That document — called the common technical document or CTD — is now being accepted by regulatory agencies in the United States, Europe, and Japan as part of a transition phase. Consensus was reached by the international pharmaceutical community in May of this year. This document will eventually replace the new drug application (NDA) and the bio logics license application (BLA) in the U.S. By July 2003 new drug submissions using this format will be mandated in Europe and Japan and will be strongly encouraged in the U.S. Congress will have to make a change in the law to mandate the use of the CTD in the U.S. The common technical document is part of a larger effort to harmonize regulations in the three regions. The goal of the effort — called the International Conference on Harmoniza tion (ICH) — is to save time and money by replacing the preparation of complex and mul tiple submissions with a single dossier. The effort also aims to standardize the scientific and data requirements that support an appli cation — so far, 47 topics have been standard ized (see box on page 22) — and remove the duplication of studies that was previously required to gain market approval in each of the three regions. In theory, a single document that meets the needs of regulators in the three regions will speed applications and approvals. In reality, the process has been long and complicated. Regulators even had to standardize the termi nology to be used (see box on page 24). “Instead of preparing one dossier for Europe, one for Japan, and one for the U.S., a common dossier will dramatically reduce the work involved for companies,” says Caroline Nutley Loew, assistant VP for international regulatory affairs, Pharmaceutical Research and Manufacturers of America. “For the regu latory agencies, standardization will facilitate their review processes, as well as facilitate interaction.” The standardization of the common techni cal document will eventually make way for electronic submissions, which the ICH is cur rently testing. In fact, issues, such as section numbering and pagination, that were addressed this spring at an ICH steering com mittee meeting in Japan were an attem make the transition to the electronic CT a bit more smoothly, Ms. Loew says. Harmonization could yield several be says Jay Nisbet, director, international ness development, DFB Pharmaceutical “Companies would no longer need to mulate products to comply with regu differences in major markets,” he says. uniform registration requirements, com could design new products to comply in world markets. In addition, clinical su for the registration process would be s fied. If each major country had the requirements for submission dossiers, a pany could conduct one set of clinical applicable in all major markets, th reducing time and cost to complete tria Harmonization efforts are likely to with the marketing of new drugs as “Both the industry and the service ag benefit,” says Barry Gowers, preside Gowers Advertising. “More markets, syn nized at the same point in the drug life will mean more noise in those markets global harmony COMES TO DRUG DEVELOPMENT A single global standard for drug development is one step closer to reality. Regulato ry bodies in the U.S., Europe,and Japan are making significant strides to standardize formatting of applications and harmonize regulato ry requirements. Is the industry ready? by Denise Myshko The vision was simple, yet ambitious: The international pharmaceutical community coming together to create a single document for the submission of new drugs. Now after more than a decade one that has included long days, extensive travel, and exhaustive meetings for regulators and industry leaders — this effort has finally hit the right note. 22 S e p t e mb e r / O c t o b e r 2001 PharmaVOICE there will be more resources concentrated on one clear strategy, often including comarket ing partners sharing the promotion budget and putting more sales reps on the ground.” Global teamwork, Mr. Gowers says, is crit ical. “This will result in a balanced group in terms of geography and responsibility, with clear definitions of processes, outputs, roles, and responsibilities thrashed out at the When we get the branding foundations erly in place, we can build a great cam This means lots of facetoface mee learning to trust one another and enjoyi process, and reserving video conferenci approvals rather than using them for storming.” A CRITICALCOMPONENTOFTHE INTERNATIONAL CONFERENCE ONHARMONIZATION (ICH) EFFORTWAS TO CREATE COMMON STANDARDSOF SCIENTIFIC PRINCIPLES AND TECHNICAL REQUIREMENTS OF DRUG DEVELOPMENT. EXPERTWORKING GROUPS IN FOUR AREAS — EFFICACY (CLINICAL TESTING PROGRAMS), QUALITY (PHARMACEUTICAL DEVELOPMENT), SAFETY (PRECLINICAL TOXICITY AND RELATED TESTS), AND MULTIDISCIPLINARY (INCLUDING REGULATORY COMMUNICATIONS, ELEC TRONIC STANDARDS, AND THE COMMON TECHNICAL DOCUMENT) — ARE WORKING TO PRODUCE SPECIFIC GUIDELINES. SO FAR, 47 GUIDELINES HAVE BEEN APPROVED. BELOW IS A LIST OF THE APPROVEDGUIDELINES. (FOR MORE INFORMATION ABOUT EACH,GO TO IFPMA.ORG/ICH5.HTML.) Q7:Specifications Q7A:GMP for Active Pharmaceutical Ingredients SAFETY S1: Carcinogenicity S1A:Need for CarcinogenicityStudies S1B:Testing for Carcinogenicity S1C: Dose Selection for Carcinogenicity Studies S1C(R):Addendum to the Dose Selection S2:Genotoxicity S2A:Guidance on Specific Aspects of RegulatoryGenotoxicity Tests S2B:A Standard Battery ofGenotoxicity Testing S3:Kinetics S3A:Toxicokinetics: the Assessment of Systemic Exposure in Toxicity Studies S3B:Pharmacokinetics:Guidance for Repeated Dose Tissue Distribution Studies S4: Toxicity S4:Duration of Chronic Toxicity Testing in Animals (Rodent and Non Rodent Toxicity Testing) S5: Reprotoxicity S5A:Toxicity to Reproduction forMedicina Products S5B:An Addendum on Toxicity to Male Fertility S6:Biotechnological Safety S6:Preclinical Safe ty Evaluation of BiotechnologyDerived Pharmaceuticals S7:Pharmacology S7:Safe ty Pharmacology Studies MULTIDISCIPLINARY M1:Medical Terminology M2: Electronic Standards for Transmission of Regulatory Information M3:Timing of Preclinical Studies in Relation to Clinical Trials M4:The Common Technical Document EFFICACY E1: Exposure E1: The Extent of Population Exposure to Assess Clinical Safety E2: Clinical Safe ty E2A: Definitions and Standards for Expedited Reporting E2B: Data Elements for Transmission of Individual Case Safety Reports E2C:Periodic Safe ty Update Reports for Marketed Drugs E3:Study Reports E3: Structure and Content of Clinical Study Reports E4:Dose Response E4:DoseResponse Information to Support Drug Registration E5: Ethnic Factors E5: Ethnic Factors in the Acceptability of Foreign Clinical Data E6: GCP E6: Good Clinical Practice: Consolidated Guideline E7:Special Populations E7: Studies in Support of Special Populations: Geriatrics E8:Clinical Trial Design E8: General Considerations for Clinical Trials E9:Statistical Considerations E9: Statistical Principles for Clinical Trials E10: Choice of Control Group E11:Pediatrics E11: Clinical Investigation of Medicinal Products in the Pediatric Population E12:Therapeutic Categories E12A: Clinical Trials on Antihype rtensives QUALITY Q1:Stability Q1A: New Drug Substances and Products Q1B: Photostability Testing of New Drug Substances and Products Q1C:New Dosage Forms Q2:Analytical Validation Q2A:Text on Validation of Analytical Procedures Q2B:Validation of Analytical Procedures:Methodology Q3: Impurities Q3A: Impurities in New Drug Substances Q3B: Impurities in New Drug Products Q3C: Impurities: Guideline for Residual Solvents Q4:Pharmacopeias Q4:Pharmacopeial Harmonization Q5:Biotechnological Quality Q5A:Viral Safe ty Evaluation of Biotechnology Products Q5B:Genetic Stability Q5C:StabilityTesting of Biotechnological/ Biological Products Q5D: Cell Substrates Used for Production of Biotechnological/Biological Products Q6:Specifications Q6A:Specifications:Chemical Substances Q6B: Specifications: Biotechnological/Biological Substances “Is it a step in the right direction? Absolutely. Is it the panacea for making my life as a regulato ry affairs professional easier GLOBAL harmony The Harmonization Guidelines GLOBAL harmony Benefits Not Immediate But harmonization has its drawbacks, says Gregory M. Hockel, VP of regulatory affairs in the Washington D.C. office of PharmaNet Inc. “Is it a step in the right direction? Absolutely,” he says. “Is it the panacea for making my life as a regulatory affairs professional easier? No. “There are some areas where ICH has had some benefits, for example, the standardiza tion of temperatures and humidity require ments for stability programs,” Mr. Hockel says. “But there are some differences that make my job more difficult on a daytoday basis. For example, to start a clinical trial under the ICH guidelines, we need about 20 essential documents. In the U.S., we only need about five of those 20 documents. The fact is that ICH guidelines, because they tried to capture the interest of all the parties, have developed the guidelines based on the greatest common denominator. If we become a strict follower of ICH guidelines, we are voluntarily obligating to do more than is required under national regulations in the U.S. since adherence to guidelines is not mandatory. My point is that we lose some efficiencies and the ability to expedite the initiation of clinical trials.” In addition, Mr. Nisbet says a harmonized regulatory environment would make price dif ferentiation difficult. “Currently, markets — and prices for drugs — are extremely diverse. In countries with strict regulatory standards, such as the U.S., there are very high costs asso ciated with the research and develop phases of a pharmaceutical product. Al tively, in other countries, regulatory pro are less stringent. In those cases, many ucts can find their way into the econ more quickly. And, in many cases, if the has approved a medicine, some govern accept the U.S. FDAapproved product able to reduce the time needed for accep The result is lower prices in those count Mr. Nisbet continues: “Therefore, th price of a worldwide drug in the U.S exist in part because it’s the developing pany that must recover development co many markets and still earn a reasonable it. In other words, price positions in c countries underwrite the development ex 24 S e p t e mb e r / O c t o b e r 2001 PharmaVOICE J ust imagine how difficult early discussions in the effort to harmonize drug regulations were with people using differ ent terms and different definitions for those terms.The inter national pharmaceutical community quickly realized that the harmonization effort would have to begin with a common dic tionarythat standardized the terminology used by regulators and the industry throughout Europe, Japan,and the U.S. Now,after more than 10 years and several versions, the Medical Dictionaryfor Regulatory Activities ( DRA) has been completed.Released in June MedDRA is a global, standardized medical di nary to be used initially for adverse event rep ing. Eventually, the goal is for this common te nology to be used in all communication with regulatory agencies.The standard dictionary help to speed the exchange of medical infor tion, facilitate research and safety monitoring allow for more specific coding and better an ses of data. In addition, the dictionarywill be to support electronic communications betw companies and regulators. The European Agency for the Evaluation o Medicinal Products (EMEA),which oversees r latory activities in the 15 European Union co tries, will mandate the use MedDRA for all electronic singlecase, adverse event reports beginning January 2002 and for all paper and electronic reports beginnin January2003.The Japanes Ministry of Health,Labor,and Welfare has targeted the end 2001 to be in full compliance.The FDA already has implem ed MedDRAwithin its adverse event reporting system. But just as daunting is the task the industry now faces t implement the new terminology.MedDRA is larger and fa more complex than previous dictionaries, such as COSTAR and WHOART,which were maintained by regulato ry bodi Recognizing this complexity, the International Conference THE PRICE FOR COMMON TERMINOLOGY DR.PATRICIA MOZZICATO PATRICK REVELLE MedDRA, the standard dictionary, will help to speed the exchange of medical information, facilitate research and safety monitoring, and allow for more specific coding and better analysis of data. GLOBAL h es incurred by companies for other countries’ benefit. If there were harmonization, price dif ferentiation would be much more difficult. Such a situation might preclude some markets from participating in the drug if they couldn’t afford the selling price.” The industry has a steep learning curve, says Louise Shibley, VP, regulatory and technical services, U.S. and Canada, in the Kansas City office of Quintiles Transnational Corp. “The organization of the CTD is totally different from the NDA.There is a regionspecific mod ule, which is module one. Module two is an analysis, which in the U.S. we’re not used to. Systems must be set up to accommodate the new numbering systems and new arrangement for the placement of data.” She notes companies that adopt the CTD format early will have the advantage of time to deal with any problems that arise. “The advan tage of getting in early is that a company can partner with regulators to get all the bugs worked out, otherwise, the company will have to comply with the regulations all at once.” Quintiles is currently working on an appli cation that conforms to the CTD format, but Ms. Shibley says Quintiles is still awaiting guidance from the FDA on some specifics. FDA is Ready Officials from the Food and Drug Administra tion say they are in the process of developing a guidance document on implementing the common technical document. The guidance awaiting clearance from FDA Commissione Dr. Jane Henney, says Justina A. Molzon, asso ciate director for international affairs, Cente for Drug Evaluation and Research, at th FDA. Ms. Molzon, who is a member of th ICH steering committee, notes that the agen cy has been conducting workshops since th spring — and will continue these workshop throughout the transition period — to trai its medical reviewers in using the commo technical document. “In the longrun MedDRA (Medical Dic tionary for Regulatory Activities) will make reviewer’s life easier,” she says. “There will b more predictable applications and this wi lead to more consistent reviews. The best par 2 PharmaVOICE S e p t e mb e r / O c t o b e r 2001 Harmonization established the MedDRA maintenance and support services organization (MSSO) to maintain and support users in implementing the new dictionary. “One of the universal challenges, especially for companies, is taking their legacy data and converting the data into MedDRA ,” says Dr. Patricia Mozzicato, medical professional/senior manag er, at MSSO/TRW Healthcare Solutions, which won the contract for the maintenance of MedDRA.“This is both an information technology issue and a medical issue.When a company con verts its legacy data, there needs to be medical oversight to make sure the data are coded correctly.There are challenges as well with training because MedDRA is so different from the pre vious terminology.” Some of the key issues, she says, for implementing MedDRA are resources: time, money,and people.“Companies need to form a team that represents drug safety, clinical, and informa tion technology people to determine what needs to be done about implementing, training, dealing with legacy systems,and maintaining the terminology.For most companies, this should take about a year or more.” Implementing the new dictionary is likely to be a significant expense for the industry.Although regulators receive the dictio nary at no charge,pharmaceutical,biotechnology,and contract research organizations must pay for a CDROM copy on a slid ingscale fee, anywhere from $3,000 to $82,000,based on a com pany’s revenue,according to Patrick Revelle,director of products and services for the MedDRA MSSO/TRW Healthcare Solutions. But, he says, cost savings will come in the form of better communication of data using the same terminology.“This is true for industrytoregulator communications,as well as for industrytoindustrycommunications.For example,codevelop ers and comarketers will be capable of sharing data seamlessly. In addition, MedDRA will promote better analysis of data,which will potentially save R&D dollars by more accurately determin ing the merits of a compound being developed.” Mr.Revelle notes that with a subscription to MedDRA,users receive a browser to help maneuver through the dictionary. The terminology is meant to work in conjunction with other clinical software programs such as Oracle’s Clinical, ClinSo ft’s ClinTrial/Trace, and Relsys’Argus Safety. “Our biggest stumbling block has been in the area of infor mation technology issues,” says Susan McAllister, manager of pharmacovigilance and medical information,Genzyme Corp. “We are dealing with IT support, system evaluation, and choos ing what mechanism we’re going to use to code the informa tion into our database, software evaluation,and making sure we have enough programmers.” She says employees are excited about MedDRA and the company is in the process of developing a training program. But all of this has added up. In fact, a needs assessment plan placed the cost of implementation alone,not including mainte nance, at $2 million for the period of 20002001.Ms.McAllister says she knows of some companies that have budgeted up to $5 million for the implementation of MedDRA. Although this is expensive, it’s the cost of doing business and maintaining a competitive edge through global harmo nization efforts.“The main point of talking about the price tag is to encourage other companies to budget for it so that imple mentation doesn’t get pushed to the side due to the lack of financial planning,” Ms.McAllister says.“MedDRA needs to be a real company goal with upper management support.” This isn’t just an information technology project, says David Pherson,Ph.D.,associate director of coding operations and pharmacovigilance,atGenzyme.“This project not only impacts IT but also regulatory, drug safety, clinical, postmarketing surveillance, central coding,and labeling.” of this exercise of increased communications between regulators should result in wider global access to new drugs sooner.” At least one company has submitted an application to the FDA using the common technical document. In August 2001, Biogen Inc. announced that it had completed a simul taneous filing in the U.S. and Europe using the CTD format for its submission for Amevive (alefacept), which is being evaluated for the treatment of moderatetosevere chron ic plaque psoriasis. Company officials say they believe that this application is the first to use the new format. Biogen had been planning this submission for more than a year, says Nadine Cohen, Ph.D., VP of regulatory affairs at Biogen. “One of the advantages that we had by using the same approach for both U.S. and Europe is that we were able to file simultaneously, within two hours of each other. As we file in Cana da and other countries, we will be using the same type of approach and this should speed the efficiency in terms of the filing.” Dr. Cohen, however, stressed the impor tance of planning during the preparation of the submission. “If a company is going to use this type of approach, it needs to get in touch with all the agencies in advance so that there are no surprises. On our end, to make this submis sion work as smoothly as it did, there was a lot of coor dination back and forth. It will be interesting to see when the agencies come out with their guidelines how this will actually work.” Biogen officials did face one challenge in putting together the application. Although the FDA is accepting paper submissions using the CTD format, the agency is not yet ready to receive the CTD electronically. Biogen tailored its electronic BLA to include content as if it were written for the common technical document. While the common technical document is a huge step toward forming a harmonized reg ulatory environment, the ICH effort is far from complete. Those involved with the effort say more work needs to be done in the area of electronic submissions as well as in the area of developing standardized scientific principles for genetherapy products, emerging sciences, and postmarketing activities. PharmaVoice welcomes comments about this article. Email us at [email protected]. 26 S e p t e mb e r / O c t o b e r 2001 PharmaVOICE NADINE COHEN,PH.D. VP regulato affairs, Biogen Inc., Cambridge,Mass. Biogen is a biotechnology company BARRYGOWERS. President,Gowers Advertising, London;Gowers is a full service advertising agency and a bus ness unit of CommonHealth GREGORYM.HOCKEL. VP regulato affairs, PharmaNet Inc.,Washington, D.C.office; PharmaNet is an internati al drug development organization SUSANMCALLISTER. Manager of pharmacovigilance and medical information,Genzyme Corp.,Cambrid Mass.;Genzyme is a biotech compan JUSTINA A.MOLZON. Associate dir tor, international affairs,The Center fo Drug Evaluation and Research, Rockv Md.;CDER is a division of the FDA PATRICIA MOZZICATO,MD. Medica professional/senior manager,MSSO TRW Healthcare Solutions, Reston Va TRW is an information technology company JAY NISBET. Director, international business development,DFB Pharmaceuticals Inc., San Antonio, Texas; DFB develops and markets pharmaceuticals and medical device CAROLINE NUTLEY LOEW. Assistan VP, international regulato ry affairs, an ICH coordinator, Pharmaceutical Research and Manufacturers of America,Washington,D.C.;PhRMA is industryassociation DAVID PHERSON. Associate directo coding operations and pharmaco vigilance in medical affairs, Genzyme Corp., Cambridge,Mass.;Genzyme is biotechnology company PATRICK REVELLE. Director of prod ucts and services, MSSO,TRWHealth care Solutions, Reston Va.;T RW is an information technology company LOUISE SHIBLEY. VP, regulato ry and technical services, U.S. and Canada, Quintiles Transnational Corp., Kansas City, Mo.; Quintiles is a contract resea organization Experts on this to European Federation of Pharmaceuti cal Industries and Associations: efpia.org European Union:www.eudra.org Food and Drug Administration: fda.gov ICH guidelines: ifpma.org/ich5.html International Federation of Pharmaceu tical Manufacturers Associations (ICH Secretariat): ifpma.org Japan Pharmaceutical Manufacturers Association: jpma.or.jp/12english/index.html Medical Dictionaryfor Regulato ry Activities (MedDRA): ifpma.org/ichMedDRA.html Ministryof Health andWelfare (Japan):mhlw.go.jp/english/ Pharmaceutical Research and Manufacturers of America: phrma.org TRW Healthcare Solutions: meddramsso.com World Health Organization: who.int/homepage/ FOR MORE INFORMATION “The best part of increased communications between regulators should result in wider global access to new drugs sooner.” GLOBAL harmony

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