The new drug application

The statistical review may also take a more global view and, in addition to evaluating the aspects of each protocol in a stand-alone fashion, evaluate how it fits in with and adds to the overall drug development program. 

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. 

Typically, sponsors meet with the FDA to discuss the content and format of an NDA prior to its preparation. Such a pre-NDA meeting can be crucial for the sponsor to understand the content and format that will best facilitate the review process for a given submission. 

The comments here focus on the statistical review of the NDA. The major difference between an IND and an NDA submission is that, when the NDA is submitted, the studies proposed in the IND have been conducted, and analysis and interpretation of the data collected are included. The FDA s review of the NDA focuses on determining if it finds the evidence concerning safety, efficacy, and manufacturing ability to be compelling and if it is therefore prepared to approve the drug for marketing. The FDA s statistical reviewers play a major role in making this determination. Statistical reviewers typically review both the Statistics and Clinical Data sections, and they are also available to review other sections. 

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. 

Upon completion of clinical trials, the sponsor will collate all the preclinical, clinical and other pertinent data (Table 4.10) and submit this to FDA in support of an application to allow the new drug to be placed upon the market. For CDER-related drugs, this submission document is termed an NDA. 

After initial submission of the NDA, the FDA has 45 days in which to undertake a preliminary inspection of the document, to ensure that everything is in order. They then file the NDA or, if more information/better information management is needed, they refuse to file until such changes are implemented by the sponsor. 

Each reviewer then prepares a review report. This is forwarded to their supervisory officers, who undertake a second review. All of the reports are then sent to the division director who, in turn, recommends rejection or approval, or asks the sponsor to provide more information. On average, this entire process takes some 12 months. 

Even when the NDA is approved and the product goes on sale, the sponsor must provide the FDA with further occasional reports. These can be in the form of scheduled annual reports, but also unscheduled reports are required in instances such as the occurrence of an unexpected adverse response to the drug. 

A small number of biotechnology products are classified as medical devices and, hence, are regulated by the Center for Devices and Radiological Health (CDRH). The first approved biotech product to come under the auspices of the CDRH was OP-1 implant. Marketed by Stryker Biotech, OP-1 implant is a sterile powder composed of recombinant human oestrogenic protein-1 (OP-1) along with bovine collagen. It is used to treat fractured bones that fail to heal. The product is mixed with sterile saline immediately before application, and entails surgical insertion of the paste into the fracture. 

A small number of biotechnology products are classified as medical devices and hence are regulated by the Center for Devices and Radiological Health. The first approved biotech product to come under the auspices of the CDRH was OP-1 implant. Marketed by Stryker 

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B. Drug Information from Phase I, II, and III Studies, The New Drug Application, and Product Approval/Launch... 

The physical properties of an API can significantly effect the physical and chemical stability of a formulation, its bioavailability and ultimately they can modify the pharmacokinetic profile of the drug. This issue will be discussed in more detail in section 3.4. For these reasons it is necessary to control the physical form of the API at the Pures crystallization step, and throughout the subsequent formulation steps, to ensure a consistent delivery profile to the patient. This control strategy must be documented in the New Drug Application... 

Common Technical Document The Changing Face of the New Drug Application... 

Excipients referenced in the New Drug Application, showing that they have been tested in laboratory and clinical trials... 

Sietsema WK. Preparing the New Drug Application—Managing Submissions Amid Changing Global Requirements, FDA News, Falls Church, VA, 2006. 

Even a modest new drug application will require a substantial investment of money and time. The financial expenditure includes the outlay for clinical trials to collect the data and to assemble the application. Time is also a crucial variable, because the only way to justify the expenditure is through sales of the product, making the remaining patent life an important variable in such a decision. If it is short, then the patent may expire before the new drug application can be assembled, submitted, and reviewed to receive labeling for that indication. 

The U.S. Food and Drug Administration (FDA) approved 22 new drugs and one biotech medicine during 1994. These new drug entities had an adjusted average review time of 19.7 months, from filing of the New Drug Application (NDA) at the FDA to time of approval. This was down from the 25.6 months for the 26 new entities approval in 1993. In the total... 

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