Changes from plenary report to adopted text

Addede) Reproductive and developmental toxicity

AddedInvestigation of possible impairment of male or female reproductive function as well as harmful effects on progeny shall be performed by appropriate tests.

AddedThese tests comprise studies of effect on adult male or female reproductive function, studies of the toxic and teratogenic effects at all stages of development from conception to sexual maturity as well as latent effects, when the medicinal product under investigation has been administered to the female during pregnancy.

AddedOmission of these tests must be adequately justified.

AddedDepending on the indicated use of the medicinal product, additional studies addressing development when administering the medicinal product of the offspring may be warranted.

AddedEmbryo/foetal toxicity studies shall normally be conducted on two mammalian species, one of which shall be other than a rodent. Peri- and postnatal studies shall be conducted in at least one species. If the metabolism of a medicinal product in particular species is known to be similar to that in man, it is desirable to include this species. It is also desirable that one of the species is the same as in the repeated dose toxicity studies.

AddedThe state of scientific knowledge at the time when the application is lodged shall be taken into account when determining the study design.

Addedf) Local tolerance

AddedThe purpose of local tolerance studies is to ascertain whether medicinal products (both active substances and excipients) are tolerated at sites in the body, which may come into contact with the medicinal product as a result of its administration in clinical use. The testing strategy shall be such that any mechanical effects of administration or purely physico-chemical actions of the product can be distinguished from toxicological or pharmaco-dynamic ones.

AddedLocal tolerance testing shall be conducted with the preparation being developed for human use, using the vehicle and/or excipients in treating the control group(s). Positive controls/reference substances shall be included where necessary.

AddedThe design of local tolerance tests (choice of species, duration, frequency and route of administration, doses) will depend upon the problem to be investigated and the proposed conditions of administration in clinical use. Reversibility of local lesions shall be performed where relevant.

AddedStudies in animals can be substituted by validated in vitro tests provided that the test results are of comparable quality and usefulness for the purpose of safety evaluation.

AddedFor chemicals applied to the skin (e.g. dermal, rectal, vaginal) the sensitising potential shall be evaluated in at least one of the test systems currently available (the guinea pig assay or the local lymph node assay).

Added5. MODULE 5: CLINICAL STUDY REPORTS

Added5.1. Format and Presentation

AddedThe general outline of Module 5 is as follows:

Added— Table of contents for clinical study reports

Added— Tabular listing of all clinical studies

Added— Clinical study reports

Added— Reports of Bio-pharmaceutical Studies

Added— Bio-availability Study Reports

Added— Comparative Bio-availability and Bio-equivalence Study Reports

Added— In vitro — In vivo Correlation Study Report

Added— Reports of Bio-analytical and Analytical Methods

Added— Reports of Studies Pertinent to Pharmaco-kinetics Using Human Bio-materials

Added— Plasma Protein Binding Study Reports

Added— Reports of Hepatic Metabolism and Interaction Studies

Added— Reports of Studies Using Other Human Bio-materials

Added— Reports of Human Pharmaco-kinetic Studies

Added— Healthy subjects Pharmaco-kinetics and Initial Tolerability Study Reports

Added— Patient Pharmaco-kinetics and Initial Tolerability Study Reports

Added— Intrinsic Factor Pharmaco-kinetics Study Reports

Added— Extrinsic Factor Pharmaco-kinetics Study Reports

Added— Population Pharmaco-kinetics Study Reports

Added— Reports of Human Pharmaco-dynamic Studies

Added— Healthy Subject Pharmaco-dynamic and Pharmaco-kinetics/Pharmaco-dynamic Study Reports

Added— Patient Pharmaco-dynamic and Pharmaco-kinetics/Pharmaco-dynamic Studies Study Reports

Added— Reports of Efficacy and Safety Studies

Added— Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication

Added— Study Reports of Uncontrolled Clinical Studies

Added— Reports of Analyses of Data from More than One Study including any formal integrated analyses, meta-analyses and bridging analyses

Added— Other Study Reports

Added— Reports of Post-marketing Experience

Added— Literature references

Added5.2. Content: basic principles and requirements

AddedSpecial attention shall be paid to the following selected elements.

Addeda) 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.

Addedb) 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.

Addedc) 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:

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

Added— 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,

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

AddedSubject'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.

AddedThe 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.

AddedThe 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.

AddedIn 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.

AddedAny change of ownership of the data shall be documented.

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

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

Added— 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