NorthWest Biotherapeutics Inc (NWBO)

[Lykiri]

We have to work towards unblinding this study. I know Marnix explained the reasons that it’s been delayed, but as a clinician, I’m still going to push for it, because I think that’s very important. That’s what we need to be able to understand the impact of this. So I shall continue asking day in, day out.

We also have to work with the regulatory bodies, and we probably ought to do that now, right, not even waiting, because we want this to be available to all the patients. Again, while it’s very nice about these studies… yes, those patients who are in better prognostic groups are going to benefit more… but there is a benefit to all patients. -- Dr. Ashkan, June 5, 2018

Dr. Keyoumars Ashkan, a senior neurosurgeon at Kings College Hospital, is the lead investigator for the DCVax-L trial in Europe. (https://nwbio.com/nw-bios-international-phase-iii-gbm-brain-trial-is-subject-of-bbc-tv-report-in-the-uk/)

In 2015, Northwest Biotherapeutics send documents regarding amendments requiring approval simultaneously to the Coordinating Ethics Committee and the Local Ethics Committees.

Further ethical review is required for any substantial amendment made once the study has started. A favourable opinion must be obtained prior to implementing the amendment, unless it is an urgent safety measure.
https://www.myresearchproject.org.uk/help/hlpamendments.aspx#1

IMO, Dr. Keymourars Ashkan signed the papers.(He is the Principal Investigator in Europe)

A1. Amendment to the study protocol

•Page signed by the Coordinating Principal Investigator for the amendment of the protocol.

Submission of applications to the Coordinating Ethics Committee in accordance with the German Medicines Act (AMG)

https://www.uniklinik-freiburg.de/ethics-commission/submission-of-applications/submission-of-applications-in-accordance-with-the-german-medicines-act-amg/as-coordinating-ethics-committee.html

The amendments received a favorite opinion from de REC. The last one on Aug.12, 2015. At the same time there was a hold on recruitment.
I strongly believe that there is a link between the two events and that Dr. Ashkan Keyoumars knows what is going on.

London REC annual reports: April 2015 – March 2016
https://www.hra.nhs.uk/documents/702/ar-lon-chelsea-15-16.pdf

RES Committee London-Chelsea Annual Report 01 April 2015- 31 March 2016

P.22 and page 23

Table 10.1: Breakdown of current status of all substantial amendments reviewed within the reporting period.

Amendment REC Reference: 11/LO/0957/AM14
Title: DC Vax-Brain Phase III trial for GBM-Current
Version: Substantial Amendment 9
Date: 21/04/2015
Number of Days on clock: 6

Amendment REC Reference: 11/LO/0957/AM15
Title: DC Vax-Brain Phase III trial for GBM-Current
Version: Substantial Amendment 06
Date: 06/05/2015
Number of Days on clock: 11

Amendment REC Reference: 11/LO/0957/AM16
Title:DC Vax-Brain Phase III trial for GBM-Current
Version: Substantial Amendment 10
Date: 22/07/2015 19
Number of Days on clock: 19

Amendment REC Reference: 11/LO/0957/AM17
Title: DC Vax-Brain Phase III trial for GBM- Current
Version: Substantial Amendment 11
Dated: 12/08/2015
Number of Days on clock: 16

I asked the REC for clarification but i didn't receive a reply.
I know that the HRA recognises that in a few limited circumstances it may be appropriate to allow for a deferral of publication of some selected fields within the Research Summary, for a specified time period; for example, for reasons of commercial sensitivity or intellectual property protection.

Sponsors may request the deferral of the publication of the research summary (within three months from the date of the final REC opinion letter) where there are concerns of commercial confidentiality. The sponsor/researcher/applicant can also request updates.
https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/

Here is a list of examples of substantial amendments:

Annex I Examples of substantial and non-substantial modifications.

The following are non-exhaustive lists of examples of substantial and nonsubstantial modifications that serve as guidance for a case-by-case decision of the sponsor. Please see Q3.2 on what is understood by the notion of substantial.

It is important to note that certain substantial modifications may lead to changes in the clinical trial to an extent that it has to be considered to be a completely new clinical trial.
In such cases an application for a new trial authorisation would be required. For examples see Q3.2.

Part I

a. Modifications that are typically considered to be ‘substantial’:
Note: Modifications marked with * may be considered to lead to a completely new clinical trial unless justified.

Protocol

1. Change of secondary endpoint which is likely to have a significant impact on the safety or scientific value of the clinical trial*;
2. Use of a new mode of measurement for the primary endpoint*;
3. New toxicological or pharmacological data or new interpretation of toxicological or pharmacological data which is likely to impact on the risk/benefit assessment;
4. A change in the definition of the end of the trial;
5. Removal of a trial arm not foreseen in the approved protocol;
6. Change of inclusion or exclusion criteria if these changes are likely to have a significant impact on the safety or scientific value of the clinical trial*;
7. Changes in the number of scheduled subject study visits;
8. Change of a diagnostic or medical monitoring procedure which is likely to have a significant impact on the safety or scientific value of the clinical trial;
9. Removal of an independent data monitoring board;
10. Change of treatment modalities (mode of administration/duration/frequency/dosing) of IMPs;
11. A change of study design which is likely to have a significant impact on primary or major secondary statistical analysis or the risk/benefit assessment*;
12. Amending the number of subjects to be included, either due to an adaptation of the sample size calculation or to maintain a previously defined sample size calculation due to more withdrawals/drop outs than expected;
13. Addition of an interim/intermediate analysis. No interim analysis was mentioned and specified in the initial protocol but during the study it is decided to do an interim analysis;
14. Deletion of an interim/intermediate analysis;
15. Additional safety monitoring and/or other type of changes in order to minimize a potential safety concern;
16. Change of safety criteria to modify or interrupt IMPs treatment.
IMPD and IB
17. Any change in the quality of the IMP (see also the relevant EMA guidelines);
18. Change in the overall risk and benefit assessment in the IMPD or IB;
19. New toxicological or pharmacological data or new interpretation of the data in the IMPD or IB which might have a significant impact on the risk/benefit ratio;
20. New clinical data e.g. from previous clinical trials and human experience in the IMPD or IB which might have a significant impact on the risk/benefit ratio;
21. Changes to the reference safety information for the annual safety report and SUSAR reporting;

Other modifications

22. A change of sponsor, co-sponsor or the sponsor’s legal representative;
23. The revocation or suspension of the IMP’s marketing authorisation.

Part II

a. Modifications that are typically considered to be ‘substantial’

1. Addition of a site, change in facilities, change in site suitability or change of principal investigator;
2. New insurance policy;
3. Change in the insurance policy, eg. a new insurance company, changes in insurance coverage, conditions and/or insured amounts;
4. Modifications in any documents for subjects such as the subject information sheet, and informed consent form, which could include change in safety information, study procedures or data handling;
5. Change in access, disclosure, dissemination, alteration or loss of information and personal data processed;
6. Change in collection, storage and future use of biological samples from clinical trial subject;
7. Change in financial arrangements;
8. Change in the compensation paid to subjects and/or investigator/site for participating in the trial;
9. Change in recruitment arrangements including procedures for inclusion of subjects and advertising material.
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/regulation5362014_qa_en.pdf

IB Investigator’s brochure
IMP Investigational medicinal product
SUSAR Suspected unexpected serious adverse reaction