As the costs of pharmaceutical development continue to increase and the new opportunities for facilitated drug and biologics development Lead to more complex decision-making, the choice of an outsource provider to aid in the regulatory process becomes even more critical. Those of us who believe that regulatory affairs is the center of the product development universe are more convinced than ever that this process can be immeasurably aided by the appropriate and targeted use of experienced consultants.

Conversely, relying on an ineffective or incompetent service provider costs time, may damage relationships with regulatory agencies and can squander precious funding as well as the competitive edge, leading to loss of market share for the eventually approved product. This article will describe the key elements of selecting an appropriate contractor and developing a sponsor/consultant partnership that assists in carrying out the important regulatory affairs functions that can make or break a product development program.

Element 1: Strategic Planning
Strategic planning is not always thought of as being associated with the practice of regulatory affairs. Usually we find the "strategic planning" in a product development firm is considered to be the sole property of Clinical Affairs, or even worse, Sales and Marketing. In fact, the entire positioning of a product development program, from early discovery through approval and post approval activities, should ideally be united with the regulatory process.

All disciplines related to product development meet in the regulatory arena, in the form of chemistry, manufacturing and controls, safety support (toxicology and Pharmacology ), clinical testing, medical writing (submissions and reports), FDA negotiations, agency review and the attendant coordination with and by the development team (project management). An experienced and highly competent outsource provider will bring the various disciplines together to discuss outstanding and potential barriers to success. The consultant should also provide a sharply focused strategy on generating, organizing and submitting the information that is both necessary and sufficient for the regulatory agencies to review, as well as incorporating additional technical capabilities in specific disciplines that may be lacking in the sponsor’s own team. When this occurs, the outcome for the client includes the reduction of uncertainty and risk, elimination of unnecessary preclinical (and often clinical) studies and minimization of costs. All of this can be accomplished while meeting established timelines for development and marketing objectives, with the ultimate result being an acceleration of time to approval for the product.

Before beginning the intensive day-to-day work of providing regulatory services to a client, the consultant should undertake a comprehensive, ob-jective analysis and assessment of the program across all key disciplines: discovery research, manufacturing controls, preclinical support and the clinical development plan. This includes review of existing regulatory documentation, such as INDs, communications with the FDA, and other submissions. The consultant should provide a frank, dispassionate assessment of the program, with the clear identification of key and secondary issues. Some of these issues are often identified by the FDA (sometimes subtly couched, using such phrases as, "we have some concern here," or, "the Sponsor might consider…"). Other program deficiencies may and should be identified by the external consultant.

A consultant, at this stage, has the absolute responsibility to bring up even the smallest issues, as it is in the client’s best interest to address all potential problems early in the planning cycle. After discussing the identified issues with the client, the consultant should develop a plan of action to deal with these issues as soon as possible to avoid the slowdown or stoppage of the program at a critical future stage. The consultant should be flexible enough to be able to provide this plan and resulting action items quickly, with whatever level of client involvement the sponsor elects. Once the action plan is agreed on, the team of sponsor and outsource provider can move ahead rapidly.


Element 2: Experience in Working With FDA
An effective outsource provider must have a broad and comprehensive knowledge of the laws, regulations, guidelines, guidances and recent case studies that provide the working body of historical knowledge specific to a client’s development program and indication. Although sound regulatory principles can be applied across many therapeutic programs, a good outsourcing match ideally involves a consultant who can provide experienced insight into the recent as well as historical results of regulatory interactions in the therapeutic areas of specific interest. The efficiency thus obtained often leads to more rapid movement in FDA negotiations, better submissions and the avoidance of clinical holds.

An ideal outsource pro-vider has a style that is supportive of the sponsor’s program while maintaining an honest and credible relationship with each FDA Reviewing Division. Upholding appropriate standards for data quality, while negotiating creatively, provides opportunities for breaking new ground in the product development process. Likewise, an outsource provider with a specific knowledge of the individual needs of Reviewing Divisions can effectively provide a sponsor with multiple product development programs in different therapeutic areas in the course of a long-term relationship. Strong ongoing relationships provide a stable platform for cost-effective product development through both comfortable awareness and aggressive pricing.

Recent events have somewhat changed the increasingly facilitative and accelerated pace of product review and approvals that have been seen since the Food and Drug Modernization Act of 1997 ( FDAMA ) and extensions of the Prescription Drug User Fee Act ( PDUFA ) began having their major effects on the industry. The number of FDA reviewers dedicated to marketing application review and a performance-based sense of urgency to meet Agency timelines for the review of drugs and biologics has increased and, overall, FDA reform led to a number of shorter reviews of products and faster average approval times, particularly for serious and/or life-threatening therapies.

However, several high-profile new drugs have been withdrawn from the U.S. market for safety reasons during the last five years. In an era when the U.S. population expects 100% benefit and 0% risk from its products, a great deal of criticism has been leveled at the FDA. As a result, increasing attention is being paid, during the IND stage and across Reviewing Divisions, to preclinical and early clinical data. This is oriented almost entirely towards safety and safety margins of the investigational products.

The need for skillful application of regulatory principles and procedures, coupled with minute attention to the quality and quantity of data that support a product development program, is more critical now than ever before. Adherence to guidelines and Reviewer comments is also essential, particularly in areas where there is concern for safety support. A knowledgeable outsource provider will have the experience, skill and up-to-date intelligence that allows the client to prepare for these concerns during this time of increased scrutiny.

This is a particularly challenging task for consultants who fulfill the role of U.S. agents of European firms. The expectations and understanding of the U.S. regulatory process by non-U.S. firms often do not reflect the excellent quality of the intellectual property and discovery data that support the investigational product. The Translation of data and other information for non-U.S. clients into reviewable documents, supported by a sound strategic and tactical approach to the Agency, is critical for success. The quality U.S. agent translates the FDA’s mission to its clients, understands and deals effectively with the Agency’s concerns about the origin and availability of non-U.S. data, provides the Reviewers with what they need, presents a clear plan of action with the rationale for the tasks to be performed, uses meetings effectively, and respects lines of authority in a scrupulous fashion. All this must be accomplished by the U.S. agent, despite a tendency for non-U.S. firms to feel that exhaustive data support is probably not necessary for FDA review.


Element 3: Assessing the Therapeutic Field
To avoid unregulated regulatory outsourcing, it takes a sponsor/consultant partnership with a healthy sharing of information and opinions about the competitive marketplace in which a potential pharmaceutical product will exist. Important considerations include the nature of clinical practice with therapies already in use, acceptability of formulation types, Compliance with present regimens in comparison with that projected for the potential product and the type of risk/benefit equation that will likely prove acceptable for any new therapy entering the marketplace.

From a regulatory and drug development perspective, the outsource provider should be familiar with recent FDA decisions and advisory committee deliberations in the area of interest. Distilling these exhaustive discussions often provides important intelligence in the "real world" of the final stages of drug and biologics approval or rejection and can proactively aid in repairing gaps in the proposed/ongoing program of the sponsor in the preclinical, clinical or labeling areas. A quality consultant will always prepare the sponsor for potential problems and be a step ahead of the ongoing program, knowing that unexpected regulatory or clinical issues can arise that may arrest the forward progress of product development. An ideal consultant must also have the ability to quickly recover and help the sponsor move effectively forward after handling unexpected issues.


Element 4: Communications and Logistics
A successful outsourcing relationship emphasizes efficient, workable and well-established means of interaction among the regulatory and product development team members. These include FDA Project Managers and CSOs, Reviewers, sponsor liaison team, outsource provider regulatory team lead, investigators and other technical leads. Logistic elements should be discussed and established early, including the primary modes of interaction (e.g., telephone, fax, e-mail, videoconferences, and periodic in-person meetings).

The physical location of the individuals involved and time zone differences must be taken into account. Effective outsourcing does not depend on close physical proximity of the parties, but rather on good organizational skills and a seasoned, consistent approach to an integrated product development plan. Adherence to commitments and agreements will also enhance the probability of success.

The importance of cultural and language differences for non-U.S. sponsors using U.S. agents to the FDA cannot be overemphasized. An open-minded, respectful, patient and cosmopolitan approach to idioms and cross-cultural differences should be as-sessed by a sponsor before choosing an outsource provider.

One common problem is that consultants often use jargon and assume that the client understands the meanings and connotations of the acronyms. This leads to miscommunication with serious consequences when the client’s first language is not English. The probability for misunderstanding and programmatic slowdowns can be minimized by a successful mutual fit in the sponsor/consultant partnership.

Element 5: Project Management
In the world of sophisticated product development and increasingly complex regulatory environments, the role of quality project management is critical. Project managers in the outsource environment are key components in identifying timeline roadblocks and fostering strong communications, which assures the progress and success of a development program.

The goals of effective regulatory project management include: the setting of realistic objectives, establishing clearly defined tasks, assigning appropriate resources to those tasks, creating mutually agreeable timelines, meeting or exceeding those timelines, reacting quickly and appropriately to changes that require modification of timelines, resources or tasks, and committing to follow-up actions that will assure continued success. Fulfilling these goals will lead to a dynamic integrated effort across the project team, the sponsor and the outsource provider.

A seasoned project manager will, even in the face of emergencies and demands for attention from multiple sources in the high-stakes nature of pharmaceutical and biologics development, be capable of sustained encouragement of team commitment and the efficient use of resources in a rapidly changing environment. Thus, when a perceived chemistry problem with a formulation is identified by the FDA and threatens the submission of an IND, NDA or BLA , the project manager will be able to marshal the needed resources, get the problem analyzed, plot a course of action and ensure a submission that will provide regulatory satisfaction.

The important tools for project management of an outsourced regulatory program for pharmaceutical or Biologic development include a robust, flexible and universally accepted system for generating timelines, assigning resources and allowing for easy change and reporting, such as Microsoft Project. An established means of sharing electronic files and managing documents should be part of the initial agreement between the sponsor/client and the consultant. Customization of the project management approach, leading to the most efficient use of resources and oriented to the specific needs of the client and the project, is important. A compact, easily modified system of information exchange and document management is the best means to ensure this result, rather than the imposition of a standardized, unwieldy approach.

The key documents with which project managers must work in pharmaceutical development include the prototype product label, clinical development plan, regulatory issues communications (in which are outlined the FDA’s concerns), and a carefully organized paper trail of the documents that provide the complete history of the development program for ready reference and forwarding to appropriate parties. Each discipline should be represented in this documentation so that duplicative effort and excessive document distribution can be avoided. The project manager must be aware (and convey to the client) that, in the regulatory and business worlds, "time to submission" is of infinitely less importance than "time to market." The latter provides revenue and profitability to the sponsor of a product. Early submissions of high quality make a statement to the regulatory agencies and establish a standard for the rest of the program. Even in a climate of urgency, taking the time to generate high quality work increases the probability of eventual success.

Regulatory submissions form the backbone of the product development process as it relates to FDA review of data and product approval. The project manager is key in ensuring that these important documents are planned for, written, reviewed and submitted in accordance with the project plan and agreed-upon timelines. Al-though the technical experts responsible for writing these submissions provide the majority of their content, the project manager is also responsible for ensuring that they meet the standards of both the client/sponsor and the outsource provider. High-quality regulatory submissions should meet the following criteria: they address issues up front, rather than hiding them in the minutiae of the text; arguments for safety and Efficacy are supported with sound rationales and references to source documents; data are presented clearly and consistently; information is easily accessible, either by incorporation in the body of the submission or precise reference to tables, figures or appendices; label claims must be supported with data; and integrated summaries should follow the FDA guidelines, rather than be constructed of a patchwork of individual study summaries. Sponsor-selected reviewers of submissions should be chosen wisely. In our experience, Ground Zero has discovered that tight deadlines and the smooth flow of the work product dictate that individuals who are tardy in providing their reviews always slow down the process of the submission, no matter how technically adept they may be.

Although the entire development team should be cognizant of the needs of the various countries represented in a multinational development program, the project manager must ultimately ensure that harmonization, in accordance with OECD, ICH and other international standards, is maximized, with recognition that the need for fulfilling FDA requirements and standards is most critical. This will minimize the need for country-specific preclinical and clinical studies and the resulting documentation as the product moves through multiple regulatory authorities and reduce or eliminate seemingly endless preliminary pilot studies that often lead to results that do not support the development plan with the attendant waste of resources and funding.

The outsource provider that can ensure appropriate and aggressive project planning before the start of work will be the most effective in saving the client time and money in a global development program. Likewise, careful data review throughout the development program will enhance the ability of studies to meet worldwide regulatory standards. In general, the FDA standards are the yardstick against which safety and efficacy data are measured and the project manager should be uncompromising in insisting that these standards, set at the beginning of the project with the development team, not be ignored during the execution of the program.


Element 6: Crisis Management
A pharmaceutical development program is a long, complex and uncertain undertaking. Only the most naïve founder or chief executive officer will assume that his new chemical entity or biologic will sail through the discovery, development, submission, review and approval process unscathed by controversy, negative data and delays. Experienced outsource providers will take this into account when working with clients and establish a mechanism for crisis management. Problems can come from any angle: a formulation that is less bioavailable than expected, a manufacturing step that leads to unacceptable contamination in a sterile product, a toxicology study that is imperfectly performed by a contractor or from whom has come unwelcome genotoxicity results, or a clinical trial which has slow enrollment and threatens the previously assumed submission of an NDA.

Appropriate crisis management should be handled in an organized manner, with a sense of urgency. The initial agreements between an outsource provider and client should include the following considerations for crisis management: time constraints for response to a problem; identify key consultants and client management who are part of the crisis management team; establish the delegation of authority, accountability and responsibility for dealing with a problem; standards for the quality control of the response; and contractual flexibility in dealing with extraordinary circumstances beyond the scope of work. The project manager must be made aware of the last consideration, for it is he/she who continually monitors the adherence of the outsource provider’s work to the terms of the contract with the client.

We have described the key elements of a sponsor/consultant relationship that can lead to a successful outsourced regulatory program for pharmaceutical or biologic development. Strategic planning sets the stage for the transition to task-oriented work. FDA experience provides the template for both knowledge-based and negotiation-oriented facilitated interaction with the regulatory authorities. Accurate intelligence in the therapeutic areas of interest and review of both regulatory failures and successes of similar products can provide valuable lessons in guiding the client’s direction. Well thought-out communications and logistics enable key players to function smoothly as a project team and avoid redundant work.

Experienced project management creates a smoothly functioning mechanism for coordinating disparate elements of the program. Crisis management, adequately prepared for, saves time, effort, money and sometimes the development program itself. The secret to assembling, organizing and harmonizing these elements is integration. The recipe for successful integration is the mutual fit of the components of the program, based on a high-quality, experienced outsource provider and a well-chosen team, led effectively by a strong project manager and consisting of seasoned professionals and technical leads.

This analysis would not be complete without at least a mention of the costs of outsourcing. There are many providers, of all sizes. Some are "one size fits all" full-service CROs. Others are individual consultants, with specific expertise in one or a few types of products, submissions and/or therapeutic areas. A third category encompasses the boutique consulting group which performs a broad variety of services within targeted areas of competence, has the ability and flexibility to perform in a client specific manner and focuses on a service portfolio with a breadth somewhere in the middle. Quality can be found across all of these categories, so can a widely variable pricing structure for services.

Excellence is never cheap, because it stems from a sound approach, experience and time-intensive work; the cost to a product development program for truly outstanding consultation is well worth avoiding the risk of a failed clinical trial, major regulatory faux PAS or even the loss of a small amount of time to market due to avoidable delays. The lowest bid rarely leads to the best service in this competitive environment, nor does the highest bid guarantee excellence. The mutual fit of the client and the outsource provider, the joining of their technical capabilities and the willingness to achieve harmony in their interactions, enhances the probability for outstanding outcomes.

The aggressive, forward-thinking and success-based execution of a product development program will prevent unregulated regulatory outsourcing.