By Cliff Mintz, - Contributing Editor
The regulatory environment for the approval and marketing authorization of pharmaceutical products has grown increasingly complex in recent years. The various worldwide regulatory agencies that oversee these products must ensure they are safe, efficacious, and manufactured according to prescribed quality standards. However, the regulations guiding the approval of pharmaceutical products in various regions of the world have evolved independently of one another. Consequently, there is an enormous amount of diversity in the regulations, laws, and procedures for registering new pharmaceutical products.
These differences, coupled with increasing globalization of the pharmaceutical industry and new opportunities in rapidly emerging markets in Asia, Latin America, the Middle East, and Africa, have renewed the call from pharmaceutical companies to standardize or “harmonize” the regulations and requirements for marketing authorization of pharmaceutical products throughout the world. “The world has gotten smaller, and the need for new medicines is growing,” said Mukesh Kumar, Ph.D., senior director of regulatory affairs and quality assurance for Amarex Clinical Research. “It makes sense to develop a set of common standards across developed and developing markets,” he added.
Proponents of harmonization contend that it helps to: 1) control research and development costs and minimize the use of animal testing without compromising safety and effectiveness, 2) prevent duplication of human clinical trials, 3) reduce drug development times and ensure economical use of resources, and 4) streamline the regulatory assessment process for new drug applications, thereby creating a transparent regulatory process that does not delay or hinder drug development and improves global access to new medicines.
Kevin Moore, Ph.D., senior scientific liaison for the United States Pharmacopoeia (USP), offered that “Harmonization primarily seeks to improve the quality of medicines and to preserve resources by reducing the amount of redundant testing required as manufacturers are increasingly multinational.” On the other hand, Tim Sandle, Ph.D., head of microbiology at United Kingdom-based, Bio Products Laboratory (BPL), suggested that the ultimate goals of harmonization vary among individual stakeholders. He said, “Politicians and businesspersons will see economic advantages, whereas scientists (like me) and regulators will see harmonization as a means by which quality, safety, and efficacy can be built into tests and processes to create international regulatory standards.” Nevertheless, there is general agreement that harmonization will benefit all stakeholders ranging from drug manufacturers to regulators and, most importantly, to patients who will ultimately use the drugs.
While much progress has been made toward harmonizing pharmaceutical regulations over the past 20 years, most of it has taken place in developed markets that include the United States, Europe, and Japan. However, over the last five years or so, regulators from emerging markets have begun to recognize the benefits of harmonization and have taken a more active role in its implementation. Amarex’s Kumar agrees that much progress has been made, but there is still a lot to be accomplished in harmonizing pharmaceutical regulations, especially in emerging markets.
Harmonization In Developed Markets
The International Conference on Harmonization of Technical Requirements for Human Use (ICH) is the organization that is largely responsible for most of the harmonization that has taken place in developed markets. ICH members include the FDA; the Pharmaceutical Research Manufacturers of America (PhRMA); the Japanese Ministry of Health, Labor, and Welfare (JMHLW); the Japan Pharmaceutical Manufacturers Association (JPMA); the European Medicines Agency (EMA), and the European Federation of Pharmaceutical Industry Associations (EFPIA). Other organizations, including WHO, USP’s Pharmacopoeial Discussion Group (PDG), the Pan American Network on Drug Regulatory Harmonization (PANDRH), and the International Pharmaceutical Excipient Council (IPEC), have also contributed to the success of the harmonization effort in developed nations.
Over the past two decades, ICH has issued more than 50 guidelines for technical requirements associated with all aspects of drug development (nonclinical, clinical, and quality), an electronic dictionary of medical terms, and — its most noticeable contribution — the common technical document (CTD), a harmonized electronic submission platform for marketing authorization, recognized by most regulatory agencies around the world. There is universal consensus among drug manufacturers and regulators that the CTD has helped to expedite the drug review and approval process and has also made the exchange of information among drug regulatory authorities much quicker and easier.
Touting the successes of the CTD and other ICH initiatives, Betty Kuhnert, Ph.D., executive director of training services at PharmaNet Development Group, observed, “Gone are the days when you had to load hundreds of volumes of paper documents on a truck for a submission to a given country.” Also gone are most of the clinical studies done for one specific country. Instead, global clinical trials and bridging studies allow extrapolation of foreign clinical data to new regions. However, it is important to note that the ICH’s guidelines are recommendations and not compulsory. In other words, while ICH guidelines exist, there is no penalty for not adhering to them. Nevertheless, some regulatory agencies (e.g. EMA), have formally adopted several ICH guidelines, while others have been officially integrated into EU legislation.
The Evolution Of The Regulatory Harmonization Institute
ICH’s successes in the U.S., European, and Japanese markets triggered an international interest in pharmaceutical harmonization that culminated in several regional harmonization initiatives (RHIs) in non-ICH countries. These include the Association of Southeast Asian Nations (ASEAN), Asia-Pacific Economic Cooperation (APEC), the Gulf Cooperation Council (GCC), the Southern African Development Community (SADC), and the Pan American Health Organization (PAHO).
Over the years, ICH and these RHIs have worked closely with one another (via ICH’s Global Cooperation Group) and, more recently, in 2007 formed a joint working group with the goals of 1) reducing country and regional differences in technical requirements that impact the availability and cost of new medicines, 2) promoting the international movement of pharmaceuticals that are safe, effective, and of high quality, and 3) promoting the conduct of human clinical trials and data collection that meet international standards.
Yet, despite these efforts, in 2012, several industry trade organizations and pharmaceutical companies, including BIO, the Generic Pharmaceutical Association (GPhA), Astra Zeneca, and Bausch and Lomb, formed the not-for-profit Regulatory Harmonization Institute (RHI). Dean Erhardt, principal of D2 Pharma Consulting, LLC and RHI’s President, said that the institute was created because global harmonization efforts to date have failed to include significant and meaningful input from nonregulators, do not provide an appropriate balance between regulators and business, and do not adequately represent the interests of emerging nations.
RHI, a membership only organization, intends to better represent the regulatory interests of emerging nations through educational and training initiatives that include whitepapers, seminars, workshops, and other activities. Interestingly, however, RHI’s membership-only requirements suggest that its education outreach activities will be fee-based. Therefore, the institute’s ability to have a broad impact on global and regional harmonization efforts (especially in emerging nations) may be somewhat limited.
The Challenges Of Harmonization
While drug manufacturers and regulators agree in principle that harmonization makes sense, “It is very difficult to implement across different markets based on historical, political, and economic issues,” said Amarex’s Kumar. Likewise, USP’s Moore suggested that full regulatory harmonization will be extremely difficult or impossible because most countries have differing regulatory and/or legal requirements that are rooted in historical practices and precedent. Finally, RHI’s Erhardt added that while harmonization offers obvious benefits to the pharmaceutical industry, drug makers have largely been excluded from the conversation. “Unless there is more industry involvement, the success of harmonization initiatives, particularly those in emerging markets, will likely be extremely limited,” he said.
The ongoing globalization of the pharmaceutical industry highlights the need for a new strategic approach to harmonize technical and regulatory standards for drug approvals and marketing authorization. Harmonization (both global and regional) will undoubtedly help to minimize duplication, better control development time and costs, and, most importantly, create a more transparent regulatory system that will ultimately allow greater patient access to medicines.
The successes of ICH and other organizations committed to harmonization suggest that it is possible both regionally and globally. However, to sustain the harmonization movement’s momentum more industry involvement will be necessary. Because regulatory harmonization is beneficial to both pharmaceutical companies and consumers, it is likely that more industry representatives will join regulators and government officials at future harmonization talks.