Changes from plenary report to adopted text

Added— audit certificate(s), if available

Added— 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

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

Addede) 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.

AddedThe 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.

Addedf) The clinical observations shall be summarised for each trial indicating:

Added1) the number and sex of subjects treated;

Added2) the selection and age-distribution of the groups of patients being investigated and the comparative tests;

Added3) the number of patients withdrawn prematurely from the trials and the reasons for such withdrawal;

Added4) where controlled trials were carried out under the above conditions, whether the control group:

Added— received no treatment

Added— received a placebo

Added— received another medicinal product of known effect

Added— received treatment other than therapy using medicinal products

Added5) the frequency of observed adverse reactions;

Added6) 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;

Added7) parameters or evaluation criteria of efficacy and the results in terms of these parameters;

Added8) a statistical evaluation of the results when this is called for by the design of the trials and the variable factors involved.

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

Added1) any signs of habituation, addiction or difficulty in weaning patients from the medicinal product;

Added2) any interactions that have been observed with other medicinal products administered concomitantly;

Added3) the criteria determining exclusion of certain patients from the trials;

Added4) any deaths which occurred during the trial or within the follow-up period.

Addedh) 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.

Addedi) 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.

Addedj) 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.

Added5.2.1. Reports of bio-pharmaceutics studies

AddedBio-availability study reports, comparative bio-availability, bio-equivalence study reports, reports on in vitro and in vivo correlation study, and bio-analytical and analytical methods shall be provided.

AddedIn addition, an assessment of bio-availability shall be undertaken where necessary to demonstrate bio-equivalence for the medicinal products referred to in Article 10 (1) (a).

Added5.2.2. Reports of studies pertinent to pharmaco-kinetics using human bio-materials

AddedFor the purposes of this Annex, human bio-materials shall mean any proteins, cells, tissues and related materials derived from human sources that are used in vitro or ex vivo to assess pharmaco-kinetics properties of drug substances.

AddedIn this respect, reports of plasma protein binding study, hepatic metabolism and active substance interaction studies and studies using other human bio-materials shall be provided.

Added5.2.3. Reports of human pharmaco-kinetic studies

Addeda) The following pharmaco-kinetic characteristics shall be described:

Added— absorption (rate and extent),

Added— distribution,

Added— metabolism,

Added— excretion.

AddedClinically significant features including the implication of the kinetic data for the dosage regimen especially for patients at risk, and differences between man and animal species used in the pre clinical studies, shall be described.

AddedIn addition to standard multiple-sample pharmaco-kinetics studies, population pharmaco-kinetics analyses based on sparse sampling during clinical studies can also address questions about the contributions of intrinsic and extrinsic factors to the variability in the dose- pharmaco-kinetics response relationship. Reports of pharmaco-kinetic and initial tolerability studies in healthy subjects and in patients, reports of pharmaco-kinetic studies to assess effects of intrinsic and extrinsic factors, and reports of population pharmaco-kinetic studies shall be provided.

Addedb) If the medicinal product is normally to be administered concomitantly with other medicinal products, particulars shall be given of joint administration tests performed to demonstrate possible modification of the pharmacological action.

AddedPharmaco-kinetic interactions between the active substance and other medicinal products or substances shall be investigated.

Added5.2.4. Reports of human pharmaco-dynamic studies

Addeda) The pharmaco-dynamic action correlated to the efficacy shall be demonstrated including:

Added— the dose-response relationship and its time course,

Added— justification for the dosage and conditions of administration,

Added— the mode of action, if possible.

AddedThe pharmaco-dynamic action not related to efficacy shall be described.

AddedThe demonstration of pharmaco-dynamic effects in human beings shall not in itself be sufficient to justify conclusions regarding any particular potential therapeutic effect.

Addedb) If the medicinal product is normally to be administered concomitantly with other medicinal products, particulars shall be given of joint administration tests performed to demonstrate possible modification of the pharmacological action.

AddedPharmaco-dynamic interactions between the active substance and other medicinal products or substances shall be investigated.

Added5.2.5. Reports of efficacy and safety studies

Added5.2.5.1. S t u d y R e p o r t s o f C o n t r o l l e d C l i n i c a l S t u d i e s P e r t i n e n t t o t h e C l a i m e d i n d i c a t i o n

AddedIn general, clinical trials shall be done as ‘controlled clinical trials’ if possible, randomised and as appropriate versus placebo and versus an established medicinal product of proven therapeutic value; any other design shall be justified. The treatment of the control groups will vary from case to case and also will depend on ethical considerations and therapeutic area; thus it may, in some instances, be more pertinent to compare the efficacy of a new medicinal product with that of an established medicinal product of proven therapeutic value rather than with the effect of a placebo.

Added(1) As far as possible, and particularly in trials where the effect of the product cannot be objectively measured, steps shall be taken to avoid bias, including methods of randomisation and blinding.

Added(2) The protocol of the trial must include a thorough description of the statistical methods to be employed, the number and reasons for inclusion of patients (including calculations of the power of the trial), the level of significance to be used and a description of the statistical unit. Measures taken to avoid bias, particularly methods of randomisation, shall be documented. Inclusion of a large number of subjects in a trial must not be regarded as an adequate substitute for a properly controlled trial.

AddedThe safety data shall be reviewed taking into account guidelines published by the Commission, with particular attention to events resulting in changes of dose or need for concomitant medication, serious adverse events, events resulting in withdrawal, and deaths. Any patients or patient groups at increased risk shall be identified and particular attention paid to potentially vulnerable patients who may be present in small numbers, e.g., children, pregnant women, frail elderly, people with marked abnormalities of metabolism or excretion etc. The implication of the safety evaluation for the possible uses of the medicinal product shall be described.

Added5.2.5.2. S t u d y r e p o r t s o f u n c o n t r o l l e d c l i n i c a l s t u d i e s r e p o r t s o f a n a l y s e s o f d a t a f r o m m o r e t h a n o n e s t u d y a n d o t h e r c l i n i c a l s t u d y r e p o r t s

AddedThese reports shall be provided.

Added5.2.6. Reports of post-marketing experience