Division 5.2 Content: basic principles and requirementsF1

Special attention shall be paid to the following selected elements.

1. a))

   The clinical particulars to be provided pursuant to Articles 8 (3) (i) and 10 (1) must enable a sufficiently well-founded and scientifically valid opinion to be formed as to whether the medicinal product satisfies the criteria governing the granting of a marketing authorisation. Consequently, an essential requirement is that the results of all clinical trials should be communicated, both favourable and unfavourable.

2. b))

   Clinical trials must always be preceded by adequate pharmacological and toxicological tests, carried out on animals in accordance with the requirements of Module 4 of this Annex. The investigator must acquaint himself with the conclusions drawn from the pharmacological and toxicological studies and hence the applicant must provide him at least with the investigator's brochure, consisting of all the relevant information known prior to the onset of a clinical trial including chemical, pharmaceutical and biological data, toxicological, pharmaco-kinetic and pharmaco-dynamic data in animals and the results of earlier clinical trials, with adequate data to justify the nature, scale and duration of the proposed trial; the complete pharmacological and toxicological reports shall be provided on request. For materials of human or animal origin, all available means shall be employed to ensure safety from transmission of infectious agents prior to the commencement of the trial.

3. c))

   Marketing authorisation holders must arrange for essential clinical trial documents (including case report forms) other than subject's medical files, to be kept by the owners of the data:

   • for at least 15 years after completion or discontinuation of the trial,

   • or for at least two years after the granting of the last marketing authorisation in the European Community and when there are no pending or contemplated marketing applications in the European Community,

   • or for at least two years after formal discontinuation of clinical development of the investigational product.

   Subject's medical files should be retained in accordance with applicable legislation and in accordance with the maximum period of time permitted by the hospital, institution or private practice.

   The documents can be retained for a longer period, however, if required by the applicable regulatory requirements or by agreement with the sponsor. It is the responsibility of the sponsor to inform the hospital, institution or practice as to when these documents no longer need to be retained.

   The sponsor or other owner of the data shall retain all other documentation pertaining to the trial as long as the product is authorised. This documentation shall include: the protocol including the rationale, objectives and statistical design and methodology of the trial, with conditions under which it is performed and managed, and details of the investigational product, the reference medicinal product and/or the placebo used; standard operating procedures; all written opinions on the protocol and procedures; the investigator's brochure; case report forms on each trial subject; final report; audit certificate(s), if available. The final report shall be retained by the sponsor or subsequent owner, for five years after the medicinal product is no longer authorised.

   In addition for trials conducted within the European Community, the marketing authorisation holder shall make any additional arrangements for archiving of documentation in accordance with the provisions of Directive 2001/20/EC and implementing detailed guidelines.

   Any change of ownership of the data shall be documented.

   All data and documents shall be made available if requested by relevant authorities.

4. d))

   The particulars of each clinical trial must contain sufficient detail to allow an objective judgement to be made:

   • the protocol, including the rationale, objectives and statistical design and methodology of the trial, with conditions under which it is performed and managed, and details of the investigational medicinal product used

   • audit certificate(s), if available

   • the list of investigator(s), and each investigator shall give his name, address, appointments, qualifications and clinical duties, state where the trial was carried out and assemble the information in respect of each patient individually, including case report forms on each trial subject

   • final report signed by the investigator and for multi-centre trials, by all the investigators or the co-ordinating (principal) investigator.

5. e))

   The particulars of clinical trials referred to above shall be forwarded to the competent authorities. However, in agreement with the competent authorities, the applicant may omit part of this information. Complete documentation shall be provided forthwith upon request.

   The investigator shall, in his conclusions on the experimental evidence, express an opinion on the safety of the product under normal conditions of use, its tolerance, its efficacy and any useful information relating to indications and contra-indications, dosage and average duration of treatment as well as any special precautions to be taken during treatment and the clinical symptoms of over dosage. In reporting the results of a multi-centre study, the principal investigator shall, in his conclusions, express an opinion on the safety and efficacy of the investigational medicinal product on behalf of all centres.

6. f))

   The clinical observations shall be summarised for each trial indicating:

   1. 1))

      the number and sex of subjects treated;

   2. 2))

      the selection and age-distribution of the groups of patients being investigated and the comparative tests;

   3. 3))

      the number of patients withdrawn prematurely from the trials and the reasons for such withdrawal;

   4. 4))

      where controlled trials were carried out under the above conditions, whether the control group:

      • received no treatment

      • received a placebo

      • received another medicinal product of known effect

      • received treatment other than therapy using medicinal products

   5. 5))

      the frequency of observed adverse reactions;

   6. 6))

      details concerning patients who may be at increased risk, e.g. elderly people, children, women during pregnancy or menstruation, or whose physiological or pathological condition requires special consideration;

   7. 7))

      parameters or evaluation criteria of efficacy and the results in terms of these parameters;

   8. 8))

      a statistical evaluation of the results when this is called for by the design of the trials and the variable factors involved.

7. g))

   In addition, the investigator shall always indicate his observations on:

   1. 1))

      any signs of habituation, addiction or difficulty in weaning patients from the medicinal product;

   2. 2))

      any interactions that have been observed with other medicinal products administered concomitantly;

   3. 3))

      the criteria determining exclusion of certain patients from the trials;

   4. 4))

      any deaths which occurred during the trial or within the follow-up period.

8. h))

   Particulars concerning a new combination of medicinal substances must be identical to those required for new medicinal products and must substantiate the safety and efficacy of the combination.

9. i))

   Total or partial omission of data must be explained. Should unexpected results occur during the course of the trials, further pre clinical toxicological and pharmacological tests must be undertaken and reviewed.

10. j))

    If the medicinal product is intended for long-term administration, particulars shall be given of any modification of the pharmacological action following repeated administration, as well as the establishment of long-term dosage.