Five key steps for e-submission ready documents to avoid pre-submission rework - By Kathie Clark

It's been said that a new drug application is 100,000 pages (or more) in support of a label. While this might be a simplified view, it does provide some idea of the scope and challenges involved in preparing the enormous body of documentation that is needed to convince a regulatory authority that a product is safe and effective.

In taking a closer look at the required documentation, it's easy to see that a number of challenges await those responsible for assembling the submission:

Administrative and prescribing information. Agencies require a variety of forms, which may be locked down PDF fillable forms, XML forms, or scanned paper. Correspondence and certifications are required that may originate from a variety of different sources. Labeling required in a submission may take several forms ranging from MS Word documents showing tracked changes for draft labeling to XML (e.g., FDA's Structured Product Information).

Summaries and overviews. Because the documents depend on being able to analyze and reference final documents in other parts of the submission, the ability to finalize them depends on the other documents being available and stable.

Quality documents. In this area, the submission publisher must locate the correct content taking into account document versions and specific authority requirements. For example, different stability documents and compendial excipients may apply in different parts of the world, despite the harmonization goals of the International Council on Harmonization. Other challenges include the need to include scanned content such as batch records as well as manufacturing documents that may be subject to late modifications during manufacturing scale-up.

Nonclinical reports. Because the nonclinical program is so lengthy for most products, reports may be needed that were created five years ago or even earlier. The reports were often created by contract research organizations (CROs) or by scientists no longer working on the drug project. These factors often contribute to difficulties in locating reports and in issues related to the fact that they were not created to current standards.

Clinical reports. Clinical reports represent the largest portion of submission content, averaging around two-thirds of an application. In this area, the publisher must work with study reports that may not have been formatted in accordance with agency requirements, or that many exist in many small pieces. In the United States, a large volume of case report forms and SAS datasets must be assembled in accordance with their own specifications.

In the world of paper submissions, the assembly process was complicated, but largely free of technical compliance requirements. In other words, the publisher could take documents in many formats, assemble and print them, with the main concern being the appearance of the final paper product. If a problem was found, often a replacement page could be slipped in at the last moment.

Now, electronic submissions standards place many technical requirements on the individual documents included in a submission, resulting in a new set of quality assurance responsibilities that sometimes fall on a documentation group, but more often end up with the regulatory publisher.


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Five key steps for e-submission ready documents to avoid pre-submission rework - By Kathie Clark