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. Company procedures and QP delegation principles vary. Medical aspects are primarily verified under other QA”.
Although a number of respondents have indicated that “Medical condition is serious, life -threatening, no other treatment options exist” and “Positive risk-benefit ratio” and these are important aspects almost universally, it is not obvious how the QP is in a position to assess these, rather than to rely on other parts of the company’s quality systems. Clearly any health authority reviewing these programs or approving Individual Patient Use, will consider these aspects. We can speculate that responses from smaller organisations would tend to focus on wider QP review rather than reliance on other systems, but there are not enough data to draw conclusions. Indeed, the differences may just reflect different interpretations of the question posed.
What defines the end of the program?
The concept of Managed Access includes the prerequisite that there are no other suitable treatment options. Obviously, this condition is no longer met when the product becomes available commercially. Thus, the expectation should be that such Managed Access should end upon commercial availability.
In reality, the situation is much more complicated:
At first, we need to define what we mean by “end of the program”:
The first endpoint is defined by the point in time, when to stop inclusion of new patients.
From a QP's point of view, you should focus on the second endpoint, that is when to stop treatment of existing patients.
Why is that? In an IMP world, it is quite unheard of, that a QP would spend very much thought on the end of a Clinical Trial – apart from archiving considerations. In the IMP world, the end of the trial is a typical filing requirementᵛⁱ and the same point in time for all participating countries.
For Managed Access, the stop-treatment-condition varies between countries and programs:
Often these approvals end after a certain period of time or it could end with the day of Marketing Authorization or with Commercial Availability or with Reimbursement, or there might be no requirement at all ever to stop treatment.
With a centralized Marketing Authorization, the approval date will be the same for all EU countries.
However, commercial availability will vary between countries based on your launch strategy and availability of product in the respective country.
Reimbursement though, may be given in some countries from the day of Marketing Authorization or in other countries may occur several years later.
Finally, there are countries that did not define a legal endpoint of their Managed Access concept where, if other considerations would not prohibit that, this Managed Access could go on forever.
This will lead to the situation where you as the certifying QP may receive a batch of Managed Access medication, e.g. 6 months after EMA approval of the respective commercial product.
This batch will not be certifiable for certain countries, where the approval of the respective Managed Access concept has expired.
To find out for which countries you can still release, please refer to our Requirement Summary on the EQPA homepage3.
A graphical representation of the conditions when to stop treatment of existing patients is provided in the following graph:
In most cases, commercial availability will define when releases of Managed Access Medication should no longer occur.
The release, based on verification of the validity of the regulatory approval – the Regulatory Release or Sponsor Releaseᵛⁱⁱⁱ - can be with functions other than the QP. At this point we would not want to go down the rabbit hole of discussing if the Regulatory Release should or should not be with the QP.
In any case, there need to be systems in place, where this requirement to stop treatment of patients upon the discussed prerequisites is taken care of.
This discussion also points out the need to define the Assignment of Responsibilities between the involved parties, e.g. Medical, Regulatory, and the QP, in an agreement (similar to the Manufacturer-Sponsor-Agreement) or in internal company procedures.
What are the labeling requirements?
Labelling of medicines must comply with requirements of directive 2001/83/EC articles 54-69 however this regulatory requirement does not extend to unlicensed medicines.
For 45% of Managed Access concepts in our requirement summary3 particular labelling requirements exist. While specific labelling requirements typically stipulate having the label in the local language(s), 50% of the described Managed Access concepts allow labels in English. For 4 out of 20 concepts, English is the native language. Requirements for local language labelling may be waived if the product is only used in a hospital setting.
Examples for labelling requirements are:
Belgium refers to Annex 13 as labelling reference with the particular notice “Compassionate use – cannot be sold”ⁱˣ.
France requires particular labelling for Cohort ATU. Interesting is the requirement to specify “Conditions for prescription and supply”ˣ, meaning e.g. the statement that the medication is used under an ATU and under the supervision of a qualified Medical Practitioner. The label shall even specify the ATU number provided in the approval letter (which then renders labelling and QP release a critical path activity).
The German regulation on Compassionate Use Programs (Arzneimittel-Härtefall-Verordnungˣⁱ, AMHV) proposes labelling that is very similar to IMPs, thus, with a specific “For Compassionate Use Only” statementˣⁱⁱ. Interesting is the request to label the expiration date on the primary container – years prior to Annex VI of the Clinical Trial Regulationˣⁱⁱⁱ.
Romanian legislation allows for labels to be in either local language, English, or French.
UK Specials program guidance is found in the British Pharmacopeia. (Guidance ref 14 British Pharmacopeia Volume III-Formulated Preparations: General Monographs Unlicensed Medicines. British Pharmacopeia Volume V – Supplementary Chapters – SC V Unlicensed Medicines.
For a comprehensive summary, please refer to our requirement summary3. It should be obvious, that labelling requires knowledge and application of local requirements.
Does release of CU medication allow more room for risk based judgement?
Heterogeneous regulatory landscapes in each individual country define more or less clearly the concepts for providing unlicensed/non-marketed medicinal product for Managed Access.
In a few countries, you can see more room for risk based judgment compared to a clinical trial setting. Some countries only require notifications instead of submitting CMC documentation or reference to CTA/MAA-application. This is often different within the same country, depending on if it is a Compassionate Use Program or Named Patient Use (for details, see our requirement summary³). Others might apply for a program similar to a clinical trial including protocols, CMC documentation etc. Some countries do not require product labelling in local language and accept English labelled medicinal products. Overall, there appears to be more room for risk-based judgement, thus, you should understand the rules to know how to balance the risks.
Named Patient Use is possible in only a subset of countries. In some it is explicitly foreseen in the legislation. In some other countries this concept is tolerated, although it is not defined by law.
The following diagram shows the relation of "Named Patient Use" vs. "Compassionate Use Program" concepts as per the Requirement Summary³.
It needs to be noted, that programs for a group of patients typically require submission and approval. This means, with the "No Submission" portion added to the "Named Patient" portion, that Named Patient Use is actually the majority.
Countries where we know that Named Patient Use is possible are the following: Austria, Belgium, Bulgaria, Denmark, France, Germany (see below), Greece, Hungary, Iceland, Ireland, Italy, Lithuania, Luxembourg, Netherlands, Poland, Portugal, Romania, Slovakia, Spain, Sweden, and the UK.
The German Named Patient approach shows peculiarities that are important to be pointed out:
German legislation only covers Compassionate Use Programs for groups of patients8, called "Härtefall" (hardship case).
However, in cases of a compelling medical need, the Named Patient Use or "Individueller Heilversuch" (Individual Healing Experiment) can be considered also in Germany, if certain prerequisites are met.
The legal justification of the Individual Healing Experiment is interesting. It uses a concept from Criminal Law, called "Rechtfertigender Notstand" (Justifying Emergency or Necessity as Justification) as per the German Criminal Code §34 (Strafgesetzbuch, StGB)ˣⁱᵛ.
By default, it is unlawful to release a product that is not approved in a Marketing Authorization, Clinical Trial, or Compassionate Use Program - as a QP who is personally liable for such action, this should raise the bar high.
Thus, §34 StGB14 – simplified – states that it may not be deemed unlawful to commit an act to prevent a present danger to life.
The acceptance of such approach varies between the competent authorities – Note: the GMP and GCP Inspectorates in Germany are organized federally.
Therefore, it is highly recommended to be transparent and communicate your Individual Healing Experiment to all authorities involved. The minority will acknowledge such a request in writing. Ideally, you will receive a written response stating that the Individual Healing Experiment will be tolerated.
It is strongly recommended, for the QP to compile evidence of certain medical aspects, e.g. the rationale to treat this patient and the contract with the health care professional to document his decision rationale.
You can do this in an emergency. Thus, if possible, you should go for a Compassionate Use Program. If you have two patients (some inspectorates say three patients), a program is the only choice.
Is Managed Access possible with marketed product?
Compassionate Use shall make unapproved medication accessible to patients and bridge the time until commercial availability. Accordingly, you might expect that there are no Managed Access types with commercial medication. This is however not the case.
Commercial product in other indication
While in some countries it is forbidden to supply an approved product for compassionate use (e.g. Germany), in others countries it is explicitly allowed, when these drugs are approved for other indications (e.g. BE, CZ, IE, IT, PL, PT, UK). This is actually “off-label use”, thus, interestingly off-label use is here a subset of the Compassionate Use regulations.
As an example, in Italy, free access to a drug therapy is allowed before the Italian Medicines Agency (“AIFA”) authorizes its marketing or, for already authorized drugs, for indications other than those for which the medicine has been authorized in Italy (this procedure in Italy is called off-label use).
Commercial product prior to re-imbursement
Several countries have extended the concept of commercial availability of a drug product from being available for sale to being affordable for an average patient. This comes with re-imbursement and may be significantly later than commercial availability.
For example, the Italian regulation (D.M. 07.09.2017 - „Disciplina dell’uso terapeutico di medicinale sottoposto a sperimentazione clinica”, also states that Compassionate Use is possible for "Medicinal product authorized but not yet available", meaning a drug not marketed, despite the authorization, with reimbursement classification at least in class C (i.e. drugs whose cost cannot be reimbursed by the National Health System and is therefore fully borne by the citizens). In exceptional cases, this definition can be extended to medicines for which the reimbursement scheme and classification have also been defined, but which for unforeseen reasons cannot be available to patients for a defined period of time.
In these cases, prior communication with the Regulatory Agency is required. This definition applies to any medicine, regardless of the authorization procedure (Centralized / Decentralized / Mutual Recognition).
Product that is unapproved, but, commercially available in another country
Several EU member states allow that medication with a marketing authorization in another Member State (or a 3rd country) can be imported by a public pharmacy or a wholesaler based on a prescription of an authorized medical professional.
In some member states, this concept falls in the Compassionate Use category:
For example in Ireland: A Pharma company may decide to import their EU-unapproved development product, recently approved in the USA, into Ireland via its local affiliate and to provide it free of charge to the prescribing physician according to his request to treat a specific patient. There is only a notification to the HA required, post-import.
However, in other countries this is something completely different.
For example in Germany: Medical doctors can prescribe medication that is unapproved, but, approved in another country to a patient. A pharmacy can import this product based on said prescription and sell it for administration to a patient. Thus, this is not Compassionate Use.
The process described for Ireland would be against German law. The import must occur through a pharmacy (See AMG §47 Special distribution channels and §73 Prohibition of Introduction). The transaction must not be free charge (AMG §47).
This is a typical example how transferring a legally defined Managed Access concept from one member state to another can bring you into non-compliance and trouble.
Managed Access with a commercial product – will it be free of charge?
The default assumption is for Compassionate Use Medication to be provided free of charge – in the true sense of “compassionate”. For some concepts, the application includes a formal commitment to provide the medication at no cost to the patient until reimbursement, in single cases even past a possible re-imbursement.
Thus, there are exceptions: E.g., products that are commercially available in another country may not be given away for free, also re-imbursement arrangements exist.
In Denmark, even development products in a Compassionate Use setting must not be given to a patient at no cost. A minimal, purely symbolic price may be assigned.
Since the topic of pricing is typically not the primary interest of a QP, we have not gone into detail here.
Trial Continuation / Post-Trial Access
It is quite common to specify in a Clinical Protocol that patients benefitting from a treatment may remain on this treatment post the end of a Clinical Trial. This specifically refers to trials with an Open Label Extension. This allows a QP to continue releasing the respective study medication.
In addition to that, there are specific Managed Access concepts in some countries that allow continuing the treatment of patients after the end of a Clinical Trial under such a Managed Access: In the UK this is called “Trial Continuation”. Our requirement summary3 lists Poland and Portugal as countries with comparable concepts. Thus, we know that within the authoring community “Trial Continuation”-like concepts are also run in CZ, ES, ET, FR, IT, NO (no claim to be complete).
It is difficult to draw a line here, since even if a country’s legislation does not foresee the concept of Trial Continuation, patients coming off a Clinical Trial may still enter a Compassionate Use Program. This is e.g. the case in Germany: In such case, you may apply for a regular “Härtefallprogram”.
Thus, the agencies and/or the Pharma Companies preference would be to include those patients in yet another trial, if such trial exists and the patients match the respective inclusion criteria (e.g. Safety Trial).
The fact that you are still reading this publication makes us guess that you belong to the small group of subject matter experts who are fighting their way daily through the regulatory minefield called Managed Access legislation.
We hope we could shed some light on the most important pitfalls.
Certainly, the authors can provide several recommendations to best deal with the described challenges:
Make sure that you know the pertinent requirements for each Managed Access (Compassionate Use/Named Patient Use) concept in every country (reading this publication was a good start);
Define release procedures for Managed Access (Compassionate Use/Named Patient Use), that take the differences to releasing IMPs into consideration;
Make sure, that all approvals relevant for your QP release are accessible to you;
If you are unsure, have someone local contact the competent authorities and ask;
Set up an agreement with your medical colleagues, that creates clarity and delineates the responsibilities of each side (like a Manufacturer-Sponsor-Agreement);
Make sure, that there are other QA systems in place and effective that cover the non-pharmaceutical aspects.
However, there will be times when you as QP are signing off for compliance, although, you are actually not so sure. Moreover, there will be times when you realize that you have just fallen into one of those traps as described above - created by the dramatic lack of consistency, common terminology, and common understanding between the Managed Access (Compassionate Use/Named Patient Use) concepts of different member states.
We acknowledge that apart from this publication and our Compassionate Use Requirement Summary on the EQPA homepage³, there are already other initiatives:
From industry: please see e.g. the recent publication in the Regulatory Rapporteurˣᵛⁱ
From patient organisations: EURORDIS offers a platform for patients suffering from rare diseases and covering Compassionate Use under https://www.eurordis.org/compassionate-use-resources
From Authorities: The HMA – Heads of Medicines Agencies – have created a “Timely Access Subgroup”ˣᵛⁱⁱ.
We particularly appreciate the substantial footprint of the HMA Timely Access initiative. The EMA stands aloof by stating “Compassionate Use programmes are coordinated and implemented by Member States, which set their own rules and procedures”ˣᵛⁱⁱⁱ.
Thus, HMA published several very interesting articles, e.g. providing a mapping of national frameworks, lists of requirements from national agencies, differentiation to off-label use and moreˣⁱˣ.
In the HMA’s mandate it says, “HMA should further explore the flexibilities that the EU regulatory framework offers for the early access of innovative products at national level“.
“Explore the possibilities” is what we are doing in this publication: explore, describe, summarize, and draw conclusions how to deal with it. This is where our exercise comes to a stop.
Though, from our regulators, the HMA and the EMA we request not to stop here, but to move further ahead:
You need to understand that those “flexibilities that the EU regulatory framework offers” are rather a regulatory nightmare for those who have to comply with it.
Therefore, after describing the differences please do the next step: Harmonize across the EU!
Harmonize the legislation for Compassionate Use, Named Patient Use, and related patient access concepts.
Make it feasible for us in industry to comply with this legislation!
We, the authors, all Qualified Persons, are by definition most sensitive, and, due to our personal liability most vulnerable to non-compliances and their consequences. So please understand our concern and the sense of urgency of this request.
Our interest is common: Provide those patients with timely access to innovative medication that may have significant impact on survival or quality of life. Moreover, to do that according to defined rules.
This publication should serve as guidance. The listed requirements have been collected with care and represent the current state of knowledge and personal interpretation of the authors on the date of publication. Liability for complying with any Regulatory Authority’s Expectations is expressly denied.
01. 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, Official Journal of the European Union, L 136/1, 30.04.2004
02. Annex 16: Certification by a Qualified Person and Batch Release, EudraLex Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, EUROPEAN COMMISSION DIRECTORATE-GENERAL FOR HEALTH AND FOOD SAFETY, Brussels, 12 October 2015
04. As applicable – Provision free of charge is a default assumption, thus, does not apply to all Managed Access concepts.
05. Product manufactured outside the EU/EEA may be re-exported under Wholesale Dealer’s Authorisation (WDA).
06. The possibility that some Managed Access concepts explicitly foresee the use of commercial products e.g. in another indication is described separately.
07. Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1), (2010/C 82/01), Section 4.2.1.
08. Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice, Draft, EMA/202679/2018, 26 April 2018.
09. In Dutch: „Uitsluitend voor Compassionate Use. Mag niet worden verkocht“.
10. Notice to applicants for marketing for Temporary Authorisation for Use (ATU), section 6.11 Labelling of the medicinal product subject to a cohort ATU; ansm; July 2015; http://dev4-afssaps-marche2017.integra.fr/var/ansm_site/storage/original/application/cadfbcf9594614d59c8915670853a28b.pdf
11. Verordnung über das Inverkehrbringen von Arzneimitteln ohne Genehmigung oder ohne Zulassung in Härtefällen (Arzneimittel-Härtefall-Verordnung - AMHV), 14. Juli 2010.
12. In German: „Dieses Arzneimittel wird ohne Genehmigung oder Zulassung im Rahmen eines Härtefallprogramms zur Verfügung gestellt“.
13. 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, Official Journal of the European Union, 27.05.2014.
14. German Criminal Code (Strafgesetzbuch, StGB) §34, English Translation: https://www.gesetze-im-internet.de/englisch_stgb/. "StGB §34 Necessity as Justification
Whoever, when faced with a present danger to life, limb, liberty, honour, property or another legal interest which cannot otherwise be averted, commits an act to avert the danger from themselves or another is not deemed to act unlawfully if, upon weighing the conflicting interests, in particular the affected legal interests and the degree of the danger facing them, the protected interest substantially outweighs the one interfered with. However, this only applies to the extent that the act committed is an adequate means to avert the danger."
15. AMG – Arzneimittelgesetz – Medicinal Products Act, https://www.gesetze-im-internet.de/englisch_amg/index.html
16. Early access in the EU: a heterogeneous landscape with room for harmonisation; Delphine Wagner, Graeme Deuchar, Manon Dutouya, Xavier Luria, Philippe Motté, Gerry McGettigan; Regulatory Rapporteur, Vol. 17, N0 9, September 2020; www.topra.org.
17. HMA - Timely Access Subgroup https://www.hma.eu/528.html?&L=0
19. HMA Key documents:
Compassionate Use program (in particular sources for information from national authorities) https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/Timely_Access/2020_04_Compassionate_use_program.pdf
Mapping of national frameworks for Early Access Programmes
Proposals and further steps regarding off-label use in the European Union
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.
Roche Pharma AG
IMP Quality Grenzach