Drug Regulation: History, Present and Future1 Lembit Rägo, Budiono Santoso

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Chapter 6 Drug Regulation: History, Present and Future1 Lembit Rägo, Budiono Santoso

I.Historyofmedicinesregulation...... 65 II.Whyregulatingdrugs?...... 66 III. What is medicines regulation? ...... 67 IV.Drugregistration...... 68 V.RoleofWHOindrugregulation...... 74 VI.Futureofmedicinesregulation...... 75 Bibliography...... 76

I. HISTORY OF MEDICINES REGULATION was issued in 1581. The standards for the manufacture of Mithridatum were established in England in Medicines are perhaps as old as mankind and the The London Pharmacopoeia only in 1618. concepts how their quality has to be ensured has The modern medicines regulation started only af- evolved gradually over the time. For example, Mith- ter breakthrough progress in the 19th century life sci- ridates VI (120 BC), King of Pontus, concocted a ences, especially in chemistry, physiology and phar- compound preparation called “Mithridatium” which macology, which laid a solid foundation for the mod- included 41 individual components and was held as a ern drug research and development and started to panacea for almost all diseases until as late as 1780s. flourish after the second World War. It took until 1540 when in England the manufac- Unfortunate events have catalysed the develop- ture of Mithridatium and other medicines was sub- ment of medicines regulation more than the evolu- jected to supervision under the Apothecaries Wares, tion of a knowledge base. In 1937 over 100 people Drugs and Stuffs Act. The Act was one of the earli- in the United States died of diethylene glycol poisoning following the use of a sulfanilamide elixir, est British statutes on the control of medicines and which used the chemical as a solvent without any it established the appointment of four inspectors of safety testing. This facilitated introduction of The “Apothecary Wares, Drugs and Stuffs”. This could Federal Food, Drug and Cosmetic Act with the pre- be seen as the start of pharmaceutical inspections. market notification requirement for new drugs in History of Pharmacopoeias, the official books of 1938. However, in countries with poor regulatory drug quality standards, probably dates back to one environment even recently medicines contaminated of the proclamations of the Salerno Medical Edict with diethylene glycol have killed patients. issued by Fredrick II of Sicily (1240), and ordered The second catastrophe that influenced the de- apothecaries to prepare remedies always in the same velopment of medicines regulation far more than way – forma curiae. The first Pharmacopoeias as we any event in history was the thalidomide disaster. know them today stared to appear in Europe from Thalidomide was a sedative and hypnotic that first 16th century e.g. the first Spanish Pharmacopoeia went on sale in Western Germany in 1956. Be- tween 1958 and 1960 it was introduced in 46 dif- 1 The views stated in this chapter reflect the views of the authors ferent countries worldwide resulting in an estimated and not necessarily those of the World Health Organization. 10,000 babies being born with phocomelia and other

Drug Benefits and Risks: International Textbook of Clinical Pharmacology, revised 2nd edition Edited 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 the Somewhat parallel with the ongoing harmoniza- medicines regulatory systems is not hard to underes- tion and movement towards creating a common mar- timate. ket for medicines inside the EU, the need for wider As a result the whole regulatory system was re- harmonization was after preliminary contacts be- shaped in the UK where a Committee on the Safety tween officials from Japan, EU and US discussed of Drugs (CSD) was started in 1963 followed by during the International Conference of Drug Reg- a voluntary adverse drug reaction reporting system ulatory Authorities (ICDRA – organized by WHO (Yellow Card Scheme) in 1964. In the United States, every second year) in Paris in 1989. The prelimi- The Drug Amendments Act of 1962 was passed by nary informal discussions had revealed a need for the Congress requiring the FDA to approve all new drug harmonization of requirements relating to the new applications (NDA) and, for the first time, demanded innovative drugs and the green light given in Paris that a new drug should be proven to be effective led to the establishment in 1990 of the International and safe. Of equal importance, the FDA was also Conference on Harmonization of Technical Require- given the authority to require compliance with cur- ments for the Registration of Pharmaceuticals for rent Good Manufacturing Practices (GMP), to of- Human Use (ICH), a collaborative initiative between ficially register drug establishments and implement the EU, Japan and the United States with observers other requirements. The EEC Directive 65/65/EEC from WHO, EFTA and Canada. ICH harmoniza- on the approximation of provisions laid down by tion focuses primarily on technical requirements for law, regulation and administrative action relating to new, innovative medicines. However, countries with medicinal products was also induced by the thalido- limited resources are mostly generic markets and mide disaster. may have difficulties of implementing numerous so- It took almost ten years for the European Com- munity (EC), since Council Directive 65/65/EEC phisticated ICH standards. Pharmaceutical regula- was introduced, to further develop harmonization tory harmonization facilitates the availability of safe, in the Community. In 1975 two Council Direc- effective and good quality pharmaceuticals. World 2 tives were introduced, the first on approximation Health Organization (WHO) supports harmoniza- of the laws of Member States relating to analyt- tion on national, regional, inter-regional and inter- ical, pharmacotoxicological and clinical standards national levels. International consensus on quality, and protocols in respect of the testing of proprietary safety and efficacy standards can accelerate the in- medicinal products (75/318/EEC), and the second troduction of new medicines and increase availabil- on the approximation of provisions laid down by ity of generic medicines through fair competition, law, regulation and administrative action relating to thereby lowering prices. medicinal products (75/319/EEC). The latter established an ‘old’ Committee on Proprietary Medicinal Products (CPMP) as an advisory committee to the II. WHY REGULATING DRUGS? EC and introduced the multistate procedure known now as the mutual recognition procedure. Directive Drugs are not ordinary consumers’ products. In most 87/22/EEC introduced the concentration procedure instances, consumers are not in a position to make which is now known as the centralized procedure. decisions about when to use drugs, which drugs to These directives, and following council regulation, use, how to use them and to weigh potential bene- were the landmarks for starting harmonization in- fits against risks as no medicine is completely safe. side the European Union with the final longstand- Professional advise from either prescribers or dis- ing aim of creating a ‘common market’ for medi- pensers are needed in making these decisions. How- cines. The Council Regulation EEC/2309/93 estab- ever, even healthcare professionals (medical doc- lished the European Medicines Evaluation Agency tors, pharmacists) nowadays are not in capacity to (EMEA) in 1993 and re-established the CPMP as a ‘new’ CPMP to formulate the opinion of the Agency on questions relating to the submission of applica- 2 WHO is the directing and coordinating technical agency for tions and granting marketing authorizations in ac- health within the United Nations system. It is responsible for providing leadership on global health matters, shaping the health re- cordance with the centralized procedure. The details search agenda, setting norms and standards, articulating evidence- of European marketing authorization procedure are based policy options, providing technical support to countries and described in detail in other publications. monitoring and assessing health trends. Drug Regulation: History, Present and Future 67 take informed decisions about all aspects of medi- Table 1. Principal medicines regulatory functions cines without special training and access to nec- • Licensing of the manufacture, import, export, distrib- essary information. The production of medicines, ution, promotion and advertising of medicines their distribution and dispensing also requires spe- • Assessing the safety, efficacy and quality of medi- cial knowledge and expertise. Among medical disci- cines, and issuing marketing authorization for individ- plines clinical pharmacology could be considered as ual products a discipline that covers most comprehensively clini- • Inspecting and surveillance of manufacturers, im- cal aspects of medicines safety and efficacy. Among porters, wholesalers and dispensers of medicines medical specialists clinical pharmacologists have the • Controlling and monitoring the quality of medicines most comprehensive training to understand all the on the market • complexities of the clinical use of medicines. Due Controlling promotion and advertising of medicines • to sophisticated scientific issues related to medicines Monitoring safety of marketed medicines including collecting and analysing adverse reaction reports just any medical training may not be enough to take • Providing independent information on medicines to fair judgments about their safety and efficacy. Also professionals and the public only basic training in pharmacy may not enable to take proper judgments about medicines quality. Source: WHO Policy Perspectives on Medicines no 7, 2003. The use of ineffective, poor quality, harmful medicines can result in therapeutic failure, exac- erbation of disease, resistance to medicines and and skills, and operates within a legal framework. sometimes death. It also undermines confidence in Regulatory functions involve interactions with vari- health systems, health professionals, pharmaceuti- ous stakeholders (e.g. manufacturers, traders, cal manufacturers and distributors. Money spent on consumers, health professionals, researchers and ineffective, unsafe and poor quality medicines is governments) whose economic, social and political wasted – whether by patients/consumers or insur- motives may differ, making implementation of reg- ance schemes/governments. Governments have the ulation both politically and technically challenging. responsibility to protect their citizens in the areas Medicines regulation has administrative part but far where the citizens themselves are not able to do more important is the scientific basis for it. All medi- so. Thus, Governments need to establish strong na- cines must meet three criteria: be of good quality, safe and effective. tional regulatory authorities (NRAs), to ensure that The judgments about medicines quality, safety and efficacy should be based on solid the manufacture, trade and use of medicines are science. There are several general and specific fac- regulated effectively. In broad terms the mission of tors contributing to effective regulation by NRAs. NRAs is to protect and promote public health. Medi- General factors include political will and commit- cines regulation demands the application of sound ment to regulation, adequate availability of medi- scientific (including but not limited to medical, phar- cines that are accessible (to avoid smuggling and il- maceutical, biological and chemical) knowledge and legal use), strong public support for drug regulation, specific technical skills, and operates within a legal effective cooperation between the NRA and other framework. The basic elements of effective drug reg- government institutions including those dealing with ulation have been laid down in several WHO docu- law enforcement (e.g. customs and police), and suf- ments. ficient qualified and experienced pharmaceutical, medical and other professionals. Political environment favouring independent science based decision- III. WHAT IS MEDICINES REGULATION? making and control of import/export and distribution (including e-commerce) of medicines is essential. Medicines regulation incorporates several mutually The specific factors for NRA include clear mission reinforcing activities all aimed at promoting and statement, adequate medicines legislation and regu- protecting public health. These activities vary from lation, appropriate organizational structure and facil- country to country in scope and implementation, but ities, clearly defined NRA roles and responsibilities, generally include the functions listed in Table 1. adequate and sustainable financial resources, includ- What makes medicines regulation effective? ing resources to retain and develop staff and appro- Medicines regulation demands the application of priate tools, such as standards, guidelines and proce- sound medical, scientific and technical knowledge dures. International collaboration with other NRAs 68 Drug Benefits and Risks

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 licensed. 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- regulations and regulations in many other countries quired to collaborate in line with respective Com- do not allow direct to patient advertising of prescrip- munity regulations) and internal collaboration with tion only medicines (in US it is allowed and has all stakeholders, transparency (making transparent increased sales of several medicines dramatically). how and based on which information decisions are These guidelines remain also useful today and pro- made) and accountability combined with good man- vide ethical criteria for different promotional activi- agement and effective internal quality system con- ties and cover, among others, advertisements to pre- tribute to the success of a regulatory authority. Min- scribers and to the general public, the availability of imum functions that a NRA should be able to carry free samples of prescription drugs for prescribers or out are laid down in Table 2. of non-prescription drugs to the general public, med- Excessive promotion of pharmaceuticals has been ical symposia and other scientific meetings, activi- associated in many countries with serious problems ties of medical representatives, packaging and label- of irrational drug use. Unethical medicines promo- ing and the information for patients in the package tion activities often convey misleading information inserts. about drugs to the different target audiences. Misin- There are few in depth comparative studies of formation can be in the form of an expansion of in- regulatory systems in different countries globally. dications or an exaggeration of efficacy but can also The study by Ratanwijitrasin and Wondemageg- present itself as downplaying the seriousness or the nehu (2002) revealed that in spite of similarities incidence of adverse reactions. Such misleading in- there are still substantial differences existing in how formation will create a wrong perception of the effi- regulatory systems in different countries carry out minimum functions required for effective medicines cacy and safety of medicinals among prescribers and regulation. A huge variety in national regulatory consumers and it will lead to a significant increased capacity does exist and not all national regulators demand for drugs. In many countries, relevant pro- can effectively implement even minimum regulatory visions regarding such control measures have been oversight of pharmaceutical market in their jurisdic- stipulated in legislation. For example, only product tion. Substandard and counterfeit medicines are still information approved during the registration process common in many parts of the world. can be included in the package inserts, leaflets or promotional materials. Regulatory or legal provisions with respect to drugs usually appreciate the IV. DRUG REGISTRATION right of patients or consumers on proper information about the drugs they take. WHO has developed Registration of drugs, also known as product licens- guidelines on Ethical Criteria for Medicinal Drug ing or marketing authorization, is an essential ele- Promotion. These guidelines in line with European ment of drug regulation. All drugs that are marketed, Drug Regulation: History, Present and Future 69 distributed and used in the country should be regis- most countries compulsory. As important as assess- tered by the national competent regulatory authority. ment of quality, safety and efficacy is ensuring ap- Only the inspection of manufacturing plants and lab- propriateness, accuracy and availability of approved oratory quality control analysis certainly does not by regulators product information. When marketing guarantee product quality and safety. Drug regula- authorization is granted for medicines a set of clin- tion should therefore include the scientific evalua- ical information including indications are approved. tion of products before registration, to ensure that The use of medicines for indications that have not all marketed pharmaceutical products meet the cri- been approved by a regulator is called ‘off-label’ teria of safety, efficacy and quality. Although these use. This means that the safety and efficacy of medi- criteria are applicable to all medicines including bi- cines for these indications has not been assessed and ological products (including vaccines, blood prod- approved by a regulator. One of the most common ucts, monoclonal antibodies, cell and tissue thera- off-label use areas is pediatric medicine. pies) and herbal medicines (also other traditional In the next section we are concentrating on giv- and complementary medicines) there are substan- ing general overview of registration requirements for tial differences in the regulatory requirements for two major groups of medicines: innovative (origina- some groups of medicines. There should also be tor) and multisource (generic) medicines. clear distinctions between medicines which can be dispensed without prescription (over the counter or IV.a. Innovative Medicines OTC medicines) and those for which a prescription is needed. Usually new medicines are introduced as Innovative medicines (originator products) are new prescription only medicines and only after obtain- medicines that have not been used in humans ear- ing knowledge and experience about their safe use lier and contain new active ingredients (usually ex- they may be considered being used as OTC for self- pressed using INN system). Nowadays these medi- medication. This is valid only in case patients are cines are usually first approved by regulators in expected to be able for adequate self-diagnosis as well resourced countries using regulatory require- well. WHO has issued Guidelines for the Regula- ments harmonized in the framework of International tory Assessment of Medicinal Products for Use in Conference on Harmonization of Technical Require- Self-Medication. In regulatory practice active phar- ments for the Registration of Pharmaceuticals for maceutical ingredients used in medicines are ex- Human Use (ICH – see also web site: www.ich.org). pressed using International Nonproprietary Names The terms of reference for ICH include to maintain (INNs). INNs are assigned upon request to a mole- a forum for constructive dialogue between regula- cular entity responsible for the pharmacological ac- tory authorities and the pharmaceutical industry on tion by WHO. The INN system as it exists today the real and perceived differences in the technical was initiated in 1950 by a World Health Assem- requirements in the EU, USA and Japan in order to bly resolution WHA3.11 and began operating in ensure a more timely introduction of new medicinal 1953. Chemical names and entire formulas are of- products, and their availability to patients, to monitor ten difficult to remember and may be incomprehen- and update harmonized technical requirements lead- sible for a non specialist (for example, perhaps few ing to a greater mutual acceptance of research and medical doctors know that 4-hydroxyacetanilide or development data and to contribute to the protection N-(4-hydroxyphenyl) acetamide is paracetamol). of public health from international perspective. The cumulative list of INN now stands at some 7500 The ICH technical Topics are divided into four plus names designated since that time, and this num- major categories and specific ICH Topic Codes ber is growing every year by some 120–150 new (such as Q1, E6, S1 and M4) are assigned accord- INN (INNs are proposed also for biological medi- ing to these categories. Q means ‘Quality’ Topics cines such as monoclonal antibodies and gene ther- i.e., those relating to chemical and pharmaceutical apy products). INNs are also widely used in scien- Quality Assurance (examples: Q1 Stability Test- tific literature and in teaching basic and clinical phar- ing, Q3 Impurity Testing). S means ‘Safety’ Top- macology. The lists of International Nonproprietary ics, i.e., those relating to in vitro and in vivo pre- Names are published in regular manner. Use of INNs clinical studies (examples: S1 Carcinogenicity Test- in product labeling and information is nowadays in ing, S2 Genotoxicity Testing). E means ‘Efficacy’ 70 Drug Benefits and Risks

Topics, i.e., those relating to clinical studies in hu- Safety section (M4S) and the Efficacy section (M4E) man subject (examples: E4 Dose Response Stud- of the harmonized application. Module 1 contains ies, Carcinogenicity Testing, E6 Good Clinical Prac- ICH region specific administrative data and prescrib- tices; Clinical Safety Data Management is also clas- ing information and is not part of CTD. Module 2 sified as an ‘Efficacy’ Topic – E2). M designates contains CTD summaries, Module 3 is dedicated to ‘Multidisciplinary’ Topics, i.e., cross-cutting Top- quality, Module 4 for non-clinical study reports and ics which do not fit uniquely into one of the above Module 5 on clinical study reports. The structure categories (examples here are M1 Medical Termi- of Common Technical Document (CTD) is given in nology – MedDRA, M2 Electronic Standards for the Fig. 1. The content for CTD has to be compiled Transmission of Regulatory Information – ESTRI, taking into consideration technical requirements in M3 Timing of Pre-clinical Studies in Relation to more than 56 ICH guidelines for Quality, Safety and Clinical Trials, M4 The Common Technical Doc- Efficacy plus 5 multidisciplinary (M) topics. Reg- ument – CTD and M5 Data Elements and Stan- istration of new medicines by less resourced regu- dards for Drug Dictionaries). ICH guidelines are not latory agencies is often based on first approval ei- mandatory for anybody per se but the strength of ther by US FDA or EMEA from EU. Indirectly ICH ICH process lies in the commitment for implemen- guidelines used by these regulatory agencies have tation by the ICH ‘regions’ (EU, USA and Japan) major impact on approval of new medicines beyond using appropriate national/regional tools. For exam- ICH regions. Many ICH guidelines, especially those ple, in the EU all ICH guidelines are submitted to the concerning preclinical and clinical research, are of Committee for Human Medicinal Products (CHMP) interest to the research community and can serve associated to European Medicines Agency (EMEA, also as educational tools. see web site: http://www.emea.europa.eu/) for en- Clinical pharmacologists should be familiar with available ICH guidelines concerning medicines ef- dorsement once they have reached certain matu- ficacy and safety. Those involved in clinical re- rity phase ICH process. The CHMP, in consultation search have to know in depth Good Clinical Prac- with the European Commission decides on the dura- tice (GCP – ICH E6) guidelines as well the guide- tion for consultation with interested parties (up to 6 lines concerning the research ethics. WHO has its months). The European Medicines Agency (EMEA) own GCP guidelines which do not contradict ICH publishes and distributes the Step 2 guidelines for guideline but which in addition describe the role comments. At Step 4 the guidelines are endorsed by of regulatory authorities. In addition, WHO has de- the CHMP and a time frame for implementation is veloped a tool for implementation of GCP which established (usually 6 months). The guidelines are provides practical advice on the principles of GCP subsequently published by the European Commis- and has an interactive CD which incorporates many sion in the Rules Governing Medicinal Products in texts related to GCP and research ethics. In research the European Union (http://ec.europa.eu/enterprise/ ethics the fundamental principle that “no one shall pharmaceuticals/eudralex/index.htm). Step 2 and be subjected without his free consent to medical Step 4 guidelines are also available from the EMEA or scientific experimentation” has found further in- site on the Internet (http://www.emea.europa.eu). terpretation in a set of principles laid down in the As more than 95% of new medicines are worked World Medical Association (WMA) Declaration of out in the ICH “regions” the technical requirements Helsinki (first edition 1964, current version from for the safety, efficacy and quality of new medi- 2004 under revision). In case of research ethics and cines is determined at large by ICH technical guide- medicines safety the work of the Council for Interna- lines. The application format for registration (mar- tional Organizations of Medical Sciences (CIOMS) keting authorization) of new medicines in ICH and should be referred to. CIOMS was founded un- associated countries (such as Canada, Switzerland der the auspices of the World Health Organization and Australia) has to follow The Common Technical (WHO) and the United Nations Educational, Scien- Document (CTD) which provides harmonized struc- tific and Cultural and Organization (UNESCO) in ture and format for new product applications. This 1949. In the late 1970s, CIOMS set out, in cooper- Common Technical Document is divided into four ation with WHO, to prepare guidelines “to indicate separate sections and 5 modules (see Fig. 1). The how the ethical principles that should guide the con- four sections address the application organization duct of biomedical research involving human sub- (M4: Organization), the Quality section (M4Q), the jects, as set forth in the Declaration of Helsinki, Drug Regulation: History, Present and Future 71

Fig. 1. Diagrammatic representation of the organization of the ICH Common Technical Document (CTD). could be effectively applied, particularly in develop- Most important of them are International Report- ing countries”. In 1991, CIOMS published the Inter- ing of Adverse Drug Reactions, which has been ba- national Guidelines for Ethical Review of Epidemi- sis for ICH guideline E2A (pre-approval reporting) ological Studies; and, in 1993, International Ethical and ICH E2B (electronic case submission of indi- Guidelines for Biomedical Research Involving Hu- vidual case safety reports – ICSRs). CIOMS Inter- man Subjects. This guideline was updated and pub- national Reporting of Periodic Drug-Safety Update lished in 2002 and is designed to be of use, particu- Summaries has been basis for ICH E2C (periodic larly to low-resource countries, in defining the ethics safety update report – PSUR). The latest CIOMS of biomedical research, applying ethical standards working group resulted in publishing The Develop- in local circumstances, and establishing or redefin- ment Safety Update Report (DSUR): Harmonizing ing adequate mechanisms for ethical review of re- the Format and Content for Periodic Safety Report- search involving human subjects. In addition, WHO ing During Clinical Trials. CIOMS has also been has created several guidance documents how to es- involved in discussing issues related to pharmaco- tablish and run Ethics Committees dealing with clin- genetics with regulators, industries and academia ical research. Several CIOMS guidelines have also which resulted in publishing Pharmacogenetics: To- influenced regulatory approach to medicines safety. wards Improving Treatment with Medicines. 72 Drug Benefits and Risks

IV.b. Multisource (Generic) Medicines in different contexts. In the pharmaceutical sense, the pharmacopoeia is an official (legally binding) Multisource (generic) medicines are formulated publication containing recommended quality speci- when patent and other exclusivity rights expire. fications for the analysis and determinations of drug These medicines have an important role to play in substances, specific dosage forms, excipients and public health as they are well known to medical com- finished drug products. A quality specification is munity and usually more affordable due to compe- composed of a set of appropriate tests which will tition. The key for generic medicines is their ther- confirm the identity and adequate purity of the prod- apeutic interchangeability with originator products. uct, ascertain the strength (or amount) of the ac- To ensure the therapeutic interchangeability generic tive substance and, when possible, certain its per- products must be pharmaceutically interchangeable formance characteristics. General requirements are (contain the same amount of active ingredient and also given in the pharmacopoeia on important sub- have the same dosage form) and bioequivalent to the jects related to drug quality, such as microbiological originator product. Bioequivalence is usually estab- purity, dissolution testing and stability. lished using comparative in vivo pharmacokinetic The underlying principles of a pharmacopoeia studies with originator products. The detailed de- are that pharmaceutical substances and products in- scription how it is carried out is described in respec- tended for human use should be manufactured in tive WHO document and national regulatory guide- sites that are adequately equipped, dispose of ap- lines. Well resourced regulatory authorities require propriate professional and technical knowledge and that a multisource (generic) medicine must meet cer- that are operated by qualified staff. General rules tain regulatory criteria. These are presented in Ta- of appropriate pharmaceutical manufacture are con- ble 3. tained in the Good Manufacturing Practices (GMP) WHO has developed comprehensive set of guide- requirements recommended by WHO and/or those lines for generic drug registration which are useful laid down by the competent national (or regional, for drug authorities in developing countries: Market- such as European Commission) regulatory authority. ing Authorization of Pharmaceutical Products with In regulatory terms GMP could belong to ABC of Special Reference to Multisource (Generic) Prod- regulatory requirements for medicines and compli- ucts – A Manual for Drug Regulatory Authorities ance with it is vital for products quality. GMP is ap- (first edition 1999, updated version to be published plicable for both innovator and generic products. It is in 2008). applicable for manufacture of active pharmaceutical In the context of generic medicines it is appro- ingredients and finished dosage forms. Even manu- priate to ask what is a “pharmacopoeia” (word is facture of investigational drugs should follow GMP. derived from Greek pharmako-poios “drug-maker”) Without GMP consistency of manufacture clinical and how it fits in nowadays regulatory systems? performance of medicines cannot be assured. The answer to this question may seem obvious, but There is a practical distinction between phar- the term “pharmacopoeia” is used in a varied way macopoeial standards and manufacturers’ release specifications, although both comprise sets of tests Table 3. Regulatory requirements for multisource to which a given product should conform. Release (generic) medicines specifications are applied at the time of manufacture of a pharmaceutical product to confirm its appropri- A generic medicines must: ate quality but they also need to have a predictive (1) contain the same active ingredients as the innovator value, to support the notion that the manufacturer is drug responsible for the product during its entire shelf- (2) be identical in strength, dosage form, and route of life. In many cases pharmacopoeial monographs are administration based on the specifications developed by the manu- (3) have the same use indications facturers of innovator (originator) products. (4) be bioequivalent (as a marker for therapeutic inter- In order to launch innovator products pharma- changeability) (5) meet the same batch requirements for identity, copoeial specifications are not necessary as the man- strength, purity and quality ufacturers quality specifications have to pass rigor (6) be manufactured under the same strict standards of scientific assessment by the competent regulatory GMP required for innovator products authorities in conjunction with pre-clinical and clinical safety and efficacy data. It is important to notice Drug Regulation: History, Present and Future 73 that the focus in regulatory environment has been WHO hosts The International Pharmacopoeia. shifting from finished dosage form quality control This pharmacopoeia is based on specifications val- to the control of the whole complex of processes and idated internationally, through an independent inter- procedures involved in the manufacture of both ac- national scientific process. tive pharmaceutical ingredients (APIs) and finished Unlike national (such as British Pharmacopoeia, dosage forms. The objective of a nowadays regula- Indian Pharmacopoeia or US Pharmacopoeia) and tory approval is to ensure that the manufacturer has regional (such as European Pharmacopoeia) phar- built quality into the product from A to Z. macopoeias, The International Pharmacopoeia has, In case of multisource (generic) medicines (which apriori, no determined legal status, but WHO Mem- are formulated after the patents and other exclu- ber States are free to adopt it and to incorporate it sivity rights expire) pharmacopoeial monographs into national legislation, either in part or in whole. are more important as they enable manufacturers The first edition was published in two volumes (1951 not to elaborate their own specifications but rather and 1955). The latest fourth edition of The Interna- develop the products to meet the requirements of tional Pharmacopoeia was published in 2006 and an pharmacopoeial standards (both for APIs and fin- update is to be published in 2008. ished dosage forms). It should be noted that not all Most importantly, a new series of monographs pharmacopoeias present monographs (quality stan- has been added for antiretrovirals. These mono- dards) for finished dosage forms. Pharmacopoeial graphs have been developed as part of the WHO standards have also certain limitations. For example, strategy to make quality antiretroviral medicines testing using pharmacopoeial methods is not neces- more widely available to HIV-positive patients. Such sarily identifying all possible dangerous impurities. specifications support the joint United Nations – Pharmacopoeial methods are usually designed to WHO Prequalification project, managed by WHO catch the impurities that are likely to occur dur- (web site: http://mednet3.who.int/prequal/). Interna- ing the route of synthesis that has been utilized by tional Chemical Reference Substances (ICRS) are the originator. In case of different route of synthe- primary chemical reference standards used in con- sis or accidental contamination with other chem- icals it may not necessarily pick up the impuri- junction with International Pharmacopoeia mono- ties even if they pose danger to the health. This is graphs. They are supplied primarily for use in phys- why nowadays well resourced regulatory authorities ical and chemical tests and assays described in the never base their marketing authorizations of mul- specifications for quality control of drugs published tisource (generic) products only on quality control in The International Pharmacopoeia or proposed in testing based on pharmacopoeial monographs. In draft monographs. fact, the pre-marketing quality control testing has di- WHO gives advice on the establishment and man- minished constantly and more accent is put on mar- agement of national quality control laboratories, ket surveillance after the product is put on the mar- prepares guidelines on their functioning, publishes ket. guidance and gives advice on Good Manufacturing Pharmacopoeial monographs help to verify the Practices (GMP) and other regulatory issues, fol- quality and in case of multisource (generic) medi- lowing the underlying principle that quality must be cines they may indicate also on pharmaceutical in- built into a product from the very beginning of the terchangeability with the originator product. How- manufacturing process. The whole area of work is ever, pharmacopoeial monographs even for finished overseen by the WHO Expert Committee on Specifi- dosage forms may have limitations in proving thera- cations for Pharmaceutical Preparations. The WHO peutic interchangeability which is very important for Expert Committee on Specifications for Pharmaceu- clinical use of medicines (Box 1). 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 Manufacturing Practice (GMP) inspection of active pharmaceutical ingredient and finished dosage form manufacturing, scientific assessment 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. 74 Drug Benefits and Risks to WHO’s Director-General and its Member States activity involves assessment of regulatory activi- in the area of quality assurance. The advice and rec- ties on country level and various technical train- ommendations provided by this Expert Committee ing courses (such as GMP and GCP, how to assess are intended to help national and regional authorities generic medicines, bioequivalence, safety monitor- (in particular drug regulatory authorities), procure- ing and pharmacovigilance, quality assurance and ment agencies, as well as major international bodies quality control) and customized technical assistance and institutions to combat problems of substandard (in cooperation with numerous WHO collaborating and counterfeit medicines. centers and other partners) to the countries. Third, The importance and role of WHO in the field of in selected areas of essential products, ensuring the quality assurance of medicines, especially for those quality, safety and efficacy of limited high public countries that have no or little means to develop their health value essential medicines (such as antiretro- own quality control specifications, persists. WHO voirals to treat HIV/AIDS, or medicines to treat has numerous activities to support member states malaria) and vaccines (used in national vaccina- such as creating necessary nomenclatures, guide- tion programs) through “prequalification”. De facto lines and guidance (WHO GMP being a good exam- prequalification, although primarily meant for UN ple) but also delivering training courses and work- procurement and international donors, is a regula- shops on various topics of regulatory sciences ded- tory activity mimicking medicines registration (mar- icated to assessment of safety, efficacy and quality keting authorization) in its all elements to ensure of medicines in order to build national capacity to that products prequalified meet all international stan- regulate medicines. dards for quality, safety and efficacy. Prequalifica- tion program has also a very strong capacity building element built into it. Fourth, WHO plays a very important role in facilitating exchange of regulatory V. ROLE OF WHO IN DRUG REGULATION information for which it has developed a number of tools. Since 1980 WHO convenes every second year WHO is the directing and coordinating authority for International Conference of Drug Regulatory Au- health within the United Nations system (see more thorities (ICDRA) and publishes their proceedings. on web site: http://www.who.int/en/). It is responsi- These conferences provide drug regulatory authori- ble for providing leadership on global health matters, ties of WHO Member States with a forum to meet shaping the health research agenda, setting norms and discuss ways to strengthen collaboration. The and standards, articulating evidence-based policy ICDRAs have been instrumental in guiding through options, providing technical support to countries and its recommendations regulatory authorities, WHO monitoring and assessing health trends. In the 21st and interested stakeholders and in determining pri- century, health is a shared responsibility, involving orities for action in national and international reg- equitable access to essential care and collective de- ulation of medicines, vaccines, biomedicines and fence against transnational health threats. herbals. WHO’s role in drug regulation is fourfold. First, WHO manages also a system for regular ex- issuing necessary norms and standards (see exam- change of information between Member States on ples above) through its Expert Committees (such as the safety and efficacy of pharmaceutical products, WHO Expert Committee on Specifications for Phar- using a network of designated national drug infor- maceutical Preparations and WHO Expert Com- mation officers. WHO ensures the prompt transmis- mittee on Biological Standardization) and Expert sion to national health authorities of new information Committee like bodies (such as International Non- on serious adverse effects of pharmaceutical prod- proprietary Names Expert Group and International ucts and it also responds to individual requests Working Group for Drug Statistics Methodology – for information. These goals are achieved by the issuing Anatomical, Therapeutic and Chemical or regular publication of regulatory information in ATC codes and Daily Defined Doses or DDDs for the WHO Pharmaceuticals Newsletter (http://www. drug utilization research). Second, supporting reg- who.int/medicines/publications/newsletter/en/index. ulatory capacity building leading to implementa- html) and by the dissemination of one-page Drug tion of drug regulation on national level and its Alerts on an ad hoc basis. Relevant restrictive regula- harmonization on regional and Global level. This tory decisions are ultimately compiled in the United Drug Regulation: History, Present and Future 75

Nations Consolidated List of Products Whose Con- and new products will create new regulatory chal- sumption and/or Sale Have Been Banned, With- lenges. For example, how will increasing public at- drawn, Severely Restricted or not Approved by Gov- tention and expectations on medicines safety shape ernments. WHO publishes updates to this list: Phar- the regulations? How using new technologies such maceuticals: Restrictions in use and availability. as nanotechnologies change the medicines regula- WHO publishes also quarterly WHO Drug Infor- tion? Issues relating to the understanding of how mation (http://www.who.int/druginformation/) jour- the nanoparticles are presented to organs, cells and nal which provides an overview of topics of cur- organelles are of the highest importance when try- rent relevance relating to drug development, safety ing to understand the different mechanisms for in- and regulation. Latest lists of proposed and recom- tracellular trafficking and use their full therapeu- mended International Nonproprietary Names (INN) tic potential. Those aspects cannot be established for Pharmaceutical Substances are also published in without improving appropriate basic knowledge of cell and molecular biology at the intracellular level. this journal. However, at the same time important quality prob- WHO cooperates very actively with national reg- lems can rise. In order to assure quality physical and ulatory authorities of all of its Member States. It tries chemical properties of nanopharmaceuticals, includ- to facilitate spreading best practices and experience. ing residual solvents, processing variables, impuri- Through its observer role in the international Confer- ties and excipients, should all be well known. There ence of Harmonization (ICH) WHO is liaising be- will be a need for well-established standard tools to tween ICH and non-ICH countries trying to ensure be used in the characterization of nanopharmaceu- that information exchange between highly industri- ticals, including availability of validated assays to alized and less resourced countries is taking place. detect and quantify nanoparticles in tissues, medicinal products and processing equipment. Toxicologi- cal aspects of nanomedicines have been highlighted VI. FUTURE OF MEDICINES REGULATION with focus on long-term toxicity. Carbon nanotubes, quantum dots and other nonbiodegradable and po- Medicines regulation has been developing together tentially harmful materials should be given closer with the sciences involved in developing new drugs. attention weather associated with medicines or di- Also developments in health delivery systems have agnostics. A special set of standards must be grad- plaid role as those involved in health service delivery ually established in the global regulatory environ- are interested in safe and effective treatments which ment. In fact, some elements already do exist. In Eu- would be cost effective and affordable. Both costs rope Directive 2004/27/EEC on medicines addresses of research and development and regulatory assess- directly the need for the study of environmental im- ment of products is increasing. There is likely no al- pact of medicines which will have major impact for ternative for more harmonization (international, re- new nanomaterails to be used in medicines. To ex- amine and predict environment impact is a new task gional and sub-regional) of regulatory requirements for regulators. and work sharing (together with information shar- Using genetic information to create safe and ef- ing) between different national regulatory authori- fective medicines offers potential for more individ- ties. The cost of full regulatory assessment of a new ualized therapies and patient benefits but will also drug is increasingly becoming not affordable (both have an impact on the use of healthcare resources. in terms of financial and human resources) for less Pharmacogenetics has been viewed as something resourced smaller regulatory agencies. What are the for the future, but real clinical examples now exist. new areas of development beyond better harmoniza- Some pharmacogenetic tests, such as the thiopurine tion, information exchange and gradual building of methyltransferase (TPMT) test that aims to predict trust in each others decisions leading to recognition the risk of severe neutropenia for the purine drugs instead of duplication? azathioprine and 6-mercaptopurine, have already Although even quality issues are still a prob- relatively low unit costs (approximately 50$ US). lem (poor quality of starting materials including However, even low unit cost tests may have a signifi- active pharmaceutical ingredients, quality problems cant cost impact if they have a high volume of uptake with finished dosage forms, spreading of counter- in a healthcare system. There may be added value as- feit medicines) it is likely that new technologies sociated with introducing a pharmacogenetic test to 76 Drug Benefits and Risks guide a prescribing decision, in terms of improved Ceci A, Felisi M, Catapano M, Baiardi P, Cipollina L, Rav- health-related quality of life resulting from fewer se- era S et al. Medicines for children licensed by the Euro- vere side effects and improved treatment response pean Agency for the Evaluation of Medicinal Products. in the patient population taking the medicine. Phar- Eur J Clin Pharmaco 2002;58:495-500. macogenetic tests broadly fall into one of two cate- CIOMS. International reporting of adverse drug reactions gories, those provided through clinical laboratories, (Report of CIOMS Working Group I). Geneva: Counsil for International Organizations of Medical Sciences; such as the TPMT test, and those for which a prod- 1990. uct license has been granted in a similar way to new CIOMS. International reporting of periodic drug-safety medicines, such as Third Wave Technologies’ (WI, update summaries (Report of CIOMS Working Group ® USA) Invader UGT1A1 Molecular Assay, which II). Geneva: Counsil for International Organizations of was approved by the US FDA in 2005. The last op- Medical Sciences; 1993. tion means that regulators are directly involved. Reg- CIOMS. International ethical guidelines for biomedical ulators are starting to regulate pharmacogenetics and research involving human subjects. Geneva: Counsil some guidance already exists in Canada, EU and US. for International Organizations of Medical Sci- Recently also ICH started to deal with pharmacoge- ences; 2002 [cited 2008 Jan 13]. Available from: URL: nomics and pharmacogenetics. The E15 guideline http://www.cioms.ch/frame_guidelines_nov_2002.htm Definitions for Genomic Biomarkers, Pharmacoge- CIOMS. Pharmacogenetics: towards improving treat- nomics, Pharmacogenetics, Genomic Data and Sam- ment with medicines (Report of the CIOMS Working Group). Geneva: Counsil for International Organiza- ple Coding Categories has been finalized. tions of Medical Sciences; 2005. Another area of challenges includes biological CIOMS. The development safety update report (DSUR): medicines including ‘generic’ biological medicines. harmonizing the format and content for periodic safety New product groups are emerging and even with reporting during clinical trials (Report of CIOMS known product groups there are challenges ahead, Working Group VII). Geneva: Counsil for International especially from the point of view of safety. Other Organizations of Medical Sciences; 2006. important areas for drug regulators remain pharmo- Declaration of Helsinki. World Medical Association; 2004 covigilance, pediatric medicines, orphan medicines [cited 2008 Feb 25]. 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