Introduction to Regulatory Affairs
There are three kinds of people in all types of organizations—rowboat people, sailboat people, and steamboat people. Rowboat people need to be pushed or shoved along. Sailboat people move when a favorable wind is blowing. Steamboat people move continuously, through calm or storm. They usually are masters of themselves, their surroundings, and their fate.
–Anonymous
The world of regulations affecting the pharmaceutical industry changes as rapidly as the world of science (usually in response to scientific and political changes), but there is an additional complicating factor in the field of pharmaceutical regulatory affairs: Whereas scientific findings and theories are the same internationally, regulations often differ markedly between countries, at least in practice. Many national regulatory authorities may focus more attention on a different set of functions or disciplines, and use different criteria to evaluate regulatory applications, even if the application is identical to one their neighboring country is also reviewing. Within the European Union, however, the countries are becoming more harmonized in their regulatory requirements. Approaches to reviewing applications and maintaining public welfare differ among countries, even though all regulatory authorities have the same intention of maintaining (or even raising) high medical and technical standards and improving the health of their country’s population. Fortunately, many regulatory authorities, particularly those in Europe, and others that have embraced the International Conference of Harmonisation (ICH) guidelines and its Common Technical Document (CTD) have moved closer together both in requirements and in terms of interauthority communication.
The regulatory affairs department within a pharmaceutical company is unique in several ways. First, the department may be located organizationally in several different areas (e.g., research, clinical research, development, legal, marketing) or it may be organizationally independent of these traditional groups. Second, regulatory affairs personnel are usually the only people within a company who are authorized to speak and interact with regulatory authorities, except at regulatory agency meetings to which other company personnel are invited. Third, because the output of their efforts is so critical to the success (and in some cases the existence) of a company, they are often in the main spotlight of a company. While being in a spotlight can be enjoyable, finding a searchlight or inquisitor’s light shining on one is generally unpleasant. The switch from being in the limelight to being under the third degree sometimes occurs very rapidly. Overall, the regulatory affairs group may be viewed as the critical liaison between the pharmaceutical industry and government regulatory authorities.
This chapter presents two approaches for viewing the roles of the regulatory affairs group of a pharmaceutical company: by function and by organizational level—and then discusses a number of issues relating to how those roles are carried out.
FUNCTIONS OF A REGULATORY AFFAIRS GROUP
Various functions of most regulatory affairs groups are listed in Table 85.1 and several of these are described in more detail in the following text.
Developing Regulatory Strategies
A simplified approach to creating regulatory strategies is to answer the following questions. The answers to each of these questions may be thought of as either points on a spectrum or as discrete choices for each question.
Should the regulatory submission contain data for a “lean” or “fat” development plan? The terms lean and fat refer to the number of studies conducted in each area of development (e.g., toxicology, medical, preclinical), the number of patients or animals in each study, and the amount of data collected on each patient or animal. The answer to this question is ideally based on a benefit-to-risk assessment for any drug, on special status or need (e.g., an important orphan drug versus a me-too drug), as well as on special regulations that may be utilized [e.g., accelerated approval, Treatment Investigational New Drug Application (IND)]. Because all data available to the company from anywhere in the world must be filed on a new drug for most regulatory authorities, the choice of a fat versus lean plan must be considered at the outset of a new drug’s development. Nonetheless, it is common for a submission to be lean in some aspects and fat in others. Failure to plan a drug’s development internationally at the outset of its development may lead to undesired data being obtained and force a company to adopt a different regulatory strategy than the preferred one.
Table 85.1 Selected functions of regulatory affairs professionals
1.
Ensure compliance of regulatory submissions with relevant regulations.
2.
Ensure compliance of relevant activities and reports with GMP, GLP, and GCP.
3.
Serve as a liaison with one or more regulatory authorities.
4.
Serve as liaison with the headquarters or subsidiaries of the company.
5.
Serve as a member on project teams and guide the direction of various activities using a regulatory perspective.
6.
Attend relevant meetings of regulatory authorities that discuss the company’s drugs.
7.
Attend relevant open meetings of the regulatory authorities discussing competitors’ drugs.
8.
Write letters and telephone regulatory authorities as appropriate to ask or answer questions or to present information.
9.
Follow relevant pharmaceutical news and events through reading professional literature, attending professional meetings, and contacting one’s network.
10.
Help develop and propose a regulatory strategy for the company and for individual drugs.
11.
Maintain records of all regulatory submissions and provide an information retrieval service for company staff.
GMP, Good Manufacturing Practices; GLP, Good Laboratory Practices; GCP, Good Clinical Practices.
Should a single regulatory submission for marketing authorization [e.g., New Drug Application (NDA)] be made for multiple dosage forms, indications or routes of administration, or should a separate regulatory submission be made for each dosage form, indication, or route of administration? The answer to this question is often a matter of senior research and development (R and D) managers trying to second-guess the reviewing policy of a specific regulatory authority as well as marketing managers trying to second-guess the reception
of the drug for each dosage form in the marketplace. Secondguessing the actions of a regulatory authority is seldom possible, despite the most sophisticated reviews of the regulatory affairs staff. A limiting factor is that many companies are unable to co-develop multiple dosage forms or routes of administration simultaneously and submit applications at the same (or nearly the same) time.
Should the initial regulatory submission for marketing authorization (e.g., NDA) be made in the country in which (a) the fastest approval is expected, (b) the least amount of data are required, (c) the largest market exists, or (d) the best opportunity exists to obtain postmarketing data? Alternatively, should the submission be delayed until it is submitted to many countries simultaneously? Most companies, particularly the mid- and large-sized companies, now follow the last approach whenever possible. Nonetheless, regulatory applications in Japan usually follow a few years later for practical reasons.
By submitting a similar dossier with the same data to many countries simultaneously, one avoids the potential problem of having to redo expert reports for new dossiers when additional data are obtained. This could create major problems if different interpretations are reached in different versions of an expert’s report, or in reports written by two or more experts at various times. Within Europe, this is becoming much less of an issue since the CTD was approved in 2000, and also because dossier generally are submitted to all European members of the European Union at one time. For many other countries, the question of resolving differences between submissions still exists; but this issue is less relevant in almost all countries that receive submissions several years after the initial ones are submitted.
Even when a company will use the ICH guidelines and follow the CTD format, there is still a question about how large the core package of data should be. Should it be as small as possible or quite large with many modules that may be used in multiple submissions? A large core package without the ability to separate it into individual modules should be avoided. The question of core size should be addressed at the outset of a new drug’s development. Many of the issues surrounding this question are discussed in Guide to Clinical Trials (Spilker 1991).
Should an electronic submission be made to a regulatory agency, and if so, what part(s) of the application should be submitted electronically? There is a range of possible options for electronic submission, from submitting submissionenabling, word-processing capabilities to be achieved to supplying raw data (plus reports), which enables the regulatory authority to freely explore new analyses. Interactions with the regulatory authority about the type and format of electronic submission [e.g., electronic CTD (e-CTD)] should begin early in the development process. The experience and skills of the regulatory affairs group with electronic submissions varies widely among companies, but the number of electronic submissions is expected to increase, even though adoption has been much slower than anticipated (see Chapter 71).
Should a company proactively interact with a regulatory authority at all stages of the development process, or should it adopt a totally reactive position—only responding to questions from the regulatory authority? The author believes it is particularly important to prepare the regulatory authority to view an application on a novel drug in the way the company believes is most appropriate. Submitting a novel regulatory application without attempting to prepare the mindset of the regulators is likely to lead to delays in its processing and review. In the United States, there are specified times during a drug’s development when it is appropriate to present and discuss data and plans with the Food and Drug Administration (FDA). These occur usually at the end of Phases 1 and 2 and at the pre-NDA stage, although meetings at other times (e.g., before the filing of an IND) are possible and generally held. The pre-IND meeting for example, may be held shortly prior to its submission or a year or more prior to this submission. The rationale for holding the meeting a long time in advance of submitting the IND is to seek regulatory agency advice on questions the company has about studies it needs to conduct for the IND in the chemistry, manufacturing, and controls or preclinical areas.
Should the company attempt to anticipate all important questions that could be raised about the application and conduct studies to answer them? While this question may seem foolish, there are companies that seek to do this. A balance should be sought between preventing the waste of company resources in attempting to be able to address all important questions and obtaining data to answer the most obvious (and most likely to be asked) questions. No company could ever obtain a sufficient amount of data to be able to address all relevant and important questions by regulatory authorities. Data that address subtle questions about nuances of the drug’s characterization or activity are unlikely to be required prior to the drug’s approval. It is possible to determine the most likely questions to be raised. Collecting data to address these questions is likely to enhance the likelihood of the drug’s approval, even if the data are collected after the application is submitted (but prior to its approval).
How should the company respond to questions from regulatory authorities about a regulatory submission? The company may respond anew to each request for information, and it may have established standard operating procedures for responding to regulatory questions. Major regulatory agency letters requesting data and information can be assigned to a task force or to an individual who can prepare a written response or coordinate the work needed to obtain a response.
Should the regulatory strategies be designed to achieve regulatory success or to achieve commercial success? The former type of strategy focuses on obtaining approvals most rapidly. The latter type involves attempts to achieve the greatest market share by influencing decision leaders, planning symposia, developing an approach to publications, and conducting appropriate clinical trials, including those evaluating quality-of-life and pharmacoeconomic endpoints. Ideally, the regulatory strategies chosen will attain both goals.
Interacting with Company Staff
Regulatory affairs staff should be present on all project teams and all relevant committees within the organization. Thus, the staff can provide regulatory input, answer questions, and instill relevant regulatory concepts to enhance drug development. Frequent personal interactions with company staff throughout the organization are required to fulfill the mission of regulatory affairs.
Interacting with Regulatory Authorities
The scope of interactions between regulatory affairs professionals and regulatory authorities depends on the country involved, the company’s philosophy, and the type of interaction being
considered. Regulatory affairs professionals often act as a liaison between personnel in the company (e.g., medical staff, technical development staff) and regulatory authorities. This coordinating role is crucial because it prevents people in the company independently or semi-independently interacting with regulatory authorities. That approach would undoubtedly lead to major problems if different people said different things to regulatory authorities, or if the statements of different people were understood differently than intended. Regulatory affairs personnel document all interactions with regulators, whether in writing, on the telephone or electronically. Some of the topics frequently discussed with regulatory authorities are listed in Table 85.2 and Table 85.3 and types of documents submitted are listed in Table 85.4.
considered. Regulatory affairs professionals often act as a liaison between personnel in the company (e.g., medical staff, technical development staff) and regulatory authorities. This coordinating role is crucial because it prevents people in the company independently or semi-independently interacting with regulatory authorities. That approach would undoubtedly lead to major problems if different people said different things to regulatory authorities, or if the statements of different people were understood differently than intended. Regulatory affairs personnel document all interactions with regulators, whether in writing, on the telephone or electronically. Some of the topics frequently discussed with regulatory authorities are listed in Table 85.2 and Table 85.3 and types of documents submitted are listed in Table 85.4.
Table 85.2 Selected topics that may be discussed between a regulatory affairs department and regulatory authorities on an investigational drug’s development or dossier | ||||||||||||||||||||||||||||||||||||
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Table 85.3 Selected topics that may be discussed between a regulatory affairs department and regulatory authorities on marketed drugs | ||||||||||||||||||||||||||
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Preparing/Publishing Documents for Regulatory Submissions
The format and content of all regulatory submissions must be evaluated to ensure that they comply with all appropriate regulations. Although regulations differ around the world, major steps toward harmonization have been and continue to occur, primarily through the aegis of the ICH. Preparing and submitting regulatory documents to a regulatory authority may be viewed as a publication activity. This activity involves collecting manuscripts and reports, and then copyediting them to assure within and between section consistency in terminology and data plus deciding if any explanation (or White Paper) is required to indicate how the data fit the overall picture. Once those steps are completed, it is necessary to paginate the documents, indexing the contents, adding cross-references, copying and binding them, and then distributing the copies (Table 85.5).
This is an extremely complex and difficult process to carry out efficiently and cannot be done rapidly. Often, the parts of a submission that are available first can be processed before the later sections are delivered. However, the final reviews and data consistency checks, when omitted, will almost always slow the Agency’s review by introducing unnecessary questions. Once errors and negative agency interpretations find their way into the regulatory file there is no way to remove them. Documents must be well organized and written in a style that is easy to read and understand.
Table 85.4 Selected types of documents submitted to regulatory authorities | ||||||||||||||||||||||||||||||||||
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The submission should also be easy for reviewers to follow in terms of scientific logic and internal consistency (e.g., the accepted practice is to proceed in order from small to large animals in presenting data and results for toxicology and pharmacokinetic studies, Phase 1 clinical data are ordinarily presented separately from the rest of the clinical data). Even though the European expert reports are not required in the CTD, they are still sometimes included in regulatory dossiers. The style of expert reports should adhere to preferences of the regulators. Every page of an NDA should have a document page number and an NDA page number, and the application must comply with appropriate formats.
Some of the problems previously encountered in this process (e.g., time required, inconsistencies of various types) resulted from the manual collection of reports, manual page numbering, retyping of reports; inability to merge text and graphics; large quantities of hardcopy to file; manual creation of indexes, references, tables of contents; and inclusion of different types and prints in the report. Electronic publishing has been an effective means of addressing and minimizing (and in some cases eliminating) these problems.
Table 85.5 Selected steps in preparing documents for regulatory submissiona | ||||||||||||||||||||||||||||||||
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MAJOR ORGANIZATIONAL LEVELS AT WHICH REGULATORY AFFAIRS PROFESSIONALS OPERATE
Regulatory Authorities
Interactions between regulatory affairs groups within a company and regulatory authorities occur on a daily basis between and across all hierarchical levels (Fig. 85.1) and on an extremely wide range of subjects.
A few of the topics discussed on investigational drug dossiers (Table 85.3) and general regulatory issues (Table 85.4) are listed. Other interactions between a company and a regulatory authority are presented in other sections of this chapter. The nature and extent of interactions depends both on the country and the specific company’s philosophy.
Pharmaceutical Company Level Interactions
Regulatory affairs is one of the most critical areas for senior corporate executives to focus on in charting the future course and prospects for a company. The head of the company’s regulatory
group will regularly report on progress and problems to all major company groups, including the board of directors. Regulatory affairs groups usually are asked to make predictions about when the company can expect to receive regulatory approval of the company’s submissions. Predictions are also requested about questions the various regulatory authorities are likely to raise on a wide variety of topics. A company’s course of regulatory action, marketing plans, and manufacturing plans are usually significantly influenced by these predictions.
group will regularly report on progress and problems to all major company groups, including the board of directors. Regulatory affairs groups usually are asked to make predictions about when the company can expect to receive regulatory approval of the company’s submissions. Predictions are also requested about questions the various regulatory authorities are likely to raise on a wide variety of topics. A company’s course of regulatory action, marketing plans, and manufacturing plans are usually significantly influenced by these predictions.
 Figure 85.1 Two schematics of the hierarchies within the FDA and a pharmaceutical company. The dark lines encase those individuals who are the primary contacts that interact and liaise with the other hierarchy; however, using a single liaison is desirable. |
Interactions of Regulatory Affairs with Other Corporate Divisions
The regulatory affairs group may play a major or minor role in determining the company’s regulatory strategy, depending on decisions made by the most senior executives. Regulatory affairs will influence and coordinate administrative activities that have a direct regulatory effect within many of the corporate divisions (e.g., R and D, marketing, legal). These interactions include conducting various analyses of the company’s performance, including time taken by regulatory agencies for approvals from year to year, and predictions for the near and long-term future submissions and approvals. Tables, graphs, and textual material are prepared to illustrate activities, status, or trends of interest to relevant managers. The best formats and presentations are those that have been well received in the past by each group. A proactive approach by regulatory affairs professionals to influence each project team will help ensure that the various departments involved in development conduct the correct studies and write reports in a way to facilitate a smooth and expeditious approval process.
Regulatory Affairs Department Interactions
Regulatory affairs act as the coordinating group that consolidates all reports and data before they are submitted to regulatory authorities. Activities that expedite dossier submission must be handled with the greatest efficiency possible within the organization. In some cases, a number of professional writers who prepare reports are based within the regulatory affairs group. Regulatory activities could be conducted using different types of organizational structure and standard operating procedures. The optimal organization and standard operating procedures would depend to some degree on the specific company and its traditions, operations, philosophy and management style. A number of organizational structures are described later in this chapter.
A SPONSOR’S ORIENTATION TO REGULATORY AUTHORITIES
Being Passive versus Active Regarding the Contents of Regulatory Submissions
Different companies have different attitudes about the value of having regulatory affairs professionals actively involved in determining the content of submissions. At one extreme, the regulatory group is viewed as a service group within a company that merely collects whatever reports other groups prepare (often based on their own research) and send to it. It in turn submits these reports to the regulatory authorities. This is an extremely narrow, out-of-date, and inefficient model for conceptualizing the roles of regulatory affairs.
The other end of that spectrum is when regulatory affairs personnel determine what data and reports should be in each regulatory dossier and direct the creation of reports. This approach is not recommended because it is likely to lead to major conflicts with line managers and project managers, who rightfully have much of this responsibility. A more moderate and realistic approach is to have regulatory personnel serve on project teams
where they interact with other professionals to influence design of studies and quality, quantity, type, data, formats, and general style of reports generated. The specific reports to include in each functional group’s contribution to the regulatory submission are likely to be greatly influenced by regulatory affairs staff.
where they interact with other professionals to influence design of studies and quality, quantity, type, data, formats, and general style of reports generated. The specific reports to include in each functional group’s contribution to the regulatory submission are likely to be greatly influenced by regulatory affairs staff.
Whether the regulatory affairs group plays an active or passive role is strongly influenced by the director of the major division to which regulatory affairs reports (e.g., R and D, legal, marketing). This person’s personal views, philosophy and managerial style, as well as that of the director of regulatory affairs, affect the exact placement of regulatory affairs in the organization, and more importantly, the nature of its role and degree of influence. The personalities of these senior managers also influence the background and level of individuals recruited into the regulatory affairs department. Another component of finding the most appropriate balance between passive and active roles for regulatory professionals is in the area of membership on, or presentations to, those committees that review and approve regulatory strategies within the company.
Being Proactive versus Reactive with Regulatory Authorities
It is widely believed that one can be proactive only with the US regulatory authority (the FDA). The actual situation is that companies may adopt a proactive posture and seek regulatory guidance on major questions in most countries. There is a trend toward increasing the number of interactions in Europe. This does not mean that it is always, or even occasionally, possible to arrange meetings to discuss the details of a development plan, regulatory strategy, or submission. But a company can generally obtain answers to general questions about plans and strategies in an informal or formal setting. The proactive role taken by the FDA in many instances, and its obvious interest in participating in and guiding drug development coupled with high standards, means that it is leading and influencing most other regulatory authorities in terms of encouraging interactions with pharmaceutical companies.
ORGANIZING A REGULATORY AFFAIRS DEPARTMENT OR GROUP
It is possible to organize a regulatory affairs group based on functions, therapeutic area, or using a combination approach. The first two approaches are described below; and within each of these organizational approaches, several variations exist. For example, staff could be responsible for all drugs in a broad therapeutic area assigned to them. Alternatively, if the company is large enough, the individual projects could be divided among the staff.
The regulatory affairs group may be situated within legal or R and D or may function independently and report to the company president. Another possibility is to decentralize the function and to have smaller regulatory affairs groups located within several different business units (e.g., neurology, cardiology). The goal of this last approach would be to provide more responsive service and to improve interactions with the staff using their services.
Organizing a Regulatory Affairs Department or Group by Function
Various functions of regulatory affairs are described at the start of this chapter. Regulatory affairs groups that are organized by function may be divided into five separate groups. Each group focuses on one of the following areas in interacting with regulatory authorities, reviewing proposed regulations, and conducting other activities discussed in this chapter. This structure is shown in Figure 85.2 for the following five functions:
Preclinical issues
Clinical issues
Chemistry, manufacturing, and controls issues; this group is concerned with coordinating, organizing, and progressing the data on a drug’s chemistry, manufacturing, and quality assurance functions
Preparing documents for inclusion in regulatory submission, including many varied functions required to collect, edit, paginate, index, cross-reference, copy, bind, and distribute documents; while these activities could be conducted manually,
current practice in most companies involves sophisticated computer systems to track reports and to operate other parts of this system.
Figure 85.3 Regulatory affairs organizational chart for a group organized primarily by therapeutic area.
Regulatory compliance is an auditing function for ensuring that Good Clinical Practices and Good Laboratory Practices are in compliance; this includes preparing sites in advance of regulatory authority inspection.
Each of the first three categories above generally includes responsibility for answering questions about the submission and status of investigational as well as marketed drugs. Over-thecounter drugs may be handled separately (i.e., by a different group). Some companies have a separate group that has responsibility for biologics projects.
Organizing a Regulatory Affairs Department or Group by Therapeutic Area
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