Developing a Regulatory Strategy


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-10-01-2008
Volume 0
Issue 0

By defining hurdles to registration, emerging companies benefit from early regulatory guidance.

Given their focus on discovering and rapidly building scientific evidence to support the safety and efficacy of their compounds, emerging pharma companies often direct their limited resources to near-term activities. In doing so, they are often unaware of or undervalue the importance of getting early regulatory guidance on long-range development strategies.

Photography: Getty Images Illustration: Paul A. Belci

In early development, emerging companies often view regulatory affairs as a function that is primarily necessary to ensure compliance. They recognize the need to manage operational activities such as preparing, submitting, and maintaining an IND (Investigational New Drug Application), submitting adverse event reports, and coordinating other routine communications with the FDA. However, this approach potentially neglects a greater value-added contribution that these experts can provide: regulatory strategy.

Benefits to realize

Starting well before clinical trials are initiated, companies need to understand both the regulatory landscape (i.e., guidelines, important stakeholders, emerging policies) and relevant precedents. Regulatory guidance in these areas can help build a crucial framework for the overall development plan and aid in determining the fastest and/or greatest value path to market for their product. Furthermore, it can facilitate assembly of a total picture of the scope of nonclinical, technical, and clinical testing that will be required for registration.

With a comprehensive regulatory strategy in hand, sponsors can fully understand the expectations, carefully evaluate potential hurdles, and create a plan to proactively address them early in development. Additionally, this plan can inform the entire development program. For example, elements from the regulatory strategic documents drive the clinical plan, identifying issues that affect clinical trial design requirements and the associated budget.

Some emerging companies may believe that it is not important for them to prepare a thorough regulatory strategy since they intend only to develop their compound independently until proof-of-concept, then they're either going to out-license the product or find a (typically larger) partner for codevelopment. While it is true that a partner or licensee is likely to develop their own regulatory strategy after joining the development program, it would be a lost opportunity to wait until this point to develop the first iteration.

Having a good understanding of the clinical, preclinical, and technical development requirements—as well as timelines, achievable commercial claims, risks, and regulatory mechanisms to enhance product value like exclusivity and accelerated approval pathways—can be extremely helpful in designing an efficient early development pathway, assessing the value of the product, and knowing how far a company can proceed before needing additional financing or a partner.

Importance for novel approaches

Many emerging companies develop agents for niche markets where there remains a significant unmet medical need (i.e., orphan or other small indications that may not be commercially attractive to large pharmaceutical companies). Other emerging companies focus on novel indications or seek unprecedented labeling claims to differentiate their product from competitors.

While each of these circumstances presents a unique set of regulatory challenges and opportunities, companies pursuing these novel approaches have at least one thing in common: They are all venturing into uncharted regulatory territory. Indications that are less commonly pursued are unlikely to have development guidelines with fewer, if any, precedents. As such, these situations dictate that sponsors develop a thorough regulatory strategy early. This is based on several realities:

  • Novel approaches often require development and validation of new endpoints.

  • Registration programs are increasingly becoming reliant on physician- and patient-reported outcomes to measure clinical meaningfulness.

  • It is not uncommon for health authorities to require utilization of multiple coprimary endpoints for registration studies when presented with a new endpoint.

These unique requirements can have a substantial impact on the size of the clinical development program as well as on the risk. As a specific example, coprimary endpoints will decrease the probability of success in comparison to the typical requirement for a single efficacy endpoint. An early understanding of the registration requirements offers efficiencies that are realized throughout the development of a novel product. Emerging companies, focusing primarily on the next stage gate, may not realize these efficiencies without an early regulatory strategic plan.

Well-established approaches

Even companies developing products for established indications with well-understood chemical classes should take the time to understand the current regulatory environment. For many indications there are either no development guidelines available from health authorities or the directives are obsolete. In the absence of current official guidelines, information from the development program for precedents can provide extremely important direction. Even so, although this information is very valuable, sponsors cannot blindly follow precedents. Health authority requirements continuously evolve as the scientific field advances. As such, even areas with multiple, consistent precedents may not represent the current requirements.

In fact, it is worth noting that the value of precedents generally declines over time as the scientific and political environment shifts. In circumstances where it is believed that policies and requirements may be "evolving," it is important to monitor public presentations made by FDA representatives. Information communicated this way often precedes the formal distribution via a new regulation or guidance. While large companies often have regulatory resources dedicated to monitoring the external environment, emerging companies generally need external regulatory support for such information.

Role of the strategist

Increasingly complex registration requirements mandate a more sophisticated regulatory staff. As a result, today's regulatory affairs professionals typically hold advanced science degrees and have extensive experience in one or more of the drug development disciplines. Armed with these credentials, they have the required depth to provide scientific and strategic guidance to development teams.

So, what roles are regulatory strategists expected to play? First, they evaluate development options, issues, and challenges based upon the needs of a key external customer: the health authorities (i.e., FDA and EMEA). In addition, they are now expected to monitor and understand all details of the regulatory "environment," including guidelines, precedents, influence of politics, government resource challenges, priorities, and emerging policy issues.

These strategists must then communicate this information to the various disciplines within development teams and translate it to the programs under their direction. Ideally, beyond sharing their findings, they become integral members of these development teams so that as issues arise, they are identified early and assessed regarding how best to address them with health authorities.

Beyond information sharing and problem-solving ability, regulatory strategists need effective presentation and negotiation skills because interpreting medical data is subjective. Moreover, they can help sponsors understand the needs of their FDA "customer," as well as the political and resource-constrained environment in which the health authorities work. Because they understand the nuances of this complex relationship, highly experienced regulatory professionals can lead FDA interactions, successfully delivering the key messages. This is particularly important for emerging companies, since early identification and appropriate resolution of issues impact not only the speed and efficiency of the project but often the financial viability of the company.

Purpose and scope

A regulatory strategy should aggregate critical regulatory information and strategic plans in a single document. It should serve three primary functions:

  • As a tracking tool that summarizes key agreements reached with health authorities

  • As a planning tool that documents timelines and lists topics to address in future meetings with health authorities

  • As a risk register to record key open issues that could impact timelines, cost or commercial value for the project.

Specifically, the document should provide information on current project status, target timelines, target product labeling, key risks, and open issues relevant to the specific scientific discipline (e.g., safety, efficacy, quality, and commercial). Policy advancement should also be tracked by listing such events as upcoming health authority meetings, including public Advisory Committees and presentations by FDA at scientific congresses. In addition, the document should essentially outline the development pathway to market approval, relative to regulatory requirements. Generally, this is coupled with the clinical development plan, which provides details of the clinical trials program needed for the marketing application.

Since data from all scientific disciplines will ultimately be submitted as part of a marketing application, and the consequent labeling (i.e., package insert or summary of product characteristics) will dictate how the product is marketed, a regulatory strategy document must be comprehensive. It must address preclinical, clinical, chemistry/manufacturing, and commercial issues.

The first version of a regulatory strategy document should be created early, before clinical testing has begun. This will allow data gathered from guidelines, precedents, and desired labeling to drive the development program and serve as the basis for early interactions with health authorities.

The regulatory strategy should also be seen as a "living document" that is regularly revised based on scientific results, as well as on changes in the regulatory environment. Given that many compounds do not survive early development, it may be prudent to "stage" preparation of regulatory strategy components. For example, it may not be worthwhile to prepare a comprehensive Target Product Label or to evaluate the merits of the centralized procedure for European registration early in development. Instead, the focus in early development should be on providing guidance that is critical for early stage decision making.

Pivotal questions

When it comes to a regulatory strategy, a number of questions need to be addressed, including:

  • What are the key differentiating characteristics of this product vs. competitor products in terms of target labeling?

  • Is there a precedent for the indication and for the key claims being sought? If not, what incremental activities (i.e., unique studies, endpoint validation, opinion leader consensus) are needed to substantiate this new approach?

  • Which currently available guidelines might impact the development program?

  • When should meetings with health authorities occur and which key issues should be addressed at each meeting?

  • What is the range of options available for registration (e.g., fast-to-market with small initial indication followed by supplemental applications vs. broad claim up front)?

  • Are any accelerated development or approval pathways applicable such as Subpart H approval, fast track designation or priority review?

  • Are there opportunities for expanded market exclusivity via such regulatory mechanisms as pediatric exclusivity, orphan drug protection, and/or Waxman-Hatch exclusivity?

  • Is there a need to influence health authorities and/or key opinion leaders to accept proposed study designs, endpoints, key claims, etc.? If so, what is the plan (who, when, how, desired outcome)?

  • What are the known regulatory risks in the program?

  • What is the plan for global registration, if applicable? Simultaneous EU and U.S. submission? Or key market first?

For a listing and description of the elements of a comprehensive regulatory strategy, see Table 1 (also available online at


While creation of a solid regulatory strategy is a critical enabling factor in the efficient development of a product for both emerging and established companies, there is particular importance for emerging companies, since they typically have fewer available resources than larger companies. For smaller organizations, an external regulatory strategist can serve as a bridge between scientific and commercial disciplines, integrating their respective needs, forming a cohesive internal strategy, and developing an external communication approach for the health authorities.

In this way, the strategist can provide efficiencies to development teams, informing the sponsor of requirements and options while outlining a pathway and defining the hurdles to registration.

As pointed out, the key to gaining the greatest efficiencies, however, is to launch development of the regulatory strategy early in development, ideally before starting clinical trials. In that way, the regulatory expert is an integral part of the team for all the subsequent critical steps, including implementation and negotiation with health authorities.

Mark A. Ammann, PharmD, is vice president of regulatory affairs at United BioSource Corporation, 2200 Commonwealth Blvd, Suite 100, Ann Arbor, MI 48105, email:

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