Ind Submitted





Fig. 7.18. Registration Process the design of the proposed pivotal clinical studies, the selected doses and comparator drugs, and the adequacy of the preclinical and drug product formulation data needed to advance the drug into phase 3 of development. This is an appropriate forum for the sponsor and the FDA to respectfully disagree and debate scientific and/or regulatory issues.

Oftentimes, the next meeting with the sponsor and the FDA comes after the completion of the pivotal phase 3 trials and before the submission of the NDA. This is an opportunity for the sponsor to present, in general, the contents of the NDA. The main objective of the meeting is to familiarize the FDA with the anticipated data package and to discuss the format of the data so that it suits the FDA requirements for review. The FDA review division may have some special requests for data analyses and presentation that will help facilitate a rapid review.

As discussed earlier, after the application is submitted and during the FDA review process, a sponsor may be invited to present their data at a FDA Advisory Committee meeting. This is typically done when the FDA is creating new policy with the potential approval of a new drug or biologic or when the FDA believes the data warrant additional scrutiny. Advisory committees are covered more fully later in the chapter.

Although it is not a regulatory requirement that a sponsor to meet with the FDA during the development and review of a new drug or biologic product, it is highly recommended that the sponsor take advantage of every opportunity to discuss their data and plans with the FDA. This helps ensure that both parties are in agreement in principle on the plans going forward and helps to avoid unpleasant surprises during the process. And during the process, a sponsor would ignore the advice of the agency at their own peril. Most face-to-face meetings with the FDA include representatives from multiple scientific disciplines from both the agency and the sponsor. They are typically excellent opportunities to learn the multi-disciplinary scientific and regulatory approach used by the FDA in their review of investigational drug products.

Though the above has described the typical face-to-face meetings with the FDA during drug development and approval, there are numerous interactions via phone, fax, and e-mail during the process. It is the responsibility of the regulatory affairs professional to be the single initial point of contact with the agency in order to manage the myriad interactions with the FDA, ensure that the sponsor is speaking with one consistent voice to the agency, and avoid pitfalls at a later time.

An IND application is required to be submitted to the FDA before a sponsor initiates any trial administering investiga-tional drugs or biologics to humans in the United States (Fig. 7.19). Countries outside the United States have a process similar to the IND that is required. As stated in the IND regulations, the primary objectives in the FDA's review of an IND are to "assure the safety and rights of human subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the r Purpose of IND r Regulatory Requirements r Contents of Investigational New Drug (IND) application: o Introductory Statement o General Investigational Plan o Investigator Brochure o Study protocol(s)

o Investigator, facilities and Institutional Review Board data o Chemistry, manufacturing and control data o Pharmacology and Toxicology data o Previous Human Experience r Types of INDs

Fig. 7.19. Investigational New Drug (IND) Application drug's effectiveness and safety." If a sponsor company elects to conduct clinical trials with investigational drugs outside the United States, an IND is not required to be submitted to the FDA, though a sponsor may opt to submit an IND. Having an IND in place at the FDA gives the sponsor access to the advice and opinion of the agency and is very useful if the trials conducted outside the United States are intended to be used to support an application for a new drug or biologic in the United States.

The regulations written to regulate the IND process include a high-level description of the requirements for data in an IND. Most of these requirements are described in more detail in guidance documents issued by CDER and CBER within FDA and provide more instruction to sponsor companies on the requirements.

Once an IND is submitted to the FDA, the agency has 30 days to review the document. If the FDA reviewers are satisfied that the proposed clinical trial can proceed safely, the sponsor can assume that they can proceed once the 30 days have passed. If however, upon review, the FDA finds that critical data are missing, or that the clinical trial is not appropriate as proposed, the agency can place a "clinical hold" on an IND. The sponsor is not allowed to begin the proposed clinical trial until the concerns of the FDA have been satisfied and the agency has notified the sponsor that the clinical hold has been lifted. A clinical hold can take a few days to resolve (a relatively small change in the clinical protocol), or take months (an additional pre clinical study is required and the data submitted to the FDA before the clinical trial can begin). A pre-IND meeting, as described in the previous discussion, can help the sponsor avoid a clinical hold by thoroughly understanding the agency's requirements and incorporating these into the IND.

The contents of an IND application are usually straightforward and can be contained in a few hundred pages. Figure. 7.19 lists the main contents of an IND, as required by the regulations. The introductory statement and general investigational plan provide a general description of the drug or biologic product, and the general nature of at least the first clinical study proposed to be conducted, as well as the therapeutic indication of interest. The investigator brochure is a required document throughout the life of the investigational product, requiring periodic updating as additional data are obtained. It is basically the precursor to the package insert of the marketed product, informing all the clinical investigators of the available, pertinent information about the drug product's safety and efficacy. The protocol submitted is the first clinical protocol that will be followed in the clinic, assuming the IND is not placed on clinical hold. A brief description of the identity and credentials of the investigator(s) and institutional review board(s) responsible for the study are reported in the IND. The remainder of the document is the accumulated information on the chemistry, manufacturing and control data for the drug substance and drug product and the preclinical pharmacology, pharmacokinetic, and toxicology data.

Once an IND is submitted to the FDA, there is an ongoing obligation by the sponsor to maintain the IND. All new clinical protocols must be submitted to the IND before they can be initiated. Additionally, updated investigator brochures, information on additional clinical investigators, additional chemistry and manufacturing data, additional preclinical information, and any clinical data that have an impact on the evaluation of the safety of the drug or biologic product are required to be submitted in a timely fashion. If at any time the FDA deems it appropriate to stop the clinical investigation of the product, they may place an entire IND or a specific clinical trial on "clinical hold."

An IND must have a sponsor, who is legally responsible for the conduct of the investigations conducted under an IND. The most common sponsors are pharmaceutical and biotechnology companies and clinical investigators. An "investigator IND" is a mechanism for a clinical investigator(s) to conduct a clinical trial with an investigational drug product. Oftentimes, they are allowed to reference the pharmaceutical or biotechnology sponsor's IND for the same drug product, to provide the necessary chemistry, manufacturing and control data, and preclinical data to support the use of the product in humans.

IND sponsors can also file a "treatment IND" as a mechanism to provide new drugs not yet approved to patients with serious or life-threatening illnesses as well as illnesses where there is no alternative treatments. In order for FDA to allow enrollment under a treatment IND, some evidence of efficacy must have been demonstrated. Patients who are enrolled under a treatment IND are not eligible to participate in pivotal studies of the drug; however, safety and efficacy data are evaluated in the context of all clinical trials. Unlike a traditional IND, sponsors can require patients who are enrolled under a treatment IND to pay for the drug prior to commercial approval. Compassionate use, also called emergency use, does not require submission of an IND and is reserved for very rare life-threatening situations where there is not time to obtain IRB approval. In this situation, the sponsor and treating physician work closely with the FDA to exchange the necessary information so that the drug can be administered expeditiously.

r Purpose of applications for NDA or BLA

r Contents of New Drug Application / Biologic License Application:

c Administrative information o Chemistry, manufacturing, and controls o Nonclinical pharmacology and toxicology o Human pharmacokinetics and bioavailability c Microbiology (for an anti-infective)

o Clinical data o Statistics o Pediatric use o Samples and Labeling o Case report forms and tabulations o Patent information and certification o Financial certification or disclosure

Fig. 7.20. Applications - NDA/BLA

Once a sponsor has completed all the required phases of drug development, and in their opinion the cumulative data demonstrate that a drug or biologic is safe and effective, the next step is submission of a NDA for a drug product or a BLA for a biologic product (Fig. 7.20). Approval of either a NDA or BLA by the FDA is required before the product can be marketed and sold in the United States. Unlike an IND, which can be as small as a few hundred pages, a NDA or BLA is voluminous, in the tens of thousands of pages, and often surpassing 100,000 pages. Given the extent of the documentation required, it is no surprise that FDA will require in the near future that all NDA or BLA submissions be made electronically, which allows for easy and efficient navigation through a large submission and access to electronic data sets for analyses by FDA reviewers.

Once a sponsor submits a NDA or BLA, the FDA has 60 days to do a high-level review of the submission to determine if it has all the required elements and is organized appropriately to facilitate the review. If they find that the submission meets this threshold determination, the FDA officially files the submission and notifies the sponsor. In the event the FDA determines that the submission does not meet the threshold requirements, it will issue a "refusal to file" letter to the sponsor. The agency will not proceed with the review until the necessary changes to the submission are made by the sponsor.

The content of a NDA or BLA is established through the regulations. There are numerous guidance documents that provide the sponsor further instruction on the content, organization, and electronic formatting of a submission. Figure 7.20 provides a listing of the content categories of every new NDA or BLA. The submission is extensive in its requirements. It includes all the scientific data to demonstrate that the product manufactured is a quality product with adequate manufacturing controls; all the pertinent preclinical data to demonstrate the acceptable pharmacology, pharmacokinetics, and toxicology of the drug substance and product; reports of clinical pharmacokinetic trials; and reports from all clinical trials for the indication under review. Case report forms of patients who died or were withdrawn from the study are also included. All clinical safety data, regardless of the clinical study from which it was collected, must be submitted. The proposed package insert also is required in a NDA or BLA.

In addition to the scientific data, there are a number of requirements for administrative documents, including information about the patents that pertain to the product being reviewed, and financial disclosure of all clinical investigators that reveal any potential conflict of interest that might have influenced the outcome of clinical studies.

As mentioned earlier in the chapter, the International Conference on Harmonization (ICH) has developed a format for the organization of a NDA or BLA and their equivalent in countries outside the United States (Fig. 7.21). This format is the CTD. This format, now accepted by the United States, European, and Japanese regulatory authorities and those of other selected countries, greatly enhances the efficiency of the assembly of a registration package for submission in multiple countries. The content of the CTD has been outlined in modules, and they build upon each other.

Starting at the bottom of the pyramid, the CTD includes a module (no. 3) for quality (drug or biologic substance and drug or biologic product), a nonclinical module (no. 4) (animal pharmacology, toxicology, and pharmacokinetics), and a clinical module (no. 5) (human pharmacokinetics, clinical pharmacology, safety, and efficacy). These modules contain all the required data in its most granular form. These modules contain the data upon which all the data interpretations and conclusions regarding the safety and efficacy of the drug or biologic product are made. The data listings provided allow the FDA reviewer to conduct their own data review, for example, statistical analyses and pharmacokinetic modeling.

The next layer of the pyramid includes a distillation, summarization, and critical evaluation of each of the three modules in the bottom layer in the form of summaries or reviews. In this module (no. 2), the sponsor needs to really understand and fairly present their interpretation of the accumulated data. It is the sponsor's responsibility not only to highlight the positive aspects of the drug or biologic product but also to critically analyze any shortcomings of the product and what additional study should be done to better understand its appropriate use.

The top layer of the pyramid does not technically fall into the CTD, as there is not commonality in module 1 across all countries. The only commonality is that module 1 is reserved for the particular administrative aspects of a registration package required by each individual country. For example, in the U.S. NDA or BLA, module 1 is the appropriate section to include information about the U.S. patents that pertain to the drug or biologic.

Based on this CTD approach to the assembly of a submission, a sponsor can prepare modules 2-5 for submission to all regulatory authorities in the developed world. The only tailoring required for each country is module 1. The advantages of the CTD approach to the sponsor are obvious, and there are also advantages to the FDA and their counterparts. In the process of developing the CTD, the FDA was able to help design the structure of a submission that makes it very efficient for their review. By having all sponsors follow the exact same format for an electronic submission that FDA helped design, they are able to more easily navigate through a large number of submissions more quickly.

An ANDA is prepared when a sponsor is seeking registration of a generic drug product. A drug product is considered a generic if it is "identical in active ingredient(s), dosage form, strength, route of administration, and conditions of use"

Fig. 7.21. Schematic of ICH Common Technical Document (CTD)

^ Basis for ANDA r Conditions of use r Active ingredients r Route of administration, dosage form, and strength r Bioequivalence r Labeling r Chemistry, manufacturing, and controls r Samples r Patent certification r Financial certification or disclosure

Fig. 7.22. Abbreviated New Drug Application (ANDA)

to an approved drug product. The sponsor of a generic drug product is not required to repeat the clinical studies necessary to determine that the drug is safe and effective.

The elements of an ANDA are listed in Fig. 7.22. The primary scientific elements of the ANDA include the chemistry, manufacturing and controls data that demonstrate that the sponsor has developed and can consistently manufacture a quality product. Data demonstrating the generic product is bioequivalent to the approved brand-name product also must be submitted unless the product is completely bioavailable, such as with an oral syrup. The sponsor must also submit the proposed labeling (package insert) of the generic product. This labeling must be fundamentally identical to the labeling for the approved drug product, including only those indications that are no longer covered by patents held by the sponsor of the brand-name product. The remainder of the ANDA is primarily administrative information.

A generic company may submit an ANDA well in advance of the expiration of all the relevant patents on the drug substance and drug product. In this case, under completion of their review, the FDA can give a "tentative approval." In the case of a tentative approval, the generic company has approval to market their generic product only after all the pertaining patents for the brand-name product have expired.

As mentioned earlier, at the time of this writing, there is not a universal regulatory mechanism for the review and approval of a generic biologic product. However, the FDA is carefully evaluating the requirements for demonstrating equivalence between two biologics products, and it is anticipated that there will be a regulatory pathway for the approval of generic biologic products (called "follow-on biologics") in the near future.

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