Clinical Submission Global Integrated Database (GIDB)

With respect to the final QC controlled and QA clinical submission GIDB and "locking the database" - is a "Database Lock Form" required?

The answer is - yes. Remember, at the clinical study level, when a database is locked, a "Database Lock Form" is required. The same holds true at the submission level with the GIDB Lock.

The Database Lock Form will include:

• Sponsor name
• Project name - usually the name of the investigational drug
• Database - GIDB - Global Integrated Database
• Version
• Statement - "After checking all items relative to the data management activities, the clinical manager and the data manager (pharma, CRO, consultant or otherwise, in-house or outsourced) indicate that the database is final and request it to be locked."
• Signed and dated by the clinical manager
• Signed and dated by the data manager
• Signed and dated by the biostatistician that wrote the SAP (GIDB) - the person performing the "Lock"
• Time and date of the GIDB Lock.

There are no changes allowed to the GIDB after the time, date and signatures are received and the Database Lock Form is fully executed on the "same day".

Make no mistake in the process, procedure, time, date or otherwise - it will invalidate the GIDB - now, the clinical submission GIDB has serious data integrity issues - sometimes reparable with GCP correction and communication with FDA, sometimes irreparable, sometimes - "a do over - the GIDB has to be created from the start" - first data point, first clinical study. Serious cost, timeline delays, quality management issues, perception of FDA - not good.

More to come from the Desk of Dante pertaining to the Clinical Submission GIDB - important points to consider.

GIDB - Global Integrated Database - Clinical/Regulatory Submission

A point to consider which is often asked and debated by pharma when considering the development, structure and SAP (Statistical Analysis Plan) of the Clinical/Regulatory Submission GIDB (Global Integrated Database). The GIDB is an integrated database which captures all data from Clinical Studies, Phases 1,2,3. The GIDB includes all data for clinical safety and clinical efficacy. FDA will often expect several "GIDBs" - one for safety and one for efficacy. The GIDB for efficacy will include data for Clinical Studies, Phase 2 and 3. The GIDB for safety will include data for Clinical Studies, Phases 1,2,3 - yes, FDA will expect, a GIDB for Phase 1 as well.

It is expected by FDA to "have some pooling across all studies" for Phase 1 safety. Most pharma disagree with the Phase 1 GIDB because they feel that Phase 1 studies are too heterogeneous in design and captures information for safety and tolerability, not detailed , much like a POC study.

However, the FDA explanation and reasoning is that even in Phase 1 an AE (adverse event) may appear and for FDA that is their main concern to make sure ALL AEs are captured, reported, reviewed and researched - the ultimate goal is not to approve a drug - it is patient safety.

Make sure you correspond with FDA, verbally and in writing as to this requirement. It is a point of consideration to the overall filing - it can trigger a RTF (Refusal to File) if FDA requested a Phase 1 GIDB and the pharma company did not include one in the filing.

Careful negotiation with FDA pertaining to the content and the TOC of the GIDB, the pooling is important. The GIDB must carry the "storyline" of the clinical submission and should be equivalent to the eventual message in the label of the drug. With careful planning and clear statistical strategy, one can negotiate with FDA how to present the data in the best way for clarity, however, don't fall short on the importance of including all safety data at all stages of clinical development. Under-reporting for any reason is not tolerated by FDA.

The Difference between TGA and EU CTD Filings

A client of mine just asked me several days ago, a drug was purchased from a company that was in distress, the "price was right". The drug was just approved in the EU. The client wanted to submit the same CTD dossier to TGA (Australia).

The client is correct on one hand and needs advice on the other. In my experience to handle sections with "identical" content for TGA, EU, FDA, others - consider first that nothing is a cut and paste, nothing is identical, nothing is exactly the same from one submission to another. Second, to save time, map similar sections from one document to another, perform a cut and paste activity from one document to another and modify as needed. A QC must be performed to deem this documentation QC final and QA certified.

The answer to the larger question - yes, TGA is happy to use the CTD documentation from EU for their review, however, there are certain sections that must be, by requirement expanded. One of these sections is clinical laboratory data, ECG and otherwise. Another difference between EU and TGA, is "narratives" - narratives (several types) may be included in Module 1 for TGA, not so with EU. So, here are two examples, the former pertaining to expansion of data and the latter pertaining to a change in content location. The point, whether minor and major - there are differences.

Communication with TGA is a must to understand fully the target TOC, the arrangement and the exact organization for the format and the entire clinical submission. Always request correspondence, minutes to the meeting, TC or face to face - this information becomes critical at the time of filing and RTF and completeness. QC the clinical submission - all Modules - for accuracy and consistency across all data and documents.

Medicines for Children - EU Pediatric Regulation - EMEA

In the previous communication, information pertaining to EU PIP was provided to the readers. A bit more about the PIP Regulation - yes, it is new - entered into force in the EU on 26 January 2007.

The objective of the Pediatric Regulation is to improve the health of children in EU by:

• facilitating the development and availability of medicines for children aged 0 to 17 years
• ensuring that medicines for use in children are of high quality
• ethically researched
• authorized appropriately
• quality-controlled
• quality-assured
• improving the availability of information on the use of medicines for children

without:

• subjecting children to unnecessary clinical studies and clinical trials
• delaying the authorization of medicines for use in adults.

The Pediatric Regulation dramatically changes the regulatory environment for pediatric medicines in EU.

In the next communication, I will provide opinion and key aspects of the changes impacting the regulatory environment for pediatric medicines in EU.

PIP EU - Pediatric Investigational Plan - Clinical/Regulatory Submission

Due to recent legislation in the EU governing the development and authorization of medicines for use in children, a PIP now needs to be written and an opinion adopted, prior to clinical/regulatory submission of a MAA - Marketing Authorization Application.

The preparation of a PIP presents the unique challenge of concisely presenting information on the disease to be treated in children and current knowledge of the drug being developed, together with assembling a convincing rationale for the pediatric development program being proposed.

PIPs can be developed, prepared and submitted in most therapeutic areas, applicable to pediatrics.

In several ways, the PIP is more complicated than most clinical/regulatory submissions. Therefore, it is strongly advised that all pharma sponsor functions be proactively involved. Literature based information, post-marketing information, safety surveillance information and otherwise as well as previously submitted and approved filing for the adult in all indications, if applicable, are readily available to the writing and QC teams at development start of the PIP.

Acceptance and use of the PIP clinical/regulatory submission in the EU is in its first year and I believe just in the recent past, the first approval was awarded, so the SOPs, the structure and content are still under scrutiny and is currently monitored and reviewed with rigor.

From the Desk of Dante and Dante Colleagues.

Clinical Documentation - Medical Writers and QC (Quality Control)

A clinical development program/CTD clinical submission for drug, biologic, device, vaccine, gene-product, stem cell, monoclonal and otherwise, require a range of documentation, regulatory, non-regulatory, clinical, non-clinical, major and minor, all require process and procedural adherence, all require QC (quality control) of data, all require QA (quality assurance) of guidance completeness and compliance. All require tracking and monitoring. All require project management for realistic timelines, resource and capacity. All require dedicated medical writers.

The range of documents required for a clinical development program which by normal progression populates your CTD (Common Technical Document) Clinical Submission includes but is not limited to the following -

• CSP (Clinical Study Protocol)
• CSR (Clinical Study Report)
• CTR (Clinical Trial Report)
• CTD Module Summaries
• Informed Consent Form
• Narratives
• Subject Patient Profiles
• PIP (Pediatric Investigative Plan)
• RMP (Risk Management Plan)
• Manuscripts
• SmPC (Summary of Product Characteristics)
• USPI (United States Package Insert)
• Posters
• PSUR (Periodic Safety Update Report)
• ASR (Annual Safety Report)
• IB Investigator Brochure
• IMPD (EMEA Product Dossier)
• CTA (Clinical Trial Application)
• IND (Investigational New Drug Application)
• NDA (New Drug Application)
• GIP (General Investigative Plan).

It is imperative to have your clinical development team and your clinical submission team work together at the beginning of your clinical development program (CDP) through to filing to ensure efficiency and quality.

It is imperative that expert medical writers and QC work together in the early document development stage, preparing thoughts and clear structured statements. Thoughts and statements that are real and can be supported by data.

By organizing the medical writers and QC teams early in the development of your documentation, it will streamline the later stages of the CTD and streamline all documentation.

Using the same teams, medical writers and QC and keeping those teams together until the filing of the dossier will ensure overall efficiency, consistency and accuracy.

When does QC begin? Which documents should be QC? At the beginning of the clinical program and all documentation, respectively.

What is the benefit of having early medical writing and QC teams? - The benefit and result can be easily measured in metrics pertaining to ROI (return on investment) -

• # of document revisions are reduced
• # of QC cycles are reduced
• # of document drafts are reduced
• # of team reviews are reduced
• time to filing is reduced
• costs of the CDP and CTD are reduced
• impact on employee manpower is reduced
• impact on pharma organization is reduced
• CRO outsourcing, timelines, efforts, materials, consultants, tasks are reduced.

Global Project Team Leadership and Task Management for Clinical Submission

Global Project Management occurs across all sponsor functions and all vendors.

The "gate-keeper" role of a global clinical submission project leader is to lead the team and manage the functions, the issues, the changes, the processes, the procedures, especially monitor and QC the data and the documentation. "On-time" timelines and targets will be achieved if the practice of leadership, management and communication are performed religiously, thoroughly, completely, logically, logistically and concisely. Find the weakest link, whatever and where ever and "support" the link.

Global Project Leadership and Management for Clinical Submission occurs across all sponsor functions and all vendors, all tasks, all deliverables, all responsibilities, all accountabilities, all teams, contributing to the filing and the eventual submission -

• Regulatory
• Clinical
• Nonclinical
• CMC
• Data Management
• Statistics
• Programming
• Project
• Publishing
• Quality Control
• Quality Assurance
• Contributing Functions
• Outsourced, Contractors, Consultants, Vendors
• All Data
• All Databases, study level and global integrated
• Experts, Advisory Committees, Opinion Leaders
• Adjudicators
• Timelines, Tracking, Milestones, Monitoring, Communication, FDA Correspondence
• Pharmacovigilence.

Did I miss anyone, any team, any task, any function?