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Replies to post #316384 on NorthWest Biotherapeutics Inc (NWBO)
We’ve discussed this all before. None of this is a new topic.
DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 November 2001 on the Community code relating to medicinal products for human use.
Article 107o
After a study has been commenced, any substantial amendments to the protocol shall be submitted, before their implementation, to the national competent authority or to the Pharmacovigilance Risk Assessment Committee, as appropriate. The national competent authority or the Pharmacovigilance Risk Assessment Committee, as appropriate, shall assess the amendments and inform the marketing authorisation holder of its endorsement or objection. Where applicable, the marketing authorisation holder shall inform Member States in which the study is conducted.
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf
3. NOTIFICATION OF AMENDMENTS AND RELATED MEASURES
3.1. Legal basis and scope
105. Article 10(a) of Directive 2001/20/EC reads as follows: ‘After the commencement of the clinical trial, the sponsor may make amendments to the protocol. If those amendments are substantial and are likely to have an impact on the safety of the trial subjects or to change the interpretation of the scientific documents in support of the conduct of the trial, or if they are otherwise significant, the sponsor shall notify the competent authorities of the Member State or Member States concerned of the reasons for, and content of, these amendments and shall inform the ethics committee or committees concerned in accordance with Articles 6 (Ethics Committee) and 9 (Commencement of clinical trial).’
106. In view of the identical legal consequences of an amendment that is ‘substantial and likely to have an impact on the safety of the trial subjects or to change the interpretation of the scientific documents in support of the conduct of the trial’ and an amendment that is ‘otherwise significant’, the term ‘substantial amendment’ used in this guidance refers to both types of amendments
3.3. The notion of ‘substantial’
112. Amendments to the trial are regarded as ‘substantial’ where they are likely to have a significant impact on:
— the safety or physical or mental integrity of the clinical trial participants, or
— the scientific value of the trial.
3.4. Examples
118. In view of these criteria the following examples should serve as guidance for the case-by-case decision of the sponsor. These examples relate only to the aspects assessed by the national competent authority of the Member State concerned. For aspects considered by the Ethics Committee, reference is made to the Commission guidance based on Article 8 of Directive 2001/20/EC.
3.4.1. Amendments as regards the clinical trials protocol
119. With regard to the protocol, the following is a nonexhaustive list of amendments that are typically ‘substantial’:
(a) change of main objective of the clinical trial;
(b) change of primary or secondary endpoint which is likely to have a significant impact on the safety or scientific value of the clinical trial;
(c) use of a new measurement for the primary endpoint;
......
3.8. Time for response, implementation
135. Article 10(a), second and third subparagraph, of Directive 2001/20/EC reads as follows:
‘On the basis of the details referred to in Article 6(3) and in accordance with Article 7, the Ethics Committee shall give an opinion within a maximum of 35 days of the date of receipt of the proposed amendment in good and due form. If this opinion is unfavourable, the sponsor may not implement the amendment to the protocol.
If the opinion of the Ethics Committee is favourable and the competent authorities of the Member States have raised no grounds for non-acceptance of the … substantial amendments, the sponsor shall proceed to conduct the clinical trial following the amended protocol. Should this not be the case, the sponsor shall either take account of the grounds for non-acceptance and adapt the proposed amendment to the protocol accordingly or withdraw the proposed amendment.’
3.8. Time for response, implementation
137. With regard to the national competent authority, no deadline is set in Directive 2001/20/EC., and in view of the approval time for requests for authorisation, the national competent authority are invited to respond within 35 calendar days of receipt of the valid notification of an amendment. Validation of the submission is included in this period. If a submission is not valid (for example, the dossier does not contain the documentation required according to this guidance), the national competent authority are invited to inform the applicant of this within the first 10 calendar days of this 35-day period. The reasons should be given. This response time may be extended if such extension is justified in view of the nature of the substantial amendment, for example if the national competent authority has to consult an expert group or committee. In such cases, the national competent authority should notify the sponsor of the duration of the extension and its reasons. If the national competent authority states that it raises no grounds for non-acceptance, the sponsor can implement the changes, even if fewer than 35 days have elapsed since the filing of the substantial amendment.
Article 10
Conduct of a clinical trial
Amendments may be made to the conduct of a clinical trial following
the procedure described hereinafter:
(a) after the commencement of the clinical trial, the sponsor may make
amendments to the protocol. If those amendments are substantial
and are likely to have an impact on the safety of the trial subjects or
to change the interpretation of the scientific documents in support of
the conduct of the trial, or if they are otherwise significant, the
sponsor shall notify the competent authorities of the Member
State or Member States concerned of the reasons for, and content
of, these amendments and shall inform the ethics committee or
committees concerned in accordance with Articles 6 and 9.
On the basis of the details referred to in Article 6(3) and in
accordance with Article 7, the Ethics Committee shall give an
opinion within a maximum of 35 days of the date of receipt of
the proposed amendment in good and due form. If this opinion is
unfavourable, the sponsor may not implement the amendment to the
protocol.
If the opinion of the Ethics Committee is favourable and the
competent authorities of the Member States have raised no
grounds for non-acceptance of the abovementioned substantial
amendments, the sponsor shall proceed to conduct the clinical
trial following the amended protocol. Should this not be the case,
the sponsor shall either take account of the grounds for nonacceptance and adapt the proposed amendment to the protocol
accordingly or withdraw the proposed amendment;
(b) without prejudice to point (a), in the light of the circumstances,
notably the occurrence of any new event relating to the conduct
of the trial or the development of the investigational medicinal
product where that new event is likely to affect the safety of the
subjects, the sponsor and the investigator shall take appropriate
urgent safety measures to protect the subjects against any
immediate hazard. The sponsor shall forthwith inform the
competent authorities of those new events and the measures taken
and shall ensure that the Ethics Committee is notified at the same
time;
(c) within 90 days of the end of a clinical trial the sponsor shall notify the competent authorities of the Member State or Member States
concerned and the Ethics Committee that the clinical trial has
ended. If the trial has to be terminated early, this period shall be
reduced to 15 days and the reasons clearly explained.
Article 11
Exchange of information
1.Member States in whose territory the clinical trial takes place shall enter in a European database, accessible only to the competent authorities of the Member States, the Agency and the Commission:
(a) extracts from the request for authorisation referred to in Article 9(2);
(b) any amendments made to the request, as provided for in
Article 9(3);
(c) any amendments made to the protocol, as provided for in point a of Article 10;
(d) the favourable opinion of the Ethics Committee;
(e) the declaration of the end of the clinical trial; and
(f) a reference to the inspections carried out on conformity with good
clinical practice.
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AI
