The Value and Benefits of ICH to     Drug Regulatory AuthoritiesAdvancing Harmonization for Better Health                 ...
This publication salutes two decades of the ICH’s groundbreaking work in       harmonizing drug regulatory requirements am...
The Value and Benefits of ICH to Drug Regulatory Authorities -                             Advancing Harmonization for Bet...
Shift in EmphasisSubstantial benefits to DRAs resulted               processes, ultimately leading to a harmonizedwhen ICH...
Prior to the advent of the CTD, regulatory          submission formats, believing it would be tooreviewers received an app...
Regulatory BenefitsThe CTD has also made the exchange                           interactions between the two agencies. Now...
Last, and perhaps most important, the                 Another benefit of a harmonized format hasCTD has facilitated electr...
The ICH guidelines are giving medical writers improved guidance on how to interpret what FDA needs  within a marketing app...
A Harmonized                               Marketing Application                              ALEX GIAQUINTO              ...
A Harmonized Marketing Application                                              (continued)although the current applicatio...
ICH Guideline Implementation                                                                                LENITA LINDSTR...
ICH Guideline Implementation                                      (continued)harmonization of the manner in which the     ...
ICH has provided a logical framework for submission content that allows companies to use streamlined processes for develop...
ICH and Domestic Regulations:Excellence Through Harmonization                                                             ...
Six months later, MHLW replaced earlier                 countries. (Fig.1 shows the number of newguidelines with the E5 gu...
clinical research cited as a specific area              The ongoing debate brought fresh perspectivesof cooperation. MHLW,...
For many years, Japanese investigators and institutions considered clinical trials to be a secondarytask, a necessary chor...
DISCUSSIONThe immediate aftermath of incorporatingthe ICH Guideline noted above into Japan’sregulations saw a significant ...
Revised ICH Terms of Reference• To maintain a forum for a constructive dialogue between regulatory authorities and  the ph...
The Global Cooperation Group –A Bridge from ICH to the World Beyond                                                       ...
the Association of the Southeast Asian Nations           challenges faced by other regions in the use(ASEAN), the Gulf Coo...
The Regulators Forum                                                                                       PETRA DOERR    ...
Key benefits from ICH harmonization activities and outcomes have come through the provision of commontechnical platforms, ...
requirements were in effect in most regions for          included Asia-Pacific Economic Cooperationthose companies servici...
Regulatory Harmonization and Public Health                                                                                ...
ICH GuidelinesFinalized as of July 2010Quality GuidelinesSTABILITYQ1A(R2) Stability Testing of New Drug Substances and Pro...
ICH GuidelinesFinalized as of July 2010                         (continued)Q4BAnnex 3    Evaluation and Recommendation of ...
ICH GuidelinesFinalized as of July 2010                                     (continued)Q4BAnnex 11             Evaluation ...
ICH GuidelinesFinalized as of July 2010                         (continued)QUALITY RISK MANAGEMENTQ9       Quality Risk Ma...
ICH GuidelinesFinalized as of July 2010                                      (continued)PHARMACOLOGY STUDIESS7A    Safety ...
ICH GuidelinesFinalized as of July 2010                               (continued)DOSE-RESPONSE STUDIESE4      Dose-Respons...
ICH GuidelinesFinalized as of July 2010                                       (continued)Multidisciplinary GuidelinesM1 Me...
Many thanks to those who helped edit this report, particularly,  Odette Morin of the International Federation of Pharmaceu...
International Conference on Harmonisation of Technical Requirements          for Registration of Pharmaceuticals for Human...
ICH 20th Anniversary_value_benefits_of_ich_for_regulators
ICH 20th Anniversary_value_benefits_of_ich_for_regulators
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ICH 20th Anniversary_value_benefits_of_ich_for_regulators

  1. 1. The Value and Benefits of ICH to Drug Regulatory AuthoritiesAdvancing Harmonization for Better Health 2010
  2. 2. This publication salutes two decades of the ICH’s groundbreaking work in harmonizing drug regulatory requirements among many global partners. The following articles were written by the drug regulatory authorities associatedwith the ICH Steering Committee, Global Cooperation Group, and Regulators Forum.We would like to thank all the technical experts, past and current, who have contributed their invaluable expertise, insights, and dedication in making the ICH a success. If you want to go fast go alone. If you want to go far go together. African Proverb
  3. 3. The Value and Benefits of ICH to Drug Regulatory Authorities - Advancing Harmonization for Better Public Health. JUSTINA A. MOLZON U.S. Food and Drug AdministrationOVERVIEWThe International Conference on submitted in the three ICH regions—facilitatingHarmonisation of Technical Requirements for simultaneous submission, approval, andRegistration of Pharmaceuticals for Human launch of new drugs. In calling the CTDUse (ICH), launched 20 years ago, is an “a topic whose value to industry cannot beunparalleled undertaking. ICH brings together underestimated,” Dr. Loew noted that with fullthe drug regulatory authorities of Europe, incorporation of the CTD and the electronicJapan, and the United States, along with the CTD (eCTD), ICH could turn its sights topharmaceutical trade associations from these disseminating guideline information to non-three regions, to discuss scientific and technical ICH countries, yielding additional benefits toaspects of product registration. It is ICH’s both regulators and industry.mission to achieve greater harmonization in Ten years later and in anticipation of ICH’sthe interpretation and application of technical 20th Anniversary, the value and benefits of ICHguidelines and requirements for product to regulators have been realized. Moreover,registration, thereby reducing duplication of implementation of the CTD in 2003 promotedtesting and reporting carried out during the the involvement of drug regulatory authoritiesresearch and development of new medicines. (DRAs) not initially part of ICH, therebyIn 2000, the 10th Anniversary of ICH, Dr. extending ICH’s harmonized approach. TheCaroline Nutley Loew of the Pharmaceutical development of the Global CooperationResearch and Manufacturers of America Group, which includes representatives from(PhRMA) wrote a report, The Value and five regional harmonization initiatives and theBenefits of ICH to Industry, which detailed newly established Regulators Forum, createdICH’s creation, procedures, and guideline to promote participation by non-ICH countriesdevelopment in the areas of safety, efficacy, interested in implementing ICH’s strategies,and quality. Dr. Loew’s report anticipated have also helped incorporate the CTD intothat the Common Technical Document (CTD) regulatory processes, creating a commonwould revolutionize the submission procedures regulatory language that promotes fasterfor industry’s regulatory staff. Dr. Loew access to life-saving treatments to patientscharacterized the CTD as “offering potential beyond ICH regions. In recognition of thebenefits to industry far greater than any other increasingly global face of drug development,single ICH topic,” and predicted the CTD ICH recently updated its logo to emphasizewould afford significant savings in time and the benefits of harmonization for better globalresources as complex multiple submissions health.were replaced by a single technical dossier 1 ICH harmonisation for better health
  4. 4. Shift in EmphasisSubstantial benefits to DRAs resulted processes, ultimately leading to a harmonizedwhen ICH shifted emphasis from the input electronic submission and e-review initiatives,of information by industry to the output of which, in turn, have enabled implementationinformation by regulators. This transition of good review practices. These activitieswas made possible by the development of are having a global effect on informationa common submission format—the CTD— review and sharing among drug regulatorywhich greatly influenced regulatory review authorities.Originally, ICH focused on input by industry— format, referred to as the CTD, which wouldthe technical submission requirements for relieve pharmaceutical companies of the time,pharmaceuticals for human use. Harmonizing workforce, and financial burdens of assemblingthe differences in these requirements through a submission for one DRA and then having toICH guidelines helped industry reduce reformat it for another. This new consistentdevelopment times and save resources. format also greatly benefited the U.S. FoodTo extend the benefits of harmonization, and Drug Administration (FDA), enabling theindustry proposed assembling the building agency to establish templates for each of theblocks of information intended for inclusion review disciplines while promoting morein a submission into a consistent harmonized consistent review practices and processes.ICHharmonisation for better health 2
  5. 5. Prior to the advent of the CTD, regulatory submission formats, believing it would be tooreviewers received an application from one disruptive to the review process. They neededcompany and spent a year or more engaged convincing that harmonizing the submissionin its review. When the review was completed, format had value. Regulators asked industryreviewers received the next application—most to do a feasibility study. That study, conductedlikely in a different format—and had to learn in May 1996, evaluated the time it tookthe structure of the new application. As a to convert an FDA new drug applicationresult, review staff were constantly on a into an European Medicines Agency (EMA)learning curve when new assignments were submission, and the reverse. It also evaluatedreceived—time they could have better used the number and types of staff needed to carryreviewing the information as opposed to out the conversion of the submission formats.simply trying to find it. Regulators quickly saw the potential value of harmonizing submission formats.When industry proposed the CTD in 1996,ICH regulators were hesitant to change their 3 ICH harmonisation for better health
  6. 6. Regulatory BenefitsThe CTD has also made the exchange interactions between the two agencies. Nowof information among drug regulatory that submissions are received in the sameauthorities easier. For a number of years, format and, generally, at the same time, theseFDA and the EMA have had a confidentiality interactions have become more efficient,arrangement in place allowing the sharing facilitating discussions of common concernsof confidential information, greatly increasing as submissions are evaluated. ICH regulators, impressed with the amount of time and effort involved in the conversion of one regulatory submission to another, agreed that the resources involved could be better used towards more research and development for new drug products. The regulators also realized that these conversions created a delay in submitting an application to the different ICH regions and, in turn, delayed patient access to new innovative medicine. The result of agreeing to work on a consistent format or table of contents is the ICH Common Technical Document. Module 1 is not part of the CTD, it represents the administrative information specific to each ICH region. Module 2 is a layering of information and includes an introduction, summaries, and overviews. More complete data are contained in modules 3, 4, and 5. Countries can, in effect, focus on modules of interest. If a regulatory authority is not interested in the complete datasets in modules 3, 4, and 5, the focus can be on modules 1 and 2. This is what some less-resourced countries are now doing.ICHharmonisation for better health 4
  7. 7. Last, and perhaps most important, the Another benefit of a harmonized format hasCTD has facilitated electronic submissions been the ease of developing and implementing(the eCTD). In the past, drug applications harmonized good review practices. Whatwere voluminous, delivered to FDA by the is evaluated in a review is closely tied totruckload due to the sheer amount of paper the requested data. As a result, there isinvolved. When the agency first transitioned considerable similarity between ICH guidanceto electronic submissions, an application was to industry and what we consider goodon a compact disc or hard drive. Although review practices. Because ICH regions havethis certainly helped with transportation harmonized much of the information submittedand storage issues, it did not necessarily for marketing authorization, ICH regulatorsenhance the review process. FDA has now could easily begin moving toward similarimplemented the FDA Electronic Submission review practices.Gateway, which allows a new drug application(NDA) to be sent electronically, essentially In general, good review practices promotevery much like e-mail. After being assessed transparency and consistency, both of whichfor completeness, a submission is immediately are very important if industry and the public areand fully accessible on the reviewer’s desktop. to understand how regulatory authorities carryThis innovation has alleviated the need for out their responsibilities. This is especiallyindustry to create and assemble the many important because of the complexity of thepieces of paper that constituted a traditional disciplines and specialties involved in thepaper-based product application, organize the review process. We needed a consistentapplication, box thousands of pages, load the approach to evaluating submissions andboxes on a truck, and deliver them to FDA— reaching conclusions, and the CTD and eCTDall before a reviewer could even begin the have helped to achieve these goals.assessment process. In summary, the CTD format influencesThe eCTD has proved critical to improving the content of the review by imposing aapplication submission efficiencies as well consistent order of information and data. Thisas reviewer efficiency. Besides delivering shapes both the conduct of the review andsubmission material to the reviewer in an the presentation of the results of the reviewexpedited manner, the eCTD format has made and promotes good review practices andit easier to develop standardized reviewer increased efficiencies. As more countriese-templates and review tools for each of the embrace ICH guidelines and the CTD format,review disciplines. a common regulatory language could evolve that will further promote interactions among drug regulatory authorities. 5 ICH harmonisation for better health
  8. 8. The ICH guidelines are giving medical writers improved guidance on how to interpret what FDA needs within a marketing application and provide the content to meet those needs. This in turn allows submission groups within drug development teams to focus their drug development plans and the communication around the data being generated from the execution of those plans. The end result has been faster, more concise, and higher quality submissions that ultimately not only aid regulators in their efforts to make decisions, but inevitably get health care products to patients in a more timely fashion. DAVID CLEMOW Scientific Communications Consultant Medical Information Sciences, Lilly eCTD Submissions by Application Type October 2003 to October 2010 Application No. of Sequences IND 87,574 NDA 35,665 ANDA 23,328 BLA 11,003 MF 2,089 OTHER 951 Total 160,606 In December 2009, the U.S. Food and Drug Administration (FDA) processed its 100,000th eCTD submission. What began as a trickle in October 2003 has become a major component of FDA’s regulatory processes. When coupled with the Electronic Submission Gateway we can begin to see an end-to-end, standards-based, electronic receipt, review, and dissemination environment taking shape. ICH efforts to standardize regulatory content and processes have moved research and healthcare data standardization efforts forward in dramatic fashion, as the recent eCTD submission statistics attest. HELLE GAWRYLEWSKI Head Alliance Management Johnson & JohnsonICHharmonisation for better health 6
  9. 9. A Harmonized Marketing Application ALEX GIAQUINTO ICH Steering Committee Member, PhRMA 1990 - 2003It was nearly 20 years ago when an bringing those medicines to the patients whoinitial discussion of a new concept called need them with new levels of efficiency and“harmonization” took place among drug product speed.regulators at an International Conference ICH’s initial harmonized guideline developmentof Drug Regulatory Authorities. Not long focused on the clinical, safety, and qualityafterwards, in April 1990, I attended a meeting areas. It demonstrated such success that, byat the European Federation of Pharmaceutical the mid-1990s, I was wondering how a similarIndustries and Associations (EFPIA), where the strategy might benefit the application andconcept was explored again in greater detail— regulatory processes. At the time, althoughfor the first time with representatives from four pharmaceutical companies developedpharmaceutical industry associations: EFPIA, the same data in the same way for newthe Japan Pharmaceutical Manufacturers pharmaceuticals and used the same guidelinesAssociation (JPMA), the International for ICH’s three regions, marketing applicationsFederation of Pharmaceutical Manufacturers in these regions varied in both how dataand Associations (IFPMA), and the were organized and formatted. There wasPharmaceutical Research and Manufacturers also much variation in how much data wereof America (PhRMA). Representatives from presented.the regulatory agencies from Japan, theEuropean Union, and the United States were The natural question was: why couldn’t wealso present. Not long after that meeting, the submit all this information in one uniform—International Conference on Harmonisation or harmonized—marketing application for all(ICH) took its place as a pivotal organization three regions?in global pharmaceutical development andregulation. ICH’s exceptional efforts in As the Third International Conference onproducing harmonized guidelines proved Harmonisation (ICH 3, 1995) approached,invaluable in helping both industry and I discussed this idea with several of myregulators assess new medicines, thereby colleagues. Most of them suggested that 7 ICH harmonisation for better health
  10. 10. A Harmonized Marketing Application (continued)although the current application system might Technical Document (CTD) was signed off forbe cumbersome, revamping would be even release to the three regions by the Steeringmore difficult. But, schooled by remarkable Committee at ICH 5 (2000).ICH successes in other areas, I felt sure there A decade has since passed, and the CTDwas a way to accomplish the goal of a unified, has driven fundamental changes in regulatoryor common marketing application document. practice. It is the required marketing applicationI presented the idea at ICH 3, citing the format for many regulatory agencies, evennumber of guidelines under development those not initially involved in ICH. Today weor issued that, in themselves, promised to have applications in a predictable format thateliminate a substantial amount of experimental are more accessible and readily reviewable,duplication. I identified what I believed to be as they facilitate analysis and exchange ofa pressing need for a single approach for information across applications. With themarketing applications. change in ICH focus from input by industry toAn ICH Steering Committee meeting was output by regulators, the CTD has been key inheld following the Conference at which I fostering this shift.hoped to raise my concept for consideration It is personally gratifying to see the benefitsas a guideline. But the proposal was quickly the CTD has brought with a harmonized,tabled until my industry colleagues and I could consensus-based approach in our globaldevelop more data to support the need for market environment. As those benefits accruesuch a guideline. We did so, and the ICH and the eCTD rapidly becomes the marketingSteering Committee ultimately agreed to take application technique of choice, regulatorson the topic. are now using the principles of the CTD as aWhile initial discussions continued to meet with springboard to still newer and better ideas inobjections, progress was made. Thanks to regulatory review practices. We have certainlythe robust and sustained efforts of numerous come a long way, and I look forward to futureindustry and regulatory colleagues, the successes.innovation we had come to call the CommonICH harmonisation for better health 8
  11. 11. ICH Guideline Implementation LENITA LINDSTROM European CommissionUnder the regulatory framework in the EU, the guidelines have the same status as otherCommittee for Medicinal Products for Human European scientific guidelines and replaceUse (CHMP), within the European Medicines existing guidelines on the subjects covered.Agency (EMA), is responsible for preparing Guidelines generally take effect six monthsscientific guidelines to help applicants prepare after adoption. Although applicants may, withmarketing authorization applications for the agreement of the competent authoritymedicinal products. When implementing ICH concerned, choose to apply a guideline inguidelines in the European Union, the CHMP advance of this period, competent authoritiesadopts the harmonized text of a guideline. should wait until this period has expiredThe CHMP has already been involved in the before requiring the guideline to be taken intoICH process at an earlier stage in that ICH account.topics are included in the work program of In the EU, there are different types ofthe relevant CHMP working parties or ad-hoc pharmaceutical guidelines, which can begroups. Once adopted by the CHMP, ICH grouped broadly as regulatory or scientific. A regulatory guideline is a European Community document with explicit legal basis referred to in the legislative framework as intended to provide advice to applicants or marketing authorization holders, competent authorities and/or other interested parties on the best or most appropriate way to fulfill a legal obligation laid down in the pharmaceutical legislation of the EU. The basic EU legislation is thus supported by a series of guidelines published by the Commission. Scientific guidelines are intended to provide a basis for practical 9 ICH harmonisation for better health
  12. 12. ICH Guideline Implementation (continued)harmonization of the manner in which the Manufacturing Practice (GMP) for ActiveEU Member States and the EMA interpret Pharmaceutical Ingredients), EU legislationand apply the detailed requirements for the was amended to require GMP for startingdemonstration of quality, safety, and efficacy. materials. Reference was made in theScientific guidelines also help facilitate the amended EU legislation to the fact that thepreparation of applications for marketing principles of good manufacturing practice forauthorizations by the pharmaceutical industry. active substances used as starting materialsThe scientific guidelines may relate to specific are to be adopted in the form of detailedissues reflecting a harmonized EU approach, guidelines. The European Commissionbased on the most up-to-date scientific subsequently modified its GMP Guidelineknowledge. New or updated guidelines (Volume 4 of The rules governing medicinalare published by the EMA on its website. products in the European Union) on the basisAdditionally, the EMA publishes technical, of the ICH Q7 guideline.procedural, and administrative guidance.ICH guidelines are part of the scientificguidelines adopted by the CHMP. However,some ICH guidelines have been integratedinto EU legislation. For example, followingthe adoption of the ICH Guideline Q7 (Good Seasoned regulatory affairs hands recall with a mix of bemused nostalgia and frank horror the days before the electronic Common Technical Document—or, to be more exact, the days, nights, months, weekends, and holidays spent by sleep-deprived regulatory staff to build an NDA for the FDA, then deconstructing and reformatting it for EU submission. For those of us who have been around long enough to remember, there were the pre-EU days when each European country required different application formats prepared in, of course, different languages. The eCTD has changed all that, allowing both industry and regulators to focus on science and medicine, rather than on the now- unjustifiable diversity of application formats. And the world is better off. ALBERTO GRIGNOLO Corporate Vice President Global Strategy and Services PAREXEL ConsultingICH harmonisation for better health 10
  13. 13. ICH has provided a logical framework for submission content that allows companies to use streamlined processes for developing and managing regulatory submissions globally, both within a company and between companies. The ICH initiative should continue its vital role by adding new guidelines, as well as revising existing guidelines, to meet our new electronic environment. SUE WILSON Senior Director, Medical Writing & Document Management Shire PharmaceuticalsICH is a unique collaboration, not only among regions, but also between regulators and industry.Harmonization achievements, including pivotal milestones such as the conduct of stability studies anddefining relevant thresholds for impurities testing, have been key breakthroughs. Current discussionson the new quality paradigm facilitate productive interfaces between scientific and technical innovationand regulatory constraints. Along with cooperative advances in regulatory science, ICH has broughtanother vital development: greater understanding of each regulatory agency’s priorities and, with that,a new mutual trust that serves our larger goals of quality medicines made available to patients. JEAN-LOUIS ROBERT European Medicines Agency Quality Working Party ChairICH guidelines have contributed to a regulatory writer’s argument for using what might be called a‘hierarchy of summarization,’ in which the fine details are covered at the bottom of the CTD pyramid,and information is increasingly summarized as it moves up the pyramid. Submissions built this waytend to be more consistent and easier to navigate, because the path from all the details to the summarysections is clearer. We assume this contributes to speedy and thoughtful review, and that those benefitsare passed along to patients using these new therapies. LINDA FOSSATI WOOD MedWrite, Inc. 11 ICH harmonisation for better health
  14. 14. ICH and Domestic Regulations:Excellence Through Harmonization TOSHIYOSHI TOMINAGA Pharmaceuticals and Medical Devices AgencyOver the last 20 years, ICH has provided well as late Phase II dose-determination andJapan’s Ministry of Health, Labor, and Welfare Phase III comparative studies performed on(MHLW) with crucial momentum in bringing the Japanese population. This policy foundour national drug regulatory program to its scientific basis in documented cases whereaccepted international standards. Regulatory race affected reactions to the same drug, butharmonization has facilitated both global the E5 EWG offered MHLW an opportunityacceptance of data obtained in Japan as to further scrutinize its policies in regard towell as MHLW’s use of the world’s data— foreign clinical data. MHLW’s expert, Dr.realizing speedier delivery of safe and effective Chikayuki Naito, led the discussion as themedicines to patients. EWG’s rapporteur.Among the many ICH guidelines that spurred The E5 EWG wrestled with how to balancevital change in MHLW’s regulations, two in acceptable variations in drug effects amongparticular fueled quantum leaps for Japan’s races and ethnicities while not compromisingdrug regulatory program: Ethnic Factors in scientific rigor in an application package. TheirAcceptability of Foreign Clinical Data (the fifth answer—the bridging study—revolutionizedEfficacy Guideline, or E5), and Good Clinical Japan’s drug regulatory policy.Practice (E6). BRIDGING STUDIES After extendedEthnic Factors in Acceptability of discussion, the EWG reached the definition of a bridging study as “a supplemental studyForeign Clinical Data (E5) performed in a new region to provideFIRST STEPS The E5 Expert Working Group pharmacodynamic or clinical data on efficacy,(E5 EWG) began considering the effect of safety, dosage and dose regimens in the newethnic factors in clinical data in the early region that will allow extrapolation of foreign1990s. At that time, MHLW required that clinical data to the new region.” The ICHapplications originating outside Japan include Steering Committee adopted the E5 guidelinethe results of a pharmacokinetic study as on February 5, 1998.ICHharmonisation for better health 12
  15. 15. Six months later, MHLW replaced earlier countries. (Fig.1 shows the number of newguidelines with the E5 guideline, reducing drug applications containing bridging data thatJapan’s regulatory burden and decreasing the were approved by MHLW.)approval time for drugs developed in foreignEthnic Factors in the 21st further clarified the guideline’s implications inCentury today’s global clinical development landscape. Building on the ICH E5 Guideline andAs the past decade saw pharmaceutical subsequent Q&As, MHLW issued the guidelinedevelopment trend toward multi-regional Basic Principles on Global Clinical Trials, whichmega-trials (simultaneous subject recruitment encourages inclusion of Japanese patients infrom many populations in many parts of the global trials from an early stage and delineatesworld), new and complex questions emerged key points to consider in designing such trials.regarding across the board extrapolations ofdata. The E5 EWG was reconvened to address In April 2007 the health ministers of China,the issue in 2003 and in 2006 to create a series Korea, and Japan issued a Joint Statementof 11 questions and answers (Q&As) that and Memorandum of Cooperation, with 13 ICH harmonisation for better health
  16. 16. clinical research cited as a specific area The ongoing debate brought fresh perspectivesof cooperation. MHLW, in cooperation with to the Japanese viewpoints on clinical trials,China’s State Food and Drug Administration illustrating how ICH initiatives both instruct andand Korea’s Food and Drug Administration, confer benefit not only in their outcomes butis now exploring ethnic factors in East Asia also in their processes. In forging consensusbased on ICH’s E5 Guideline. the roles played by the Japanese E6 EWG experts and opinion leaders, Dr. Keiji Ueda andGuideline for Good Clinical Mr. Osamu Ebi, cannot be overemphasized.Practice (E6) As the E6 Guideline reached Step 4 in 1996,When the ICH Good Clinical Practice Guideline MHLW embarked on a major amendment in(E6) EWG convened in the mid-1990s, Japan Japan’s Pharmaceutical Affairs Law (PAL),had only incomplete GCP guidelines— designed to implement the E6 Guideline withessentially a rough outline of the functions of increased legal sanctions and enforceability.principal investigators, study sponsors, and Soon after Parliament passed the amendment,other key players in clinical studies, with very MHLW issued the relevant GCP ordinancesweak provisions for monitoring and auditing. and related guidelines known collectively asEnrollment of study participants was allowed Japanese GCP. On the day these ruleswith oral consent. became fully effective—April 1, 1997—As the EWG made progress with E6 Guideline Japanese clinical trials assumed globallydevelopment, vigorous debate continued in acceptable quality, paving the way for JapanJapan. The concepts of informed consent to generate globally usable clinical data. Thiswere undeveloped at best among Japan’s led to GCP inspections by MHLW inspectorsmedical professionals, and quality assurance/ abroad and those by foreign inspectors inquality control (QA/QC) was an overtly Japan and enabled exchange of inspectionforeign concept. Claims were made that reports with other drug regulatory authorities.written informed consent defied Japanese MHLW is now trying to help non-ICH countriescultural values, or that QA/QC would increase adopt ICH GCP (E6) by sharing its expertisemonitoring and auditing, raise administrative through GCG activities and other cooperativecost of trials—and also alienate investigators, ventures.all to the detriment of clinical development inJapan.ICH harmonisation for better health 14
  17. 17. For many years, Japanese investigators and institutions considered clinical trials to be a secondarytask, a necessary chore of drug development, but not one they needed to pay much attention to.This attitude was primarily due to insufficient education about clinical trials in medical and graduateschools, and contributed to vigorous debate when ICH first began to consider its Good Clinical PracticeGuideline (E6). But Japan has slowly come to understand the importance of E6 and of a drug researchand development program that meets or exceeds global standards—in turn providing patients with themost advanced medical care available. The E6 Guideline continues to be adopted throughout Japan,and, as that process continues, E6 will be ranked as one of the most important contributions that ICHhas given to Japan. OSAMU EBI Ex-officer, Takeda Chemical Industries, Ltd.ICH has provided the structural framework on which to build standardized applications to healthauthorities worldwide. As new information becomes available during the drug development program,it now has a place and a purpose. BARBARA R. KAMM Senior Manager II, Medical Writing Projects Allergan Inc. 15 ICH harmonisation for better health
  18. 18. DISCUSSIONThe immediate aftermath of incorporatingthe ICH Guideline noted above into Japan’sregulations saw a significant decline in thenumber of clinical trials conducted in Japan(Fig. 2), a development clearly due to both theneed for increased rigor in clinical trials as wellas a reduced need to perform trials in Japan.Although critics objected to what they thoughtwere drastic changes, relaxing the rules anddeviating from world standards were neveroptions for MHLW.MHLW instead took (and continues to take)constructive measures to galvanize Japaneseclinical development, such as improving theinfrastructures of the trial sites and encouragingtraining for clinical research coordinators. Asa result, the number of multi-national trialsconducted in Japan has steadily increased,demonstrating the country’s emergence asan international center of pharmaceuticalinnovation (Fig. 3).World-class drug regulation benefits theJapanese public, and MHLW has set a clearcourse to pursue international regulatoryharmonization. ICH is the most importantmechanism Japan employs to reach that goal.ICH harmonisation for better health 16
  19. 19. Revised ICH Terms of Reference• To maintain a forum for a constructive dialogue between regulatory authorities and the pharmaceutical industry on the real and perceived differences in the technical requirements for product registration in the EU, USA and Japan in order to ensure a more timely introduction of new medicinal products, and their availability to patients;• To contribute to the protection of public health from an international perspective;• To monitor and update harmonised technical requirements leading to a greater mutual acceptance of research and development data;• To avoid divergent future requirements through harmonisation of selected topics needed as a result of therapeutic advances and the development of new technologies for the production of medicinal products;• To facilitate the adoption of new or improved technical research and development approaches which update or replace current practices, where these permit a more economical use of human, animal and material resources, without compromising safety;• To facilitate the dissemination and communication of information on harmonised guidelines and their use such as to encourage the implementation and integration of common standards 17 ICH harmonisation for better health
  20. 20. The Global Cooperation Group –A Bridge from ICH to the World Beyond MIKE WARD Health CanadaFor the first decade of its existence, ICH From the outset, the GCG established afocused on the development of guidelines number of important operating principles thatand standards for use in the ICH member have guided its work to this day, notablyregions (European Union, Japan, and the that ICH will never impose its views on anyUnited States). By the late 1990s, however, country or region and that the GCG will workICH recognized the growing interest in ICH closely with WHO and other internationalguidelines beyond the ICH regions. Reasons organizations to achieve its goals.for this interest were rooted in several In November 2003, a decision was madeinterrelated factors. There was a growing to pursue further harmonization, recognizingrecognition of the utility of ICH guidelines as the need to actively engage with otherreference documents that define science- harmonization initiatives showing an interestbased principles and approaches and many in ICH. The immediate goal was to betterof the ICH guidelines were not limited to new understand regional needs, leverage modestdrugs giving them broader relevance. The resources, and achieve the GCG’s overallglobalization of industry, both innovative and goal as captured in its mission statement:generic, drove (and continues to drive) a need “to promote mutual understanding offor common standards, and the overall trend regional harmonization initiatives to facilitatetowards global drug development strategies the harmonization process related to ICHspurred the interest of non-ICH countries in guidelines regionally and globally and tostimulating innovation, building local capacity, facilitate the capacity of drug regulatoryand promoting earlier access to important new authorities and industry to utilize them.”therapies. Partnerships were created with RegionalIn response to this growing interest, ICH Harmonization Initiatives (RHI) who werecreated the Global Cooperation Group (GCG) invited to attend the GCG. In June 2004, RHIin March 1999. The GCG serves to promote a representatives were invited to listen to ICHbetter understanding of ICH guidelines and ICH technical discussions at all levels, from Expertitself, facilitated through open communication Working Group through Steering Committeeand fluid dissemination of information. The levels.choice of name for the group was reflective Today, representatives from five RHIs activelyof the desire to establish global linkages that participate in GCG discussions, including theextend beyond the three ICH regions. Asia-Pacific Economic Cooperation (APEC),ICHharmonisation for better health 18
  21. 21. the Association of the Southeast Asian Nations challenges faced by other regions in the use(ASEAN), the Gulf Cooperation Council of ICH guidelines.(GCC), the Pan American Network for Drug More recently, ICH recognized the needRegulatory Harmonisation (PANDRH), and for further change to GCG principles andthe Southern African Development Community procedures to mirror the global face of drug(SADC). development. This led to the November 2007Training is a key GCG focus, with an overall decision to create an expanded GCG with thestrategy for effective use of training resources, creation of a Regulators Forum to permit thefocused on developing resources and tools representation of individual drug regulatoryto maximize the effect of training efforts, authorities (DRAs) that were either a majorincluding a clearing house that identifies source of active pharmaceutical ingredientstraining opportunities, public access to a (APIs), clinical trial data, or had adopted ICHgrowing library of training materials on the guidelines. Just as the participation of DRAsICH website, and an evaluation template to is distinct and complementary to that of RHIhelp assess whether training objectives were representatives, so too are the GCG andachieved. Regulators Forum complementary. Much progress has been made to date throughRecent workshops on clinical trial assessment the GCG in promoting a better knowledge ofand inspection have moved training beyond ICH guidelines and of the challenges faced bysimply an understanding of ICH guidelines other regions in their use. GCG efforts haveto their active application from a regulatory evolved from simply information sharing toperspective—critical to a regulator’s ability active dialogue to the current results-orientedto assess studies and data developed in action. Important new developments willaccordance with ICH guidelines. build on this progress. A pivotal factor in allOver the last decade, the GCG has established of the ICH gains is exemplified by the GCG’san open and productive dialogue and fostered fostering of a spirit of trust and cooperationa spirit of collaboration that has spread the between ICH representatives and colleaguesmessage of harmonization. At the same time, from RHIs and DRAs—perhaps the mostICH has gained a better understanding of the important key to our future success. The strongest benefit of ICH harmonization for the Southern African Development Community (SADC) is the ease of comparability in international regulatory information. Harmonization has improved regulatory standards throughout the SADC, helped those standards be consistent with both local and national conditions and, in the process, saved time and money previously spent to consolidate divergent pharmaceutical information when more than one set of standards was required to comply with different national laws and practices. Harmonization has made a major difference in improving access to vital medicines in developing countries. JOSEPH MTHETWA Senior Programme Officer Southern African Development Community Secretariat 19 ICH harmonisation for better health
  22. 22. The Regulators Forum PETRA DOERR Swissmedic, Swiss Agency for Therapeutic ProductsThe first Regulators Forum, hosted by the A discussion also took place on the purpose,U.S. Food and Drug Administration, was held focus, and benefit of the group. There wasin Portland, Oregon, in June 2008. Regulators consensus that the Forum would provide anwere invited from countries with a history excellent opportunity for non-ICH regulatorsof ICH guideline implementation (Australia, and RHIs to learn about implementation ofChinese Taipei, Singapore, and South Korea) ICH guidelines and that participation in the ICHas were regulators from countries where major process would confer trust and confidence inproduction and clinical research is done, such those guidelines while developing links toas Brazil, China, India, and Russia. Also in other regulatory efforts and challenges.attendance were representatives from the The fourth Regulators Forum was held in St.Regional Harmonization Initiatives (RHI) also Louis, Missouri, in October 2009. Discussionsparticipating in the Global Cooperation Group suggested that the scope of topics to be(GCG). considered in the future may extend beyondThe first Regulators Forum saw the formulation the original concerns of the Forum—ICHof a vision statement: guidelines—to include numerous other topics of common interest. But the more• To discuss and share best practices on immediate benefits of the Forum are clear and issues related to the implementation of ICH substantive: guidelines and their impact on regulatory systems in non-ICH countries • Ease of communication and personal contact with increased interactivity between• To assist in identifying training and capacity meetings needs for action by the GCG. The Forum will support GCG activities and objectives • Receiving updates from other regulators on and promote a more comprehensive current issues understanding of ICH guidelines • Learning from each others’ experiences• Create a regulator-only environment Analyzing differences in the interpretation of for open discussion of important issues ICH guidelines regarding the implementation of ICH guidelines for regulators around the world• To supplement—not replace—the GCGICHharmonisation for better health 20
  23. 23. Key benefits from ICH harmonization activities and outcomes have come through the provision of commontechnical platforms, exemplified by the Common Technical Document (CTD) and the ICH guidelines.Although ICH requirements presented an initial challenge in adopting and adapting to guidelines, the ICHhas emerged as a significant contributor to the quality, safety, and efficacy of medicinal products, bringinggreater access to medicines as it delivers a beneficial impact on public health. DAGMAR STARA Comenius University Bratislava, SlovakiaGuideline Information Dissemination/Uptakein Non-ICH Countries LEONIE HUNT Australian Therapeutic Goods AdministrationAs other authors have noted, it was clear Unique regional- or country-specific standards,from the early days of ICH that drug by placing additional and/or differingregulatory harmonization efforts, guidelines, requirements on companies in respect ofand processes would affect countries and smaller markets, had the potential to act asregions beyond the European Union, Japan, barriers, delaying appropriate market access,and the United States. At the inception of sometimes indefinitely, for important medicines.ICH, the World Health Organization (WHO), Governments under pressure to ensure accessHealth Canada, and European Free Trade to such medicines saw real benefit in theAssociation (EFTA) had ICH observer status, adoption of a generally internationally acceptedwith WHO seeking to represent the interests standard. This was often supported by localof non-ICH member countries. industry as additional benefits can potentially accrue to regional pharmaceutical industryIn the early 1990s, some countries, such as suppliers when adoption of internationalAustralia, sought to minimize their own unique standards facilitates local industry entry intorequirements by adopting what were then the global market. Effectively, the market entryseen as international best practice standards. standard that applies in any major marketA factor in those decisions, however, was the region will be applied at all stages of productemerging reality: the pharmaceutical industry delivery for products to be supplied globally.was increasingly globalized and the majormarket regulatory requirements for new and Global production of medicines meansinnovative medicines were best reflected in manufacture, testing, and sale of any onethe developing ICH guidelines. product will usually encompass more than one region and, by the late 1990s, the ICH 21 ICH harmonisation for better health
  24. 24. requirements were in effect in most regions for included Asia-Pacific Economic Cooperationthose companies servicing the global industry. (APEC), Association of Southeast Asian Nations (ASEAN), Gulf Cooperation CouncilThe reality of globalization of production, in (GCC), Pan American Network on Drugturn, obliged countries involved in medicine Regulatory Harmonization (PANDRH), anddevelopment at any stage, or depending on Southern African Development Communitysuch development to meet health needs, to (SADC). The aims of the groups revolvedconsider how they would ensure appropriate around harmonizing technical requirements,standards for market entry. By the end of facilitating market entry within regions, and1999, with WHO encouragement a number of providing appropriate skills to industry andsignificant regional harmonization initiatives regulators to meet regional needs.(RHI) had focused their attention on accessto medicines and established groups tospecifically deal with these issues. The RHISeven years after its implementation, the CTD has provided a great saving of resources and shortenedthe gap for registration in the ICH regions. The CTD is the basis for preparing a single dossier that can besubmitted for registration in all ICH regions. Although this requires careful thought and planning and evenmore for the eCTD, as more countries decide to accept the CTD submission format, innovative medicineswill be reaching many more patients all over the world with fewer hurdles and faster. FARID BENHAMMOU Head of Regulatory Affairs Novagali Pharma S.AThe establishment of the Global Cooperation Group (GCG) within the ICH led to a major paradigm shift inconference principles—from regional thinking to global dimensions. The GCG helped shift the focus frominformation sharing to active engagement of various regions in guideline development, then expanding theinternational regulatory community’s scope beyond guideline development to broader regulatory issues. Thekey lesson learned from participation in GCG is that with a little harmonization you can help regulators andindustry achieve their goals with minimum cost. Harmonization is the magic word! PROF. SALEH A. BAWAZIR Saudi Food and Drug Authority Gulf Cooperation Council (GCC) RepresentativeICH harmonisation for better health 22
  25. 25. Regulatory Harmonization and Public Health LEMBIT RAGO World Health OrganizationWe have seen substantial improvement over The ICH experiment in harmonization hasthe last several decades as pharmaceutical seen its proof borne out in practice as manymanufacturing has followed the business approved medicines have reached andstrategies a global marketplace demands. As continue to reach patients in need.globalization continues, the prevailing objective As ICH launches its second 20 years, it servesof drug regulation everywhere remains the to remember the lessons of the first:promotion of public health. Indeed, in allcases where harmonization of registration • Strong commitment with allocation ofrequirements is supported by the international necessary resources from majorcommunity, the target objective has always stakeholders involved, governments andbeen, and continues to be, measurable public industries alike, has contributed to thehealth gains. The main question, however, successremains the same: how can regulatorsbest contribute to the public health with the • Information sharing and harmonizationresources they have? reduces workload and improves overall regulatory performanceValue added is a relatively new phrase inscience and business, and it succinctly • Harmonization is the value added thatexpresses a core asset of the ICH’s first two directs expert knowledge and resources todecades as public health advances have functions that improve public and personalbeen realized through the direct benefits of health and facilitates access to essentialharmonization: improved quality, safety, and medicinesefficacy of marketed products that mitigate • Formation of effective networks amongthe risks of harm by medicines; less time national regulatory authorities participatingconsumed and greater transparency in review in various harmonization initiatives facilitatesand approval processes; and decreased sharing of scarce resources; eliminatescosts for industry as a harmonized application duplication of activities; saves money forformat (CTD and eCTD) reduces the expense all; supports cooperation, collaboration,of preparing registration dossiers. Aside and international understanding; facilitatesfrom helping drug developers and regulatory in building regulatory capacity; andauthorities, all of these value added innovations enhances public trust in our effortsserve to increase public trust in approvedmedicines—a vitally important achievement inits own right. 23 ICH harmonisation for better health
  26. 26. ICH GuidelinesFinalized as of July 2010Quality GuidelinesSTABILITYQ1A(R2) Stability Testing of New Drug Substances and ProductsQ1B Stability Testing: Photostability Testing of New Drug Substances and ProductsQ1C Stability Testing for New Dosage FormsQ1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and ProductsQ1E Evaluation for Stability DataANALYTICAL VALIDATIONQ2(R1) Validation of Analytical Procedures: Text and MethodologyIMPURITIESQ3A(R2) Impurities in New Drug SubstancesQ3B(R2) Impurities in New Drug ProductsQ3C(R4) Impurities: Guideline for Residual SolventsPHARMACOPOEIASQ4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH RegionsQ4BAnnex 1 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Residue on Ignition/Sulphated Ash General ChapterQ4BAnnex 2 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Test for Extractable Volume of Parenteral Preparations General ChapterICHharmonisation for better health 24
  27. 27. ICH GuidelinesFinalized as of July 2010 (continued)Q4BAnnex 3 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Test for Particulate Contamination: Sub-Visible Particles General ChapterQ4BAnnex 4A Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests General ChapterQ4BAnnex 4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Microbiological Examination of Non-Sterile Products: Tests for Specified Micro-Organisms General ChapterQ4BAnnex 4C Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Microbiological Examination of Non-Sterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use General ChapterQ4BAnnex 5 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Disintegration Test General ChapterQ4BAnnex 7 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Dissolution Test General ChapterQ4BAnnex 8 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Sterility Chapter General ChapterQ4BAnnex 9 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Tablet Friability General ChapterQ4BAnnex 10 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Polyacrylamide Gel Electrophoresis General Chapter 25 ICH harmonisation for better health
  28. 28. ICH GuidelinesFinalized as of July 2010 (continued)Q4BAnnex 11 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Capillary Electrophoresis General ChapterQ4BAnnex 12 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Analytical Sieving General ChapterQUALITY OF BIOTECHNOLOGICAL PRODUCTSQ5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal OriginQ5B Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein ProductsQ5C Quality of Biotechnological Products: Stability Testing of Biotechnological/ Biological ProductsQ5D Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological ProductsQ5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing ProcessSPECIFICATIONSQ6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical SubstancesQ6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological ProductsGOOD MANUFACTURING PRACTICEQ7 Good Manufacturing Practice Guide for Active Pharmaceutical IngredientsPHARMACEUTICAL DEVELOPMENTQ8(R2) Pharmaceutical DevelopmentICHharmonisation for better health 26
  29. 29. ICH GuidelinesFinalized as of July 2010 (continued)QUALITY RISK MANAGEMENTQ9 Quality Risk ManagementPHARMACEUTICAL QUALITY SYSTEMQ10 Pharmaceutical Quality SystemSafety GuidelinesCARCINOGENICITY STUDIESS1A Guideline on the Need for Carcinogenicity Studies of PharmaceuticalsS1B Testing for Carcinogenicity of PharmaceuticalsS1C(R2) Dose Selection for Carcinogenicity Studies of PharmaceuticalsGENOTOXICITYS2(R1) Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use (this guideline replaces and combines S2A and S2B)TOXICOKINETICS AND PHARMACOKINETICSS3A Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity StudiesS3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution StudiesTOXICITY TESTINGS4 Duration of Chronic Toxicity Testing in Animals (Rodent and Non Rodent Toxicity Testing)REPRODUCTIVE TOXICITYS5(R2) Detection of Toxicity to Reproduction for Medicinal Products and Toxicity to Male FertilityBIOTECHNOLOGICAL PRODUCTSS6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 27 ICH harmonisation for better health
  30. 30. ICH GuidelinesFinalized as of July 2010 (continued)PHARMACOLOGY STUDIESS7A Safety Pharmacology Studies for Human PharmaceuticalsS7B The Non-clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human PharmaceuticalsIMMUNOTOXICOLOGY STUDIESS8 Immunotoxicity Studies for Human PharmaceuticalsS9 Nonclinical Evaluation for Anticancer PharmaceuticalsEfficacy GuidelinesCLINICAL SAFETYE1 The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening ConditionsE2A Clinical Safety Data Management: Definitions and Standards for Expedited ReportingE2B(R2) Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety ReportsE2C(R1) Clinical Safety Data Management: Periodic Safety Update Reports for Marketed DrugsE2D Post-Approval Safety Data Management: Definitions and Standards for Expedited ReportingE2E Pharmacovigilance PlanningE2F Development Safety Update ReportCLINICAL STUDY REPORTSE3 Structure and Content of Clinical Study ReportsICH harmonisation for better health 28
  31. 31. ICH GuidelinesFinalized as of July 2010 (continued)DOSE-RESPONSE STUDIESE4 Dose-Response Information to Support Drug RegistrationETHNIC FACTORSE5(R1) Ethnic Factors in the Acceptability of Foreign Clinical DataGOOD CLINICAL PRACTICEE6(R1) Good Clinical Practice: Consolidated GuidelineCLINICAL TRIALSE7 Studies in Support of Special Populations: GeriatricsE8 General Considerations for Clinical TrialsE9 Statistical Principles for Clinical TrialsE10 Choice of Control Group and Related Issues in Clinical TrialsE11 Clinical Investigation of Medicinal Products in the Pediatric PopulationPRINCIPLES FOR CLINICAL EVALUATION BY THERAPEUTIC CATEGORYE12 Principles for Clinical Evaluation of New Antihypertensive DrugsCLINICAL EVALUATIONE14 The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic DrugsPHARMACOGENOMICSE15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding CategoriesE16 Genomic Biomarkers Related to Drug Response: Context, Structure and Format of Qualification Submissions 29 ICH harmonisation for better health
  32. 32. ICH GuidelinesFinalized as of July 2010 (continued)Multidisciplinary GuidelinesM1 MedDRA Medical TerminologyM2 ICSR (R2) Electronic Transmission of Individual Case Safety Reports Message SpecificationM3(R2) Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for PharmaceuticalsM4(R3) Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human UseM4Q(R1) The Common Technical Document for the Registration of Pharmaceuticals for Human Use: QualityM4S(R2) The Common Technical Document for the Registration of Pharmaceuticals for Human Use: SafetyM4E(R1) The Common Technical Document for the Registration of Pharmaceutical for Human Use: EfficacyM5 Data Elements and Standards for Drug DictionariesICHharmonisation for better health 30
  33. 33. Many thanks to those who helped edit this report, particularly, Odette Morin of the International Federation of PharmaceuticalManufacturers and Associations and Richard Currey and Nancy Derr of the U.S. Food and Drug Administration. Special thanks to Wendy Stanfield and Elena Ketelhut for the design and graphics. 31 ICH harmonisation for better health
  34. 34. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Secretariat C/O International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) 15 Chemin Louis-Dunant P.O. Box 195 1211 Geneva 20 Switzerland Tel: +41 (22) 338 32 06 Fax: +41 (22) 338 32 30 e-mail: admin@ich.org http://www.ich.org

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