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Introducing the International Conference on Harmonization Guidelines Into the World Trade Organization:

A Strategy to Remove Technical Trade Barriers 
for Pharmaceutical Products



 Alessandra Cortez
MACD Project
Spring 2002  


William Arrocha
Geza Feketekuty
William Monning


List of Abbreviations

Executive Summary

International Conference on Harmonization

Historical Overview
Products and Services
Policy Background
The Need for Testing
Understanding the General Market Approval Process
Good Manufacturing Practices
Commercial Background
Political Stakeholder Background 
International Conference on Harmonization
World Trade Organization
World Health Organization
World Bank
The Group of 77
Developing Countries within the WTO
Regulatory Agencies
Commercial Analysis
Policy Analysis
Legal Analysis
Political Analysis

Appendix I- ICH Terms of Reference
Appendix II- ICH Schedule of Meetings
Appendix III- Module of ICH Common Technical Document
Appendix IV- ICH Guidelines
Appendix V-Stakeholders’ Interest Chart


List of Abbreviations

API                              Active Pharmaceutical Ingredients
                            Center for Biologics Evaluation and Research (within FDA)
Center for Drug Evaluation and Research (within FDA)
Common Technical Document (ICH)
Dispute Settlement Body (within the WTO)
             European Commission
                            European Free Trade Area
                           European Federation of Pharmaceutical Industries and Associations
                            European Agency for the Evaluation of Medicinal Products
Electronic Standards for the Transfer of Regulatory Information and Data
European Union
Expert Working Groups (ICH)
United States Food and Drug Administration
                             General Agreement of Tariffs and Trade (WTO)
                               Global Cooperation Group (ICH)
                               Good Manufacturing Practices
International Conference on Harmonization
                            International Federation of Pharmaceutical Manufacturers Association

IND                                 Investigational New Drug Application

                              International Office for the Control of Medicine (within EFTA)
                              Japan Pharmaceutical Manufacturers Association
                             Ministry of Health, Labor and Welfare , Japan
                              Maintenance and Support Services Organization (for ICH’s MedDRA)
                              Ministry of Foreign Affairs, Japan
New Drug Application
                               National Institute of Health Sciences, Japan
                            Pharmaceutical Research and Manufacturers of America
                              Pharmaceutical and Medical Safety Bureau (within MHLW)
                            Pharmaceuticals and Medical Devices Evaluation Center (within NIHS)
                                   Steering Committees (ICH)
                                 Agreement on Technical Barriers to Trade (WTO)
                                 Therapeutic Products Programme (Canada)
                                   United States
                               United States Trade Representative
                              World Health Organization
                                World Trade Organization
DC Producers                 
Developing countries within the WTO with pharmaceutical production.
DC Non-Producers    
      Developing countries within the WTO with no pharmaceutical production.



The pharmaceutical industry is one of most complex business in the global economy. There are a multitude of ethical and economic issues surrounding the business from safety assurances to profit margins to patent rights and protection. Each of these issues affects the trade of pharmaceutical products.  This project will focus on one specific facet that greatly affects the trade of pharmaceutical products: testing requirements used to establish the safety of pharmaceutical products for human use. Testing requirements are set by national regulatory agencies and they vary from country to country.  The differences in requirements can sometimes act as trade barriers, greatly delaying foreign market access. This type of delay is a disadvantage for both the exporting manufacturer and the importing consumer.  Over ten years ago the European Union, Japan and the United States decided harmonize their regulations for pharmaceutical market approval.  In this project I lay out the steps and challenges involved in extending the International Conference on Harmonization (ICH) guidelines to the members of World Trade Organization (WTO).  

The goal of ICH is to harmonize testing requirements of pharmaceutical products intended human use; therefore, it does not address pharmaceutical products for animal use, nor does it address patent rights, price controls or medical equipment.



For the purpose of this project I will assume the role of a staff member on the ICH Secretariat.  The ICH board members would like to extend their testing guidelines to the World Trade Organization (WTO).  I have been asked to research the issues surrounding this potential project.


The pharmaceutical industry is one of the largest sectors of international trade.  Global sales of pharmaceutical products are currently estimated to be over $300 billion dollars[1].  Despite the magnitude of trade activity for this sector, the WTO does not currently have an agreement that addresses testing requirements for pharmaceutical products.  Most nations require pharmaceutical products to be tested for safety.  The tests are mandated by regulatory agencies of each specific nation, so they vary from country to country.  WTO members can currently refuse market access for pharmaceutical products based on these testing requirements. Country A, the importing country, can ban the entry of a pharmaceutical product if it has not been tested according to Country A’s specific requirements even if the product has passed all safety tests in Country B, the exporting country. Exporting countries cannot contest this action within the WTO Dispute Settlement Body (DSB) because there are no guidelines in WTO agreements that address testing requirements for pharmaceutical products.  Until guidelines are set importing nations can continue to refuse market access based on Article XX (General Exceptions) of the General Agreement on Tariffs and Trade, which allows members to disregard other trade rules in order to protect human safety.  

Recognizing the problems cause by varying testing requirements the EU, Japan and the US decided to harmonized their testing requirements. Manufacturers and regulatory authorities from all three parties joined together to design a set of testing guidelines that would ensure consumer safety without creating trade barriers. They called the initiative the International Conference on Harmonization.  

The ICH initiative addresses the problem of duplicate testing between the three parties, but challenges remain for many other countries.  ICH membership covers only eighteen of the 144 member nations of the WTO; introducing ICH guidelines into the WTO would expand that membership to an additional 126 countries. 


Executive Summary  

Technical barriers currently obstruct the trade of pharmaceutical medication. Each nation has its own testing requirements. In order to export their products, manufacturers are often required to repeat similar tests containing slight variations. Duplicate testing results in extraneous costs for manufacturers, wasted resources (animals and human volunteers) and delayed market access.  Delayed market access poses great disadvantages for exporting manufacturers and importing consumers.  This problem can be solved by having trade partners agree to harmonize testing requirements. Recognizing the benefits of harmonized testing standards, the European Union, Japan and the United States formed a join initiative between the industry and regulators called the International Conference on Harmonization, but barriers still remain for non-ICH member nations. The ICH members would like to solve the trade problems caused by duplicate testing on a larger scale, not just among themselves. ICH members have opened their doors to any country interested in adopting their guidelines, but there is no enforcement mechanism.  ICH and WTO members alike are powerless to contest pharmaceutical testing standards as a trade barrier because the WTO agreements do not currently contain any set testing guidelines. WTO adoption of ICH guidelines would remove technical trade barriers for pharmaceutical products.

Potential Obstacles to Consider:
Introducing ICH standards into the WTO is a complex process with a multitude of issues to consider.  In proposing this project to the WTO, ICH members will first have to consider where in the WTO agreements these guidelines should be placed.  Next ICH members will have to consider how to gain support from regulatory authorities. ICH members should be prepared to convince regulatory agencies that the pharmaceutical products are completely safe; this involves not only guaranteeing the safety of the actual ICH guidelines, but also assuring the agencies that all WTO members follow good manufacturing processes.  ICH members should also expect potential resistance from developing countries concerned that ICH guidelines (considered the most stringent in the world) may stifle the development of their own industries by enforcing standards they are not financially or technologically capable of following. Before ICH members attempt to introduce their guidelines into the WTO they should first be prepared to address and solve each of these potential issues.

Key Recommendations:

  • Convince WTO member countries to adopt ICH guidelines for market approval requirements of pharmaceutical products.  The guidelines can be adopted into an annex of the Agreement on Technical Barriers to Trade.  The process can take place during the next WTO Ministerial Round.

  • Address developing nations concerns by providing technical and financial assistance.  Allow a longer time frame for developing countries to adopt ICH guidelines.

  • Address the safety concerns of regulatory agencies by ensuring that all participating parties operate on the same level. ICH currently has an Expert Working Group developing Good Manufacturing Practices (GMP).  The World Health Organization also has a code for GMP. All participating parties will be required to adhere not only to ICH guidelines, but also the GMP in order to ensure the highest level of consumer safety.  


The current provisions of the WTO agreements allow importing countries to impose technical barriers to trade for pharmaceutical products.  The technical barriers are applied in the form of testing requirements mandated to evaluate the safety, efficacy and quality of a product. Testing requirements are typically mandated by the regulatory agency of the importing country, so they vary from nation to nation. Many nations have similar testing requirements with only slight variations. Manufacturers find themselves repeating similar tests for each market they export their products to.

As stated earlier testing requirements vary form nation to nation. Developed nations with greater resources to devote to regulatory agencies tend to have the most stringent testing standards; these nations also tend to have the largest consumer share.  European Union member nations, Japan and the United States alone represent 85% of worldwide consumption. Typically testing procedures for pharmaceutical products are extremely time consuming and costly.  The testing requirements for most developed nations take twelve to fifteen years to complete.

For the past ten years the EU, Japan and the US, the three industry leaders for drug development, have been working towards harmonized testing requirements for the safety evaluation process of pharmaceutical products. The three parties formed an initiative called the International Conference on Harmonization. The ultimate goal of the ICH is to eliminate duplicate testing for pharmaceutical products.  Over the past twelve years ICH members have harmonized over fifty guidelines to ensure the quality, safety and efficacy of their pharmaceutical products.  ICH members entered into the initiative with the understanding that they would work together to eliminate duplicate testing, but there are no legal provisions mandating the agreement.  Introducing ICH guidelines into the WTO would not only enforce the ICH initiative, it would also harmonize all WTO members, thereby removing technical barriers to trade on a much larger scale.

In order to ensure successful adoption of ICH guidelines into the WTO agreements members will have to address the potential obstacles listed above. Following is a strategy outlining recommended actions for handling these potential obstacles.


The overall strategy to introduce ICH guidelines into the WTO involves three phases:

  • A strategy to introduce ICH guidelines into the WTO

  • A strategy to gain support from regulatory agencies for this project

  • A strategy to gain support from developing countries for this project

Strategy to Introduce ICH guidelines into the WTO:
In order to introduce ICH guidelines into the WTO, ICH members will have to act through their trade representatives. This will involve lobbying their trade representatives and convincing them to introduce this topic for negotiations in the WTO.  ICH members should provide their trade representatives with the suggestion that the guidelines be adopted as an annex to the TBT agreement.  ICH members should form a coalition with the World Health Organization to gain their support for the project.  WHO support may help advance acceptance of this proposal.

Strategy to Gain Support from Regulatory Agencies:  
Regulatory agencies of both the ICH member regions and the other WTO member nations may resist the idea of facilitated market access because they may mistake it as increased safety risks. The ICH guidelines on testing requirements only address drug approval.  Regulatory agencies need to feel secure that imported pharmaceutical products will not pose any safety risks once they are released on the market. Continued safety of pharmaceutical products involves the manufacturing process, including storage and sealing. The WHO has issued universal guidelines on good manufacturing practices.  In order to ensure that regulatory agencies feel secure with the provisions of this project, ICH members should suggest that the WHO guidelines on GMPs accompany the ICH testing guidelines in the annex to the TBT.

Strategy to Gain Support from Developing Countries:
In order to gain support from the developing countries within the WTO we will have to convince them that they will benefit from WTO adoption of ICH guidelines. The key to gaining support from developing countries is to target developing countries with pharmaceutical production.  Show those countries the potential harmonized testing requirements provide to develop their own industries. Developing countries may argue that the short-term sacrifices of adjusting their current procedures to a much more costly and stringent procedure will hamper their industries to the point that they may not be able to reach the long-term benefits we suggest.  ICH members should answer these concerns by providing financial and technical assistance to developing countries in order to ensure a smooth transition from their current procedures to the ICH and WHO guidelines.  ICH members will also have to consider the concerns of developing nations that do not have any pharmaceutical production. These developing countries may be concerned that compliance with ICH guidelines will lead to higher prices, due to more expensive testing procedures.  Once again, technical and financial assistance to developing countries with pharmaceutical production is the answer.  Financial and technical assistance will help contain the costs of compliance to more stringent testing procedures, thereby avoiding increasing costs for consumers.

ICH members should work with the World Health Organization, the World Bank and the Group of 77 on this project.  Support from the three organizations could help convince developing countries to support the project.



The International Conference on Harmonization: 

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]. 

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. 

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].

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].  

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.   

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.  

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.  

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.

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 16th 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.

* Appendices II and IV were collected from PDFs and could not be entered into the electronic version of this paper, therefore they are not part of the numbered pages. Appendix III is 1 page and Appendix IV is 11 pages.

[1] United States.  Department of Commerce.  US Industry and Trade Outlook 2000 Washington 2000

[2] “Questions & Answers About ICH” International Conference on Harmonization 5 September 2001 <>

[3] The various sources I checked did not provide an exact year.

[4] For the purpose of this paper the member nations of the European Commission, later to become the European Union will be considered as one party, making it the ICH a trilateral as opposed to multilateral agreement.  I will use the term multilateral for my proposal to adopt ICH standards into the WTO.

[5] ICH does not have “offices” per se because it is a voluntary cooperative effort between regulators and industry of the three regions, but because IFPMA runs ICH headquarters can be considered to be in Geneva, Switzerland, where IFPMA is located. The address for contacting ICH is in Geneva.  


[6] “Structure” International Conference on Harmonization  27 November 2001 <>

[7] “Structure”

[8] Please see Appendix 1 for ICH Terms of Reference.

[9] “Questions and Answers About ICH”

[10] From 1990 to 1997 Conferences were held every two years, from 1997 to 2003 conferences are scheduled every three years.  See Appendix 2 for the exact schedule of meetings.

[11] “ICH Information Brochure” International Conference on Harmonization 10 January, 2002 <> 10

[12] Chew, Nancy J. “ICH Now: Harmony at the End of the Century.” Biopharm 12 (1999): 24-32

[13] See Appendix 3 for a detailed description of ICH guidelines.

[14] These tools will be covered in greater detail in the next section of the ICH background: ICH Products and Services.

[15] Burley, Joanna and Nancy J. Chew. “ICH Regulatory Communications.” Biopharm Sep 1999: 12, pg. 20-24

[16] “ICH Regulatory Communications” p. 21

[17] “Questions and Answers about ICH” p. 11

[18] “ICH Regulatory Communications” p.21

[19] “Synopsis of ICH Guidelines and Topics” International Conference on Harmonization 10 November, 2001 <>

[20] Wechsler, Jill. “Biologics, CTD and BSE.” Biopharm May 2001: p.60-64

[21] United States. Food and Drug Administration. Guidance for Industry M4S:The CTD-Safety. Washington, DC: August 2001.

[22] Wechsler, Jill. “Risks and Rewards in the Global Marketplace.” Pharmaceutical Technology May 2001: 16-24

[23] See Appendix 4 for an outline of the CTD.  This outline states that Module 1 is not technically part of the CTD, but every CTD application must include module 1, so for the purpose of this section module 1 is considered to be a part of the CTD.

[24] “Biogen Completes International Registration Filing.” Cambridge, MA.  August 6, 2001 <>

[25] “Risk and Rewards in the Global Marketplace” p.18

[26] “Risk and Rewards in the Global Marketplace” p. 18

[27] “Global Cooperation Group” International Conference on Harmonization 10 November, 2001 <>

[28] Principles taken from “Global Cooperation Group”

[29] “Global Cooperation Group” 

[30] I chose to focus on the United States because the US is currently the industry leader for research and development and the US represents the some of the most stringent guidelines. I have included minimal information on Europe and Japan because their laws are incorporated into the current ICH guidelines.

[31] Heil, Scott, ed. Gale Encyclopedia of Global Industries Detroit: Gale Research, 1999 p. 126

[32] This information was gathered from two sources Gale Encyclopedia of Global Industries p.126 and Carson, Thomas, ed. Gale Encyclopedia of U.S. Economic History, Volume 2, L-Z Detroit: Gale Research, 1999 p.788

[33] Marlow-Ferguson, Rebecca, ed. Encyclopedia of American Industries Detroit: Gale Research, 2001 p. 491

[34] Immel, Barbara “A Brief History of GMPs for Pharmaceuticals” Pharmaceutical Technology vol. 25 July 2001 p.44-52

[35] “A Brief History of the ICH” International Conference on Harmonization <> 9 October, 2001



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