Protocols amendments

PROTOCOL AMENDMENT(S) n NEW PROTOCOL n CHANGE IN PROTOCOL n NEW INVESTIGATOR... 

System software maintenance presents some challenges. System updates may be needed to fix a glitch, incorporate protocol amendments, respond to changes in business rules, add, change, or disable reports, forms, or variables. 

The Study Director/Principal Investigator should ideally discuss all multi-site studies with QA personnel prior to study initiation (or prior to the issue of the protocol amendment if work is not detailed in the protocol). When acting as Study Director, a copy of the current GLP certificates should be requested from sub-contracted facilities and should be retained in QA. 

One aspect of specimen analysis that often occurs and should be highlighted is the situation that arises when a study has been initiated (protocol has been signed), but the analytical procedure has not yet been determined or worked out, or perhaps has not been fully validated by the performing laboratory. In this case, the approved protocol should fully describe the situation, and once the method has been developed and/or validated an approved protocol amendment should be issued, thus formalizing the inclusion of the analytical methodology. Likewise, during the validation process or during the study itself, if there is an analytical method modification then the protocol also needs to be formally amended. 

Verify that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCPs, and with applicable regulatory require-ment(s). 

Copy of the protocol/amendments (title of study purpose, including expected benefits obtained by doing the study participant selection criteria par ticipant exclusion criteria study design, including as needed, a discussion of the appropriateness of research methods description of methods performed)... 

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

The chief investigator is also responsible (with support from the sponsor) for notifying the lEC of any new safety information and of any protocol amendments that will require approval. Annual or more frequent reports of the progress of the... 

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. 

In June 2005, Chiron began US and UK phase 1 trials in MM. Data from this trial were presented at the 42nd ASCO meeting, Jime 2006. A total of 35 patients were treated in four intermittent dosing cohorts (25, 50, 75, and 100 mg/day) and three continuous dosing cohorts (100,125, and 175 mg/day) all once daily. Treatment was 7 days on, 7 days off with a subsequent protocol amendment to daily dosing. The plasma PK values were hnear between 25 and 175 mg doses with respect to Cmax and AUC. DLTs occurred at 175 mg and the MTD was 125 mg. Treatment was associated with stable disease. 

There are differing opinions as to whether the preliminary study should be performed to GLP, but if the in-life portion, together with any post-life activities (e.g., fetal assessment), is to GLP the study can be upgraded to lull GLP status by adding a QA report review by protocol amendment. 

A proper discharge of QAU responsibilities requires a knowledge of protocol requirements. One of the QAU s responsibilities is to inspect study conduct to assure that there are no deviations from protocol requirements. Preparation for and conduct of those inspections require ready access to a copy of the protocol and all protocol amendments. 

Docmnentation of protocol changes or revisions and the reason for them is best accomphshed by issuing formal protocol amendments, which must be dated and signed by the study director and should be attached to the front of aU copies of the protocol. Such attachments immediately alerts study personnel to protocol changes and help prevent study personnel from overlooking amendments that are hidden at the back of the protocol. 

If deviations from a protocol are intended to be permanent, a protocol amendment should be issued to document the change. If a deviation from the protocol is an error, the deviation should be promptly corrected and should be documented in the study records and described in the final report. 

To the extent possible, protocol amendments should be prospective that is, issued and distributed before the change is intended to occur. In some circumstances (e.g., an emergency decision to lower test article dose levels in a chronic study because of an unexpected toxic response to protocol-specified doses or a decision to collect additional tissue specimens where that decision is made on the basis of findings during the course of an autopsy) prospective distribution of a protocol amendment may not be possible. In such cases, a protocol amendment should be issued as soon as possible. 

The question frequently arises as to what date should appear on a protocol amendment. The author is of the opinion that an effective date, whether prospective or retrospective. 

Sections 8.130(a) and (b) should not be regarded as a straitjacket that prevents scientifically justified changes in research as a study progresses. Any changes in the research can occur as long as they are properly documented in the form of protocol amendments. There is no limit on the number of amendments. 

As the trial is ongoing there is also an opportunity to change some of the planned methods of analysis for example, information that a particular covariate could be important or that a different kind of effect could be seen in a certain subgroup may have become available based on external data from a similar trial that has now completed and reported. Such changes can be incorporated by modifying the SAP and if they represent major changes to the analysis, for example if they were associated with the analysis of the primary endpoint, then a protocol amendment would need to be issued. The reason for this, as mentioned earlier, is that only methods specified in the protocol can be viewed as confirmatory. 

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. ... 

Deviations in the conduct of the study from the protocol must be properly documented. There must be a formal protocol amendment signed and dated by the study director Eor any prospective change in the conduct of the study. This includes changing such things as the location of the trial, the application rate, or the formulation of the test chemical. Unavoidable changes such as those caused by adverse weather, seasonal variations, or wildlife damage must be clearly documented in the raw data and a written opinion by the study director about the impact of each change on the study must be put in the study file. 

Protocol amendments Submitted to report changes in previously submitted protocols or to add protocols not previously submitted. 

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. 

Amendments (protocol amendments and information amendments), annual reports... 

Relationship of shipping and storage conditions to stability studies Compliance with internal company and regulatory requirements Review, approval, and revision process, especially QA involvement Reason and justification for protocol amendments, especially... 

Document Control Systems—SOPs, protocols, protocol amendments, final reports... 

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... 

Following initial clearance of an IND (INDs are never formally approved ) and throughout the time that the studies included in it are being conducted, the IND application must be updated continuously. In addition to annual reports, protocol amendments must be submitted any time that a protocol is changed or if the sponsor wishes to use a new study protocol. Study reports of completed trials are also submitted so that documentation is submitted as it becomes available. This build as you go concept is central to the IND philosophy, and a company should not withhold information about an investigational product from the FDA. 

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. 

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