Regulatory enviroment and clinical trials in south east asia
Ellick Wong/ Regulatory environment and clinical trials in SEA - 1 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaRegulatory Environment and Clinical Trials in South East AsiaEllick Wong PhDVice PresidentPharmaceutical Development CentrePharmacia Corp.SINGAPOREAbstractSouth East Asia is a growing pharmaceutical market. The regulatory environment hassimilar characteristics but drug registration requirements and processes differ among thecountries. An ASEAN initiative to harmonize the requirements for drug registration isin progress. Many multi-national research-based pharmaceutical companies have begunto conduct multi-center trials in their global drug development programs involvingAsian medical centers for faster patient recruitment to achieve faster drug development.In the recent years, there is a steady increase in clinical trial activities in South East Asia.Key wordsRegulatory, drug registration, clinical trial, South East Asia, ASEANIntroductionThe Association of Southeast Asian Nations (ASEAN) is a growing region inSouth East Asia (SE Asia) with 10 member countries namely, Indonesia,Malaysia, Philippines, Singapore, Thailand, Brunei Darussalam, Vietnam, Laos,Myanmar and Cambodia. The ASEAN region has a population of about 500million, a total area of 4.5 million square kilometers, a combined gross domesticproduct of US$737 billion, and a total trade of US$ 720 billion. Thepharmaceutical market in SE Asia is relatively small but the region remainsattractive to the pharmaceutical industry due to its growth potentials. Among theten ASEAN members, the five founding member countries (Singapore, Malaysia,Thailand, Philippines & Indonesia) are more progressive with drug registrationand drug development clinical trial activities. This review will therefore confinethe discussion on the regulatory environment, drug registration and clinical trialdevelopments in the 5 countries. Some key demographic and economicperformance figures for the countries are given in Table 1.
Ellick Wong/ Regulatory environment and clinical trials in SEA - 2 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaTable 1. South East ASIA1,02527.0%1.0629.7%7802.0%3082.3%2413.4%Pharma Market (MUSD)Y2001Growth Rate(2001/2000) LCD7302.5%9533.9%1,9503.0%3,8404.5%27,3505.0%GDP/head (USD)Growth Rate (2002)209.678.462.423.84.0Population (Million)IndonesiaPhilippinesThailandMalaysiaSingaporeCountriesSource : ECN, IMSRegulatory Environment in SE AsiaThe regulatory environment in the SE Asian countries has certain features thatare similar but, in general, there are differences in systems and practices. Thecharacteristics of the regulatory environment are listed in Table 2. Many of theregulatory agencies in the countries suffer from having rather weakinfrastructures primarily due to limited human resources. Some of the agencieshave less than five staff in handling the registration matters of new drugs. As aresult, the agencies traditionally performed mainly administrative work and simplyendorse approvals of new drugs after other so-call advanced countries havepreviously approved them. This has set the scene for the existing approvalsystems in these counties relying heavily on the Free Sales Certificate orCertificate of Pharmaceutical Product (CPP) issued by reference or advancedcountries for registration of new drugs.Although there appears to be a lack of available scientific guidelines and very fewof them have been established in the region, the ICH guidelines are well adaptedin most countries. Most countries still have the problem of lack of consistencyand transparency in the review procedure. In some countries we seeimprovement as more direct communications are becoming possible betweenregulator and the industry. The requirement of CPP from country of origin (COO)still remains a key barrier to the registration of new drugs in the region.
Ellick Wong/ Regulatory environment and clinical trials in SEA - 3 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaTable 2. Regulatory Environment S.E. AsiaRegulatory agencies: relatively weak infrastructure,small resources, structurally differentDiversity of regulatory processes / requirementsDiversity of approval timelinesStandards of scientific guidelines not well-establishedLack of consistency & transparency but improving withmore dialogues with industryRequirement of CPP from COO or reference countriesThe regulatory agencies in the SE Asia countries, listed in Table 3, have beenorganized differently and some changes have taken place in the recent years.The most significant change in the system was seen in Singapore. In 2001, theSingapore agency was reorganized into a statutory board known as the HealthSciences Authority that run in a corporative fashion. The agency has establishedtwo centers to deal with drug registration; the Centre of PharmaceuticalAdministration (CPA) is the licensing body that performs administrative workrelated to drug registration while the Centre of Drug Evaluation (CDE) to performscientific and medical evaluations of new drug applications. The CDE hasestablished for the first time in-house capability for scientific and medical reviewsof submissions and provide regulatory consultations to the industry. Howeverpartly due to the small number of staff available at the CDE, the center still haveto rely heavily on external reviewers, many of them academic pharmaceuticaland medical scientists from the local university. Many other regulatory agenciesin SE Asia have similar constraint in in-house resources dealing with new drugapplications, the reviewing process involves external experts in their countries atsome points.
Ellick Wong/ Regulatory environment and clinical trials in SEA - 4 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaTable 3. Regulatory Agencies in S.E. AsiaIndonesia : National Agency of Drug & Food ControlMalaysia :Drug Control Authority, NCE UnitPhilippines :BFAD, DoHThailand : ThaiFDA, Drug Control Div.Singapore : Health Sciences Authority (HSA)Centre for Pharmaceutical Admin. (CPA)Centre for Drug Evaluation (CDE)Dug Registration in SE AsiaIn the region, drug registration processes vary considerably among the countrieswith different sets of requirements for new drug approvals. From the pastexperience, the approval timelines in the countries vary from 6 to 24 months.The author has analyzed available in-house data on 6 new drugs recentlyregistered in the 5 ASEAN countries and the approval timelines are shown inFigure 1. The data also allowed estimation of the ranges of registration timelinesin the countries to be made: Singapore and Thailand, 6-12 months, Indonesiaand the Philippines 12 –18 months and Malaysia may take up to 2 years.8.323.98.822.214.171.124126.96.36.199.188.8.131.526.84.3184.108.40.206.29.9220.127.116.11.57.20.05.010.015.020.025.030.035.040.0SingaporeMalaysiaThailandIndonesiaPhilippinesNo. of MonthsProduct A Product B Product C Product D Product E Product FFigure 1. NCE Approval Time7.518.104.22.1685.3
Ellick Wong/ Regulatory environment and clinical trials in SEA - 5 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaRegistration RequirementsTable 4 shows the requirements of various regulatory and administrativedocuments for new drug registration in the 5 countries. All countries require CPPand GMP certificates. All countries prefer to have CPP from COO, however forSingapore, Indonesia and Thailand, CPP from selected countries other thanCOO could be used. With the exception of Malaysia, all countries require CPP atthe point of filing. Table 5 shows more details on the CPP requirements andtiming of submission.Indonesia authority would require additional Free Sales Certificate issued by anadvanced country. For Philippines and Thailand, the CPP and GMP certificateswould need to be legalized. Most countries also demand submission of copiesof manufacturing licenses of the manufacturers and packagers for products to beregistered. Because of cultural and religious reasons, Indonesia, Malaysia andPhilippines authorities require information on sources of all ingredients of animalorigin. The Indonesian authority will not approve products containing anyingredient of porcine source.IndonesiaMalaysiaPhilippinesSingaporeThailandRemarksRegulatory / AdministrativeDocumentsCPP (COO) Y Y Y Y Y MALAYSIA: CPP at Stage 3Y track IIGMP Certificates (Manufacturer &Packager)Y Y Y Y YNotarized & Legalized of above? Y YY Y YPatent Information Y Y YYY Y Y YY Y Y INDONESIA : porcine sourcesnot acceptable.For ingredient of animal origin:Declarations specifying the origin (animalspecies)Manufacturers RegistrationTable 4. REGISTRATION REQUIREMENTSAdditional FSC (2)Manufacturing license (Manufacturer &Packager)Info of manufacturers of ingredients.
Ellick Wong/ Regulatory environment and clinical trials in SEA - 6 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaTable 5. CPP REQUIREMENTSSubmissionCOO is required for approval. Export certificate can beused in place of a CPP from COO for submission, butCPP from COO is required for approval.PHILIPPINESSubmissionCOO – for Track I and Track IIITrack II – Assessment Reports + 2 CPPs (EMEA &/orcountries with GES) or Assessment Reports + 3 CPPs(countries with GES)INDONESIASubmissionCOOTHAILANDStage 3COO (Manufacturer or final packager/ product releaser)MALAYSIASubmissionCOO or from the recognized countries (with CPA’spermission)SINGAPORERequired atCPP RequirementsCountryTable 6 shows the other requirements for new drug registration. The commonfiles are formulation, manufacturing method, method of analysis andspecifications, cert of analysis, and stability report. The Philippines authorityrequires additional documents such as in-process control, validation documentsand plant descriptions. Most countries require samples of product, samples fortesting and working standards. All countries also would need to have proposalfor labeling and pack insert. Documents on pre-clinical, pharmacology,toxicology, clinical pharmacology and clinical studies are standard requirements.The Malaysian and Thai authorities require additionally 3 published studies; thisrequirement has often presented difficulties for companies to fulfill and delay theregistration.
Ellick Wong/ Regulatory environment and clinical trials in SEA - 7 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaIndonesiaMalaysiaPhilippinesSingaporeThailandRemarksBasic CMC DocumentsIn Process Control Y Y YFormulation Y Y Y Y YManufacturing Method Y Y Y Y YMethod of Analysis & Specifications Y Y Y Y YValidation DocumentsY Y Y Singapore - Protocol, Reportsand Summary of Results.Plant Facility Description Y Y YY Y YY Y Y Y Y Philippines - numerical /descriptive results.Y Y Y Y YRegistration Samples3 5 2 2Samples for Analytical Testing with CoA Y Y Y YY Y YPackaging MaterialsY Y Y Y Y3 5 5 2 5Y Y Y Y YPre-Clinical & Clinical DocumentsY Y Y Y YPharmacology & Toxicology Y Y Y Y YPD / PK Y Y Y Y YY Y Y YClinical Documents Y Y Y Y YPublished Clinical Papers 3 3Visual Samples (Commercial Packs) withOriginal CoASamples of Working standardsPre -Clinical DocumentsBioavailability study reportTable 6. REGISTRATION REQUIREMENTSProposal for labeling (artwork; carton,labels, blisters, package insert)No. of sets requiredCoA for each excipientsCoA of Final ProductStability ReportPack InsertRegulatory Review and Approval ProcessThe review processes vary from country to country in the region. In Indonesia, apre-registration consultation should take place before formal submission of files.The procedures are defined by three tracks. Track I is for orphan drugs or drugsfor treating life-threatening diseases. Track II and III are for products carryingdifferent approval status. The agency sets target review timelines for Track Iat100 days, Track II at 150 days, and Track III at 300 days. For Track II products,assessment reports are required on top of a CPP, although CPP from non-COOis acceptable. The fee for registration is Indonesian Rupiah 20 million (aboutUS$2,000).In Malaysia, the drug registration process is in 3 stages with differentdocumentations submitted at each stage. CPP from COO is submitted only at
Ellick Wong/ Regulatory environment and clinical trials in SEA - 8 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaStage 3. This facilitates early new product filing in Malaysia while the product isunder review by health authorities elsewhere, in COO and other advancedcountries. The registration fee is RM1000 (about US$300). The target reviewtimeline ranges 38 to 66 weeks.In Thailand, after filing, the company can choose to make a formal presentationto the agencies staff and medical reviewers on data submitted. After approval,most new drugs are subjected to post-marketing surveillance (PMS) for severalyears and hence the authority would demand PMS study protocol to besubmitted before product approval is granted. The registration fee is Thai Baht2,000 (about US$50). The target review timeline is 7 months.In the Philippines, the agency may request the company to perform localregistration trial if there is no proof of the product’s clinical use in more than5,000 patients in the COO; even the product is approved in the COO. The fee forproduct registration is around PhP 20,000 (about 400 USD) and the target reviewtimeline is 12 to 18 months.In Singapore, since the establishment of the CDE, the submission of new drugapplication via the so-called ‘CDE route’ could be done prior to any approval ofthe product elsewhere and hence one can file for new drug registration inSingapore simultaneously as the NDA is filed in the COO or in other advancedcountries. The fee is in the region of S$8,000 (about US$4,500) for a file of10,000 pages. More detailed fee structure for submission could be found in CDEweb-site(http://www.hsa.gov.sg/hsa/CDE/CDE_service_directory_feesschedulefornda.htm). Target review timeline is 30 weeks.In Singapore, one can also file product registration following a conventional routeof registration via the CPA office. As this route of filing demands the submissionof CPP, this is only possible for products previously approved in COO or in otheradvanced countries. The registration fee is S$545 (about US$280) and thetarget review timeline is 17 weeks. There is a fast track review route but theauthority requires assessment reports on the product from two advancedcountries.ASEAN Regulatory Harmonization InitiativeA recent Centre of Medicine Research International survey (1) showed that mostinternational companies would prefer to submit registration files simultaneously inAsia when the NDA is submitted to the COO or other developed countries.However due to various reasons, not many companies can achieve this goal andcertainly not with all their products. It is well recognized that there are still manyregulatory barriers hindering simultaneous submission in SE Asia and thediversity in requirements is one of the most important. In view of this, the ASEAN
Ellick Wong/ Regulatory environment and clinical trials in SEA - 9 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East Asiacountries have started a harmonization initiative in 1999. The initiative, known asthe ASEAN Consultative Committee for Standards and Quality – PharmaceuticalProduct Working Group (ASEAN CCCSQ-PPWG), aimed at establishingcommon technical requirements and to develop quality guidelines for productregistrations. When these documents are ready and be implemented in 2003 -2004, the registration timelines in ASEAN will be significantly aligned.While waiting for the ultimate harmonization to become a reality, the Singaporeagency HSA has been progressive in making international cooperation. HAS hasrecently signed pact with the health authority of Australia, TGA. The cooperationis aiming at a better sharing of experiences and this will bring an improvedreviewing process to Singapore.Clinical Trials in SE AsiaAsia is increasingly being recognized as an important base for R&D. Many multi-national research-based pharmaceutical companies are beginning to see thepotential of Asia in contributing to drug development. Several companies andCROs have established their trial monitoring organizations and built facilities inAsia to perform trials to international standards and meeting regulatoryrequirements. The large patient pool available for trials in Asia has potential forfaster patient recruitment, and hence trials involving Asia medical centers maycontribute to shortening the development time of new drugs. A recent review hasdiscussed the challenges and benefits of conducting drug development clinicaltrials in SE Asia (2).Many companies have already successfully conducted many drug developmentglobal studies in SE Asia. With close clinical trial monitoring and professionalproject management, many medical centers particularly those located in majorcities could perform high quality GCP studies and they often can compete veryfavorably in terms of patient recruitment and costs with other centers in theEurope, USA or Latin America.For the past many years, although SE Asian countries had demonstrated theircapabilities in performing clinical trials, there were still many issues whichdiscouraged companies from bringing in Phase II and III studies to the region.One of the issues was the long clinical trial approval process. It sometimes tooklonger than 6 months for an approval to be granted in some countries and hencelimits their participation. With the joint efforts of industry, hospital and regulatoryauthorities, there has been a steadily improvement in shortening the timelineslately. In some countries nowadays, IRB and regulatory submissions could bedone simultaneously and this has significantly improved the overall timeline fornew trial start-up. In general, the approval timeline now is 3 to 4 months in SEAsia and for most trials it is acceptable for them to join. Table 7 shows theaverage timelines for clinical trial approvals in the 5 ASEAN countries.
Ellick Wong/ Regulatory environment and clinical trials in SEA - 10 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaTable 7. Clinical Trial Approval Timelines in SE Asia6Y1659Philippines3N1469Thailand3412No ofstudiesN14105MalaysiaY13117IndonesiaN1138SingaporeParallel(Y/N)Approvalperiod(weeks)RegulatoryApproval(median weeks)IRBApproval(Median weeks)In many of the SE Asian countries, the governments have identified thebiomedical/life sciences industry as a key segment for future economic growth.Among them, the Singapore government has been particularly active in this area.They offer support and financial incentives to pharmaceutical and biotechnologycompanies to build research facilities and train manpower resources to developR&D. Figure 2 shows that the effort of the Singapore government in promotingclinical trials in the past few years has really paid off. The number of clinical trialsreflected by the numbers of Clinical Trial Certificates applications to the healthauthority has increased exponentially over the past years. Also it is worth to notethat majority of the trials conducted in Singapore these days are in Phase II andIII. In Singapore, the number of Phase I trials has also significantly increasedafter two Phase I laboratories were established by multi-national pharmaceuticalcompanies recently.
Ellick Wong/ Regulatory environment and clinical trials in SEA - 11 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaTotal no. of Clinical Trial Applications020406080100120140160180197819791980198119821983198419851986198719881989199019911992199319941995199619971998199920002001YearNo.ofApplications Figure 2. Number of Clinical Trial CertificateApplications in SingaporeDrug Trials Growing in AsiaDrug Trials Growing in AsiaSingaporeSingaporeSingapore – Clinical Trials (2001)SingaporeSingapore –– Clinical Trials (2001)Clinical Trials (2001)Phase I Phase II Phase III Phase IV30% (50)12% (19)17% (28)41% (68)Phase IPhase IIPhase IVPhase III
Ellick Wong/ Regulatory environment and clinical trials in SEA - 12 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East AsiaIn the other ASEAN countries, the clinical trial activities have just begun. Table 8shows the number of clinical trial approvals issued by the authorities in Malaysia,Philippines and Indonesia in year 2000 and 2001. Although the numbers of trialsin Phase III are still rather low in these countries, there is a trend that thenumbers are increasing. It is foreseeable that SE Asia countries’ contribution toglobal drug development will grow from strength to strength in the near future.Figure 8 . Clinical Trials in SE AsiaFigure 8 . Clinical Trials in SE AsiaFigure 8 . Clinical Trials in SE AsiaPhilippines85 (2000) 100 (2001)Indonesia(mainly phase IV)Phase IVPhase III106 (2000) 60 (2001)23 (2000) 42 (2001)29 (2000) 53 (2001)Phase IVPhase III8 (2000) 9 (2001)MalaysiaData provided by the health authorities in the respective countriesGlobal Drug Development and Simultaneous Drug RegistrationThe Centre of Medicine Research International conducted recently reported asurvey (3) they did with multinational pharmaceutical companies on theirinvolvement of Asian countries (ex-Japan) in conducting their drug developmenttrials. Based on the responses from 13 companies, 8 routinely conducted clinicaltrials in Asian countries; all 8 companies used local trial data for regulatorysubmissions. Three companies had conducted pivotal studies in Asia, and 2 ofthem had included Asian data in their ICH submissions.The results from the survey were indicative of some multinational research-basedpharmaceutical companies’ strategy in including Asia in their globalised drugdevelopment program. Increase in the participation in global drug developmentprograms by Asian medical centers will contribute to shorten development timeand to achieve simultaneous drug registration, and thereby to reach the goalshared by all in drug industry and regulatory agencies: ensuring quicker access
Ellick Wong/ Regulatory environment and clinical trials in SEA - 13 –Ellick Wong--Regulatory Enviroment and Clinical Trials in South East Asiato new and innovative medicines for all patients and to meet their medical needswherever they are.References1. Center of Medicine Research International, CMR Report, June 2001 (web-site:www.cmr.org)2. CF Fenn, E Wong, D Zambrano. The contemporary situation for the conductof clinical trials in Asia, Int. J. Pharm. Medicine 2001, 15: 169-1733. Center of Medicine Research International, CMR R&D Briefing No 37.December 2002 (web-site: www.cmr.org)