Drug Regulation History Present Future

Chapter 6

Drug Regulation: History, Present andFuture1

Lembit Rägo, Budiono Santoso

I. History of medicines regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65II. Why regulating drugs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

III. What is medicines regulation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67IV. Drug registration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68V. Role of WHO in drug regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

VI. Future of medicines regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

I. HISTORY OF MEDICINES REGULATION

Medicines are perhaps as old as mankind and theconcepts how their quality has to be ensured hasevolved gradually over the time. For example, Mith-ridates VI (120 BC), King of Pontus, concocted acompound preparation called “Mithridatium” whichincluded 41 individual components and was held as apanacea for almost all diseases until as late as 1780s.It took until 1540 when in England the manufac-ture of Mithridatium and other medicines was sub-jected to supervision under the Apothecaries Wares,Drugs and Stuffs Act. The Act was one of the earli-est British statutes on the control of medicines andit established the appointment of four inspectors of“Apothecary Wares, Drugs and Stuffs”. This couldbe seen as the start of pharmaceutical inspections.History of Pharmacopoeias, the official books ofdrug quality standards, probably dates back to oneof the proclamations of the Salerno Medical Edictissued by Fredrick II of Sicily (1240), and orderedapothecaries to prepare remedies always in the sameway – forma curiae. The first Pharmacopoeias as weknow them today stared to appear in Europe from16th century e.g. the first Spanish Pharmacopoeia

1 The views stated in this chapter reflect the views of the authorsand not necessarily those of the World Health Organization.

was issued in 1581. The standards for the manufac-ture of Mithridatum were established in England inThe London Pharmacopoeia only in 1618.

The modern medicines regulation started only af-ter breakthrough progress in the 19th century life sci-ences, especially in chemistry, physiology and phar-macology, which laid a solid foundation for the mod-ern drug research and development and started toflourish after the second World War.

Unfortunate events have catalysed the develop-ment of medicines regulation more than the evolu-tion of a knowledge base. In 1937 over 100 peoplein the United States died of diethylene glycol poi-soning following the use of a sulfanilamide elixir,which used the chemical as a solvent without anysafety testing. This facilitated introduction of TheFederal Food, Drug and Cosmetic Act with the pre-market notification requirement for new drugs in1938. However, in countries with poor regulatoryenvironment even recently medicines contaminatedwith diethylene glycol have killed patients.

The second catastrophe that influenced the de-velopment of medicines regulation far more thanany event in history was the thalidomide disaster.Thalidomide was a sedative and hypnotic that firstwent on sale in Western Germany in 1956. Be-tween 1958 and 1960 it was introduced in 46 dif-ferent countries worldwide resulting in an estimated10,000 babies being born with phocomelia and other

Drug Benefits and Risks: International Textbook of Clinical Pharmacology, revised 2nd editionEdited by C.J. van Boxtel, B. Santoso and I.R. Edwards. IOS Press and Uppsala Monitoring Centre, 2008. © 2008 The authors. All rights reserved.

66 Drug Benefits and Risks

deformities. The role of this disaster in shaping themedicines regulatory systems is not hard to underes-timate.

As a result the whole regulatory system was re-shaped in the UK where a Committee on the Safetyof Drugs (CSD) was started in 1963 followed bya voluntary adverse drug reaction reporting system(Yellow Card Scheme) in 1964. In the United States,The Drug Amendments Act of 1962 was passed byCongress requiring the FDA to approve all new drugapplications (NDA) and, for the first time, demandedthat a new drug should be proven to be effectiveand safe. Of equal importance, the FDA was alsogiven the authority to require compliance with cur-rent Good Manufacturing Practices (GMP), to of-ficially register drug establishments and implementother requirements. The EEC Directive 65/65/EECon the approximation of provisions laid down bylaw, regulation and administrative action relating tomedicinal products was also induced by the thalido-mide disaster.

It took almost ten years for the European Com-munity (EC), since Council Directive 65/65/EECwas introduced, to further develop harmonizationin the Community. In 1975 two Council Direc-tives were introduced, the first on approximationof the laws of Member States relating to analyt-ical, pharmacotoxicological and clinical standardsand protocols in respect of the testing of proprietarymedicinal products (75/318/EEC), and the secondon the approximation of provisions laid down bylaw, regulation and administrative action relating tomedicinal products (75/319/EEC). The latter estab-lished an ‘old’ Committee on Proprietary MedicinalProducts (CPMP) as an advisory committee to theEC and introduced the multistate procedure knownnow as the mutual recognition procedure. Directive87/22/EEC introduced the concentration procedurewhich is now known as the centralized procedure.These directives, and following council regulation,were the landmarks for starting harmonization in-side the European Union with the final longstand-ing aim of creating a ‘common market’ for medi-cines. The Council Regulation EEC/2309/93 estab-lished the European Medicines Evaluation Agency(EMEA) in 1993 and re-established the CPMP as a‘new’ CPMP to formulate the opinion of the Agencyon questions relating to the submission of applica-tions and granting marketing authorizations in ac-cordance with the centralized procedure. The detailsof European marketing authorization procedure aredescribed in detail in other publications.

Somewhat parallel with the ongoing harmoniza-tion and movement towards creating a common mar-ket for medicines inside the EU, the need for widerharmonization was after preliminary contacts be-tween officials from Japan, EU and US discussedduring the International Conference of Drug Reg-ulatory Authorities (ICDRA – organized by WHOevery second year) in Paris in 1989. The prelimi-nary informal discussions had revealed a need for theharmonization of requirements relating to the newinnovative drugs and the green light given in Parisled to the establishment in 1990 of the InternationalConference on Harmonization of Technical Require-ments for the Registration of Pharmaceuticals forHuman Use (ICH), a collaborative initiative betweenthe EU, Japan and the United States with observersfrom WHO, EFTA and Canada. ICH harmoniza-tion focuses primarily on technical requirements fornew, innovative medicines. However, countries withlimited resources are mostly generic markets andmay have difficulties of implementing numerous so-phisticated ICH standards. Pharmaceutical regula-tory harmonization facilitates the availability of safe,effective and good quality pharmaceuticals. WorldHealth Organization (WHO)2 supports harmoniza-tion on national, regional, inter-regional and inter-national levels. International consensus on quality,safety and efficacy standards can accelerate the in-troduction of new medicines and increase availabil-ity of generic medicines through fair competition,thereby lowering prices.

II. WHY REGULATING DRUGS?

Drugs are not ordinary consumers’ products. In mostinstances, consumers are not in a position to makedecisions about when to use drugs, which drugs touse, how to use them and to weigh potential bene-fits against risks as no medicine is completely safe.Professional advise from either prescribers or dis-pensers are needed in making these decisions. How-ever, even healthcare professionals (medical doc-tors, pharmacists) nowadays are not in capacity to

2 WHO is the directing and coordinating technical agency forhealth within the United Nations system. It is responsible for pro-viding leadership on global health matters, shaping the health re-search agenda, setting norms and standards, articulating evidence-based policy options, providing technical support to countries andmonitoring and assessing health trends.

Drug Regulation: History, Present and Future 67

take informed decisions about all aspects of medi-cines without special training and access to nec-essary information. The production of medicines,their distribution and dispensing also requires spe-cial knowledge and expertise. Among medical disci-plines clinical pharmacology could be considered asa discipline that covers most comprehensively clini-cal aspects of medicines safety and efficacy. Amongmedical specialists clinical pharmacologists have themost comprehensive training to understand all thecomplexities of the clinical use of medicines. Dueto sophisticated scientific issues related to medicinesjust any medical training may not be enough to takefair judgments about their safety and efficacy. Alsoonly basic training in pharmacy may not enable totake proper judgments about medicines quality.

The use of ineffective, poor quality, harmfulmedicines can result in therapeutic failure, exac-erbation of disease, resistance to medicines andsometimes death. It also undermines confidence inhealth systems, health professionals, pharmaceuti-cal manufacturers and distributors. Money spent onineffective, unsafe and poor quality medicines iswasted – whether by patients/consumers or insur-ance schemes/governments. Governments have theresponsibility to protect their citizens in the areaswhere the citizens themselves are not able to doso. Thus, Governments need to establish strong na-tional regulatory authorities (NRAs), to ensure thatthe manufacture, trade and use of medicines areregulated effectively. In broad terms the mission ofNRAs is to protect and promote public health. Medi-cines regulation demands the application of soundscientific (including but not limited to medical, phar-maceutical, biological and chemical) knowledge andspecific technical skills, and operates within a legalframework. The basic elements of effective drug reg-ulation have been laid down in several WHO docu-ments.

III. WHAT IS MEDICINES REGULATION?

Medicines regulation incorporates several mutuallyreinforcing activities all aimed at promoting andprotecting public health. These activities vary fromcountry to country in scope and implementation, butgenerally include the functions listed in Table 1.

What makes medicines regulation effective?Medicines regulation demands the application ofsound medical, scientific and technical knowledge

Table 1. Principal medicines regulatory functions

• Licensing of the manufacture, import, export, distrib-ution, promotion and advertising of medicines

• Assessing the safety, efficacy and quality of medi-cines, and issuing marketing authorization for individ-ual products

• Inspecting and surveillance of manufacturers, im-porters, wholesalers and dispensers of medicines

• Controlling and monitoring the quality of medicineson the market

• Controlling promotion and advertising of medicines• Monitoring safety of marketed medicines including

collecting and analysing adverse reaction reports• Providing independent information on medicines to

professionals and the public

Source: WHO Policy Perspectives on Medicines no 7, 2003.

and skills, and operates within a legal framework.Regulatory functions involve interactions with vari-ous stakeholders (e.g. manufacturers, traders,consumers, health professionals, researchers andgovernments) whose economic, social and politicalmotives may differ, making implementation of reg-ulation both politically and technically challenging.Medicines regulation has administrative part but farmore important is the scientific basis for it. All medi-cines must meet three criteria: be of good quality,safe and effective. The judgments about medicinesquality, safety and efficacy should be based on solidscience. There are several general and specific fac-tors contributing to effective regulation by NRAs.General factors include political will and commit-ment to regulation, adequate availability of medi-cines that are accessible (to avoid smuggling and il-legal use), strong public support for drug regulation,effective cooperation between the NRA and othergovernment institutions including those dealing withlaw enforcement (e.g. customs and police), and suf-ficient qualified and experienced pharmaceutical,medical and other professionals. Political environ-ment favouring independent science based decision-making and control of import/export and distribution(including e-commerce) of medicines is essential.The specific factors for NRA include clear missionstatement, adequate medicines legislation and regu-lation, appropriate organizational structure and facil-ities, clearly defined NRA roles and responsibilities,adequate and sustainable financial resources, includ-ing resources to retain and develop staff and appro-priate tools, such as standards, guidelines and proce-dures. International collaboration with other NRAs


Table 2. Minimum regulatory functions for a national regulatory authority (NRA)

As an absolute minimum NRAs should• Ensure that all medicines manufacturing, importation, exportation, wholesale and distribution establishments are li-

censed. Activities and premises must comply with Good Manufacturing Practices (GMP) and Good Distribution Prac-tice requirements

• Before medicines are marketed, assess their safety, efficacy and quality• Monitor the quality and safety of medicines on the market to prevent harmful, substandard and counterfeit medicines

from reaching the public• Regularly inspect and control the informal market, including e-commerce, to prevent illegal trade of medicines• Monitor advertising and promotion of medicines, and provide independent information on their rational use to the

public and professionals• Participate in sub-regional and regional regulatory networks and international meetings of drug regulatory authorities

to discuss issues of mutual interest and concern, facilitate timely exchange of information and promote collaboration• Monitor and evaluate performance to assess if perceived regulatory objectives have been met, to identify weaknesses

and take corrective action

Source: WHO Policy Perspectives on Medicines no 7, 2003.

(for example, in the EU national regulators are re-quired to collaborate in line with respective Com-munity regulations) and internal collaboration withall stakeholders, transparency (making transparenthow and based on which information decisions aremade) and accountability combined with good man-agement and effective internal quality system con-tribute to the success of a regulatory authority. Min-imum functions that a NRA should be able to carryout are laid down in Table 2.

Excessive promotion of pharmaceuticals has beenassociated in many countries with serious problemsof irrational drug use. Unethical medicines promo-tion activities often convey misleading informationabout drugs to the different target audiences. Misin-formation can be in the form of an expansion of in-dications or an exaggeration of efficacy but can alsopresent itself as downplaying the seriousness or theincidence of adverse reactions. Such misleading in-formation will create a wrong perception of the effi-cacy and safety of medicinals among prescribers andconsumers and it will lead to a significant increaseddemand for drugs. In many countries, relevant pro-visions regarding such control measures have beenstipulated in legislation. For example, only productinformation approved during the registration processcan be included in the package inserts, leaflets orpromotional materials. Regulatory or legal provi-sions with respect to drugs usually appreciate theright of patients or consumers on proper informa-tion about the drugs they take. WHO has developedguidelines on Ethical Criteria for Medicinal DrugPromotion. These guidelines in line with European

regulations and regulations in many other countriesdo not allow direct to patient advertising of prescrip-tion only medicines (in US it is allowed and hasincreased sales of several medicines dramatically).These guidelines remain also useful today and pro-vide ethical criteria for different promotional activi-ties and cover, among others, advertisements to pre-scribers and to the general public, the availability offree samples of prescription drugs for prescribers orof non-prescription drugs to the general public, med-ical symposia and other scientific meetings, activi-ties of medical representatives, packaging and label-ing and the information for patients in the packageinserts.

There are few in depth comparative studies ofregulatory systems in different countries globally.The study by Ratanwijitrasin and Wondemageg-nehu (2002) revealed that in spite of similaritiesthere are still substantial differences existing in howregulatory systems in different countries carry outminimum functions required for effective medicinesregulation. A huge variety in national regulatorycapacity does exist and not all national regulatorscan effectively implement even minimum regulatoryoversight of pharmaceutical market in their jurisdic-tion. Substandard and counterfeit medicines are stillcommon in many parts of the world.

IV. DRUG REGISTRATION

Registration of drugs, also known as product licens-ing or marketing authorization, is an essential ele-ment of drug regulation. All drugs that are marketed,


distributed and used in the country should be regis-tered by the national competent regulatory authority.Only the inspection of manufacturing plants and lab-oratory quality control analysis certainly does notguarantee product quality and safety. Drug regula-tion should therefore include the scientific evalua-tion of products before registration, to ensure thatall marketed pharmaceutical products meet the cri-teria of safety, efficacy and quality. Although thesecriteria are applicable to all medicines including bi-ological products (including vaccines, blood prod-ucts, monoclonal antibodies, cell and tissue thera-pies) and herbal medicines (also other traditionaland complementary medicines) there are substan-tial differences in the regulatory requirements forsome groups of medicines. There should also beclear distinctions between medicines which can bedispensed without prescription (over the counter orOTC medicines) and those for which a prescriptionis needed. Usually new medicines are introduced asprescription only medicines and only after obtain-ing knowledge and experience about their safe usethey may be considered being used as OTC for self-medication. This is valid only in case patients areexpected to be able for adequate self-diagnosis aswell. WHO has issued Guidelines for the Regula-tory Assessment of Medicinal Products for Use inSelf-Medication. In regulatory practice active phar-maceutical ingredients used in medicines are ex-pressed using International Nonproprietary Names(INNs). INNs are assigned upon request to a mole-cular entity responsible for the pharmacological ac-tion by WHO. The INN system as it exists todaywas initiated in 1950 by a World Health Assem-bly resolution WHA3.11 and began operating in1953. Chemical names and entire formulas are of-ten difficult to remember and may be incomprehen-sible for a non specialist (for example, perhaps fewmedical doctors know that 4′-hydroxyacetanilide orN -(4-hydroxyphenyl) acetamide is paracetamol).The cumulative list of INN now stands at some 7500plus names designated since that time, and this num-ber is growing every year by some 120–150 newINN (INNs are proposed also for biological medi-cines such as monoclonal antibodies and gene ther-apy products). INNs are also widely used in scien-tific literature and in teaching basic and clinical phar-macology. The lists of International NonproprietaryNames are published in regular manner. Use of INNsin product labeling and information is nowadays in

most countries compulsory. As important as assess-ment of quality, safety and efficacy is ensuring ap-propriateness, accuracy and availability of approvedby regulators product information. When marketingauthorization is granted for medicines a set of clin-ical information including indications are approved.The use of medicines for indications that have notbeen approved by a regulator is called ‘off-label’use. This means that the safety and efficacy of medi-cines for these indications has not been assessed andapproved by a regulator. One of the most commonoff-label use areas is pediatric medicine.

In the next section we are concentrating on giv-ing general overview of registration requirements fortwo major groups of medicines: innovative (origina-tor) and multisource (generic) medicines.

IV.a. Innovative Medicines

Innovative medicines (originator products) are newmedicines that have not been used in humans ear-lier and contain new active ingredients (usually ex-pressed using INN system). Nowadays these medi-cines are usually first approved by regulators inwell resourced countries using regulatory require-ments harmonized in the framework of InternationalConference on Harmonization of Technical Require-ments for the Registration of Pharmaceuticals forHuman Use (ICH – see also web site: www.ich.org).The terms of reference for ICH include to maintaina forum for constructive dialogue between regula-tory authorities and the pharmaceutical industry onthe real and perceived differences in the technicalrequirements in the EU, USA and Japan in order toensure a more timely introduction of new medicinalproducts, and their availability to patients, to monitorand update harmonized technical requirements lead-ing to a greater mutual acceptance of research anddevelopment data and to contribute to the protectionof public health from international perspective.

The ICH technical Topics are divided into fourmajor categories and specific ICH Topic Codes(such as Q1, E6, S1 and M4) are assigned accord-ing to these categories. Q means ‘Quality’ Topicsi.e., those relating to chemical and pharmaceuticalQuality Assurance (examples: Q1 Stability Test-ing, Q3 Impurity Testing). S means ‘Safety’ Top-ics, i.e., those relating to in vitro and in vivo pre-clinical studies (examples: S1 Carcinogenicity Test-ing, S2 Genotoxicity Testing). E means ‘Efficacy’


Topics, i.e., those relating to clinical studies in hu-man subject (examples: E4 Dose Response Stud-ies, Carcinogenicity Testing, E6 Good Clinical Prac-tices; Clinical Safety Data Management is also clas-sified as an ‘Efficacy’ Topic – E2). M designates‘Multidisciplinary’ Topics, i.e., cross-cutting Top-ics which do not fit uniquely into one of the abovecategories (examples here are M1 Medical Termi-nology – MedDRA, M2 Electronic Standards forTransmission of Regulatory Information – ESTRI,M3 Timing of Pre-clinical Studies in Relation toClinical Trials, M4 The Common Technical Doc-ument – CTD and M5 Data Elements and Stan-dards for Drug Dictionaries). ICH guidelines are notmandatory for anybody per se but the strength ofICH process lies in the commitment for implemen-tation by the ICH ‘regions’ (EU, USA and Japan)using appropriate national/regional tools. For exam-ple, in the EU all ICH guidelines are submitted to theCommittee for Human Medicinal Products (CHMP)associated to European Medicines Agency (EMEA,see web site: http://www.emea.europa.eu/) for en-dorsement once they have reached certain matu-rity phase ICH process. The CHMP, in consultationwith the European Commission decides on the dura-tion for consultation with interested parties (up to 6months). The European Medicines Agency (EMEA)publishes and distributes the Step 2 guidelines forcomments. At Step 4 the guidelines are endorsed bythe CHMP and a time frame for implementation isestablished (usually 6 months). The guidelines aresubsequently published by the European Commis-sion in the Rules Governing Medicinal Products inthe European Union (http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm). Step 2 andStep 4 guidelines are also available from the EMEAsite on the Internet (http://www.emea.europa.eu).

As more than 95% of new medicines are workedout in the ICH “regions” the technical requirementsfor the safety, efficacy and quality of new medi-cines is determined at large by ICH technical guide-lines. The application format for registration (mar-keting authorization) of new medicines in ICH andassociated countries (such as Canada, Switzerlandand Australia) has to follow The Common TechnicalDocument (CTD) which provides harmonized struc-ture and format for new product applications. ThisCommon Technical Document is divided into fourseparate sections and 5 modules (see Fig. 1). Thefour sections address the application organization(M4: Organization), the Quality section (M4Q), the

Safety section (M4S) and the Efficacy section (M4E)of the harmonized application. Module 1 containsICH region specific administrative data and prescrib-ing information and is not part of CTD. Module 2contains CTD summaries, Module 3 is dedicated toquality, Module 4 for non-clinical study reports andModule 5 on clinical study reports. The structureof Common Technical Document (CTD) is given inthe Fig. 1. The content for CTD has to be compiledtaking into consideration technical requirements inmore than 56 ICH guidelines for Quality, Safety andEfficacy plus 5 multidisciplinary (M) topics. Reg-istration of new medicines by less resourced regu-latory agencies is often based on first approval ei-ther by US FDA or EMEA from EU. Indirectly ICHguidelines used by these regulatory agencies havemajor impact on approval of new medicines beyondICH regions. Many ICH guidelines, especially thoseconcerning preclinical and clinical research, are ofinterest to the research community and can servealso as educational tools.

Clinical pharmacologists should be familiar withavailable ICH guidelines concerning medicines ef-ficacy and safety. Those involved in clinical re-search have to know in depth Good Clinical Prac-tice (GCP – ICH E6) guidelines as well the guide-lines concerning the research ethics. WHO has itsown GCP guidelines which do not contradict ICHguideline but which in addition describe the roleof regulatory authorities. In addition, WHO has de-veloped a tool for implementation of GCP whichprovides practical advice on the principles of GCPand has an interactive CD which incorporates manytexts related to GCP and research ethics. In researchethics the fundamental principle that “no one shallbe subjected without his free consent to medicalor scientific experimentation” has found further in-terpretation in a set of principles laid down in theWorld Medical Association (WMA) Declaration ofHelsinki (first edition 1964, current version from2004 under revision). In case of research ethics andmedicines safety the work of the Council for Interna-tional Organizations of Medical Sciences (CIOMS)should be referred to. CIOMS was founded un-der the auspices of the World Health Organization(WHO) and the United Nations Educational, Scien-tific and Cultural and Organization (UNESCO) in1949. In the late 1970s, CIOMS set out, in cooper-ation with WHO, to prepare guidelines “to indicatehow the ethical principles that should guide the con-duct of biomedical research involving human sub-jects, as set forth in the Declaration of Helsinki,


Fig. 1. Diagrammatic representation of the organization of the ICH Common Technical Document (CTD).

could be effectively applied, particularly in develop-ing countries”. In 1991, CIOMS published the Inter-national Guidelines for Ethical Review of Epidemi-ological Studies; and, in 1993, International EthicalGuidelines for Biomedical Research Involving Hu-man Subjects. This guideline was updated and pub-lished in 2002 and is designed to be of use, particu-larly to low-resource countries, in defining the ethicsof biomedical research, applying ethical standardsin local circumstances, and establishing or redefin-ing adequate mechanisms for ethical review of re-search involving human subjects. In addition, WHOhas created several guidance documents how to es-tablish and run Ethics Committees dealing with clin-ical research. Several CIOMS guidelines have alsoinfluenced regulatory approach to medicines safety.

Most important of them are International Report-ing of Adverse Drug Reactions, which has been ba-sis for ICH guideline E2A (pre-approval reporting)and ICH E2B (electronic case submission of indi-vidual case safety reports – ICSRs). CIOMS Inter-national Reporting of Periodic Drug-Safety UpdateSummaries has been basis for ICH E2C (periodicsafety update report – PSUR). The latest CIOMSworking group resulted in publishing The Develop-ment Safety Update Report (DSUR): Harmonizingthe Format and Content for Periodic Safety Report-ing During Clinical Trials. CIOMS has also beeninvolved in discussing issues related to pharmaco-genetics with regulators, industries and academiawhich resulted in publishing Pharmacogenetics: To-wards Improving Treatment with Medicines.


IV.b. Multisource (Generic) Medicines

Multisource (generic) medicines are formulatedwhen patent and other exclusivity rights expire.These medicines have an important role to play inpublic health as they are well known to medical com-munity and usually more affordable due to compe-tition. The key for generic medicines is their ther-apeutic interchangeability with originator products.To ensure the therapeutic interchangeability genericproducts must be pharmaceutically interchangeable(contain the same amount of active ingredient andhave the same dosage form) and bioequivalent to theoriginator product. Bioequivalence is usually estab-lished using comparative in vivo pharmacokineticstudies with originator products. The detailed de-scription how it is carried out is described in respec-tive WHO document and national regulatory guide-lines. Well resourced regulatory authorities requirethat a multisource (generic) medicine must meet cer-tain regulatory criteria. These are presented in Ta-ble 3.

WHO has developed comprehensive set of guide-lines for generic drug registration which are usefulfor drug authorities in developing countries: Market-ing Authorization of Pharmaceutical Products withSpecial Reference to Multisource (Generic) Prod-ucts – A Manual for Drug Regulatory Authorities(first edition 1999, updated version to be publishedin 2008).

In the context of generic medicines it is appro-priate to ask what is a “pharmacopoeia” (word isderived from Greek pharmako-poios “drug-maker”)and how it fits in nowadays regulatory systems?The answer to this question may seem obvious, butthe term “pharmacopoeia” is used in a varied way

Table 3. Regulatory requirements for multisource(generic) medicines

A generic medicines must:(1) contain the same active ingredients as the innovator

drug(2) be identical in strength, dosage form, and route of

administration(3) have the same use indications(4) be bioequivalent (as a marker for therapeutic inter-

changeability)(5) meet the same batch requirements for identity,

strength, purity and quality(6) be manufactured under the same strict standards of

GMP required for innovator products

in different contexts. In the pharmaceutical sense,the pharmacopoeia is an official (legally binding)publication containing recommended quality speci-fications for the analysis and determinations of drugsubstances, specific dosage forms, excipients andfinished drug products. A quality specification iscomposed of a set of appropriate tests which willconfirm the identity and adequate purity of the prod-uct, ascertain the strength (or amount) of the ac-tive substance and, when possible, certain its per-formance characteristics. General requirements arealso given in the pharmacopoeia on important sub-jects related to drug quality, such as microbiologicalpurity, dissolution testing and stability.

The underlying principles of a pharmacopoeiaare that pharmaceutical substances and products in-tended for human use should be manufactured insites that are adequately equipped, dispose of ap-propriate professional and technical knowledge andthat are operated by qualified staff. General rulesof appropriate pharmaceutical manufacture are con-tained in the Good Manufacturing Practices (GMP)requirements recommended by WHO and/or thoselaid down by the competent national (or regional,such as European Commission) regulatory authority.In regulatory terms GMP could belong to ABC ofregulatory requirements for medicines and compli-ance with it is vital for products quality. GMP is ap-plicable for both innovator and generic products. It isapplicable for manufacture of active pharmaceuticalingredients and finished dosage forms. Even manu-facture of investigational drugs should follow GMP.Without GMP consistency of manufacture clinicalperformance of medicines cannot be assured.

There is a practical distinction between phar-macopoeial standards and manufacturers’ releasespecifications, although both comprise sets of teststo which a given product should conform. Releasespecifications are applied at the time of manufactureof a pharmaceutical product to confirm its appropri-ate quality but they also need to have a predictivevalue, to support the notion that the manufacturer isresponsible for the product during its entire shelf-life. In many cases pharmacopoeial monographs arebased on the specifications developed by the manu-facturers of innovator (originator) products.

In order to launch innovator products pharma-copoeial specifications are not necessary as the man-ufacturers quality specifications have to pass rigorscientific assessment by the competent regulatoryauthorities in conjunction with pre-clinical and clin-ical safety and efficacy data. It is important to notice


that the focus in regulatory environment has beenshifting from finished dosage form quality controlto the control of the whole complex of processes andprocedures involved in the manufacture of both ac-tive pharmaceutical ingredients (APIs) and finisheddosage forms. The objective of a nowadays regula-tory approval is to ensure that the manufacturer hasbuilt quality into the product from A to Z.

In case of multisource (generic) medicines (whichare formulated after the patents and other exclu-sivity rights expire) pharmacopoeial monographsare more important as they enable manufacturersnot to elaborate their own specifications but ratherdevelop the products to meet the requirements ofpharmacopoeial standards (both for APIs and fin-ished dosage forms). It should be noted that not allpharmacopoeias present monographs (quality stan-dards) for finished dosage forms. Pharmacopoeialstandards have also certain limitations. For example,testing using pharmacopoeial methods is not neces-sarily identifying all possible dangerous impurities.

Pharmacopoeial methods are usually designed tocatch the impurities that are likely to occur dur-ing the route of synthesis that has been utilized bythe originator. In case of different route of synthe-sis or accidental contamination with other chem-icals it may not necessarily pick up the impuri-ties even if they pose danger to the health. This iswhy nowadays well resourced regulatory authoritiesnever base their marketing authorizations of mul-tisource (generic) products only on quality controltesting based on pharmacopoeial monographs. Infact, the pre-marketing quality control testing has di-minished constantly and more accent is put on mar-ket surveillance after the product is put on the mar-ket.

Pharmacopoeial monographs help to verify thequality and in case of multisource (generic) medi-cines they may indicate also on pharmaceutical in-terchangeability with the originator product. How-ever, pharmacopoeial monographs even for finisheddosage forms may have limitations in proving thera-peutic interchangeability which is very important forclinical use of medicines (Box 1).

WHO hosts The International Pharmacopoeia.This pharmacopoeia is based on specifications val-idated internationally, through an independent inter-national scientific process.

Unlike national (such as British Pharmacopoeia,Indian Pharmacopoeia or US Pharmacopoeia) andregional (such as European Pharmacopoeia) phar-macopoeias, The International Pharmacopoeia has,a priori, no determined legal status, but WHO Mem-ber States are free to adopt it and to incorporate itinto national legislation, either in part or in whole.The first edition was published in two volumes (1951and 1955). The latest fourth edition of The Interna-tional Pharmacopoeia was published in 2006 and anupdate is to be published in 2008.

Most importantly, a new series of monographshas been added for antiretrovirals. These mono-graphs have been developed as part of the WHOstrategy to make quality antiretroviral medicinesmore widely available to HIV-positive patients. Suchspecifications support the joint United Nations –WHO Prequalification project, managed by WHO(web site: http://mednet3.who.int/prequal/). Interna-tional Chemical Reference Substances (ICRS) areprimary chemical reference standards used in con-junction with International Pharmacopoeia mono-graphs. They are supplied primarily for use in phys-ical and chemical tests and assays described in thespecifications for quality control of drugs publishedin The International Pharmacopoeia or proposed indraft monographs.

WHO gives advice on the establishment and man-agement of national quality control laboratories,prepares guidelines on their functioning, publishesguidance and gives advice on Good ManufacturingPractices (GMP) and other regulatory issues, fol-lowing the underlying principle that quality must bebuilt into a product from the very beginning of themanufacturing process. The whole area of work isoverseen by the WHO Expert Committee on Specifi-cations for Pharmaceutical Preparations. The WHOExpert Committee on Specifications for Pharmaceu-tical Preparations is the highest level advisory body

Box 1. Pharmacopoeial standards

Pharmacopoeial standards should be used in the framework of all regulatory measures such as Good ManufacturingPractice (GMP) inspection of active pharmaceutical ingredient and finished dosage form manufacturing, scientific as-sessment of all quality specifications, interchangeability data and labeling information provided by the manufacturer.The most of their value is in post-marketing surveillance of the quality of multisource (generic) medicine.


to WHO’s Director-General and its Member Statesin the area of quality assurance. The advice and rec-ommendations provided by this Expert Committeeare intended to help national and regional authorities(in particular drug regulatory authorities), procure-ment agencies, as well as major international bodiesand institutions to combat problems of substandardand counterfeit medicines.

The importance and role of WHO in the field ofquality assurance of medicines, especially for thosecountries that have no or little means to develop theirown quality control specifications, persists. WHOhas numerous activities to support member statessuch as creating necessary nomenclatures, guide-lines and guidance (WHO GMP being a good exam-ple) but also delivering training courses and work-shops on various topics of regulatory sciences ded-icated to assessment of safety, efficacy and qualityof medicines in order to build national capacity toregulate medicines.

V. ROLE OF WHO IN DRUG REGULATION

WHO is the directing and coordinating authority forhealth within the United Nations system (see moreon web site: http://www.who.int/en/). It is responsi-ble for providing leadership on global health matters,shaping the health research agenda, setting normsand standards, articulating evidence-based policyoptions, providing technical support to countries andmonitoring and assessing health trends. In the 21stcentury, health is a shared responsibility, involvingequitable access to essential care and collective de-fence against transnational health threats.

WHO’s role in drug regulation is fourfold. First,issuing necessary norms and standards (see exam-ples above) through its Expert Committees (such asWHO Expert Committee on Specifications for Phar-maceutical Preparations and WHO Expert Com-mittee on Biological Standardization) and ExpertCommittee like bodies (such as International Non-proprietary Names Expert Group and InternationalWorking Group for Drug Statistics Methodology –issuing Anatomical, Therapeutic and Chemical orATC codes and Daily Defined Doses or DDDs fordrug utilization research). Second, supporting reg-ulatory capacity building leading to implementa-tion of drug regulation on national level and itsharmonization on regional and Global level. This

activity involves assessment of regulatory activi-ties on country level and various technical train-ing courses (such as GMP and GCP, how to assessgeneric medicines, bioequivalence, safety monitor-ing and pharmacovigilance, quality assurance andquality control) and customized technical assistance(in cooperation with numerous WHO collaboratingcenters and other partners) to the countries. Third,in selected areas of essential products, ensuring thequality, safety and efficacy of limited high publichealth value essential medicines (such as antiretro-voirals to treat HIV/AIDS, or medicines to treatmalaria) and vaccines (used in national vaccina-tion programs) through “prequalification”. De factoprequalification, although primarily meant for UNprocurement and international donors, is a regula-tory activity mimicking medicines registration (mar-keting authorization) in its all elements to ensurethat products prequalified meet all international stan-dards for quality, safety and efficacy. Prequalifica-tion program has also a very strong capacity build-ing element built into it. Fourth, WHO plays a veryimportant role in facilitating exchange of regulatoryinformation for which it has developed a number oftools. Since 1980 WHO convenes every second yearInternational Conference of Drug Regulatory Au-thorities (ICDRA) and publishes their proceedings.These conferences provide drug regulatory authori-ties of WHO Member States with a forum to meetand discuss ways to strengthen collaboration. TheICDRAs have been instrumental in guiding throughits recommendations regulatory authorities, WHOand interested stakeholders and in determining pri-orities for action in national and international reg-ulation of medicines, vaccines, biomedicines andherbals.

WHO manages also a system for regular ex-change of information between Member States onthe safety and efficacy of pharmaceutical products,using a network of designated national drug infor-mation officers. WHO ensures the prompt transmis-sion to national health authorities of new informationon serious adverse effects of pharmaceutical prod-ucts and it also responds to individual requestsfor information. These goals are achieved by theregular publication of regulatory information inthe WHO Pharmaceuticals Newsletter (http://www.who.int/medicines/publications/newsletter/en/index.html) and by the dissemination of one-page DrugAlerts on an ad hoc basis. Relevant restrictive regula-tory decisions are ultimately compiled in the United


Nations Consolidated List of Products Whose Con-sumption and/or Sale Have Been Banned, With-drawn, Severely Restricted or not Approved by Gov-ernments. WHO publishes updates to this list: Phar-maceuticals: Restrictions in use and availability.WHO publishes also quarterly WHO Drug Infor-mation (http://www.who.int/druginformation/) jour-nal which provides an overview of topics of cur-rent relevance relating to drug development, safetyand regulation. Latest lists of proposed and recom-mended International Nonproprietary Names (INN)for Pharmaceutical Substances are also published inthis journal.

WHO cooperates very actively with national reg-ulatory authorities of all of its Member States. It triesto facilitate spreading best practices and experience.Through its observer role in the international Confer-ence of Harmonization (ICH) WHO is liaising be-tween ICH and non-ICH countries trying to ensurethat information exchange between highly industri-alized and less resourced countries is taking place.

VI. FUTURE OF MEDICINES REGULATION

Medicines regulation has been developing togetherwith the sciences involved in developing new drugs.Also developments in health delivery systems haveplaid role as those involved in health service deliveryare interested in safe and effective treatments whichwould be cost effective and affordable. Both costsof research and development and regulatory assess-ment of products is increasing. There is likely no al-ternative for more harmonization (international, re-gional and sub-regional) of regulatory requirementsand work sharing (together with information shar-ing) between different national regulatory authori-ties. The cost of full regulatory assessment of a newdrug is increasingly becoming not affordable (bothin terms of financial and human resources) for lessresourced smaller regulatory agencies. What are thenew areas of development beyond better harmoniza-tion, information exchange and gradual building oftrust in each others decisions leading to recognitioninstead of duplication?

Although even quality issues are still a prob-lem (poor quality of starting materials includingactive pharmaceutical ingredients, quality problemswith finished dosage forms, spreading of counter-feit medicines) it is likely that new technologies

and new products will create new regulatory chal-lenges. For example, how will increasing public at-tention and expectations on medicines safety shapethe regulations? How using new technologies suchas nanotechnologies change the medicines regula-tion? Issues relating to the understanding of howthe nanoparticles are presented to organs, cells andorganelles are of the highest importance when try-ing to understand the different mechanisms for in-tracellular trafficking and use their full therapeu-tic potential. Those aspects cannot be establishedwithout improving appropriate basic knowledge ofcell and molecular biology at the intracellular level.However, at the same time important quality prob-lems can rise. In order to assure quality physical andchemical properties of nanopharmaceuticals, includ-ing residual solvents, processing variables, impuri-ties and excipients, should all be well known. Therewill be a need for well-established standard tools tobe used in the characterization of nanopharmaceu-ticals, including availability of validated assays todetect and quantify nanoparticles in tissues, medici-nal products and processing equipment. Toxicologi-cal aspects of nanomedicines have been highlightedwith focus on long-term toxicity. Carbon nanotubes,quantum dots and other nonbiodegradable and po-tentially harmful materials should be given closerattention weather associated with medicines or di-agnostics. A special set of standards must be grad-ually established in the global regulatory environ-ment. In fact, some elements already do exist. In Eu-rope Directive 2004/27/EEC on medicines addressesdirectly the need for the study of environmental im-pact of medicines which will have major impact fornew nanomaterails to be used in medicines. To ex-amine and predict environment impact is a new taskfor regulators.

Using genetic information to create safe and ef-fective medicines offers potential for more individ-ualized therapies and patient benefits but will alsohave an impact on the use of healthcare resources.Pharmacogenetics has been viewed as somethingfor the future, but real clinical examples now exist.Some pharmacogenetic tests, such as the thiopurinemethyltransferase (TPMT) test that aims to predictthe risk of severe neutropenia for the purine drugsazathioprine and 6-mercaptopurine, have alreadyrelatively low unit costs (approximately 50$ US).However, even low unit cost tests may have a signifi-cant cost impact if they have a high volume of uptakein a healthcare system. There may be added value as-sociated with introducing a pharmacogenetic test to


guide a prescribing decision, in terms of improvedhealth-related quality of life resulting from fewer se-vere side effects and improved treatment responsein the patient population taking the medicine. Phar-macogenetic tests broadly fall into one of two cate-gories, those provided through clinical laboratories,such as the TPMT test, and those for which a prod-uct license has been granted in a similar way to newmedicines, such as Third Wave Technologies’ (WI,USA) Invader® UGT1A1 Molecular Assay, whichwas approved by the US FDA in 2005. The last op-tion means that regulators are directly involved. Reg-ulators are starting to regulate pharmacogenetics andsome guidance already exists in Canada, EU and US.Recently also ICH started to deal with pharmacoge-nomics and pharmacogenetics. The E15 guidelineDefinitions for Genomic Biomarkers, Pharmacoge-nomics, Pharmacogenetics, Genomic Data and Sam-ple Coding Categories has been finalized.

Another area of challenges includes biologicalmedicines including ‘generic’ biological medicines.New product groups are emerging and even withknown product groups there are challenges ahead,especially from the point of view of safety. Otherimportant areas for drug regulators remain pharmo-covigilance, pediatric medicines, orphan medicinesand medicines for diseases outside ICH regions.There are few financial incentives to create medi-cines for tropical and neglected diseases but recentlydue to public private partnerships for drug develop-ment and creation of specific regulatory pathwayssuch EU Article 58 procedure that enables EuropeanMedicines Agency to assess these products and pro-vide scientific advise for WHO has improved the sit-uation. There are even calls for ‘complete rethink’of the regulatory systems in order to prepare for thenext 20–30 year.

The present short overview of medicines regula-tion is clearly not comprehensive but rather an at-tempt to give idea about the complexities of this im-portant area of work that has many direct links withclinical pharmacology. Clinical pharmacologists asmedical specialists equipped with unique knowledgeabout medicines have a role and responsibility to de-velop and contribute to medicines regulation.

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