Background

The International Conference on Harmonization: 

Overview:
The International Conference on Harmonization (ICH) is an agreement between the European Union (EU), Japan and the United States (US) to harmonize regulatory requirements for the testing, application and approval process of pharmaceutical medications. The official name is the “International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.”  ICH is a joint initiative between government regulators and industry manufacturers. ICH strives to deliver medications to consumers in the EU, Japan and the US in the most efficient, timely and cost effective manner[2].

Historical Overview:  
The first attempt to harmonize pharmaceutical regulatory requirements was undertaken by the European Commission (EC) member nations during the 1980’s[3].  Recognizing the mutual benefits to both industry and consumers, the EC decided to facilitate the trade of pharmaceutical products through the development of a single market.  The undertaking was a success and demonstrated that multilateral harmonization for pharmaceutical products could be accomplished without jeopardizing consumer safety. Concurrently, the EC began bilateral discussions on possible pharmaceutical harmonization with both Japan and the United States.  It was not until 1989 that all three parties joined together and considered a trilateral harmonization[4].  Specific plans began to materialize at the World Health Organization’s (WHO) Conference on Drug Regulatory Authorities held that year in Paris.  One year later ICH was formed to oversee and carry out harmonization plans. The European Federation of Pharmaceutical Industries and Associations (EFPIA) hosted the original meeting, which took place in Brussels.  ICH headquarters would later be set up in Geneva, Switzerland and the International Federation of Pharmaceutical Manufacturers Association (IFPMA) would take over administrative duties for ICH[5]. 

Members:
Each of the three founding members has two active parties in ICH, one representing the government regulators and one representing industry manufacturers. Government and industry representatives work together closely to ensure a smooth development of ICH guidelines that address industry concerns while maintaining the most prudent standards for consumer safety.  

European Union:  The European Commission and European Federation of Pharmaceutical Industries’ Associations are the two representatives for the EU. 

• The EC represents the fifteen member countries of the EU.  ICH activities are handled by the European Agency for the Evaluation of Medicinal Products, which was established by the EC specifically for this purpose (EMEA)[6].  EMEA is located in London.
    

• EFPIA represents pharmaceutical companies from sixteen countries in Western Europe, including all of Europe’s major research based pharmaceutical companies. The association works closely with the EC and EMEA to ensure that ICH activities are representative of the entire European industry, not just the EU member nations[7].
    

Japan: Ministry of Health, Labor and Welfare (MHLW) and Japan Pharmaceutical Manufacturers Association (JPMA) are the representatives from Japan.  

• oversees social welfare, social security and public health in Japan. The Pharmaceutical and Medical Safety Bureau (PMSB), a division of MHLW manages ICH activities. MHLW and PMBS work closely with Japan’s National Institute of Health Sciences (NIHS), which carries out research and testing on drugs and vaccines. The agencies also work with the Pharmaceuticals and Medical Devices Evaluation Center (PMDEC), a division within NIHS, which focuses on the development of new drugs.  

• JPMA represents ninety Japanese pharmaceutical companies, including all the major research-based pharmaceutical manufacturers in Japan.  One of JPMA’s primary goals is to improve the industry’s understanding of international issues. 
    

United States: The US Food and Drug Administration (FDA) and Pharmaceutical Research and Manufacturers of America (PhRMA) are the two parties representing the US in ICH.  

• The FDA staff includes administrative, scientific and regulatory specialists organized under the Office of the Commissioner.  The FDA deals with safety evaluations for a wide range of products including drugs, biologicals, medical devices, cosmetics and radiological goods.  ICH activities are handled by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).  

• PhRMA represents seventy-two research based pharmaceutical companies in the US. The association also represents twenty-four affiliates that conduct biological research related to drug and vaccine development.  PhRMA’s Scientific and Regulatory Affairs division handles ICH activities.

In additional to the six participating parties, ICH also includes three observers who act as a liaison between ICH and non-ICH countries and regions.  The three observers are the WHO, the European Free Trade Area (EFTA), and Canada. The International Office for the Control of Medicines (IOCM) represents EFTA at ICH. Switzerland has observer status through EFTA.  IOCM, like ICH is located in Switzerland.  The Therapeutic Products Programme (TTP) is the group representing Canada at ICH. TPP is affiliated with Health Canada.  Each of the observers has a seat in ICH. 
   

Structure:
The structure of ICH contains four main groups: the Steering Committee, the Expert Working Groups (EWGs), the Secretariat and the Coordinators. The SC and EWGs develop the work and process of ICH.  The Secretariat and the Coordinators carry out the administrative duties of ICH. 

The Steering Committee  
The Steering Committee is comprised of two representatives from each of the six member parties and one representative from each of the three observing parties. The Steering Committee is responsible for determining ICH policies and procedures and selects topics for harmonization; the committee also monitors the progress of harmonization initiatives.  All Steering Committee work is done according to ICH Terms of Reference[8].

Expert Working Groups
The Steering Committee assigns an EWG to each of the technical topics selected for harmonization. EWG represent each of the six members, the observers and any other relevant parties (such as the generic drug industry, pharmacopoeias etc.)[9].  The groups are comprised of industry specialists on the topics discussed; the members are nominated by each of the six parties. EWGs do not have a fixed membership, they participate for the timeframe in which their relevant topic is being discussed and/or reviewed.  

The Secretariat
The primary duties of the Secretariat involve preparations for and documentation of all ICH meetings (both Steering Committee and EWGs meetings) and liaisons with any speakers who attend those meetings. The Secretariat is provided by IFPMA in Geneva, Switzerland.

The Coordinators
ICH coordinators act as the main contact between the six member parties and the Secretariat.  The coordinators also ensure that ICH documents are distributed properly.             

Meeting Structure  
The ICH meeting structure is similar to the meeting structure of the World Trade Organization (WTO) in that there is an umbrella timeframe in which various topics are addressed and a set meetings within that timeframe to handle the details of the topics discussed; in the WTO the timeframe is referred to as a “Round” in the ICH it is referred to as a “Conference.”  Conference sessions take place roughly every two to three years[10].  Within each conference session there is a series of meetings that take place twice a year; the location of meetings rotates between the three member regions.  During these meetings, the Steering Committee reviews proposals for new topics and guidelines; the Steering Committee also reviews previously established guidelines to ensure that the harmonization process is carried out smoothly.  

ICH also offers occasional workshops on the implementation and use of ICH guidelines. Traditionally the workshops have been offered simultaneously with the biennial meetings in order to benefit from the presence of the Steering Committee members.  ICH would like to continue to offer workshops in the future, even though no official schedule or plans have been finalized as of yet[11].
   

Topics:
When the ICH initiative first started in 1990, its creators introduced eleven possible topics to address; twelve years later, fifty guidelines have been harmonized between the three regions[12].  ICH guidelines are divided into four main categories: quality, safety, efficacy and multidisciplinary[13].  

Quality
Sixteen different guidelines fall under the category of quality.  The guidelines cover various issues including stability, temperature, trial duration, light sensitivity, residual solvents, and impurities.  The Quality section also evaluates viral safety for medications created using biotechnological engineering.   

Safety
There are thirteen guidelines covered in the Safety section. This section deals with detailed scientific issues including: carcinogenicity, genotoxicity, toxicokinetics (including reproductive toxicity testing), and pharmacokinetics. The guidelines in this section also look at toxicity issues during the testing phases and pre-clinical safety evaluations.  

Efficacy
The Efficacy section covers fourteen guidelines. The guidelines addressed in this section are a combination of technical and administrative issues. Technical issues include: the effectiveness of long-term treatment for non-life treating conditions and dose response information.  Administrative issues include: clinical safety data management and standards for successful expedited reporting, maintenance of ICH guidelines, structure and content of clinical safety reports and ethnic factors in the acceptability of foreign clinical data.  

Multidisciplinary
The Multidisciplinary section covers topics that do not traditionally fit into one of the three sections discussed above.  Many of the subjects in this section are actually tools that ICH helped create such as a medical terminology dictionary and a common marketing application for new pharmaceutical products[14].   

Products and Services:
In addition to the guidelines ICH has developed, they have also created various products and services to facilitate the harmonization process. Over the twelve years member parties have been working on the ICH initiative, they have learned that their initial goal of tripartite pharmaceutical harmonization is a constantly evolving process, particularly considering the fast paced R&D nature of the medical industry.  As the ICH SC and EWGs move further along the development of harmonization and the creation of new guidelines they may create new products and services.  To date, they have developed four main products and services: MedDRA, the Electronic Standards for the Transfer of Regulatory Information and Data (ESTRI), the Common Technical Document (CTD) and the Global Cooperation Group (GCG).  These tools aid member parties’ manufacturers adhere to ICH guidelines and increase transparency of those guidelines and other ICH activities for non-members.

MedDRA:
Pharmaceutical R&D teams in the EU, Japan and the US all used different terminologies to record drug development materials. Early in the ICH process the Steering Committee and EWGs realized true harmonization would not be feasible as long as regulatory communication barriers existed, and so they decided to create a medical terminology vocabulary that would allow all three parties to use one medical language; they named this dictionary MedDRA.  

MedDRA is modeled after MEDDRA, a similar version of common medical terminology used by the EU[15].  The ICH Steering Committee and EWGs began the creation of MedDRA in 1994; it took four years to reach a point where the industry could actually use the dictionary.  The MedDRA process will never actually be completed; it is an ever-evolving dictionary that will change in response to the future needs of the pharmaceutical industry[16].   IFPMA was granted the rights to MedDRA.  Pharmaceutical regulators,  researchers and manufacturers can access MedDRA on the Internet. MedDRA is available to regulators free of charge.  Industry pays for the publication fees[17].  

The nature of MedDRA requires active maintenance of the dictionary.  Updated terminology  and online availability of MedDRA both require the continuous attention of specialized experts.  ICH and IFPMA decided to contract such duties to separate companies able to carry out each specific task.  The result is an intricate system involving five different companies that work to ensure that MedDRA successfully serves the needs of both regulators and industry.  The main company that leads the MedDRA workgroup is BDM International, based in Virginia. BDM handles the maintenance and support services for MedDRA terminology.  The group that works on MedDRA is called MSSO (Maintenance and Support Services Organization). MSSO implements updates to MedDRA, it also provides customer support services for MedDRA subscribers such as training, quarterly updates and a twenty-four hour help desk. Lead by BDM, the MSSO team is aided in the complete maintenance by four other companies: Quintiles Transnational Corporation in North Carolina, Stellar Systems in Virginia, Cyntergy in Maryland and Ernst & Young in New York. Quintiles handles medical review and translation of all MedDRA terminology. Stellar Systems operates the engineering services for development of the information systems and the standard operating procedures. Cyntergy runs the international help desk. Ernst & Young supports the user groups. The multiple dictionaries that were used prior to the creation of MedDRA were often incompatible with one another and lead to communication problems when manufacturers reported their information to multiple regulatory agencies[18].  The creation of MedDRA helps ensure a certain level of public safety when dealing with the development and production of pharmaceutical medications through one harmonized terminology. 

Electronic Standards for the Transfer of Regulatory Information and Data (ESTRI):
The ICH initiative took place during the height of the technology and Internet boom. The founding parties of ICH spread across three different continents, making the use of high-speed technology and the Internet the most efficient means for information exchange and application processing.  The ICH Steering Committee assigned an EWG to oversee the development of an electronic system for informational exchange between manufacturers and authorities.  ESTRI covers the evaluation of encryption technologies, physical media (floppy disks and CD-ROMs), network messaging, message formats and electronic document transfers[19].  In 1996 the EWG selected the appropriate software to handle ICH needs for electronic information transfer; they selected Templar Software, based in Virginia[20].  By 1997 ICH members had successfully used the software to transfer drug reports.

The Common Technical Document (CTD)
ICH members initially worked to harmonize the technical requirements for the registration of pharmaceutical medications.  The goal of harmonization was to improve and expedite access to foreign markets in a cost-effective manner; while harmonization of technical requirements helped reach this goal, the submission process continued to slow exportation of pharmaceutical products.  Each of the three regions had their own requirements for the organization of marketing applications.  The EU Expert Dossier required expert reports and tabulated summaries, while the Japanese Gaiyo required written summaries[21].  Another problem for manufacturers was the significant disparities in the timeframe for approval; the Gaiyo ran hundreds of pages and could in some cases takes a few years to produce, greatly delaying market access in Japan[22].   ICH members addressed this problem by harmonizing the application for market approval.  They created the Common Technical Document, an application for all three regions that follows the same guidelines for submission of new products.  

Five modules divide the CTD[23].  Module 1, Administrative and Prescribing Information, includes product name, manufacturer, and dose indication information. Some of the information in this module is region specific, for example the type of labeling used in the particular country.  Module 2, Common Technical Document Summaries, addresses pharmacologic class, proposed clinical use, toxicology studies, and other topics assessing the quality, safety and efficacy of the medication.  This module contains seven sections, and three separate documents. The seven sections are:  

• Table of Contents

• Introduction

• Quality Overall Summary

• Nonclinical Overview

• Clinical Overview

• Nonclinical Written and Tabulated Summaries

• Clinical Summary

The seven sections should be presented as one document.  Following that document are three individual reports. The three individual reports are M4Q Quality, M4E Efficacy and M4S Safety.  M4Q, M4E and M4S of Module 2 provide overall summaries of their respective topics.  More detailed information follows in modules 3, 4 and 5.  Module 3, Quality, provides detailed information on development of dosage form, formulation, container closure system and additional manufacturing information. Module 4, Clinical Study Reports, provides a critical assessment of clinical data on the effectiveness of the medication. Module 5, Nonclinical Study Reports, provide extensive summaries and discussions of nonclinical information on pharmacology, pharmakinetics and toxicology.  

Manufacturers have already used the CTD successfully.  In August of 2001, Biogen, a US pharmaceutical company, used the CTD to simultaneously file a marketing application in the US and EU.  The CTD allowed the US manufacture to file in a foreign market less than one hundred days after Phase III clinical results[24].  Currently the use of the CTD is optional in all three regions.  The EU and Japan plan to mandate the use of the CTD sometime within the next two years; the US does not have plans to require use of the CTD, it will however provide guidance to manufacturers who choose to file using the CTD[25].  Global use of the CTD has already been discussed.  Canada, an ICH observer plans to use the CTD in order to allow its manufacturers the benefit of concurrently filing in the ICH member countries.  The World Health Organization is considering recommendations to 190 countries to adopt use of the CTD[26].  Although the CTD primarily harmonizes application format, it may eventually lead to a standardized registration process. 

The Global Cooperation Group (GCG):
The members of ICH have made an effort from the onset of the initiative process to maintain a transparent code of practice that would keep all ICH guidelines and documents open to authorities and manufacturers of all countries, not just ICH member nations.  Representatives from non-member nations are able to attend ICH plenary sessions as observers and the ICH information is available on the websites of all member parties, the ICH and IFPMA.  In an effort to ensure smooth communication with non-member parties, the ICH created a specific group to serve as an information liaison between ICH participants and non-member parties.  This panel, the Global Cooperation Group was formed in 1999 as a subcommittee of the Steering Committee.  The GCG is comprised of one representative form each of the six parties on the Steering Committee, the Secretariat, and one observer from the WHO and Canada[27].  The GCG created a set of principles to follow when handling requests from outside parties[28]:  

• ICH will not seek to impose its views on any country, region or company, but will serve as a resource for information and data

• ICH will provide non-ICH member countries or companies with any document related to the GCG initiative without charge

• This subcommittee will not cause or require any change to the current ICH structure or procedures of operation

• While some non-ICH countries are not in a position to utilize ICH guidelines at present, these guidelines will be used as the basis of ICH’s response whenever information is requested

• The Global Cooperation Group will provide information upon request from non-ICH countries and will make information available about the existence of the ICH website, the address for communications and related information.  

The ICH welcomes non-members to adopt its guidelines and the GCG works to address the needs of those parties[29].  The ICH has also published various informational brochures on the ICH.

Policy Background:

The Need for Testing[30]: 
Pharmaceutical practices dates back over thousands of years. It began with the use of herbs, minerals and other compounds to treatment aliments of the human body.  The first official guide on the preparation of medicinal products can be traced as early as the 16^th century (published in Germany) and by 1617 the first pharmaceutical association, The Society of Apothecaries, was established in London[31].  Overtime the nascent production of medications through the use of natural resources evolved to the development of chemical based treatments. By the nineteenth century the mass production of potent medicinal compounds were already a common practice in several European nations and the United States.  Modern day industry leaders such as Bayer, Hoechst, Parke Davis and Eli Lily were already established businesses in the two regions and the majority of their products were chemical based[32].    

With the growth spur of new medicinal products came new dangers in consumption of these goods.  The first realization that the products taken to improve human ailments could result in detrimental health consequences occurred in the early 1900’s.  Opiates such as morphine, cocaine, opium and heroin were commonly used in medicinal products.  Because there were no laws regulating the industry, the danger of using opiates in pharmaceutical products was not realized until patients started to develop addictions to their medications. Currently, a journalist named John Sinclair wrote a book called, The Jungle, which revealed the unsanitary practices of the Chicago meat packing industry.  The two incidents propelled the U.S. Congress to pass the 1906 Pure Food and Drug Act.  For the first time regulators were granted the authority to ban dangerous drugs.  The law also mandated accurate labeling practices.  All ingredients had to appear on the label and manufacturers could not make unsupported or misleading claims about the targeted treatment.

The 1906 law was an initial step to protect consumers of pharmaceutical products, but as the industry grew, so did evidence of the need to more prudent guidelines. The 1930’s marked an unprecedented situation illustrating the dire need for improved regulations. In 1935, The Massengill Company marketed a sore throat remedy containing diethylene glycol, now the main ingredient in antifreeze.  One hundred and seven people died from using this cough syrup before the problem ingredient was discovered[33].  In response to the tragedy, Congress passed The Food and Drug Cosmetic Act of 1938, which required that all medicinal products pass tests for safety before they are put on the market.  This was the first time pharmaceutical products tested for toxicity in the US.  

Pharmaceutical testing procedures were extended to cover indirect side effects during the 1960’s when a popular European sleeping pill was identified as the cause of over ten thousand birth defects in Europe.  Infants whose mothers took the sleeping pill during the first trimester suffered severe deformities in their arms and legs.  The realization propelled more stringent guidelines for market approval in both Europe and the US[34].  Japan mandated government regulations for the sale of pharmaceutical products during the 1950’s[35].  As the use of synthetic chemicals in pharmaceutical products has increased, all three regions have adapted their regulatory guidelines in order to ensure consumer safety.

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