Principles and Practice of Pharmaceutical Medicine

above). Note that the guidance foresees the possibi-
lity for sponsors to supply further information once
without extension of the review timeframe (under
ideal circumstances). Clinical trial can only begin
when the favorable opinion of both the ethics com-
mittee and the RA’s notification of no grounds for
objection (see above) have been received in writing.

Protocol amendments

Usually, if, in the course of a trial, a substantial
amendment to the protocol becomes necessary,
then a repeat opinion of the ethics committee
must be sought before implementing any change.
Substantial amendments are defined as amend-
ments to the terms of the research ethics commit-
tee’s (REC’s) application, or to the protocol or any
other supporting documentation that is likely to
affect to a significant degree

the safety or physical or mental integrity of the
subjects of the trial;

the scientific value of the trial;

the conduct or management of the trial or

the quality or safety of any IMP used in the trial.

Note, however, that amendments that are made to
reduce an immediate clinical hazard to the trial
participants may be implemented immediately,
and remains the primary responsibility of the
designated medical monitor for the study, without
prior written approval from the ethics committee.
However, the investigator is under obligation to
inform the ethics committee, the sponsor must
inform the RA, both as soon as possible and in
any case within 72 h (see European Commission
Directive 2003/94/EC, 2005/28/EC).
Minor amendments – also called ‘administrative
amendments’ – do not have to be approved by the
ethics committee or RA, although most research
sites choose to notify the ethics committee of such
changes on a periodic basis. These would include,
for example, typographical errors, amended con-
tact information, appointment of new support staff

and changes in the logistical arrangements for

storing or transporting samples.

Lastly, the guidance also lays out the procedure

of informing the ethics committee at the termina-

tion of a trial, and lists the required documentation

to be submitted.

Clinical trial authorization (CTA)

by national competent authorities

The relevant Guidance is the ‘Detailed guidance for

the request for authorisation of a clinical trial on a

medicinal product for human use to the competent

authorities, notification of substantial amendments,

and declaration of the end of the trial’ (April 2004).

The CTA procedure became mandatory on May

1, 2004 (existing trial authorizations from the pre-

Directive period, for example in the United King-

dom a CTX, CTC or DDX, retained their validity,

and automatically became CTAs). The CTA appli-

cation process is a relatively straightforward

written procedure, and requires no extensive

preparatory meetings with the regulators.

The information on the IMP in the CTA is neces-

sarily not as complete as in a MA, and the overall

intent is that the extent of information should be

proportional to the clinical phase of the protocol,

while complying with the new Guidance document

forGood Manufacturing Practicesas they apply to

IMPs (Annex 13, Rev 1 of the document). A further

guideline is forthcoming on the requirements to the

chemical and pharmaceutical quality documenta-

tionconcerningIMPsinclinicaltrials(seeEuropean

Commission Directive 2003/94/EC).

The core of a CTA application in all MS includes

the following, which is submitted both to RAs and

ethics committees:

Covering letter

EuDRACT number

Application form

Investigator’s brochure

Protocol and amendments

Protocol summary

450 CH34 MEDICINES REGULATION IN THE EUROPEAN UNION