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Manufacturers work with international authorities to harmonize drug registration and supply-chain oversight.
The globalization of biomedical product development is prompting a new look at the barriers erected by divergent national and regional data requirements and policies governing drug production and quality. While efforts to establish common standards for drug testing and product quality through the International Conference on Harmonization (ICH) have streamlined biopharmaceutical development and regulation in industrialized nations, the emergence of more active national regulatory authorities and regional alliances illustrate the need for a broader international approach to setting regulatory requirements. The new goal is convergence of policies and practices, if not total harmonization.
Pharmaceutical manufacturers regard common regulatory policies as key to facilitating access to foreign markets, to patients from other regions for clinical trials, and to lower cost suppliers and operational support, observed Peter Honig, vice-president global regulatory affairs at AstraZeneca. Honig noted the importance of standards in reducing the cost and time of drug development in a February workshop organized by the Institute of Medicine (IOM) Forum on Drug Discovery, Development and Translation (1). In recent years, IOM has examined clinical trial operations and development of medical countermeasures, new treatments for tuberculosis, and drug-diagnostic combinations. This gathering of regulatory authorities and industry leaders from around the world sought to take a fresh look at international regulatory issues in the face of uncertainty about the future of the ICH standards-setting process, concerns about the growing cost of new drug development, and alarm over the increase in substandard medical products in all regions.
In addition to highlighting problems created by divergent clinical research and data requirements, participants emphasized the need for common technical standards to ensure drug quality, reduce redundant manufacturing plant inspections, and help regulators detect substandard products and ensure the integrity of increasingly long supply chains. Individual countries differ in how they implement ICH quality standards, adding specifications and content to the common dossier format for submitting chemistry, manufacturing, and controls (CMC) information, reported Diane Zezza, vice-president and global head for regulatory CMC at Novartis, in summarizing concerns related to manufacturing standards and processes. And postapproval changes are even more divergent in terms of data requirements and timing of filings, a situation that can inhibit continuous improvement efforts.
The group urged harmonization efforts to target differing import-testing requirements, which can lead to product recalls and shortages. A related goal is to reduce differences in how field inspectors apply and interpret GMPs and cite violations in inspection reports. Multiple pre-approval inspections by different regulatory authorities are a perennial burden on manufacturers. One encouraging sign is the willingness of more countries to accept inspection standards established by the Pharmaceutical Inspection Convention and Co-operation Scheme (PIC/S) and to voluntarily share redacted GMP information and inspection reports on active ingredients.
Another positive development is efforts by regulatory authorities in Latin America, Asia, and Africa to develop regional standards and cooperative arrangements that reflect local needs and capacities. A clear goal is to attract more pharmaceutical production and investment to spur economic development programs. Regulatory capacity building is a top priority, and benefits from FDA providing technical expertise through the agency's Forum for International Drug Authorities.
The Pan American Network for Drug Regulatory Harmonization (PANDRH) was established in 2000 by the Pan American Health Organization (PAHO) to promote technical agreements on drug regulation and to build regulatory capacity at national agencies, with the aim of encouraging convergence in drug regulation, explained PAHO senior advisor James Fitzgerald. More experienced regulatory authorities in Argentina, Brazil, Colombia, Cuba, and Mexico have begun to share GMP inspection reports, information on product recalls, and inspection schedules to strengthen oversight activities. A PANDRH GMP working group is developing a harmonized questionnaire for inspections to verify compliance with manufacturing standards based on World Health Organization (WHO) standards; a goal is to provide GMP certificates to firms based on inspections by one of the advanced authorities.
African officials similarly are looking to spur pharmaceutical production in the region to ensure a sustainable supply of quality essential medicines and promote industrial development. The over-arching strategy is to shift drug oversight from 54 divergent national regulatory authorities to 5 to 7 regional economic communities with harmonized policies and laws that permit fewer dossiers and clear timelines for drug registration, explained Margareth Ndomondo-Sigonda of the African Union's New Partnership for Africa's Development. Under the Medicines Registration Harmonization Project of the East African Community (EAC), for example, health and regulatory officials are developing guidelines on label formats, patient information leaflets, stability requirements, and registration forms. A GMP technical working group is finalizing a GMP inspection manual, standard operating procedures for conducting GMP inspections, and formats for writing GMP summaries and reports.
Mike Ward, manager of international programs at Health Canada, outlined efforts by the Asia-Pacific Economic Cooperation (APEC) organization to promote technical cooperation through its Life Sciences Innovation Forum. A Regulatory Harmonization Steering Committee was formed in 2008 to promote medical product innovation, followed by the APEC Harmonization Center, which provides resources for APEC to serve as a catalyst for regulatory convergence and capacity building. One priority work area is to describe best practices for ensuring supply-chain integrity, while others are examining good review practices, pharmacovigilance, and clinical inspections.
Vaccine development and oversight provides a prime area to test harmonization approaches. The African Vaccine Regulatory Forum (AVAREF) brings together regulators and ethics committees to examine and jointly review applications from vaccine manufacturers seeking to conduct clinical trials in the region. Such a process not only promotes convergence, but also can build "mutual trust" between neighboring countries as participants can see the quality of inputs from their peers, noted David Wood, WHO coordinator of quality, safety, and standards for vaccines and biologicals.
One danger is that collective efforts to establish common regulatory approaches among national authorities will lead to policies and standards that differ between key regions. To achieve simultaneous global drug development and near-simultaneous registration around the world, said Honig, all parties have to agree on expectations for clinical-trial operations, pharmacovigilance processes, and data transparency. The role of regulators, said Douglas Throckmorton, deputy director, Center for Drug Evaluation and Research, is to provide clarity on rules and regulations and to ensure a level playing field between domestic and foreign manufacturers. Harmonization requires regulators to "give up some control" over their policies and programs, observed Deborah Autor, FDA deputy commissioner for global regulatory operations and policy. She urged workshop participants to further articulate the business case for global regulatory convergence, spelling out the gains and efficiencies it can provide, and a plan for addressing key gaps to get global coalitions moving. Steven Galson, vice-president for global regulatory affairs at Amgen and co-chair of the workshop, said the next step is for industry and regulators to craft an economic analysis documenting the enormous savings in resources from harmonization. The parties represented at the gathering, he commented, have the power, force, and creativity to "go forth and converge" and should do so without delay.
1. IOM, International Regulatory Harmonization Amid Globalization of Biomedical Research & Medical Product Development, Workshop (February 13-14, 2013).