Clinical Protocols amendments

Clinical Trial Protocol and Protocol Amendments Investigator s Brochure... 

One of the measures of the quality of the preregistration clinical programme is the total time from the decision to enter full development to the first regulatory approval in a major market. It is also important to monitor quality in other ways. One option is to assess the frequency with which predetermined milestones are achieved. More subtly, quality can be assessed by examining the number of incomplete, inaccurate or indecipherable CRFs that are returned or the number of protocol amendments made which are not based on new information. Milestones may still be achieved when quality is poor, that is, when there is inefficiency, but this means that they were wrongly established and can be improved if efficiency improves. 

A revised sample size may then be calculated using suitably modified assumptions, and should be justified and documented in a protocol amendment and in the clinical study report... The potential need for re-estimation of the sample size should be envisaged in the protocol whenever possible. ... 

Information amendments Submitted to report new information that would not be included as a protocol amendment or safety report. Examples include the results of animal testing, chemistry, manufacturing, and controls data, reports of completed or discontinued clinical trials, or changes in administrative information. 

Protocols [ 312.23(a)(6)], protocol amendments [ 312.30], previous human experience [ 312.23(a)(9)], safety reports [ 312.32] and informational amendments related specifically to clinical [ 312.31] including adverse reactions, consent forms, investigator information, general investigational plan, Investigator s Brochures, IRB approval, new protocols, revised protocols, site information, investigator data, CVs, and 1572s... 

The statisticians conducting the review of an NDA evaluate the statistical relevance of the data presented so that they can provide the medical officers with information concerning how well the findings are likely to generalize to the larger patient population in the country. They evaluate the extent of any deviations from the protocols submitted in the IND in the conduct of the study as well as the overall quality of the data collected. All clinical study protocol amendments are reviewed to see what deviations from the original study design have occurred and how these (and deviations that were not detailed in protocol amendments) may have influenced the data. 

The appropriate box(es) briefly describing the submission should be checked in item 11. It is possible that one IND amendment may contain protocol amendments and information amendments. In such a case, the applicable boxes are marked. If the filing is for the initial IND, a response to a clinical hold, an initial or follow-up IND safety report, a response to an FDA request for information, an annual report, or general correspondence, the appropriate box should be checked. Finally, there is a box if the sponsor is requesting reinstatement of an IND that has been withdrawn, inactivated, terminated, or discontinued. 

Protocol Amendments. It is the obligation of the sponsor to amend the IND to ensure that the clinical investigations are conducted according to protocols included in the IND application. This section will describe the provisions under which new protocols may be submitted and the changes in previously submitted protocols that may be made. 

Information Amendments. A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report. Examples of information or data requiring an information amendment include new toxicology, chemistry, or other technical information or a report regarding the discontinuance of a clinical investigation. Information amendments to the IND should be submitted as necessary but, to the extent feasible, not more than every 30 days. 

Institutional review board records that do not adequately track or log research documents that have been submitted by the clinical investigator, including protocols, amendments, consent forms, Investigator Brochures, IND safety reports, advertisements, patient information sheets, and correspondence between the investigator and the IRB. 

Once an IND is active, then it can be amended with further clinical protocols, additional toxicology data and so on, as the development program proceeds. 

The CA in whose territory the CT takes place enters the details into a new European Drug Regulatory Affairs Clinical Trial (EUDRACT) database. It allocates a unique EUDRACT number that cannot be reallocated to another trial if the original one does not proceed if an International Standard Randomized Controlled Trial Number (ISRCTN) is available, this detail is also entered. These EUDRACT entry data are accessible only to the CA, the EMEA, and the Commission and details the request for authorization, the protocol, any proposed protocol amendments, approvals by the CA and IEC, any suspension, the declaration at the end, and reference to any GCP inspections. 

The structure of an IND the application is contained in the regulation and is quite easily followed. Almost all pharmaceutical companies, contract research organizations, and universities have templates for the writing of these documents. All the animal data, the proposed clinical study protocol, a clinical investigators brochure, and the chemistry and manufacturing controls must be described. Once an IND is active, then it can be amended with further clinical protocols, additional toxicology data, etc., as the development program proceeds. 

Since the Kefauver-Harris Amendmenf was adopted in 1962, pharmaceutical manufacturers have been held responsible by the FDA for providing new medications fhaf are bofh safe and effective. In addition to the Kefauver-Harris Amendment, the Belmont Report (written in 1979), established the ethical principles and guidelines for conducting research. The FDA requires that clinical trials be conducted in compliance with a protocol that has been... 

The application for a clinical trial authorisation (CTA) for the first administration of a NME to man comprises the same elements as all other CTAs but, of course, there will be no clinical data. The regulatory authority known as the competent authority (CA) of the EU member state requires receipt of confirmation of the EU clinical trials database (EUDRACT) number, a covering letter, a completed application form, the protocol with all current amendments, the IB and a full Investigational Medicinal Product Dossier (IMPD) (see below). If the study is to be conducted in more than one member state, a list of CAs should be included. If the opinion of the lEC is available, it should be provided. 

Unfortunately, amendments to the approved protocol are frequent. These will require the same sign-off/approval of signatures as required for the original protocol. If the amendment has any impact on the clinical trial, either medically or statistically, it will need to be approved by an lEC. 

Inspectors will visit the investigator site and may possibly wish to visit the sponsor s office. They will review the documentation of the study file (see Box 7.1). Approval documents of the lEC will be compared with any amendments made to the protocol or to the subject s information sheet/ICR Consent forms for the study subjects will be inspected to establish who actually gave consent and whether this was before entry into the clinical study. A thorough source data verification of the CRF with the source documents, including the medical records, will be undertaken. Documentation relating to drug accormtability wiU be matched with each subject s CRF The facilities wiU be reviewed and the site staff interviewed. Further information can be obtained from... 

Protocol means the description of the Clinical Trial and all amendments thereto as the Parties may from time to time agree. Such amendments will be signed by the Parties and form a part of this Agreement. 

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