Clinical trials result reports according section 42b of the Medicinal Product Act
If a medicinal product was licensed after 1 January 2011, does the pharmaceutical entrepreneur generally have to submit the result reports in accordance with Section 42b sub-section 1 AMG for publication within 6 months if it is placed on the market in Germany? If, for example, the pharmaceutical entrepreneur does not place the newly licensed medicinal product on the market until after 12 months, does he have to submit the result report immediately, i.e. at the same time or which time-limits apply?
The publication obligation in accordance with Section 42b sub-section 1 AMG applies to medicinal products that are on the market. However, Section 42b sub-section 1 AMG links the deadline for submission to the time of licensing. If a medicinal product is not being marketed when the time-limit expires pursuant to sub-section 1, there is no legal obligation to submit a result report for publication. However, if the pharmaceutical entrepreneur subsequently places the medicinal product on the market after expiration of the first 6 months after granting of the marketing authorisation, the result report is to be submitted for publication at the latest at that time. It is therefore recommended to submit the result reports early.
If a medicinal product was licensed before 1 January 2011, the transitional regulation pursuant to Section 145 AMG applies, i.e. the pharmaceutical entrepreneur must transmit the result reports at the latest by 1 July 2012 if the medicinal product is placed on the market in Germany. What is to be done if the marketing is stopped prior to 1 July 2012? What is to be done if marketing is resumed after 1 July 2012?
As already stated above, the publication obligation in accordance with Section 42b sub-section 1 AMG applies to medicinal products that are on the market; this is also true for Section 145. If a medicinal product is not (or no longer) being marketed by 1 July 2012, there is no legal obligation to submit a result report for publication. However, if the pharmaceutical entrepreneur places the medicinal product on the market again after 1 July 2012, the result report is to be submitted for publication at the latest at that time. It is therefore recommended to submit the result reports early.
How is a medicinal product the marketing authorisation of which has been suspended dealt with in accordance with Section 42b sub-section 1 AMG?
It is against the law to place a medicinal product on the market if its marketing authorisation has been suspended. Thus, there is also no legal obligation to submit result reports pursuant to Section 42b AMG and/or Section 145 AMG during the period of suspension. However, if the ruling of suspension is cancelled and the medicinal product is placed on the market again, the obligations in accordance with Section 42b and, if applicable, Section 145 AMG are revived. It is therefore recommended to submit the result reports early.
How are clinical trials with medicinal products that are licensed but not being marketed dealt with in accordance with Section 42b sub-section 2 AMG? What if the marketing authorisation is likewise suspended during the study?
Section 42b sub-section 2 AMG applies only to the licensing but not to the marketing of a medicinal product. Consequently, the obligations laid down in Section 42b sub-section 2 AMG are fully applicable. Thus, the corresponding reports are to be submitted 12 months after completion of the clinical trial even if the medicinal product is not yet on the market at this time. This also applies if the marketing authorisation has been suspended.
If a clinical trial was performed in order to remove the grounds for the suspension of a marketing authorisation or in connection with possible declarations of voluntary commitment or follow-up measures but did not lead to a change of the marketing authorisation, is it subject to the publication obligation of Section 42b sub-section 1 AMG?
If a clinical trial does not lead to (renewal of) a marketing authorisation or a change of an existing marketing authorisation it is not affected by Section 42b sub-section 1 AMG. However, as the clinical trial was performed with a licensed medicinal product it is subject to Section 42b sub-section 2 AMG. Therefore, result reports are also to be submitted for such clinical trials.
Section 42b sub-section 2 AMG in conjunction with Section 145 AMG specifies 1 January 2011 as the date of coming into force of Section 42b sub-section 2 AMG. To what does this effective date refer – to the authorisation of the clinical trial, its commencement or its completion?
The specification of the deadline '1 January 2011' in Section 42b sub-section 2 AMG in conjunction with Section 145 AMG does not refer to the granting of the authorisation of the clinical trial but to its completion. This means that the provisions of Section 42b sub-section 2 AMG apply directly to all clinical trials that a sponsor has completed with a licensed medicinal product after 1 January 2011 (12-month deadline after completion of the clinical trial).
The transitional regulations of Section 145 AMG apply for all clinical trials with a licensed medicinal product already completed by the sponsor prior to 1 January 2011; this means that the result report does not have to be submitted within one year at the latest but must have been submitted at the latest by 1 July 2012.
How is sentence 2 of Section 145 AMG: "Sentence 1 is applicable to clinical trials subject to Sections 40 to 42 in force as of 6 August 2004" to be understood?
Based on the modifications in Section 145 sentence 2 AMG, the transitional regulations only apply to those clinical trials that were subject to an authorisation by the competent higher federal authority.
How is it ensured that the result reports published in accordance with Section 42b AMG are not used for circumventing the document protection (against referencing) by manufacturers of generic medicinal products, e.g. by submitting a complete bibliographical application?
The publication obligation is legally regulated in Section 42b AMG but it does not affect the document protection pursuant to Section 24b AMG. Section 24b AMG does not constitute protection from publication but merely the protection of the data and/or documentation from exploitation by unauthorised third parties. Thus, the publication of a result report in accordance with Section 42b AMG does not mean that reference can be made such a result report by third parties prematurely without the consent of the original applicant.
Who is responsible for the submission of the result report if the marketing authorisation holder is located in the EU and the medicinal product is marketed by a different pharmaceutical entrepreneur in Germany – the marketing authorisation holder or the pharmaceutical entrepreneur who places the medicinal product on the market in Germany?
In accordance with Section 4 sub-section 18 AMG any natural or legal person who places a medicinal product on the market in Germany under his own name is a pharmaceutical entrepreneur. Thus, the obligation pursuant to Section 42b sub-section 1 AMG also applies to the distributors in Germany. In cases in which there are several pharmaceutical entrepreneurs for one medicinal product, basically every one of these is responsible. However, the prerequisite for fulfilling the obligation pursuant to Section 42b sub-section 1 AMG is that the pharmaceutical entrepreneur has access to the documentation of the clinical trial. As the result reports in accordance with Section 42b sub-section 1 AMG are closely related to the authorisation, it is recommended that the marketing authorisation holder should submit such reports. Should this not be possible, the marketing authorisation holder can mandate a co-distributor of the medicinal product to make the submission. Multiple submissions of identical reports by several different co-distributors are explicitly to be avoided.
If the clinical trial was performed in Germany but the sponsor is located in another non-European country, does the legal representative have to submit the result report in accordance with Section 42b sub-section 2 AMG?
The provision of Section 42b sub-section 2 AMG is directed at the sponsor of a clinical trial. The legal representative of the sponsor assumes the legal responsibility if the sponsor he represents does not fulfil his obligations. Therefore, it is recommended that the legal representative should also submit the reports in accordance with Section 42b sub-section 2 AMG; at least, however, he should ensure that the sponsor not located in the EU/EEA fulfils his obligation pursuant to Section 42b sub-section 2 (and sub-section 3) AMG in due time.
In the case of multinational multicentric trials – do all centres have to be listed in the result report or only the German centres?
The information on where and in which study population the trial was conducted is very important for understanding and evaluating the results of clinical trials and is therefore – according to the ICH E3 Guideline – a fundamental part of the study report and its synopsis which is to be provided for each clinical trial after completion or termination as a requirement of Good Clinical Practice. Therefore, all centres – including those outside of Germany – are to be listed in the result report pursuant to Section 42b AMG.
Does Section 42b AMG also apply to the currently still "fictively licensed" medicinal products?
Medicinal products that are deemed to be authorised for marketing as defined by Section 105 sub-section 1 AMG, are generally subject to all provisions of the AMG, i.e. the specifications of Section 42b sub-section 2 AMG and the corresponding transitional regulations of Section 145 AMG also apply to clinical trials with such medicinal products.
What are the reporting time-lines for generic medicinal products?
The same legal deadlines apply to generic medicinal products as to non-generic medicinal products.
Both confirmatory studies of the pharmaceutical entrepreneur and treatment studies are submitted for an extension of indication. Does the obligation in accordance with Section 42b sub-section 1 and Section 42b sub-section 2 AMG result in duplicate reporting since the product is already licensed?
Yes, clinical trials with a licensed medicinal product as the investigational product can entail reporting obligations pursuant to Section 42b sub-section 1 as well as to sub-section 2 AMG, if the clinical trial is also confirmatory for a change of marketing authorisation. For such cases the web portal offers the possibility of indicating that that a specific result report is being submitted in accordance with the provisions of both sub-section 1 and sub-section 2. This allows fulfilling both obligations with one submission, provided the reporting obligation pertains to one and the same natural or legal person. Please bear in mind that different deadlines are to be observed.
How is the situation with clinical trials the data of which were not yet available during the licensing procedure and are subsequently not contained in the licensing documentation, but which were completed before the marketing authorisation was granted? Do the provisions of Section 42b AMG even apply to these studies, and if so, those of sub-section 1 and/or those of sub-section 2?
Since the obligation to submit the entire licensing documentation is subject to criminal sanction, this constellation should only occur in very few cases. If a clinical trial was not confirmatory for marketing authorisation and had also been completed at the time the marketing authorisation was granted, Section 42b AMG does not apply. However, if the data from this clinical trial are subsequently used for a change of marketing authorisation, Section 42b sub-section 1 AMG is applicable.
How is a clinical trial evaluated that was started prior to marketing authorisation but completed after granting of the marketing authorisation?
If the medicinal product was licensed at any time during the clinical trial, a result report in accordance with Section 42b sub-section 2 AMG is to be submitted. This also applies if the medicinal product was not yet licensed at the time the clinical trial was authorised but was granted marketing authorisation in the course of the clinical trial.
Does Section 42b AMG affect clinical trials with registered traditional medicinal products? Example: A clinical trial in accordance with Sections 40 to 42 is/was performed with a medicinal product registered pursuant to Sections 39a to d AMG, e.g. in order to gain a renewal of the marketing authorisation. However, the marketing authorisation is then either not granted or it is not applied for due to the results of the study.
In Germany, clinical trials with homoeopathic or registered traditional herbal medicinal products are subject to authorisation in accordance with Section 42 AMG. However, result reports pursuant to Section 42b AMG are only to be submitted for medicinal products that have been granted marketing authorisation/centralised marketing authorisation. Only registered medicinal products are not subject to the obligation in accordance with Section 42b AMG. However, if a registered medicinal product is additionally granted a marketing authorisation, corresponding reports pursuant to Section 42b sub-section 1 AMG are to be submitted.
Placing medicinal products with duplicate marketing authorisations but different marketing authorisation holders on the market: In the case of different legal persons, can one marketing authorisation holder also enter the processing number ("Einreichungs¬nummer", ENR) of another marketing authorisation holder's duplicate marketing authorisation in the web portal when submitting his report and does this mean that the other marketing authorisation holder's obligation ceases?
As a rule, a pharmaceutical entrepreneur can mandate another pharmaceutical entrepreneur to make a submission via the web portal. However, in the case of duplicate or "informed consent" marketing authorisations no report is necessary as these marketing authorisations are not based on own studies (complete reference).
What if the competent higher federal authority has not yet assigned a processing number ("Einreichungsnummer", ENR) for a centralised license. Can it be omitted in that case?
No, the ENR is necessary so that result reports that are submitted in accordance with Section 42b sub-section 1 AMG can be allocated to the appropriate medicinal product in the PharmNet.Bund system. If the ENR is not known to the pharmaceutical entrepreneur upon submission, he is requested to contact the competent higher federal authority so that an ENR can be assigned.
Do the statements on test or reference investigational products have to include all dose strengths used or is it sufficient to enter a medicinal product with one dose strength standing for all strengths?
Different dose strengths also have different marketing authorisation numbers; therefore, linkage in the Drug Information System makes it necessary to list all strengths.
Are all processing numbers ("Einreichungsnummer", ENR) belonging to the investigational product to be entered in the input box for processing numbers or only those corresponding to the dose strengths that were actually used in the clinical trial?
If a report in accordance with Section 42b sub-section 1 AMG is submitted, those ENRs are to be given for which the study was confirmatory for the granting (or change) of marketing authorisation. If a report in accordance with Section 42b sub-section 2 AMG is submitted, all ENRs of the medicinal products which were in fact used as investigational products are to be stated, i.e. those medicinal products listed in the EudraCT Clinical Trial Application Form.
As a rule, there are several marketing authorisation numbers for centralised marketing authorisations per product and/or dose strength. Can the marketing authorisation numbers be entered as numerical series (e.g.: EU/1/04/xxx/005 – 008) in such cases or does each marketing authorisation number have to be entered individually and completely?
Currently, it is not possible to enter numerical series in the web portal for technical reasons; therefore, all marketing authorisation numbers have to be listed individually.
Example: After 1 January 2011, a pharmaceutical entrepreneur is granted an extension of indication for a medicinal product that was already licensed before 1 January 2011. Do result reports of the studies supporting this extended indication have to be submitted 6 months after granting thereof even if no trial centre in Germany was concerned?
Yes. The legal basis for this is Section 42b sub-section 1 AMG. In contrast to sub-section 2, the provision in sub-section 1 aims at where the medicinal product is placed on the market (scope of the AMG) and not at where the study is performed (cf. Item 1 of the Announcement regarding the publication of the results of clinical trials in accordance with Section 42b of the Medicinal Products Act)
How is the regulatory situation if the marketing authorisation expires after the study has been completed but before the 1-year publication deadline?
Since the medicinal product was licensed at the time the clinical trial was performed, a result report in accordance with Section 42b sub-section 2 AMG is to be submitted.
Can a CRO enter the data in the name of the marketing authorisation holder/sponsor?
Yes, any person (including a CRO) thus commissioned by the marketing authorisation holder (Section 42b sub-section 1 AMG) or sponsor (Section 42b sub-section 2 AMG) can submit the data.
How are biosimilars viewed with regard to the reporting obligation in accordance with Section 42b AMG?
Medicinal products licensed as biosimilar require confirmatory clinical trials in order to obtain a marketing authorisation. Therefore, these are to be submitted in accordance with Section 42b sub-section 1 AMG. Clinical trials with licensed biosimilar medicinal products are also subject to the obligations pursuant to Section 42b sub-section 2 AMG. Accordingly, Section 145 also applies to these medicinal products.