Blog

Globalization in a Heterogeneous World

There is a strong need for and a sense of urgency regarding products that are acceptable and commercially successful across global regulatory systems. But, in a heterogeneous world harmonization varies from one locality to another. These discrepancies are largely due to:

• disease complexities and varying medical standards of care (SOC)
• population dynamics including metabolic and ethnic features
• emerging markets with different regulatory challenges and opportunities
  • Asia-Pacific
  • Latin America
  • Eastern Europe
  • Middle East/Africa
• drug lag and the need to close gaps in the face of disparate regulatory requirements

Evolving Regulatory Landscape

The global regulatory landscape has been evolving since the International Conference on Harmonization (ICH) was established in 1992. Agencies around the world actively contribute to initiatives that help improve research and development. The European Medicines Agency (EMEA) and US Food and Drug Administration (FDA), for example, see the value of communicating with such agencies as Health Canada and Australia's Therapeutic Goods Administration to make better decisions for public health. More than ever, data assessment reports are shared and the pharmaceutical industry, governments and the public are demanding greater transparency in the regulatory process. Electronic filing makes simultaneous submissions to multiple regulatory bodies possible and, by bringing new products onto the market more quickly, is beneficial to both individual pharmaceutical companies and patients.

The common requirements on which the major regulatory agencies agree (such as the ICH technical requirements and common technical document) have simplified some processes for the industry. However, regional dynamics and local needs have led to a sophisticated, heterogeneous world rather than a harmonized global state.

Historically, three main regulatory bodies have dominated the global oversight of drug approvals: FDA, EMEA and the Japanese Ministry of Health Labor and Welfare (MHLW). These three determined the fate of many drug products around the world, as agencies in other countries often accepted or were largely persuaded by their decisions.

Increasingly, individual countries have begun to redefine their own requirements and pharmaceutical companies must evaluate a much broader set of regulatory obligations.

This decade has seen a steady decrease in the number of approved New Chemical Entities (NCEs) and longer regulatory review times, with many applications rejected or withdrawn due to inadequate short- and long-term safety profiles and unfavorable benefit:risk assessments. As the number of available alternatives in drug categories has risen, with some moving to generic status, the relative value and cost-effectiveness of innovator NCEs are critically scrutinized and the bar for regulatory approval has been elevated significantly, creating a new and evolving regulatory environment.

Stakeholder Expectations-Product Differentiation

From outside the biopharmaceutical industry, the regulatory agency may be perceived as the gatekeeper and key stakeholder for new drug approval and market viability. However, multiple stakeholders determine an NCE's entry into the marketplace and patient access.

These stakeholders include regulators, payers, physicians and patients. For each group, pivotal questions must be addressed satisfactorily. For regulatory authorities, the question is: "Why should this drug be approved?" The answer entails not only demonstrated safety and efficacy versus a placebo, but also evidence of a favorable benefit:risk profile in comparison with available alternative therapies. EMEA usually requires comparative evaluation of available alternative therapy to enable assessment of an investigational product's place in the therapeutic arsenal. Other regulatory authorities are beginning to expect sponsors to provide such comparisons to available alternative therapies, and are taking these data into consideration.

For the second key stakeholder group, payers, the question is, "Why should I pay for this drug?" Sponsors must address this question by providing data that demonstrate product differentiation from available alternative therapies. The product benefits must be translated into clinically meaningful outcomes. Health outcome and pharmacoeconomic measures become crucial in justifying the NCE's relative cost-effectiveness, warranting its formulary inclusion and, thus, permitting physician and patient access.

Physicians and healthcare providers, the third stakeholder group, ask, "Why should I prescribe this drug?" They need to be convinced of the product's safety, risk management/mitigation and added value for the patient.

Finally and most importantly, the patient asks, "Why should I take this drug?" Patients are taking an increasingly active role in determining their healthcare treatment and are empowered by ready access to medical information. Armed with that knowledge, they are engaging more with healthcare providers to demand compelling reasons for healthcare advice and recommendations.

Each of these stakeholders, like the pharmaceutical industry, is focused on the patient and is equally as determined to address benefit:risk in the best interest of the patient.

Call to Action-Blueprint

This rapidly evolving landscape called for a change by industry. There was an urgent need to re-evaluate how regulatory leveraged opportunities to significantly contribute and drive excellence and success. Wyeth global regulatory affairs (GRA) team took on the Blueprint project to position regulatory as an integral, strategic contributor, and transform product assessment to ensure success in the prevailing environment.

This required a new way of working, a new mindset and operational change across regulatory by every GRA team member.

Figure1: Multiple forces contribute to the challenging conditions impacting the pharmaceutical industry's ability to predict and achieve successful outcomes.

Regulatory Challenges

• Product Differentiation
• Data Requirement
• Assurance of safety
• Benefit / Risk Balance

Commercial Challenges

• Cost /Time for Drug Development
• Generic Challenge
• Advertising / Promotion

Difficulty in drug development

Approach and Process

To start, we sought input on regulatory and stakeholder expectations and suggestions on the direction of change. We conducted more than 60 interviews with key internal stakeholders such as the heads of the technical functional groups, heads of the regional groups and global executives, as well as key technical team members across Wyeth at all levels across the globe. In addition, we reviewed literature to benchmark the Wyeth regulatory organizational structure against other relevant industry organizations.

From the feedback and functional assessment, we concluded that the Blueprint initiative would focus on three key objectives, with the overall goal of achieving welldifferentiated, value-added, sustainable products with competitive product labels and favorable benefit:risk profiles:

• enhance strategic regulatory contributions
• eliminate inconsistency in individual approaches
• deliver predictable regulatory outcomes

In addition, five guiding principles emerged that guided the initiative's deliverables, and have become the GRA team's regulatory excellence principles. The Blueprint guiding principles and deliverables are listed in Figure 1.

Strategic Contribution-Differentiation

“Start with the end in mind" to deliver the right indication, product profile and payer/physician/ patient value.

This is the principle underlying the strategic approach that integrates and aligns the technical groups involved in developing products around the Target Product Profile (TPP). It emphasizes the need to focus on the end goal, which is the final competitive product label. The TPP is the pivotal point upon which global development efforts and assessments are based.

Outcomes

Global Regulatory Strategy

The approach to developing Global Regulatory Strategy (GRS) was broadened to ensure welldefined global input and diligent consideration of all relevant aspects of regulatory components. These components include technical aspects (regulations, guidances and precedents), nontechnical factors (objective expert input) and environmental input (regulatory intelligence and landscape dynamics) with emphasis on benchmarking competitive products to assess product differentiation, assessing regulatory standards from relevant precedents, and evaluating regulatory intelligence to provide environmental trend analysis.

A due diligence guide was developed that outlines all key questions and topics, including reviews to be conducted, in developing the GRS.

Learn and Confirm Grid

The concept of starting with the end in mind was translated into a critical tool—a template for rigorous product assessment called the Learn and Confirm Grid. This tool ensures thorough, comprehensive asset assessment and transparency in gap analysis and product differentiation. It also aligns all contributing functions to the aspirational TPP, which drives the global development and manufacturing plan to achieve the desired outcome: right indication, well differentiated product profile sustainable product supply and product success.

Templates

Templates were designed to provide a framework for a consistent, concise, yet comprehensive account of the competitive benchmarking and inferential analysis for product differentiation, alignment of TPP-driven boards of health (BOH) feedback to support regulatory assessments and mitigation plans.

This thorough approach increases the probability of achieving success and accurately predicting outcomes.

Process Efficiency and Integration Do it right the first time

This principle reflects the imperatives to ensure that speed and quality are mutually inclusive and to eliminate high costs from iterative work. The deliverable was a detailed, end-to-end regulatory process map, integrated with key development, commercial and manufacturing deliverables and milestones. This map ensures proactive, consistent, systematic, timely and synchronized planning across functions to efficiently deliver key milestones and eliminate unpleasant surprises and disruptions from inadequate planning.

Alignment Best strategic guidance forward

This principle emphasizes rigorous due diligence to apprise all involved parties of the aligned regulatory position and eliminate individual regulatory opinions that may no longer be relevant, leading to a well-defined global regulatory team, empowered for success, coordinating allregional/affiliate regulatory input and consolidating it into a comprehensive global regulatory strategy. That strategy is communicated to a senior, strategic regulatory review committee for vetting, challenging and endorsement. This process enhances confidence in the regulatory deliverable and promotes a unified regulatory voice to support the guidance provided.

Accountability Shared ownership and pride of outcome

With regulatory sharpening its strategic contribution, roles and responsibilities of the regulatory teams across the globe required clear definition for headquarters, regions and countries, while promoting a strong sense of accountability with shared ownership of the challenge and shared pride of outcome. Key areas of functional responsibility and accountability rely upon the accuracy of regulatory communications and predictions of the regulatory outcomes in setting and managing product performance expectations of internal and external stakeholders. With well-informed and effectively coordinated global regulatory strategies, and competitive benchmarking and environmental/landscape assessment, regulatory is better placed to provide this accountability to the organization.

Success metric

Excellence and benchmarking: "right people,right process, right performance lead to right products" To assess the value of Blueprint as a regulatory framework for transformation, the team identified metrics in the following areas:

• quality/strategic nature of regulatory contributions
• efficiency/proactivity/timeliness of regulatory input
• accountability of regulatory to meet internal and external stakeholder expectations

Conclusion: Blueprint-Current and Future Impact

In today's evolving landscape, where multiple stakeholders determine new products' fates, Blueprint is an excellent approach for transforming regulatory and enhancing its strategic focus and contributions to the company. Blueprint transforms the drug development and product assessment approach while targeting the desired outcome to satisfy key stakeholders and achieve success. With the appropriate operating model and processes, Blueprint provides the tools and approach for transparent and rigorous comparative asset assessment. This will enable increasingly accurate regulatory outcome predictions, improved organizational planning and decision making, and precise communications to internal and external stakeholders.

Blueprint as a project no longer exists, but has transitioned into a way of life for the Wyeth global regulatory affairs team. The initiative emphasized differentiation of products, integration and efficiency of processes, alignment of people, and enhancement of regulatory's contribution and performance. It strengthened regulatory's voice and accountability and positioned regulatory as the honest broker for the organization.

Conclusion: Blueprint-Current and Future Impact

In today's evolving landscape, where multiple stakeholders determine new products' fates, Blueprint is an excellent approach for transforming regulatory and enhancing its strategic focus and contributions to the company. Blueprint transforms the drug development and product assessment approach while targeting the desired outcome to satisfy key stakeholders and achieve success. With the appropriate operating model and processes, Blueprint provides the tools and approach for transparent and rigorous comparative asset assessment. This will enable increasingly accurate regulatory outcome predictions, improved organizational planning and decision making, and precise communications to internal and external stakeholders.

Blueprint as a project no longer exists, but has transitioned into a way of life for the Wyeth global regulatory affairs team. The initiative emphasized differentiation of products, integration and efficiency of processes, alignment of people, and enhancement of regulatory's contribution and performance. It strengthened regulatory's voice and accountability and positioned regulatory as the honest broker for the organization.

Authors

Henrietta Ukwu, MD, FACP is vice president, global regulatory affairs for Wyeth Pharmaceuticals. Previously, she was vice president of worldwide regulatory affairs-vaccine development and, subsequently,vice president of global regulatory policy at Merck &Co. Ukwu is an internist and infectious diseases physician by training.

Hilary Malone, PhD, is senior vice president and head of global regulatory affairs for Wyeth Pharmaceuticals. Previously she was vice president for AstraZeneca Europe regulatory affairs, after working at SmithKlineBeecham. Malone holds a PhD in molecular neuropharmacology.

Acknowledgements

Wyeth's Blueprint Breakthrough Project was sponsored by Hilary Malone, PhD, senior vice president and head global regulatory affairs; led and designed by Henrietta Ukwu, MD, vice president, global regulatory affairs; and supported by Nicole Faust Cohen, senior manager and Stephanie Bichet, executive partner, pharmaceutical R&D practice at Accenture and members of the Wyeth global regulatory affairs group.