understood to require, QP release of product provided for Managed Access. Surprisingly there are no countries that gave different responses for different types of supply (individual patient or compassionate use program) although this may reflect company practice and the lack of well-defined regulation.
The following exceptions have been identified:
Irish regulation states that if the product has an EU authorization, it can be imported by a wholesaler.
Polish legislation defines that if the product has an EU authorization, no “further” QP certification is required.
Greece’s ministerial decision does not explicitly require QP release, but this is inferred from the fact that an IMP manufacturing authorization is required for this category of medicinal products.
In UK there is no certification by a QP required for individual patient treatments (under the “Specials” license, since QPs are not named on such licenses). However, MHRA Guidance Note 14 states that QP release is required prior to export outside the EU/EEA . Under the fairly recently introduced “Early Access to Medicines Scheme”, a dossier at least as detailed as an IMPD is required and it is possible to negotiate that release will be under a “Specials” license (i.e. without QP), although MHRA have requested a QP Declaration to cover the active substance!
In general, where Member States permit supply under a continuation of a clinical trial, QP certification will of course be required.
Submission and Approval
Is there a submission or approval required?
For most Managed Access Concepts, there is some kind of interaction with an authority, and some kind of submission or approval is required.
According to our recently published requirement summary³ the following types of interaction occur:
The vast majority - 75% - of those concepts require an explicit approval. Thus, there are other concepts, where a notification is sufficient, or a receipt confirmation is provided.
And, there are cases, where there is no interaction with any authority at all.
Which Authorities approve Managed Access Programs?
(Note: Bar chart is used since more than one response is possible).
In most cases (93%), the approval is issued by a national Health Authority. In about 20%, an Ethics Committee needs to be involved.
Who applies for a Managed Access Program?
In the majority of cases, the Pharma Company will submit an application to the authorities. This is typical for Compassionate Use programs. For Named Patient Use, it is often the Medical Practitioner who performs the application and is ultimately responsible for the treatment.
What is actually approved?
While the majority of Managed Access concepts are programs, typically for a group of patients, there are a similar number of concepts, where the approval refers to a single patient (Named Patient Use).
Approvals might include further restrictions: Quite often an approval refers to a single hospital or to one health care professional.
In cases where approvals refer to one import or a specific amount of product, quite often the term "import license" is used. It needs to be noted, that in this case and in contrast to the idea of free movement of goods, import includes transfers between EU member states. Such import license may refer to a single shipment.
What are the review timelines for a Managed Access Submission?
Not surprisingly, the reported review timelines show the same variation as everything else in this area. The distribution of stated review timelines was:
Excluding the responses "undefined", "N/A – no submission required", "may take longer than defined" or "may be much quicker if urgent", the distribution of the noted review timelines stretches from 1 day to 60 days with a Median of 30 days.
Several authorities set short official review timelines commensurate with treating patients with life-threatening or seriously debilitating disease that cannot be adequately treated otherwise.
There are however other authorities, where the official review period is rather long considering the circumstances.
Are CMC data to be filed?
Approximately 40% of the responses stated that there is no submission or no CMC data filed. In most of the other cases, the CMC data may be submitted in several different ways, by an IMPD or by cross reference to a clinical study or MAA (the latter of course may not yet be submitted at the time the Managed Access submission is made). Although some information on which specific sections are required is provided in the Response Comments, a detailed list of the individual requirements was beyond the scope of this survey. We advise that your colleagues responsible for submissions should seek local expertise, either from local Regulatory Affairs or from the published Health Authority guidance where available. Since local Regulatory Affairs may not be specialists in these programs and Health Authority guidance often does not give very much detail, you may have to contact the Authority directly for advice, although that may also vary depending on who in the Authority answers your question! The message here being that Authority staff may be as unsure of the exact requirements as we are, although they do share with us the common goal of getting quality innovative medicines to seriously ill patients as rapidly as safely possible.
Analysing the data from the survey in more detail shows that the Named Patient Use options are less likely to require submission of CMC data than the wider Compassionate Use programs. This is not surprising, given that the former place an extremely high emphasis on the responsibility of the individual prescriber.
What medical aspects are important for QP release?
The following chart summarises the responses to the question in the survey regarding the medical aspects considered important for QP release.
Similarly to the situation with IMPs and as described in the section above on Quality Framework, a two-step release process can be envisaged for Managed Access supplies, comprising the QP release activities, primarily focused on GMP and CMC compliance if applicable, and the sponsor activities, such as submissions to Health Authorities and Ethics Committees and approvals (if required). The medical aspects are generally covered by these sponsor activities and as such 22/40 respondents either answered “None” to this question or stated that “other quality systems” ensured that these requirements are met. Another 6 responses indicated that other Quality Systems cover most of the requirements. The most common medical aspects for QP consideration were “Medical approval of program or patient available” and/or that there is an unsolicited request from a healthcare professional, and these requirements may well be linked, with a company medical team only approving requests following receipt of an unsolicited request.
Note that the legal basis for Compassionate Use programs (Article 83 of Regulation 726/2004) does not require unsolicited requests, although regulations regarding the promotion of such programs will vary between countries. This is generally considered to be outside the scope of the QP, but not of the wider company quality/compliance system. This is in contrast to the legal basis for “Named Patient” access (Article 5(1) of Directive 2001/83/EC) which states:
“A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorised health-care professional and for use by an individual patient under his direct personal responsibility.”
“Special needs” in this context would appear to encompass the “patients with a chronically or seriously debilitating disease, or a life threatening disease, and who cannot be treated satisfactorily by an authorised medicinal product” from Article 83 of Regulation 726/2004 but would go wider to include customized formulations as covered by UK Specials Manufacturers (which can be considered as the equivalent of US Compounding Pharmacies). Therefore, if manufacturers require unsolicited requests for Compassionate Use supply this may be a reflection of the general confusion of the terminology and lack of harmonised regulation in this area.
As covered elsewhere in this paper, there are variations in what QPs assess to be appropriate for them to verify (or delegate to other quality colleagues). This is summed up admirably by a response from Germany stating (for the Named Patient Use “Individueller Heilversuch”) “there is a tendency for QPs to check more than for a Compassionate Use program. C