5

Characteristics of Harmonized Regulations and Regulatory Structures

This session, describing harmonized regulations and standards-setting in other sectors, offered two in-depth reports. The first was a look at international harmonization efforts for a completely different field—radiation safety management—to see how that discipline has approached issues similar to those faced in medicines regulation. Session chair James Fitzgerald, PAHO, WHO, noted that important safety standards for radiation protection have been adopted by various international organizations, such as the World Health Assembly and the International Atomic Energy Agency (IAEA). Afterward, the workshop turned to a detailed discussion of WHO’s experiences in setting a variety of standards.

RADIATION SAFETY STANDARDS1

The U.S. Nuclear Regulatory Commission (NRC) is engaged in ongoing efforts to align its radiation protection regulations with international recommendations, said Cindy Flannery, Senior Health Physicist, Office of Federal and State Materials and Environmental Management Programs, NRC. Much has changed with respect to the amounts of radiation people are exposed to from multiple sources, and scientific knowledge regarding the health harms of radiation because the standards on which U.S.

______________________

1 This section is based on the presentation by Cindy Flannery, Senior Health Physicist, Office of Federal and State Materials and Environmental Management Programs, NRC.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 49
5 Characteristics of Harmonized Regulations and Regulatory Structures This session, describing harmonized regulations and standards-set- ting in other sectors, offered two in-depth reports. The first was a look at international harmonization efforts for a completely different field— radiation safety management—to see how that discipline has approached issues similar to those faced in medicines regulation. Session chair James Fitzgerald, PAHO, WHO, noted that important safety standards for radia- tion protection have been adopted by various international organizations, such as the World Health Assembly and the International Atomic Energy Agency (IAEA). Afterward, the workshop turned to a detailed discussion of WHO’s experiences in setting a variety of standards. RADIATION SAFETY STANDARDS1 The U.S. Nuclear Regulatory Commission (NRC) is engaged in ongo- ing efforts to align its radiation protection regulations with international recommendations, said Cindy Flannery, Senior Health Physicist, Office of Federal and State Materials and Environmental Management Programs, NRC. Much has changed with respect to the amounts of radiation people are exposed to from multiple sources, and scientific knowledge regard- ing the health harms of radiation because the standards on which U.S. 1  This section is based on the presentation by Cindy Flannery, Senior Health Physicist, Office of Federal and State Materials and Environmental Management Programs, NRC. 49

OCR for page 49
50 INTERNATIONAL REGULATORY HARMONIZATION regulations are mostly based originally were adopted several decades ago, she said. According to Flannery, the NRC’s broad mission is to license and regulate the nation’s civilian use of byproduct, source, and special nuclear materials to ensure adequate protection of public health and safety, pro- mote the common defense and security, and protect the environment. Its regulations apply to a broad range of activities and sources—nuclear power plants, medical applications, diagnostic and therapeutic applica- tions, industrial radiography, spent fuel, nuclear waste, and so on. NRC rulemaking is a multistep process of revising current regulations that takes several years to complete. Flannery described the steps: • Identify the need for rulemaking—The request for a change in the rules can come from any source: Congress, the public, professional associations, NRC staff, or others. If this request is approved by the NRC commissioners, staff often begin with a period of seeking input from interested stakeholders. • Establish the regulatory basis for the new rule—A sound regulatory basis reduces the risks for misdirection of licensees; delays or fail- ure of the rulemaking effort; and successful defense of the rule if it is challenged in court. • Ongoing stakeholder involvement—NRC staff may make presenta- tions at meetings of professional organizations and the public, conduct webinars, or use other means to solicit comment on the relevant issues. As the process moves forward, the requests for public input become more detailed and specific. • Develop a proposed rule—The proposed rule is published in the Federal Register and other government websites, with a specified comment period. • Develop the Final Rule—The final language of the rule is published in a Federal Register notice, which includes a “comment resolution” section providing responses to all the comments on the proposed rule. In a real-life example, said Flannery, in 2007 the independent Interna- tional Commission on Radiological Protection announced revised recom- mendations related to preventing radiation-induced diseases. NRC staff analyzed these recommendations and found that some of the changes warranted similar revision to U.S. rules. The five-member NRC agreed, and staff began the process of engaging stakeholders. That information- gathering process has been under way for 3 years, including three public workshops, presentations at conferences and meetings, and solicitation of comments through the Federal Register. The policy issues they uncovered were addressed in a set of recom-

OCR for page 49
CHARACTERISTICS OF HARMONIZATION 51 BOX 5-1 Differing Units of Measurementa The issue of units is one to be addressed in the pharmaceutical arena. In many countries where U.S. firms file drug applications, they are asked to use the International System of Units (SI units)—the modern metric system—but for FDA, applications must be in standard U.S. units. As a result, companies need to main- tain two datasets and, essentially, write two applications. ICH’s common technical document does not solve this. The lack of common units affects not just the manufacturers or just the United States; it makes the work of regulators in less-resourced settings more confusing and difficult. Put more broadly, in a globalizing world, what regulators do has impact outside their home jurisdictions. Such problems occur within the United States, as well; for example, the root cause of the loss of the Mars Climate Orbiter (total mis- sion cost: more than $655 millionb) was that the spacecraft team in Colorado used English units and the mission navigation team in California used metric. Workshop participants were hard pressed to understand how this situation persists in an environment where there is so much interaction among regulators. Common units would be a small step toward harmonization that would have a large impact. a Issues discussed by several individual workshop participants. b See http://mars.jpl.nasa.gov/msp98/orbiter/fact.html (accessed April 22, 2013). mendations to the commissioners, who, after consideration, asked the staff to move forward with developing the regulatory basis for some of them, said Flannery. For example, staff recommended that NRC update the method required for calculating radiation dose exposures to align with international recommendations, and the commission approved pro- ceeding with this potential change. By contrast, staff recommended reduc- ing occupational dose limits from 5 rem (Roentgen equivalent man) per year to the international standard of, effectively, 2 rem per year, but the commission voted against this change. In general, the use of different units of measurement around the world is a challenge to harmonization efforts (see Box 5-1). For example, the rest of the world measures radiation exposure and doses in sieverts, but the United States uses rems. The staff recommendation that the NRC align its measurement units with the international standard was denied, and the U.S. units will be retained in the NRC regulations.2 2  It was noted that the first study of the National Academy of Sciences was on the topic of whether the United States should convert its weights and measures systems to be aligned internationally, and the Academy’s recommendation was “yes.”

OCR for page 49
52 INTERNATIONAL REGULATORY HARMONIZATION In some areas of radiation protection, the United States is moving into alignment with international recommendations, and in some it is not. International recommendations are viewed as a point of reference for developing U.S. regulations and guidance, and, while there likely are benefits to consistency, alignment is not automatic, Flannery explained. The extensive opportunities that the NRC offers for public input also may move the final outcome away from consistency with international recommendations—a source of divergence not often considered. One workshop participant suggested that proposals to incorporate cost-benefit analysis in rulemaking processes might weaken the impact that public participation currently has in NRC regulation development. Flannery said the NRC recognizes that its decisions will never make everyone happy, but having an open and collaborative process lets stakeholders know they have an opportunity to participate and that their views are being heard. The benefits of regulatory alignment Flannery described are • establishing coherence within NRC regulations and updating them to a common basis; • reflecting a more current estimate of radiation risk and advances in scientific knowledge; and • consistency with the regulatory schemes of other countries. REFLECTIONS ON THE EXPERIENCES OF WHO3 WHO is the directing and coordinating authority on international health within the UN system, and it is therefore owned by the UN’s 193 member states. In addition to the Geneva headquarters, WHO has six regional offices—in Manila, the Philippines; New Delhi, India; Cairo, Egypt; Copenhagen, Denmark; Brazzaville, Republic of the Congo; and Washington, DC, as well as 147 country offices. The country offices vary considerably in size and in the technical sophistication of staff. According to Lembit Rägo, Coordinator for Quality and Safety of Medicines, WHO, in the field of regulating health products—medicines, biologicals, vaccines, and devices—WHO’s role is to set norms and stan- dards and, in a broad sense, to assess national regulatory systems, pro- vide regulatory support to countries building up functional systems, and engage in other capacity-building activities. Many hundreds of people go through WHO’s training courses conducted in different part of the world. Regional offices and some country offices may supplement the global training effort. WHO also promotes harmonization and information 3  This section is based on the presentation by Lembit Rägo, Coordinator for Quality and Safety of Medicines, WHO.

OCR for page 49
CHARACTERISTICS OF HARMONIZATION 53 exchange on safety, quality, and best practices. Perhaps most important to developing countries, said Rägo, it ensures the safety and quality of selected products for UN members through its prequalification programs for medicines, vaccines, and diagnostics. WHO Harmonization Activities In its constitution, WHO is mandated “to develop, establish, and promote international standards with respect to food, biological, pharma- ceutical and similar products” (WHO, 2013). These standards are arrived at through the deliberations of WHO expert committees. For example, Rägo noted: • The Expert Committee on Specifications for Pharmaceutical Prepa- rations develops standards in many areas, from good manufactur- ing processes, to finished dosage forms, to bioequivalence, to good distribution practices. • The Expert Committee on Biological Standardization develops standards for vaccines and biological products. The expert committees include global experts and may have observers who are representatives from industry and professional organizations. Their process is transparent, with drafts circulated for comment, and everyone may comment on them, he said. By policy, WHO standards-development efforts do not compete with those of other standard-setting entities, like ICH, but complement them, said Rägo. Some WHO standards have become de facto ICH standards. For example, its good manufacturing practices standard for active phar- maceutical ingredients has become a common standard used by many countries. Rägo suggested that another important harmonization activity is WHO’s project on International Nonproprietary Names. When this ini- tiative began in 1950, numerous nomenclature bodies were issuing simi- lar nonproprietary names; today, few continue this work, and the WHO names are the world standard. This is a huge advance, as these names are used in drug regulation, labeling, prescribing, pharmacopeias, advertis- ing, and the scientific literature. A biennial WHO conference brings together drug regulators from a hundred or so nations, Rägo said. The conference promotes sharing of information and best practices, international cooperation, and harmoni- zation and convergence. Several major initiatives—including ICH and AMRH—began with discussions at this meeting. Similarly, WHO has taken the lead in convening the few remaining global pharmacopeias.

OCR for page 49
54 INTERNATIONAL REGULATORY HARMONIZATION Rägo concluded that WHO has promoted regulatory collaboration and harmonization for a long time, through various means, and will con- tinue to do so. Its main objective in all such efforts, he said, is to produce measurable public health gains, primarily by improving access to needed medicines. Challenges WHO’s long and multifaceted experience with international, regional, and national harmonization initiatives demonstrates that these initiatives themselves are not harmonized. They are different in how they are orga- nized, in the entities involved, in their focus, and in how they are imple- mented. Several workshop participants underscored the importance of harmonizing the functional networks, while in the meantime strengthen- ing the capacity of the smaller countries, in order to facilitate their eventual full participation in one or more networks. Rägo asserted that countries engaged in successful harmonization initiatives typically have a number of characteristics, including • an enabling environment and a strong foundation, including effec- tive governance principles—transparency and accountability—and modern legal systems that allow certain flexibilities; • political will and a common vision; • socioeconomic development similar to that of other participating countries; • well-functioning regulatory authorities that have the necessary capacity and resources; • willingness to invest in harmonization and commit to implement- ing, updating, and revising guidelines; and • use of good regulatory practice principles when implementing harmonized guidelines. Gaps in implementing harmonized standards persist. One gap is the uneven training that regulators receive, which is exacerbated by a lack of consensus on what kinds of training regulators actually need or how to provide it. Even when common technical documents are in use, effec- tive cooperation and work sharing are needed for effective implementa- tion, Rägo argued. Ultimately, a set of good decision-making practices is needed, he said. The regulations may be harmonized and the regulatory practice principles may be in place, but regulators still need time and training to learn how to make good decisions. Finally, Rägo suggested that the most effective ways to regulate many of the new product groups coming on line have not yet been established.

OCR for page 49
CHARACTERISTICS OF HARMONIZATION 55 Countries are still learning how to regulate them, and prospective harmo- nization has not yet occurred, he said. Despite these many requirements and various gaps, the EU experi- ence shows harmonization can be successfully achieved. Laws and regula- tions pertaining to pharmaceuticals in the EU’s 27 states are all the same. Implementation variation has been minimized by dividing the tasks. Only a couple of member states take the lead on scientific assessments, for example. The others benefit from that work, they do not duplicate it, and countries that do not take the lead in this area can put their resources else- where, he said. No correlation exists between the size of the EU country and its regulatory impact. Countries relatively small in population—like Sweden and the Netherlands—have a relatively high impact in medicines regulation, and the converse is also true. The WHO PQP has been a success in making treatments affordable. Lower costs are achieved by relying on international-standard-quality generic medications. Competition among generics manufacturers brings costs down further. With fair competition and no artificial trade standards or other double-standard policies, the goal of more affordable medicines is achievable. Trends Encouraging Harmonization Joint review of clinical trial applications and products is an emerging trend, which Rägo believes has considerable potential. In this approach, regulators from different countries—even different regions—work on the same products or the same clinical trial applications. AVAREF works in this general way, as does the WHO PQP. The approach is especially promising for products with high public health value, but relative small potential markets. In both the above examples, the regulators have an incentive to har- monize. Incentives can take many forms: the perceived gains from har- monization may be high and visible, or harmonization may be preferable to the political pressure that inaction would precipitate. Another trend Rägo noted is to use staff exchanges to promote har- monization and improve regulatory reviews. These exchanges help staff understand other regulators’ thinking about the decision-making process. For example, WHO has a 3-month rotation post for assessors from differ- ent countries. As the production of medicines has become global, the era of only locally operating regulators may become increasingly untenable, with the future of medicines regulation more collaborative and networked. Unfor- tunately, many regulations and regulatory systems operating around the

OCR for page 49
56 INTERNATIONAL REGULATORY HARMONIZATION world are merely unnecessarily redundant. Rägo suggested that ensuring that each regulatory review adds value to the process would require • taking account one another’s work with a view to improving the global system’s efficiency; • committing resources to form cooperative networks based on uni- formity of standards and inspections systems; and • engaging with regional and international initiatives promoting harmonization, information sharing, and use of shared data. Although some of this is happening, a more structured and efficient approach would move the process along more quickly. “Not all national regulators can fulfill all the functions themselves. National decisions have to be made regarding which areas to focus on, where to build capac- ity, and in which areas to rely on other regulators’ work,” Rägo said. If smaller countries aspire to creating regulatory systems akin to those of Europe, the United States, or Japan, the resultant overload of work will delay their people’s access to valuable biomedical products. Next Steps In the discussion session following this panel, Rägo proposed several specific ways to move forward, including the following: • Rewrite WHO’s guideline for small regulatory authorities based on today’s realities and trends. The original version, in its comprehen- siveness, was impossible for small agencies to implement. • Disseminate the best practices of small regulatory agencies that have integrated themselves into collaborative networks for some necessary tasks so they can focus their own work on local value- added tasks. • Develop a vision and understanding of how to implement good review practices.