Submissions to Regulatory Authorities

This section of the chapter is an introduction to the submissions to regulatory authorities that are required under the regulations. It covers both the timing of submissions in relation to the drug development cycle and the content of submissions. Although this section is focused on FDA requirements, there are similar submission requirements for other developed countries. Once the data and documents have been assembled for a submission to the FDA, they can be used for similar submissions in other countries. Investigational New Drug (IND) applications, New Drug Applications (NDA), Biologic License Applications (BLA), and Abbreviated New Drug Applications (ANDA) will be covered.

All sponsors of investigational drugs or biologics are required to complete the registration process before they can legally market their product (Fig. 7.17). If any trials are conducted in human subjects or patients in the United States, this requires that the sponsor submit an IND application to the FDA. Technically, the FDA does not approve an IND. If the sponsor has not heard from the FDA 30 days after submission of their IND, they may proceed with clinical trials.

r Registration process r Contents of Investigational New Drug (IND) application r Applications for registration: c Contents of New Drug Application (NDA) and Biologics License Application (BLA):

Use of Common Technical Document c Contents of Abbreviated New Drug Application (ANDA)

Fig. 7.17. Submissions to Regulatory Authorities

Once a drug product has been developed and the sponsor believes it is ready for approval, they must prepare an application for its registration, which allows the sponsor to market the product. If the product is a new drug product, a NDA is submitted to the FDA for review and approval. If the product is a new biologic product, a BLA is submitted to the FDA for review and approval. The basic outline of the content of the NDA and the BLA are the same. Obviously, the content of the two submissions will differ based on one product being manufactured by a synthetic chemical process and another being manufactured by a biologic process. A supplemental NDA (sNDA) is used to change the labeling of a product, usually for new indications, formulations, dosing schema, and adverse experiences.

As discussed earlier in the chapter, under ICH, the format and outline of a CTD has been developed. As of 2005, sponsors can organize their submissions according to the older NDA/BLA outline. In the future, sponsors will be required to submit their registration packages according to the CTD format, and the submission must be made electronically. While legally the document is still considered a NDA or BLA, it is in the format of a CTD.

An ANDA is the appropriate registration package for a generic drug product. This package is a much smaller registration package than the NDA (hence the title "abbreviated"), because it is not necessary to repeat and report all the testing (e.g, toxicology studies, clinical trials) required for a new drug product. The focus is on pharmacokinetics studies ("bioequivalence"), manufacturing, and product quality. Currently, there is not a universal mechanism for the approval of a generic biologic product, primarily due to the complexity of the manufacturing process and the resultant impact on product performance in patients. However, the regulatory environment on that issue is changing, and it is believed that in time, there will be a legal mechanism for their approval.

Figure 7.18 illustrates the drug development process, with the interactions with the FDA added at the appropriate milestones during this process. Before an IND is submitted to the FDA, a pre-IND meeting with the appropriate review division of the FDA can be requested by the pharmaceutical company. A pre-IND meeting is not required but is highly recommended by FDA when a novel or innovative drug or biologic product is being developed. A pre-IND meeting, in which the development of the drug to date is discussed and the available data shared, provides a valuable exchange of information to assure both the FDA and the sponsor that the appropriate pre-clinical and chemistry work is completed prior to introducing the drug product into humans. This meeting can help avoid a "clinical hold" on the IND, a FDA regulatory action that will be discussed later in the chapter.

The sponsor is also encouraged, though not required, by FDA to meet sometime during the drug development process, typically in what's known as an "end-of-phase 2" meeting. It is at the end of phase 2 that a sponsor already has learned important elements regarding the performance of the investi-gational drug and is ready to launch into large, expensive, pivotal phase 3 trials, the results of which will be the basis for a drug or biologic product approval. Typically, the number of patients exposed to the investigational product will increase significantly in phase 3. For these reasons, it is in the best interest of the sponsor to gain feedback from the review division at the FDA on the remainder of the drug development program. This can help ensure that when the pivotal trials are completed, they will provide data considered scientifically necessary and complete for the drug's approval by FDA. During these meetings, the FDA is expected to comment on

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