Regularizing Regulatory Requirements In Clinical Research: 25 years Of Harmonization And The Path Forward

By Brian D. Bollwage, JD, VP of global regulatory affairs, Theorem Clinical Research; Evanthia Fritz, manager, regulatory affairs, Theorem Clinical Research; Tracy Jia, senior manager, Regulatory affairs, Theorem Clinical Research; Kristine Skjolaas, PhD, senior manager, regulatory affairs, Theorem Clinical Research

The European Community was the birthplace of regulatory harmonization. Efforts at standardizing regulatory requirements date back to the 1980s. These efforts were encouraged by the rapid increase in regulatory controls developed in the 1960s and 1970s in response to notable tragedies, such as that with thalidomide in Europe in the 1960s. The early experience in Europe showed that harmonization could be achieved, leading eventually to multiregional discussions involving Europe, Japan, and the U.S. under the early auspices of the World Health Organization (WHO).

The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) was created in April 1990 at a meeting in Brussels that involved regulatory authorities and industry associations from Europe, Japan, and the U.S. Initial efforts at harmonization were focused on three principle areas: safety, quality, and efficacy.

In April 2015, we celebrate the accomplishments of 25 years of harmonization efforts. This article will review some of the more significant milestones in that 25-year history, examine current initiatives, and speculate how far additional harmonization efforts might take us toward the ultimate goal of regularizing regulatory requirements.

Scientific Consensus Important To ICH Process

The ICH process emphasizes the development of scientific consensus between industry and regulatory experts. Progress has therefore been slow and deliberate with extensive dialogue required before agreements can be reached and before harmonization programs can be implemented. A substantial library of focused guidances has been developed in the areas of quality, safety, and efficacy, covering topics such as GMP, stability, impurities, life cycle management, pharmacovigilance, GCP, clinical study reports, clinical trials in special populations, toxicity testing, genotoxicity testing, carcinogenicity testing, and pharmacology studies, just to name a few.

In addition to these focused technical guidances, other significant multidisciplinary achievements that the ICH process can account for are the development of the Medical Dictionary for Regulatory Activities and the Common Technical Document (CTD). The ICH GCP Guidance E6 has become the global touchstone for all clinical research and has led to the development of corollary standards for clinical research with medical devices, the ISO 14155.

Europe

One of the aims of the European Clinical Trials Directive 2001/20/EC [1] that was adopted in 2001 was to harmonize the regulation and conduct of clinical trials throughout Europe in order to facilitate drug research. The directive suggested that each country have a central ethics committee (EC) that provides a single opinion for that country; it also suggested that applicants be permitted to submit a trial application in parallel to the country’s competent regulatory authority (CA) and to the EC. Moreover, a maximum assessment time of 60 days was specified for both ECs and CAs in Articles 8 and 9 of the directive.

However, the fact that the directive had to be implemented by each EU member state allowed for different interpretations and systems in each country. As a result, developers often must submit multiple applications of nearly identical dossiers in multinational trials, a situation that leads to multiple assessments and then to divergent decisions, with uncertain timelines and outcomes.

Thus, despite the aim to facilitate the conduct of clinical trials in the EU, there are several factors that complicate rather than facilitate the start of a multinational trial. One of these factors is the required documentation. Some documents required by member states are identical: the cover letter, protocol, investigator’s brochure (IB), investigational medicinal product dossier (IMPD), and the EudraCT application form.

Other required documents, however, differ from country to country, leading to additional administrative burden for the sponsors, while clinical trial applications (CTAs) that are not identical lead to a lack of harmonization between the member states. In countries like Bulgaria, Poland, and Romania where fully executed contracts with the sites have to be available for submission to the CA and EC, the time needed to prepare the complete documentation is prolonged noticeably. Also, some member states, like Italy, Spain, and the Netherlands, request the application form and/or a summary of the protocol in the national language — another requirement that takes time and is contrary to harmonization.

While parallel submission to the EC and CA is possible in most member states, Spain, for example, requires EC submissions be made during the first five days of each month; the CA submission is usually done subsequently. Similarly, in Croatia and Italy, submission to the EC should precede the submission to CA.

The timelines for assessment differ from country to country. Although a maximum of 60 days is requested by the directive, validation periods and clock-stops for responses to questions have to be taken into account and lead to longer approval times. Belgium is the only EU country where the approval timeline of both CA and EC is four weeks. In most of the other member states, the CA approval timelines are in the range of six to nine weeks with short approval timelines in the Netherlands (two weeks), Estonia (four weeks), and Austria (five weeks), and longer timelines of up to 14 weeks in Czech Republic, Germany, Hungary, and Italy.

The EC approval timelines in most member states range up to nine weeks, with short approval times in Croatia (four weeks) and considerably longer timelines in Bulgaria (13 weeks) and the Netherlands (18 weeks). Additional subsequent approvals — like that of the German radiation board in the case of ionizing radiation procedures outside the routine care, or the R&D approval in the U.K. — are additional factors that lengthen the time needed before the start of a trial.

A step toward a better harmonization and facilitation of the process was the Voluntary Harmonization Procedure (VHP) [2], launched by the Clinical Trial Facilitation Group in 2009. VHP enables joint assessments of clinical trials and exchanges between CAs of member states concerned. The VHP is applicable to all clinical trial applications involving more than two countries and is based on the concept of a voluntary parallel submission of a CTA core dossier to all participating member states followed by an individual application for approval to the individual national competent authorities. The advantages of the VHP are an electronic submission of an identical dossier, strict timelines, a harmonized scientific discussion, and reduced workload for sponsors as there is only one list of questions to be answered. A recent publication of the Paul-Ehrlich-Institute [3] in January 2015 shows that sponsors have been increasingly turning to the VHP since 2009 (15 in 2009 and 173 in 2014) with almost 20 percent of all multinational trials being submitted through VHP in 2014.

Since its application in 2004, the EU Clinical Trials Directive has contributed to a drop in the number of clinical trials in the EU. The new EU Regulation (536/2014), which entered into force on June 16, 2014, offers a streamlined procedure to assess and authorize new clinical studies, removing duplications and reducing delays for launching clinical trials by introducing a single dossier submitted through an EU portal to all concerned member states.

Asia-Pacific

In this region, Japan is the only ICH member country. However, non-ICH members have made significant efforts to strengthen cooperation and exchange with ICH. For example, the Regional Harmonization Initiative of the Association of Southeast Asian Nations (ASEAN) was adopted to harmonize the drug regulation of its member countries. Ten countries belong to ASEAN: Singapore, Malaysia, Thailand, Indonesia, Philippines, Vietnam, Brunei, Laos, Cambodia, and Myanmar. ASEAN Common Technical Dossier (ACTD) and ASEAN Common Technical Requirements (ACTR) were developed and adopted by its member countries’ respective regulatory authorities.

Another example of ICH cooperation in this region occurred in 2009 when the China Food and Drug Administration’s Drug Registration Department founded the ICH Study Group, whose objectives were to study and disseminate ICH guidelines, strengthen cooperation and exchange with ICH, and promote harmonization of China drug registration standards with global standards. Translating and publishing ICH guidelines and related documents are a very significant part of this group’s important contribution to harmonization. At this writing, this group has completed translation of about 150 FDA, EMA and ICH guidelines and published the translated guidelines to the CFDA website for industry reference. Drug regulatory authorities of Australia, India, Taiwan, and South Korea also have been invited to designate permanent representatives to participate in the ICH meetings. In a word, ICH global cooperation is developing.

However, in this region, the regulatory process and timeline for performing clinical drug trials can be very different. For most Asia-Pacific countries, obtaining clinical trial approval from local authorities is needed. Australia is a relatively quick startup country with three to four months for EC approval and clinical trial notification through its Therapeutic Goods Administration. In India, Malaysia, Hong Kong, Singapore, South Korea, and Taiwan, EC submission and regulatory submission can be made in parallel; EC and regulatory authorities can approve the trials independently. The timeline of trial approvals by EC and regulatory authorities in these countries would usually be three to four months. The timeline is longer in India, where obtaining approval from the Drugs Controller General of India may take six to eight months. In Thailand, Indonesia, The Philippines, and Vietnam, the EC approval letter needs to be enclosed within the regulatory submission package, so regulatory submission can be made only after EC approval. Therefore, obtaining trial permits from the EC and regulatory authorities in these countries may take four to seven months.

The required submission order is reversed in China, where the approval letter from the China Food and Drug Administration must be enclosed with the EC submission package. Trial approval timelines in China typically require more than a year for multinational studies. Moreover, China’s Center for Drug Evaluation has different review channels and review timelines for global and regional studies than it does for China-only studies, which currently take more than two years. However, the CFDA is well aware of the slow startup situation and is making efforts to improve. In February 2015, the CFDA requested stakeholder comments on a draft China GCP that proposes EC and regulatory submissions in parallel. It is therefore expected we will see continued improvements in China very soon.

Regulatory and EC package languages are also very different. In China, all documents in the submission package need to be in Chinese, and translation of CMC, preclinical, and clinical information can take about two months. In South Korea, the CMC section needs to be translated into Korean, which also takes about two months. In contrast, some local FDAs, e.g., the Taiwan FDA and Thailand FDA, can accept technical documents, such as CMC and preclinical documents, in English. Malaysia, Singapore, Hong Kong, The Philippines, and India accept submission packages in English, but require documents for the subjects to be translated into the local language. Meanwhile, the application fees in these countries differ markedly; some are free of charge while others can range from several hundred to even thousands of dollars.

Although the regulatory process, timeline, language, and fees have obvious differences, these differences do not impede the conduct of global and regional studies in the region. These non-ICH member countries are making efforts to maintain close global cooperation and are introducing effective policies to encourage global and regional trial conduct in the area. Some authorities, e.g., authorities in China and Taiwan, are even now employing priority reviews for innovative drug studies.

The Americas

Canada, the United States, and Latin America have all been involved with the ICH regulations and guidances to varying degrees. The U.S. has been involved in ICH from its inception in 1990 with the U.S. Food and Drug Administration (FDA) and Pharmaceutical Research and Manufacturers of America (PhRMA) serving as members of the ICH Steering Committee and its subcommittee. Canada has been a close ICH observer since ICH inception and serves as a non-voting member of the ICH Steering Committee and its sub-group. Latin America has also begun to adopt ICH GCP practices more recently by incorporating ICH regulations and guidelines into the “Good Clinical Practices: Document of the Americas” that was adopted by the IV Pan American Conference on Drug Regulatory Harmonization in March 2005 [4].

The ICH guidelines and the harmonization of quality, safety, and efficacy information into a common technical document (CTD) have contributed to the streamlining of the pharmaceutical industry’s research processes, reducing regulatory authority review times, and contributing to the access of new medicines [5,6]. The U.S. FDA and Health Canada have both adapted the CTD standard, and both have review times of 30 days for clinical trial applications. In the U.S., these include investigational new drug (IND) applications for drugs and biologics and investigational device exemption applications for devices. In Canada, these include clinical trial applications for drugs and biologics, as well as applications for investigational testing for devices. Clinical trial application review by health agencies in Latin American countries, including Mexico, is generally much longer and can range from three to more than seven months.

Even with the harmonization that has been introduced by implementing ICH guidelines, each country’s health agency can still maintain an independent review focus. For example, Health Canada focuses heavily on CMC information provided in a CTA, whereas the FDA's review also dissects full toxicology reports and previous human experience. In addition, the fees associated with regulatory filing vary by country. Currently, both the U.S. and Canada generally do not have fees associated with clinical trial applications, except for the fee the U.S. FDA imposes for biosimilar IND submissions and for veterinary clinical trial applications. Likewise, each Latin American country also has varying fee structures related to regulatory filings.

Regional efforts to streamline and standardize requirements are also underway in the Americas. For example, Health Canada is collaborating with the U.S. FDA to reduce the regulatory burden as part of the Canada-U.S. Regulatory Cooperation Council Action Plan. In 2013, Health Canada and the U.S. FDA entered into a cooperative research and development agreement that authorizes the Health Products Food Branch and the FDA to collaborate on a joint initiative to adapt and share the FDA's electronic submissions gateway for regulatory review by Health Canada. This will ultimately enable the pharmaceutical industry to seamlessly send electronic regulatory transactions to both Health Canada and the FDA, thereby making it easier and less time-consuming to initiate the regulatory process while maintaining independent reviews and approvals by each agency. In addition, the U.S. FDA also allows for the export of unapproved devices under the “Tier 1” country approach, whereby a firm whose device has received marketing authorization in any “Tier 1” country can export that device to any country in the world (including the U.S.) as long as the device meets applicable requirements of the Federal Food, Drug, and Cosmetic Act and the marketing authorization is acceptable to the importing country. Some South American countries have also taken this approach and now permit marketing of any medical device with a CE (“European Community”) mark, which is compliant with European Union legislation.

Conclusion

As can be seen from our region reviews, in its 25-year history ICH has truly become an effective engine, driving considerable progress in establishing common grounds for regulatory decision making. Initially, the scientific consensus process, while admittedly time-consuming, drove significant agreement and commonality on technical issues relating to drug development. This progress is expected to continue at the somewhat deliberate even pace that we’ve observed over the past 25 years.

In recent years, regional harmonization efforts have also paid considerable dividends, and this progress is expected to continue, especially as individual countries and their relevant authorities experience the benefits of harmonization — most significantly the bringing of new therapeutic solutions to their citizens. For example, many countries interested in developing their regulatory systems are inviting the participation of more established regulatory authorities to establish a local presence; for example, the U.S. FDA has established local in-country outposts at the request of China and India. The wave of adoption of ICH standards continues and the momentum, while gradual, is steady and seems to be increasing. Even still, significant differences remain between and even within regions based on language, local custom, and long-established local process requirements. It would be unreasonable to expect that any government would jettison long-standing systems in favor of a regional, unified system that might not accommodate local needs or customs. However, as globalization continues, solutions that work will continue to be leveraged and adopted. Each country, being separate sovereignties, would be expected to retain and even jealously guard their authority and control over parochial interests. The tension between joining in the global harmonization movement and retaining significant local control is expected to proceed in a deliberate and measured fashion.

References

1. Directive 2001/20/ED of the European Parliament and of the Council on the Approximation of the Laws, Regulations, and Administrative Provisions of the Member States Relating to the Implementation of Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use – April 4, 2001.
2. Guidance Document for a Voluntary Harmonization Procedure (VHP) for the Assessment of Multinational Clinical Trial Applications, version 3.2 – December 2014.
3. Results of the Voluntary Harmonization Procedure 2009 –2014 – Paul Ehrlich Institute VHP Coordination. January 20, 2015.
4. Pan American Health Organization. Working Group on Good Clinical Practice. Background Report. Available at: http://www1.paho.org/english/ad/ths/ev/GCP-Background-Eng.pdf?ua=1 (Accessed March 16, 2015).
5. WHO (2002) The Impact of Implementation of ICH Guidelines in Non-ICH Countries - Regulatory Support Series No. 009. Report of a WHO Meeting Geneva, 13-15 September 2001. Regulatory Support Series, No. 9. Ref: WHO/EDM/QSM/2002.3. 19–22. http://apps.who.int/medicinedocs/pdf/h2993e/h2993e.pdf (Accessed March 16, 2015).
6. ICH (2010) The Value and Benefits of ICH to Drug Regulatory Authorities Advancing Harmonization for Better Health. Available at: http://www.ich.org/fileadmin/Public_Web_Site/News_room/C_Publications/ICH_20_anniversary_Value_Benefits_of_ICH_for_Regulators.pdf  (Accessed March 16, 2015).