E. General Information on the Trial

This sub-section is intended to detail the medical condition or disease under investigation.

1. In E.1.1, click in the free text field and enter:
   1) In the case of healthy volunteer trials, state 'healthy volunteers' as well as the intended indication for the product under development, which should be provided in parentheses.
   2) If the trial is to be conducted on patients, only the name of the disease, which is the indication for which the Investigational Medicinal Product is administered, is required (up to 500 characters).
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2. Click in the free text field E.1.1.1 and include a description of the medical condition in non-medical language - e.g. Avian Influenza Virus A (H5N1) might be described as Bird Flu (up to 200 characters).
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3. In E.1.1.2, click the drop-down list, then select the Therapeutic Area from the list of options. If an option is too long for the drop-down box, move your mouse over it and the entire option appears in a tooltip.
   Note: This list is based upon on one taken from the Medical SubjectA person participating in a Clinical Trial - the subject may be a patient or a healthy volunteer. Headings list (MeSH®). MeSH® is the National Library of Medicine's controlled vocabulary thesaurus (http://www.nlm.nih.gov/mesh/). It consists of sets of terms naming descriptors in a hierarchical structure that permits searching at various levels of specificity. 
4. To add new MedDRA® data in field E.1.2, enter search details for the MedDRA® term and/or level on the following page. Alternatively enter the classification code you wish to add. Then click 'Search' button.
   You should routinely use the level 'LLT' (Lowest Level Term).Click the adjacent check box to select found terms from the Results list, then click 'Add Selected' button to add them to the CTAAcronym: Clinical Trial Application.
   Note: MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA).
5. In E.1.3, if, in the view of the sponsor, the indication investigated in the clinical trial answers the below definition, select 'Yes'. If not, the applicant should select 'No'.
   
   Definition: A rare disease concerns a restricted number of patients in the general population and shows evidence of gravity (because it is life-threatening, invalidating or serious and chronic). The limit accepted in Europe is 1 / 2000 person affected by the disease.
   Note: Points to consider on the calculation and reporting of the prevalence of a condition for Orphan drug designation: COM/436/01.
6. Click 'Next' to complete MedDRA information for the Clinical Trial.

Now go to the "E.1.2 MedDRA information"  section below for more detailed information on completing the next sub-section.

This sub-section is to ensure that the correct and accepted terminology is used within the Clinical Trial Application.

For more information on MedDRA see:http://www.meddramsso.com

Note: MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA).

1. To add new MedDRA data, enter search details for the MedDRA term and/or level.
Detailed MedDRA Search Instructions
1. First set the Term filter, using the filter drop-down options to narrow or widen your search look-up.
2. Click in the Term free text field (on the right) and enter the MedDRA term (or part of a term).
3. Next, set the level in the MedDRA hierarchy you wish to search at then click the 'Search' button.
4. Alternatively enter the classification code you wish to add. Then click the 'Search' button.
Note:It is recommended that users should routinely use the Lowest Level Term (LLT).
Key to MedDRA Hierarchy Codes
• SOC (System Organ Class);
• HLGT (High Level Group Term);
• HLT (High Level Term);
• PT (Preferred Term);
• LLT (Lowest Level Term).
  
Note:For more information on MedDRA see: http://www.meddramsso.com/
2. If your search criteria allow, a Results list appeats beneath the Search window:
   
Note:If the results run over more than one page, use the navigation buttons at the bottom of the list.
3. Click the adjacent check box to select found terms from the Results list, then click 'Add Selected' button at the bottom of the Results list to add them to section E.1.2 MedDRA information section of the CTA:
   
4. Repeat the above process to add additional terms, as necessary.

Click 'Next' to move to the "E.2 Objective of the Trial" section.

This sub-section details the objectives of the Clinical Trial.

1. Click in the free text field E.2.1 and include a description of the main objectives of the trial, if applicable (up to 1000 characters). The main (primary) objectives of the trial should be described in this section. The wording used here should be consistent with the wording in the protocol.
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Note: This is a MANDATORY FIELD.
2. Click in the free text field E.2.2 and include a description of the secondary objectives of the trial, if applicable (up to 1000 characters). The wording of the objective(s) mentioned here should be consistent with the wording in the protocol.
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Note: This is a MANDATORY FIELD.
3. In field E.2.3, select 'Yes' if a sub-study is planned and if this sub-study is taking place in the Member State concerned by the application. If not, select 'No'.
Note: A sub-study, or ancillary study, is a study performed on a sub-group of the subjects included in the clinical trial. For example, a pharmacokinetics or pharmacogenetic sub-study may include a sample of the patients participating in the clinical trial.
4. Click in the free text field E.2.3.1 and include the details of each sub-study (up to 4000 characters). If a sub-study does not have a title, the nature of the sub-study should be entered here instead of a title (for example: pharmacogenomic study).
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Note: This is a mandatory field if there is a sub-study planned.

Click 'Next' to move to the "E.3 Principal inclusion criteria, E.4 Principal exclusion criteria and E.5 End point(s)" section.

This sub-section details the criteria surrounding inclusion in or exclusion from the Clinical Trial, as well as end points in the Clinical Trial.

1. Click in the free text field E.3 and list the details of the most important reasons for the inclusion of subjects in the clinical trial (up to 5000 characters).Click the to add text in another language than English.
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Note: This is a mandatory field.
2. Click in the free text field E.4 and list the details of the most important reasons for exclusion of subjects from the clinical trial from among the exclusion criteria described in the protocol (up to 5000 characters). Click the to add text in another language than English.
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Warning: Exclusion criteria should not be described as the contrary of the inclusion criteria listed in the free text field E.3.
Warning: The principal exclusion criteria should not be mistaken for the criteria of study termination or treatment halt.
Note: This is a mandatory field.
3. Click in the free text field E.5.1 and list the primary end points of the clinical trial (up to 5000 characters). Click the to add text in another language than English.
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Warning: The primary end point(s) should not be mixed with the objectives described in the section E.2.1. For example, for a trial which objective is to evaluate the efficacy of a treatment for hypercholesterolemia, the primary end point could be a 20% decrease of the cholesterol level.
4. Click in the free text field E.5.1.1.and include a time point for each of the primary end points detailed in the section above (up to 800 characters). Click the to add text in another language than English.
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5. Click in the free text field E.5.2 and list the secondary end points of the clinical trial (up to 5000 characters).Click the to add text in another language than English.
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Warning: The secondary end point(s) should not be mixed with the objectives described in the section E.2.1.
6. Click in the free text field E.5.2.1 and include a timepoint for each of the secondary end points detailed in the section above (up to 800 characters). Click the to add text in another language than English.
   
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Click 'Next' to move to the "E.6 and E.7 Scope of the Trial, Trial Type and Phase" section.

This sub-section covers the scope of the Clinical Trial, the type of Clinical Trial and the Phase.

E.6 is a MANDATORY section and each sub question should be answered. Take into account all the objectives of the Clinical Trial (not only the primary objectives) and all the assessments conducted during the clinical trial.

1. Select 'Yes' for E.6.1 if the assessment of the IMPAcronym: Investigational Medicinal Product. A pharmaceutical form of an active substance or placebo being tested or used as a reference in a Clinical Trial, including products already with a marketing authorisation but used or assembled in a different way from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form. efficacy as a diagnostic tool is within the clinical trial objectives.
2. Select 'Yes' for E.6.2 if the assessment of the IMP efficacy as a prophylactic preventive intervention is within the clinical trial objectives.
3. Select 'Yes' E.6.3 if the assessment of the IMP efficacy as a therapeutic intervention is within the clinical trial objectives.
4. Select 'Yes' for E.6.4 if the study includes the assessment of the safety of use of the IMP(s).
5. Select 'Yes' for E.6.5 if the study assesses efficacy of the IMP(s).
6. Select 'Yes' for E.6.6 if the study will determine pharmacokinetic parameter of the IMP(s).
7. Select 'Yes' for E.6.7 if the study will determine pharmacodynamics of the IMP(s).
8. Select 'Yes' for E.6.8 if the study will determine bioequivalence of two or more IMP(s). Note: You should also mark 'Yes' in E.7.1.2."
9. Select 'Yes' for E.6.9 if the study will determine dose-response patterns of the IMP(s).
10. Select 'Yes' for E.6.10 if the study will involve pharmacogenetic research of the IMP(s).
11. Select 'Yes' for E.6.11 if the study will involve pharmacogenomic research of the IMP(s).
12. Select 'Yes' for E.6.12 if the study will involve pharmacoeconomic research of the IMP(s).
13. Select 'Yes' for E.6.13 if the Clinical Trial's scope is other than those options available above. If applicable then complete the free text field E.6.13.1, below.
14. Click in the free text field E.6.13.1 and include details of the trial scope, if E.6.13 is 'Yes' (up to 500 characters). Click the to add text in another language than English.
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E.7 Trial and Phase - Further Information.

E.7 is a MANDATORY section and each sub question should be answered. Identify the trial type and phase (Phase IPhase I is the first stage of the clinical development of a medicinal product. It includes the first administration of that product in human subjects. Phase I Clinical Trials include a small number of subjects (up to 30) and frequently involve healthy volunteers, but may also involve patients. They generally have no therapeutic intent and are initial studies of the safety and tolerability of an IMP. They also include pharmacokinetc and sometimes pharmacodynamic studies., II, III or IV). Emphasis is placed on the ICH terms, human pharmacology, and therapeutic exploratory, therapeutic confirmatory and therapeutic use.


Tip: Please refer to the ICH E8 Note for Guidance on general Considerations for Clinical Trials (CHMPAcronym: Committee for Medicinal Products for Human Use. The Committee for Medicinal Products for Human Use (CHMP) is responsible for preparing the Agency's opinions on all questions concerning medicines for human use. It was established by Regulation (EC) No 726/2004 and replaced the former Committee for Proprietary Medicinal Products (CPMP)./ICH/291/95), in particular Table 1 and section 3.1.3 of that guidance at:

http://www.ema.europa.eu/pdfs/human/ich/02915en.pdf
Note: If the trial is a combination of more than one phase, select the item most applicable to this trial. Explanation of more than one phase trials should be given in the covering letter.
15. For E.7.1, human pharmacology (Phase I) trials are the first stage of testing in human subjects, generally comprising a small group of healthy volunteers. This phase includes trials designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug.
    Note: If 'Yes' is selected, one item from E.7.1.1. to E.7.1.3. should be marked 'Yes' too.
16. In E.7.1.1, select 'Yes if this trial is the first time the Investigational Medicinal Product will be administered to humans. All the following trials will not be considered as a first administration to humans, in any country. Select 'No' in the case of new generics or new formulations of a medicinal product.
Warning: If the medicinal product has been administered to humans in a previous trial, the trial in the present application cannot be considered a first administration to humans, even if this trial is the first administration to a new population or in a new indication. For example, if previous trials have been conducted on adults, and if the new trial is conducted on children, this new trial (concerned by the present application) cannot be considered the first administration to humans.
17. In E.7.1.2, select 'Yes if this trial is a nioequivalence study. Otherwise, select 'No'.
18. In E.7.1.3, select 'Yes' if the phase 1 trial is neither a first administration to humans nor a bioequivalence study. Then complete the free text field 'Trial type Other specification' below.
19. If E.7.1.3 was answered 'Yes', click in the free text field and include details of the trial type (up to 100 characters). Click the to add text in another language than English.
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20. In E.7.2, select 'Yes, if the Clinical Trial is a therapeutic exploratory (Phase IIPhase II Clinical Trials are conducted in patients with the intended target disease. They are conducted to investigate the safety and efficacy of an IMP, and to determine the doses to be used in the larger Phase III trials. They usually involve 100-300 people in total.) trial. These trials are performed on larger groups and are designed to assess how well an Investigational Medicinal Product works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.
21. In E.7.3, select 'Yes, if the Clinical Trial is a therapeutic confirmatory (Phase IIIPhase III Clinical Trials are the large Clinical Trials (several hundred to several thousand subjects) used to determine the safety and efficacy of the IMP. They are usually multicentre and very often multi-country Clinical Trials. It is usually on completion of the Phase III Clinical Trials that a Marketing Authorisation application is made.) trial. Therapeutic confirmatory (Phase III) trials are randomized clinical trials on large groups, designed to be a definitive assessment of how effective the drug is, in comparison with current best alternative treatment.
22. In E.7.4, select 'Yes, if the Clinical Trial is a Therapeutic use (Phase IVThese are studies carried out after the Marketing Authorisation has been granted, and are carried out within the terms of the marketing authorisation (therapeutic use and dose) and using the authorised product Post marketing studies to delineate additional information including the medicine's risks, benefits, and optimal use. These studies are designed to monitor effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use.) trial. A therapeutic use (Phase IV) trial involves products with a marketing authorisation.

Click 'Next' to move to the "E.8 Design of the Trial"section.

This sub-section covers the design of the Clinical Trial.

This is a MANDATORY section and each sub question should be answered.

1. If E.8.1 is 'Yes', E.8.1.1-E.8.1.7.1 applying to the design of the trial should be completed.
Note: In a controlled trial, the tested product is compared to a reference treatment. The reference treatment can be, for example, a placebo, a product known to be effective, a surgical procedure, or a different dose of the same product.
2. In E.8.1.1, if each subject in the trial is randomly assigned to receive either the study treatment or a placebo, select 'Yes'.
3. In E.8.1.2, if the investigators and the subjects know which treatment is actually given, select 'Yes'.
4. In E.8.1.3, if the subjects (healthy volunteers or patients) included in the trial don't know which treatment they are given, select 'Yes'.
5. In E.8.1.4, if the investigators and the subjects included in the trial (healthy volunteers or patients) don't know which treatment is given, select 'Yes'.
6. In E.8.1.5, select 'Yes', if the trial compares groups of subjects concurrently, each group receiving different dose or treatment.
7. In E.8.1.6, select 'Yes', if comparing two (or more) treatments in which patients are switched to the alternative treatment after a specified period of time.
8. In E.8.1.7, if there is another methodological characteristic to the trial design, select 'Yes' and complete free text field E.8.1.7.1 with a description.
9. In E.8.1.7.1, click in the free text field and include details of the trial design (up to 100 characters). Click the to add text in another language than English.
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10. In E.8.2.1, select 'Yes' if the comparator drug is another medicinal product.
11. In E.8.2.2, select 'Yes' if the comparator drug is a placebo.
Warning: If the placebo is only used in the trial in order to maintain the blind, the placebo should not be considered as a comparator and 'No' should be selected.
12. In E.8.2.3, if the comparator is neither another medicinal product nor a placebo, select 'Yes' here and provide details in the free text field below.
13. In E.8.2.3.1, click in the free text field and include details of comparators which are neither other medicinal products nor placebos - e.g. A medical device, a surgical procedure, the lack of treatment, a different treatment schedule, different dosage of the same product (up to 100 characters). Click the to add text in another language than English.
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14. In E.8.2.4, click in the free text field and include the number of treatment arms (groups) in the trial (up to 10 characters).
Note on Section E.8.2:

In a comparative trial, the investigational product or marketed product is compared against a standard drug (or placebo). The standard (or reference) or placebo medication is called the comparator drug.

Ref: "ComparatorAn investigational or marketed product (i.e active control) or placebo, used as a reference in a Clinical Trial. drug". Pharmaceutical Medicine Dictionary. Philadelphia: Elsevier Health Sciences, 2001. Credo Reference. Web. 26 January 2010.

Warning: If the placebo is not used as a comparator but is only used in the trial in order to maintain the blind, the placebo should not be considered as a comparator and 'No' should be ticked for the item E.8.2.2.

15. In E.8.3, select 'Yes' if the trial is conducted in a single centre (clinical trial site) in the Member State concerned by the application.
16. In E.8.4, select 'Yes' if the trial is conducted in multiple sites in the concerned Member State. In this case, the number of sites in the Member State concerned should be entered in section E.8.4.1, below.
17. Click in the free text field E.8.4.1 and include the number of sites in the Member State concerned where the trial will take place (up to 2 numbers).
18. In E.8.5, select 'Yes' if the trial will be conducted in more than one Member State of the EEAAcronym: European Economic Area. Created in 1994, the EEA combines the countries of the European Union and member countries of EFTA (European Trade Association) Countries that belong to the EEA are: Austria, Belgium, Bulgaria, Czech Republic, Cyprus, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom. Countries that are EEA member countries but NOT part of the European Union are: Norway, Iceland, and Liechtenstein..
19. In E.8.5.1,click in the free text field and include the number of sites in the European Economic Area where the trial is planned to take place (up to 2 numbers).
    
Note: Please include the sites in the Member State concerned in your total.
20. In E.8.6.1, select 'Yes' if the trial involves InvestigatorA doctor or a person following a profession agreed in the Member State for investigations because of the scientific background and the experience in patient care it requires The investigator is responsible for the conduct of a Clinical Trial at a trial site If a trial is conducted by a team of individuals at a trial site, the investigator is the leader responsible for the team and may be called the principal investigator. Sites in at least one Member State and at least one third country. A third country means a country which is not a Member State of the EUAcronym: European Union./EEA.
21. In E.8.6.2, select 'Yes' if the trial only involves Investigator sites in third country. A third country means a country which is not a Member State of the EU/EEA.
22. In E.8.6.3, select the countries if either of the previous two questions were answered 'Yes'. Multiple selection of Options:To select one value, click the value and then click 'Copy'.
    To select more than one value, hold CTRL then click the other value you wish to select, then click 'Copy'.
    To delete all selected values from the right-hand field, click 'Remove All' button. Note: The above technique can be used for any options organised in the same format of two fields.
23. In E.8.6.4, click in the free text field and include the number of sites outside the European Economic Area where the trial is planned to take place (up to 2 numbers).
24. In E.8.7, select 'Yes' if an independent data monitoring committee will be used for this trial.
25. In E.8.8, click in the free text field and, if it is the last visit of the last subject, enter 'LVLS'. If it is not 'LVLS', provide the definition and justification (up to 500 characters).Click the to add text in another language than English.
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26. In E.8.9, the duration should be measured from the 1st inclusion until the last visit of the last subject (LVLS).
27. In E.8.9.1, click in each field and enter relevant numbers for years, months and days (up to 2 numbers per field).
28. In E.8.9.2, click in each field and enter relevant numbers for years, months and days (up to 2 numbers per field).
Note: E.8.9.2 should not be answered if the clinical trial takes places in a single country (i.e. E.8.5 and/or E.8.6.1 are answered 'No'.).
29. In E.8.10.1, enter the date on which recruitment of subjects for the trial is planned to commence in the MS concerned in the following format: YYYY-MM-DD.
Tip:Alternatively, click the calendar and select the start date.
30. In E.8.10.2,enter the date on which recruitment of subjects for the trial is planned to commence in all countries in the following format: YYYY-MM-DD.
Tip:Alternatively, click the calendar and select the start date.
Note: E.8.10.2 should not be answered if the clinical trial takes places in a single country (i.e. E.8.5 and/or E.8.6.1 are answered 'No'.).
31. Click 'Done' and the Clinical Trial Application Menu appears again.