Harmonizing Harmonization

Regulations for bringing new drugs to the patients who need them vary around the world. Yet each of the dozens of drug regulatory organizations—from Argentina’s Administración Nacional de Medicamentos, Alimentos y Tecnología Médica, to Zimbabwe’s Medicines Control Authority—strives to achieve the same goal: universal health through access to safe and effective medicine.

To understand the challenges these varying regulations present, imagine many friends, in many vehicles, on a road trip from Los Angeles to San Francisco, all of whom want to arrive together. It sounds easy enough until I add this caveat: There are no uniform maps, and every county and city implements its own traffic laws. So, without a set route, the convoy of friends splits into groups going in different directions, inevitably triggering delays in what started out as a simple road trip. In addition, the lack of standard rules of the road adds complexity, confusion and cost, not to mention frustration.

The global regulatory approval process suffers from similar delays, complexities and confusion, along with the added costs they incur. Indeed, in the June 2010 issue of the Journal of Clinical Pharmacy and Therapeutics, researchers from the Health Care Science Institute in Tokyo reported that new drugs approved in the U.S. from 1999 to 2007 took an average of 41 months—more than three years—to gain approval in Japan. Such drug lags could continue and even expand. (For a broader perspective, see Drug Info. J. 43:339–347, 2009.) Among the roadblocks prompting these delays is a lack of consensus in the interpretation and application of technical guidelines and drug approval requirements worldwide. Frequently these inconsistencies force pharmaceutical companies to duplicate testing carried out during R&D, imposing an unnecessary drain on resources and slowing down the approval process.

The industry’s solution to these problems is harmonization: generating a common set of guidelines that result in convergence of regulatory requirements and practices. The goal of harmonization is to achieve the most economical use of human, animal and material resources possible while maintaining standards of quality, safety and efficacy.

Decades of Duplication

In the 1960s and 1970s, as the pharmaceutical industry expanded internationally, individual nations developed their own regulatory laws and guidelines concerning new medicines. Even then, such diverging regulations required pharmaceutical companies to duplicate the testing carried out during the R&D process.

A fundamental step toward harmonization was taken in Brussels in April 1990. Representatives of regulatory agencies from Europe, Japan and the U.S. laid the groundwork for the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, which is now known simply as ICH. This conference continues on an annual basis with the goal of making recommendations on ways to achieve greater unification in the interpretation and application of technical guidelines and requirements for product registration.

Despite 20 years of work by the ICH, the regulatory review and approval times in various parts of the world have not decreased. On the contrary, they seem to be increasing. In addition, drug lags appear more pronounced in several of the major emerging markets. Furthermore, as the need for harmonization grows, so do the number of organizations involved. The industry’s coordination efforts themselves have yielded a new layer of complexity in the form of more bodies working toward the objective of harmonization. The ICH has spawned several initiatives serving regions in Asia, Africa and the Americas, while regulatory agencies from different nations have developed programs to recognize the rules of others. Industry groups have gotten into the game as well. Worst of all, these dozens of harmonization efforts often work independently, rather than coordinating their agendas or even communicating with each other. Now more than ever, the various stakeholders need to act together to harmonize harmonization.

Opening an Umbrella

Talk to each other and work together, pharmaceutical companies and global health organizations must keep certain objectives in mind. For one thing, regulatory harmonization is not homogenization. Since drug regulations are associated with sovereign laws of the land, regulations per se cannot be harmonized. However, having a common set of guidelines that results in the convergence of regulatory requirements and practices is an achievable goal.

For example, various drug regulatory authorities now cooperate in the form of reviews, mutually recognizing each other’s opinions. The European Medicines Agency pioneered this approach, and other drug regulatory authorities have since expanded upon it. Collaborations include shared information repositories and a query system on the national registration status of medicines. Connectivity between national registration systems is another direction that various drug regulatory authorities are taking to harmonize the regulatory process.

Complementing the strides made through ICH regional harmonization initiatives, the World Health Organization (WHO) administers a medicines prequalification program on behalf of the U.N. that is particularly strong in Africa and Latin America. The WHO also organizes the International Conference of Drug Regulatory Authorities, which provides member states with a forum to meet and discuss ways to strengthen collaboration.

Likewise, the industry’s technical groups work together to promote good manufacturing practice (GMP) rules for producing and testing substances that include pharmaceuticals. Thirty-nine regulation authorities—from the Belgian Federal Agency for Medicines and Health Products to the Ukrainian State Inspectorate for Quality Control of Medicines, as well as the U.S. Food and Drug Administration—work together through a program developed by the Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Co-operation Scheme.

Perhaps it is time to establish an umbrella body that will provide a forum for regulators and industry to help harmonize harmonization. This body would focus our efforts toward collaboration, cooperation, mutual recognition, technical standardization, uniformity and partnership. If we succeed in this, we will have reduced the delays and confusion on the roadways that deliver rapid—and possibly simultaneous—access to medicines for patients worldwide.

EXAMPLES OF GLOBAL HARMONIZATION INITIATIVE AND ORGANIZATIONS

ICH Global Cooperation Group

• Asia-Pacific Economic Cooperation, Life Sciences Innovation Forum (APEC LSIF)
• Association of the Southeast Asian Nations, Pharmaceutical Product Working Group (ASEAN, PPWG; Observer)
• Gulf Cooperation Council (GCC)
• Pan American Network for Drug Regulatory Harmonization (PANDRH)
• Southern African Development Community (SADC)

WHO Sponsored

• International Council of Drug Regulatory Authorities (ICDRA)
• Pan American Health Organization/World Health Organization (PAHO/WHO)
• African Medicines Regulatory Harmonization Initiative (AMRHI)
• Developing Countries’ Vaccine Regulators Network (DCVRN)
• WHO Prequalification Program (supports procurement with a strong regulatory focus)
• WHO Uppsala Monitoring Centre (UMC; post marketing data on safety, efficacy and product quality)

Technical Topics
(Good Manufacturing Practice)

• Pharmaceutical Inspection Convention and Co-operation Scheme (PIC/S)
• Pharmacopoeial Harmonization—ICH Expert Working Group (Q4B)
• International Pharmaceutical Excipients Council (IPEC)
• International Organization for Standardization (ISO)

Drug Regulatory Agencies—bilateral, multilateral or regional

• European Medicines Agency (EMA)
• African Drug Regulatory Agencies Network (AFDRAN)
• Mutual Recognition Agreements (MRAs) between national regulatory agencies

Major Industry Groups

• Pharmaceutical Research and Manufacturers of America (PhRMA)
• European Federation of the Pharmaceutical Industries and Associations (EFPIA)
• Juvenile Products Manufacturers Association (JPMA)

Medical Devices

• Global Harmonization Task Force (GHTF)
• Latin American Harmonization Working Party (LAHWP)
• Asian Harmonization Working Party (AHWP)

Regional Alliances—economic, geopolitical

• North American Free Trade Agreement (NAFTA; Canada, Mexico and U.S.)
• Southern Common Market (MERCOSUR; Brazil, Argentina, Paraguay and Uruguay; Chile and Bolivia observers)
• Central American Integration System (CAIS; Costa Rica, El Salvador, Honduras, Guatemala and Nicaragua)
• Andean Community (CAN; Bolivia, Colombia, Ecuador and Peru)
• Caribbean Community (CARICOM)
• Association of Southeast Asian Nations (ASEAN)
• Asia-Pacific Economic Cooperation (APEC)
• South Asian Association for Regional Cooperation (SAARC)