# The Medicines for Human Use (Clinical Trials) Regulations 2004, Regulation 11B: Definition of Route B substantial modification


(1) In these Regulations, “Route B substantial modification” means a modification to the approval of a clinical trial (“the relevant clinical trial”)—
(a) where there are no new significant safety concerns with any of the investigational medicinal products, as far as the sponsor is aware having made reasonable enquiries; and
(b) which meets either Condition A, Condition B or Condition C.
(2) Condition A is that—
(a) the relevant clinical trial does not involve an investigational medicinal product that is used for the first time in humans;
(b) the modification has been reviewed and approved by the appropriate authority responsible for the licensing of clinical trials in one or more of the following—
(i) the European Union;
(ii) an EEA State;
(iii) the United States of America; and
(c) the particulars and documents that have been reviewed in connection with the approval of the modification by the authority referred to in sub-paragraph (b)—
(i) are the same as those that accompany the modification request, and
(ii) do not include any particulars that are specific to the United Kingdom.
(3) Condition B is that the modification is limited to one or more of the following changes to the protocol for the relevant clinical trial—
(a) a change to the primary objective of the relevant clinical trial;
(b) an inclusion of new measurements for the primary endpoint;
(c) a change to the design of the relevant clinical trial, which has a significant impact on the statistical consideration;
(d) a change in the criteria by reference to which the relevant clinical trial ends;
(e) where the relevant clinical trial involves an investigational medicinal product that has been authorised for use in the United Kingdom, and which is used in accordance with the terms of that authorisation in the trial, a change to the number of planned interactions with the participants to assess their ongoing safety as a participant in the trial, which is not in response to a new safety concern;
(f) a change to the list of concomitant medication that a participant in the relevant clinical trial is or is not allowed to use;
(g) in relation to a clinical trial which is conducted in more than one country in accordance with a global protocol, a change to that protocol to include all requirements specific to the United Kingdom that were approved by the authorities in a separate protocol or addendum to the global protocol that is specific to the United Kingdom, where this change does not result in a change to the safety reporting requirements as set out in Part 5.
(4) Condition C is that the modification is limited to one or more of the following changes to the investigator’s brochure or the summary of product characteristics for the relevant clinical trial—
(a) an inclusion of new toxicological or pharmacological data related to the investigational medicinal product, where there are no changes to the protocol of the relevant clinical trial as a result of safety concerns with the data;
(b) a change to the reference safety information which involves an increase in the frequency of adverse reactions, where there are no new expected adverse reactions;
(c) a change to the investigator’s brochure which is not a change to—
(i) the assessment of the risks and benefits of the relevant clinical trial as approved by the authorities, or
(ii) the safety profile of any of the investigational medicinal products used in the relevant clinical trial;
(d) an update to the section of the summary of product characteristics which deals with undesirable effects of the investigational medicinal product.
(5) In this regulation—
“concomitant medication”, in relation to a clinical trial, means any medicinal product that is not used for the purposes of the trial;
“primary endpoint” means the variable or measure capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial, for example, the period between the first receipt of treatment or a placebo by a participant and the occurrence of a pre-defined event;
“reference safety information” means information in the product information relating to expected serious adverse reactions associated with an investigational medicinal product, which is used to determine the adverse reactions that are to be treated as suspected unexpected serious adverse reactions in relation to that investigational medicinal product.

---
Source: https://www.legislation.gov.uk/uksi/2004/1031/regulation/11B (the official version)
Page: https://openlegislation.uk/medicines-for-human-use-clinical-trials-regulations-2004/regulation-11B
Contains public sector information licensed under the Open Government Licence v3.0. Source: legislation.gov.uk, The National Archives.