Clinical trials for medicines: Current issues

Applications for first time in man (FTIM) trials with novel compounds

Introduction
For certain FIH trials the MHRA will seek advice from an Expert Advisory Group (EAG)/Commission on Human Medicines (CHM) before approval for the trial can be given. Sponsors are requested to make contact with the Agency before making the clinical trial authorisation (CTA) application for such trials and to make available a data package which will allow that advice to be obtained. The normal CTA application timeline will follow receipt of a valid application. 

Sponsors of all FIH trials should take account of the CHMP Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products (external link). For those planning a first-in-human clinical trial, sponsors and investigators should identify the factors of risk and apply risk mitigation strategies accordingly as laid down in that guideline.

Scope
The decision to refer applications for expert advice will be based on assessment of risk factors and the proposed mitigation strategy. Areas for consideration when determining risk factors include mode of action, nature of the target and the relevance of animal species and models.

Examples of trials where expert advice may be sought include First in Human trials with novel compounds :-

• where the mode of action involves a target that is connected to multiple signalling pathways (target with pleiotropic effects) eg leading to various physiological effects or targets that are ubiquitously expressed
• acting (directly or indirectly) via a cascade system where there may be an amplification effect which might not be sufficiently controlled by a physiological feedback mechanism
• acting (directly or indirectly) via the immune system with a target or mechanism of action which is novel or currently not well characterised.
• where there is novelty in the structure of the active substance eg a new type of engineered structural format such as those with enhanced receptor interaction as compared with the parent compound
• where the level of expression and biological function of the target receptor may differ between healthy individuals and patients with the relevant disease
• where there is insufficient available knowledge of the structure, tissue distribution, cell specificity, disease specificity, regulation, level of  expression and biological function of the human target, including down-stream effects
• acting via a possible or likely species specific mechanism or where animal data are unlikely to be predictive of activity in humans

In addition, the MHRA may refer other applications if particular issues are identified during the assessment process.

Process

• Sponsors should decide, based on the scope criteria above, whether their application comes within this category. Sponsors, who wish to, may seek pre-submission advice on whether or not the compound in question comes within the category of ‘higher risk’.
• When advice is sought, a summary of the nature of the compound, its target/mechanism of action and the relevance of the animal model(s) should be submitted on disk directly to the Clinical Trials Unit, 12th Floor, MHRA, 1 Nine Elms Lane. London SW8 5NQ.  An e-mail should be sent to the Clinical Trials helpline (clintrialhelpline@mhra.gsi.gov.uk) no later than the date of dispatch advising of the request. The title of this e-mail should be ‘URGENT – FIH QUERY’ responses to such queries will usually be sent within 7-14 days.
• Sponsors should select the date of the EAG/CHM at which they wish their proposed trial to be discussed.
• A data package should be prepared containing all relevant documents (see below) other than the application form/xml file. The data package should be submitted directly to the Clinical Trials Unit, 12th Floor, MHRA, 1 Nine Elms Lane. London SW8 5NQ to arrive in the Unit no later than the latest submission date for the selected EAG/CHM.
• An e-mail should be sent to the Clinical Trials helpline (clintrialhelpline@mhra.gsi.gov.uk) no later than the date of dispatch, providing the sponsor name, the product name, the EudraCT number and the anticipated arrival date of the package. The title of this e-mail should be ‘URGENT – FIH SUBMISSION’.
• Following initial assessment, feedback on the content and completeness of the data package may be provided to the sponsor.
• The application form/xml file and fee should be sent directly to the Clinical Trials Unit to arrive during the week of the relevant EAG/CHM meeting.
• The sponsor should note that data packages submitted prior to the latest submission date will follow the timeline as listed.
• A formal response to the sponsor will be sent within 7-14 days of the CHM meeting date.

Dates of Expert Advisory Groups and corresponding timelines for 2007

Dates of Expert Advisory Groups and corresponding timelines for 2008

IMP dossier
Investigator’s brochure
Protocol
Responses to required CHM areas for discussion
Labelling
Manufacturer’s authorisation
QP declaration on GMP (if necessary)
EudraCT receipt
Covering letter

Commission on Human Medicines (CHM) required areas for discussion

1. A discussion of the function of the target in man.
2. A discussion of the ability of the subject to maintain a normal physiological response to challenge in the presence of the investigational product.
3. A discussion for the transition from preclinical to human testing, particularly with regard to highly species specific molecules
4. A discussion of the potential for on-target and off-target effects and how this will be handled in the clinic
5. A discussion of the doses used in the relevant animal species(particularly with regard to the use in the animal model of the starting dose to be administered to man)
6. A rationale for the starting dose in man (including, for example receptor occupancy)
7. A rationale for the study population (particularly for the use of healthy volunteers.
8. A rationale for the administration schedule for the initial and subsequent cohorts. This should include the time interval between doses administered to individual subjects
9. A rationale for the dose escalation particularly with regard to potential adverse effect.
10. A rationale for the proposed trial site, including the facilities available.

Further guidance on first-in-human clinical trials is available below:
› EMEA/CHMP/SWP/28367/07 Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products

Applications for trials with integrin antagonists

Introduction
The MHRA proposes that, for trials in patients with integrin antagonists targeting leucocyte trafficking, they will seek advice from an Expert Advisory Group (EAG)/Commission on Human Medicines (CHM) before approval for the trial can be given. Sponsors will be requested to make contact with the Agency before making the clinical trial authorisation (CTA) application for such trials and to make available a data package which will allow that advice to be obtained. The normal CTA application process will then follow.

Scope
Trials in patients with compounds which modulate leucocyte trafficking except Phase I studies in subjects with no previous immunosuppression .

1. The following applications for clinical trial authorisations will not routinely require referral to the CHM:

a. Compounds which modulate angiogenesis but not leukocyte trafficking nor have any cross-reactivity to integrins that modulate leukocyte trafficking.
b. Phase I Healthy Volunteer studies and Patient studies in subjects with no previous immunosuppression using compounds which modulate leukocyte trafficking. Provided all of the following provisions are met in the protocol:

2. The following applications for clinical trial authorisations will require referral to the CHM:

a. Phase I Patient studies with compounds which modulate leukocyte trafficking.
b. in previously immunosuppressed subjects or where subjects will receive concomitant immunosuppressant therapy
c. All Phase 2 and 3 studies with compounds which modulate leukocyte trafficking.
d. Any application falling into (1) above where there is an area of concern.

Decision tree: Referral of CTA applications for integrin antagonists to CHM.

1 = i.e modulates angiogenesis but does not modulate leukocyte trafficking nor has any cross-reactivity to integrins that modulate leukocyte trafficking.

2 = three months follow-up and
Subject alert card and
Neurological monitoring during the study and
MRI for study of neurological conditions (patients only) and
PML Management algorithm

Process

• Sponsors should decide, based on the scope criteria above, whether their application comes within this category.

• Sponsors should select the date of the EAG/CHM at which they wish their proposed trial to be discussed.

• A data package should be prepared containing all relevant documents (see below) other than the application form/xml file. The data package should be submitted directly to the Clinical Trials Unit, 12 th Floor, MHRA, 1 Nine Elms Lane. London SW8 5NQ to arrive in the Unit no later than the latest submission date for the selected EAG/CHM.

• An e-mail should be sent to the Clinical Trials helpline (clintrialhelpline@mhra.gsi.gov.uk) no later than the date of dispatch, providing the sponsor name, the product name, the EudraCT number and the anticipated arrival date of the package. The title of this e-mail should be ‘URGENT – INTEGRIN ANTAGONIST’.

• Following initial assessment, feedback on the content and completeness of the data package may be provided to the sponsor.

• The application form/xml file and fee should be sent directly to the Clinical Trials Unit to arrive during the week of the relevant EAG/CHM meeting.

• The sponsor should note that data packages submitted prior to the latest submission date will follow the timeline as listed.

• A formal response to the sponsor will be sent within 7-14 days of the CHM meeting date.

Dates of EAGs and corresponding timelines for 2008

Relevant Documents

IMP dossier
Investigator’s brochure
Protocol
Responses to required CHM areas for discussion
Labelling
Manufacturer’s authorisation
QP declaration on GMP (if necessary)
EudraCT receipt
Covering letter

CHM required Areas for Discussion

1. A statement should be provided about whether the compound blocks or interacts with an integrin receptor or a cell adhesion molecule ( CAM).

2. For integrin antagonists, the specificity of the compound for a particular integrin should be discussed.

3. For CAM antagonists, the site of blockade or interaction should be identified.

4. A view should be given as to how the risk of the development of progressive multifocal leukoencephalopathy (PML) relates to the condition considered in the proposed trial.

5. A view should be provided as to whether previous immuno-suppressive therapy plays a crucial role in the development of PML. A comment should be made on specific immunotherapy regimens.

6. A discussion of the measures taken in the trial design to address the potential risks of the development of PML should be presented, in particular in relation to:

Based on the nature of the compound and the population under investigation, it is accepted that additional measures, as outlined above, might not be appropriate. However, a clear rationale should be provided.

7. A concise description and safety analysis of all relevant non-clinical and clinical data pertaining to the product under consideration should be provided.

8. A full appraisal should be presented of current risks against benefits for the trial population.