A. Investigational Compounds
An increasing number of worldwide regulatory authorities require the submission of relevant information supporting proposed clinical trials prior to the introduction of an experi-mental compound into man in their country. The terminology used for these investigational submissions differs from agency to agency. In the United States, the documentation is called an Investigational New Drug Application (IND); in the U.K.
its a Clinical Studies Exemption (CTX); in other European and international markets, the term used is Clinical Studies Authorization (CSA); and in Canada the document is referred to as an Investigational New Drug Submission (INDS). Gen-erally, the document covers a specific clinical program for a desired therapeutic indication in a target patient population, and must be kept current throughout the clinical develop-ment program. Modifications of the indication or target population often require a separate original investigational application.
The original investigational applications and subsequent updates are formally reviewed by the agencies. For original applications, the clinical studies may typically be initiated
after a prescribed time following submission, unless the company is informed otherwise by a particular agency (e.g., clinical hold). The agency reviewers may and often do submit questions to the company based on the investigational applica-tion, and should clearly communicate whether studies may proceed prior to the resolution of the issues. Frequently, guidance for the ongoing development program is provided by the agency through these questions. Formal responses on all issues should be provided to the agency in an expeditious manner. Often, the responses include commitments for addi-tional investigations as development progresses.
This investigational documentation typically includes CMC information on the chemical characteristics, manufac-ture, control and stability of the API, and any formulations planned for evaluation in the clinic. For early development candidates, often a brief overview of the API synthesis and summaries of the characterization of the compound and applicable specifications (tests and acceptance limits) are suf-ficient to allow initiation of clinical trials. As the development program progresses and the compound is to be introduced into larger numbers of patients, more detailed supporting docu-mentation is generally required for the API. Significant changes in the manufacture, characteristics, or controls for the API must be communicated to the regulatory agencies prior to use of the material in ongoing clinical studies, through updates or amendments to the investigational appli-cation. Periodic updates documenting other, less critical changes, should also be submitted during the clinical program (e.g., on an annual basis). Often, the updates to the investiga-tional filings provide useful references for generating histori-cal background information on the development program for inclusion in original marketing applications.
B. Application for Marketing
Research-oriented companies will evaluate a number of investigational compounds for potential therapeutic indica-tions. A majority of the potential candidates do not survive the safety and efficacy studies conducted as part of the clinical
development program. Those that are found to be safe and effective toward a specific indication must be registered with regulatory agencies worldwide, prior to their being made avail-able for sale in that market. The process by which compounds are submitted for approval to market is very similar through-out most of the world. Specifically, a detailed application must be submitted to the recognized regulatory authority in the country, and that authority reviews the contents and renders their acceptance, conditional acceptance, or rejection of the application. As is the case for the investigational application, several different names are used to describe the marketing application in various countries. These include an NDA in the United States, an NDS in Canada, and a Pharmaceutical Dossier in Europe.
While the registration procedure is similar and the recent adoption of the common technical document (CTD) has begun to standardize the format for regulatory submis-sions, the content of the quality (CMC) section of the market-ing application required by different countries, particularly as it relates to information on the API, varies significantly. In a number of countries, very limited, if any, information is required on the manufacture and control of the API, while in others (e.g., the United States, the EU, Canada, Israel, and Australia) very detailed information and supporting data are required on the characterization, manufacture, control, and stability of the API. A subsequent portion of this chapter covers the information supporting the API to be included in marketing applications for these concerned markets.
Following submission of the application, certain agencies will perform a high-level review of its content to assure that all basic elements are contained in the submission. Once the application is considered accepted for filing, the reviewing chemist or authority from each agency will perform a very detailed evaluation of the CMC documentation, and where appropriate will provide specific questions or comments on the content of the documentation. The CMC questions often seek clarification or additional information or data on specific items, or state concerns the reviewer has with the content or conclusions provided for certain aspects of the application.
Formal responses to each question must be provided to the agency. Timing for responses varies from country to country, but generally the rapid submission of complete responses is desirable to both the reviewer and the company. In most instances, delays in responding to the questions will result in a delay in the approval timing for the marketing application.
It should be noted that knowledge of, and adherence to the expectations documented in published agency guidelines gen-erally could minimize the number and=or severity of chemistry questions received on a specific application.
Once the concerns on all aspects of the application, including CMC, are addressed to the satisfaction of the reviewing authority, an official ‘‘action letter’’ is typically provided to the sponsor of the application, to formally allow marketing of the product in that country. Sometimes, condi-tions for approval are stated in the letter. These condicondi-tions should be specific with respect to their impact on the market-ing of the product, and often must be satisfied before product is sold.
In the mid to later part of the 1990s, procedures were established to allow for more timely review and approval of marketing applications in the both European Union and the United States. The review process to be used and the timing for approval are defined by the local regulations, and are dependent upon the immediate therapeutic need for the pro-duct. The EU mutual recognition and centralized procedures and the U.S. Prescription Drug User Fee Act (PDUFA) will be discussed in more detail later in this chapter.
C. Postapproval Requirements
Following approval of the marketing applications, it is neces-sary that the CMC information on file with each regulatory agency remains current and accurate. Unfortunately, there are a wide variety of mechanisms that must be followed in the various countries=regions to communicate changes that are required or desired post approval. The mechanisms to be used are often linked to the nature of the proposed change, and its potential to impact the quality (chemical and physical)
or safety of the API and ultimately, the quality, potency, safety, or efficacy of the final drug product. Changes having a moderate to significant chance of impacting any of these characteristics generally require approval by the agency prior to the marketing of product containing API made or tested by the changed route. In certain markets, changes having a minimal chance of impacting these characteristics can gener-ally be implemented (i.e., product using API made=tested by the changed route can be marketed), and the agencies are simultaneously or even subsequently notified of these changes via an appropriately defined mechanism. Further details on evaluating and reporting postapproval changes are provided later in this chapter.
Of critical importance in the maintenance of registered information is the existence and implementation of strong change control procedures. For the API, procedures should be in place to address changes to the manufacturing process, (controls and parameters), specifications (analytical test procedures and acceptance criteria), equipment cleaning pro-cedures, raw materials, and=or their acceptance criteria, packaging, etc. These procedures should be consistent with current cGMPs and are often the focus of agency inspections.
Defined change control procedures should also be included as part of supply agreements with certain vendors (e.g., suppli-ers of key starting raw materials and packaging components), since changes made by these suppliers could result in the need for regulatory submissions by the user, which poten-tially could require prior agency approval.
III. CONTENTS OF REGULATORY