The regulatory submission

Ultimately, the non-clinical data will form a substantial part of the regulatory submission that is required for marketing authorisation. 

The amount and type of data required in the regulatory submissions depends on the quantity of substance supplied. The tonnage requirements are ... 

Most clinical trials have problems, sometimes detected by inspection and audit. These can usually be resolved and, if so, the regulatory submission must include a full explanation of how they were dealt with. Therefore, an audit trail with all the data should be available, accompanied by a statement by QA confirming that the procedures have been audited. 

The position of the regulatory authorities is best illustrated by a recent Marketing Authorisation Application by Eli Lilly (www.emea.europa.eu/ humandocs/PDFs/EPAR/cymbalta/19256704en6.pdf) for their anti-depressant duloxetine. The phase III protocols specified a repeated measures ANOVA as the primary method of analysis and the regulatory submission was based on such analyses. The CPMP, however, asked for an additional simpler analysis based on change from baseline as the outcome measure and using LOCF. 

Once the regulatory submission has been made there will inevitably be questions and issues coming back from the regulators. There may be concerns about the way the data has been handled from a statistical point of view. There may be requests for additional specific analyses to resolve uncertainty. There may be more open issues that the regulators are unhappy with which may require a substantial amount of further analysis. At the extreme end there may be outright rejection and the company may then be back to the drawing board in terms of the product. In all of these cases there will usually be a need for further statistical considerations. 

Whereas the regulatory submissions must be in English, the FDA expects that raw data and original records may be in the native language, and this is acceptable there is no need to translate documents that are... 

Once the scale-up studies have been completed, it may be necessary to manufacture one or more batches at full scale to confirm that the entire manufacturing process, comprising several different unit operations, can be carried out smoothly. This may occur prior to or after the regulatory submission, depending on the strategy used in filing. 

Are stress-testing studies, the data from which may be included in the regulatory submission for a new drug entity, considered GMP studies ... 

The entire purpose of this report is to point the FDA toward a document that delineates the science and technology that went into making the product and that includes all preliminary studies right up to the regulatory submission stage. 

Lack of QA oversight and guidance during these critical final steps usually results in significant disparities between the material used during clinical trials and the information contained in the regulatory submission s CMC section. 

Naming the Main Folder. The main folder for the original submission should be named IXYZ, where XYZ contains abbreviations for the sponsor name, product, and indication. For this submission, you do not know the IND number nor can you generate it before the arrival of the regulatory submission. All amendments to the application should use the same main folder name as the original submission. 

At the commencement of the project there were several routes available for the synthetic construction of prostanoid compounds our challenge was which to choose. For this, we were mindful of the stereochemical features of the molecule and the need for a full stereochemical characterization of the active pharmaceutical ingredient (API) produced. This was required in the regulatory submissions,... 

Mindful of the various options available for the synthesis of travoprost by reference to the known chemical syntheses of the natural prostaglandins, our main concern, as stated earlier, was to ensure rigorous stereocontrol to simplify product-purihcation aspects and the regulatory submission. 

The fact that data, when generated with a certificate or a compliance statement, will now be accepted by all OECD member countries means that once the study is completed and the regulatory submission made, the time for acceptance several countries (if submissions are made in a multistate procedure) will be reduced dramatically. 

Research reports are also emphasized in early development before regulatory documentation is required. However, recent changes with respect to reductions in the documents and extent of data that must be provided in IND submissions are increasing the importance of internal documentation through early clinical development (i.e., phases 1 and 2). Specifically, FDA guidances on IND CMC requirements have reduced the amount of data required for inclusion in the IND. Summaries are often allowed in lieu of detailed data. However, from both a compliance and historical perspective, it is critical to collect these data in a report for future reference. Thus, the documentation requirements overall have not been reduced but have been removed from the regulatory submissions and added to the in-house archives. 

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