MEDICINE REGULATION REGULATORY DEPARTMENTS GOOD REGULATORY PRACTICE

1. MEDICINE REGULATIONREGULATORY DEPARTMENTS GOOD REGULATORY PRACTICE SAAPRA 1 June 2012

2. OVERVIEW • Development of Legislation • Medicines Regulation and Regulators • Regulatory Affairs Department (RAD) • Good Regulatory Practice (GRP)

3. Development of Medicines Legislation • Typically medicine regulations have been developed ‘after the fact’ • Triggered by unwanted and sometimes disastrous events • Information and knowledge on the use of medicines increases exponentially • Result - Medicines legislation proliferates

4. Development of Legislation USA • 1846 – 1848 Mexican-American War • American troops supplied with substandard medicines • 1848 – Import Drug Act passed • 1901 – concern over unsanitary condition in meat packing industry and also quality of medicines • Medicines legislation outgrowth of food legislation

5. Development of Legislation • 1902 – 12 children died from contaminated diphtheria toxin in St Louis • Result - Biologics Act of 1902 • Demanded licensing of biological products and facilities • 1902 – 1907 Study on safety of food additives with human volunteers • Led to - 1906 Pure Food and Drugs Act • First federal drugs law

6. Development of Legislation • Prohibited mislabelling and adulteration of medicinal products and • Introduced USP and NF as official standards • Legal system still allowed for unacceptable bizarre practices - false therapeutic claims • 1912 - US vs Johnson case – promoters of “Dr. Johnson’s Mild Combination Treatment for Cancer” challenged • 1912 Act amended –prohibited labelling with false therapeutic claims

7. Development of Legislation • 1937 – Massengill Company place throat lozenge on market • Sulfanilamide dissolved in diethylene glycol (common car antifreeze agent) • 107 people died (mostly children) • Legislators acted rigorously to prevent reoccurrence • 1938 – Food, Drug and Cosmetic Act passed • Medicine could only be marketed after 60 days if no FDA objections

8. Development of Legislation • Required proof of safety and efficacy • 1951 – another amendment to Act • Divided products into OTC and prescription requiring professional supervision • 1962 amendments made proof of efficacy mandatory • Introduced GMP

9. Development of Legislation • Further amendments over 20 years such as - 1983 Orphan Drugs Act – for marketing and commercialisation of medicines to treat rare diseases - 1990 Nutrition and Labelling Act - 1984 Drug Price Competition and Patent Term Restoration Act - 1996 Generic Drug Enforcement Act

10. Development of Legislation • 1988 Prescription Drug Marketing Act • To ensure that medicines purchased by consumers are safe and effective, and • To avoid the unacceptable risk to American consumers from counterfeit, adulterated, misbranded, subpotent, or expired drugs. • Additionally Guidance documents to be taken into account by industry • Other reform bills constantly under consideration

11. Development of Legislation EUROPEAN UNION (EU) • Germany and other countries originally focussed on pharmacies only • No Marketing Authorisation required for industrially produced medicines • 1961 registration introduced to determine what was on market – notification process only • In Germany 55 000 medicinal products on market at time

12. Development of Legislation • Beginning 1960s sleeping pill Contergan (thalidomide) caused birth defects • Taken by mothers in early stages of pregnancy • Children born without arms - hands starting at the shoulders • Called ‘flipper babies’

13. Development of Legislation • An estimated 10 000 children were affected in Europe • 1968 appetite suppressant Menocil (aminorex) caused many deaths – withdrawn from market • Led to implementation of medicines legislation in UK and other EU member states • Today legislation in EU member states mirrors EU Directive

14. Development of Legislation SOUTH AFRICA • 1965 Medicines and Related Substances Control Act published and first medicines called up in 1968 • 2002 Medicines and Related Substances Act amended making provision for inter alia licensing of manufacturers, wholesalers, distributors, etc. • 2008 Amendment Act 72 introduced SAHPRA • Latest draft amendment makes provision for the structures required for the new juristic body

15. International Conference on Harmonisation(ICH) • ICH began to take place in 1989 • Project of both Regulatory Bodies and pharmaceutical industry from EU, Japan and United States • Harmonisation the major factor • Goal - to expedite development and approval processes for medicinal products • Does not compromise safeguards on Q/S/E

16. World Health Organisation (WHO) • An intergovernmental organisation • 166 member states within the Charter of the United Nations • Activities include support for ministries of health concerning development of methods for assessing quality, effectiveness and efficiency • Publications cover: - essential drugs - drug policies - quality control - ethical guidelines - safety assessment, drug research and development and - laboratories

17. Medicines Regulation and Regulators • Medicine legislation makes provision for Regulatory Authorities or Bodies • Have developed and continue to develop legislation • This had and continues to have a significant effect on pharmaceutical industry

18. Medicines Regulation and Regulators • Common misunderstanding – that Regulators register our medicines • They keep medicines off the market unless the applicant can prove quality, safety and efficacy • Ensure compliance with legislation • Control the use and minimise the abuse of medicines • Re-evaluate the medicines on the market

19. Regulatory Affairs Departments (RAD) • Why have companies established Regulatory Affairs Departments ? • Simple answer – because there are regulations and regulators • To understand and fulfil regulators’ needs as environment has become more and more complex

20. Regulatory Affairs Departments (RAD) • Mistakes cost a lot of money • Worst mistake – calling in RA after plans have been finalised • Pitfalls of product development: - Not involving RA in plans - Suppressing critics in the company – they are valuable in identifying problems - Hiding critical issues chances good reviewer will spot them - Telling all you know – leads to confusion

21. Regulatory Affairs Departments (RAD) - Trying to make it perfect – a lot of time will be lost - Doing all the studies as early as possible e.g. marketing studies - Using in-house methods to structure the documentation – adapt to Regulator’s structure

22. Regulatory Affairs (RA) • RA is usually recognised as having three basic functions: - The outlet of the company to Regulatory Bodies - The interpreter of regulations to companies - The influencer of new regulations • Makes RA the interface between companies and Regulatory Bodies and • Key player in the product development and maintenance process

23. Activities of the Regulatory Affairs Department (RAD) • Activities depend on each company’s structure and organisation • Start at the initial development of medicinal products • Continue through until the launch of the product • Steer and maintain an application through the legislative framework - allows a Regulatory Authority to reach a scientific decision • Once launched, the RAD fully involved in Marketing Authorisation (MA) maintenance and post-marketing activities

24. Activities of the RAD Product Development • RAD should be involved in the creation and evaluation of all aspects of research and development plans • Advise departmental heads and project managers on the requirements and any upcoming legal changes with potential impact for registration • RAD should give advice for optimising development plans • By an accurate interpretation of the requirements of the existing guidelines • Ideally should be done within the scope of a Regulatory Strategy Document

25. Activities of the RAD Product Development • Ideally RAD should be able to liaise with Regulatory Authorities on any scientific aspect of: • future Marketing Authorisation (MA) • dossier and co-ordinating with the other departments • the briefing document including the questions and company’s positions On our wish list!

26. Activities of the RAD New Registrations • RADresponsiblities: - proposing the best registration strategy - taking into account the possible registration procedures - the impact of intellectual property rights - the peculiarities of the product - the scientific content of the different part of the dossier • RAD preparation of Regulatory Strategy Document (RSD) - containing all the essential global regulatory aspects of product development - including scientific advice - meeting with the Regulatory Authority

27. Activities of the RAD New Registrations • RAD – ensure all activities related to obtaining registration comply with existing legislation i.e. • laws, regulations, directives and guidelines • need to be proactive • RAD - should establish ethical, practical, technical and regulatory standards: - laid down in policies and SOPs - specify the responsibility of each staff member involved - describe the process - ensure content of dossiers in compliance with existing legislation and standard needed to obtain registration of the product

28. Activities of the RAD New Registrations • RADresponsiblities: • writing, co-writing, editing and/or authorising all documentsfor use in registration dossiers or communication with the Authority e.g. manuscripts, expert reports, method of use, standard advice for patients and labels • should strive for world-wide implementation of harmonised prescribing information • should be responsible for the accurate planning and co-ordination of compiling the dossiers • Take into account the possibilities for electronic submission of the dossier or parts of it especially in terms of submission of eCTDs

29. Activities of the RAD New Registrations • Ensuring administrative validation • Chasing up the dossier throughout the assessment and • Anticipating the possible questions from the Regulatory Authority in order to optimise the timing, quality of the answer and Marketing Authorisation (MA) approval and package insert (PI) wording • Queries from the RA should be answered in a consistent manner and within the time limits set by the agency when indicated, according to internal guidelines • Status reports should be issued regularly in order to provide information on the world-wide registration situation

30. Activities of the RAD Registrations • submission strategies (timing, responsibilities, free sale certificates and answers to the Authority, questions, intellectual property • dossier updates (variations and safety) • dossier renewals • Periodic Safety Update Reports (PSURs) planning and a contingency plan • must address the proposed labelling with Marketing and Sales • the impact on discussion with pricing and reimbursement authorities

31. Activities of the RAD Maintenance of Existing Registrations • All existing registrations should be carefully maintained and regularly updated to reflect the current standards and knowledge • Variations and change control: • Management of change control forms are an important element of GRP - Such changes include: • Product data or specifications • Manufacturing of analytic methods • Facilities or suppliers as well as line extensions • Additional indications, etc. • All such changes have to be communicated to the RA in accordance with the respective legal requirements affected

32. Activities of the RAD Maintenance of Existing Registrations • Queries raised by the RA to ensure regulatory compliance • RAD and quality assurance department should liaise closely on all aspects affecting variations and change control • Responsibility of RAD, Responsible Pharmacist and QA (Quality Assurance) to ensure manufacturing and QC (Quality Control) comply at all times with the registration dossier • RAD should assure regulatory compliance by the manufacturer, packager and marketing department

33. Activities of the RAD Maintenance of Existing Registrations • Changes to PI and/or PIL - Changes might be initiated by marketing or medical department - Can also be requested for new safety data - RAD and medical / pharmacovigilance c liaise closely for the preparation and timely implementation once the revised wording is approved • RAD in close collaboration with the Drug Safety department and a Qualified Person for Pharmacovigilance - Do PSURs planning on a yearly basis for each product - Collect all the information needed for their submission, taking into consideration post-approval commitment or follow-up measures

34. Activities of the RAD Maintenance of Existing Registrations It is the duty of RAD • to ensure activities related to post marketing studies are carried out in compliance with and reported according to, existing legislation. • to inform the Regulatory Authorities of any pharmacovigilance issue and to implement and file the necessary data into the official documents • this will be done in close co-operation with the medical department and Qualified Person for Pharmacovigilance

35. Activities of the RAD Regulatory intelligence – Objective 1 RAD should – • have a system in place to ensure the tracking of all the versions, either approved or a draft for comment, of regulations guidelines and concepts papers • on an on-going basis review relevant world-wide legislation, guidelines, discussion papers, codes of conduct, etc. • interpret the scope and possible consequences arising from such legislation and codes and inform the company accordingly(may affect the activities of the company) • ensure and co-ordinate the necessary activities arising from changes to ensure that compliance with regulations will be met.

36. Activities of the RAD REGULATORY INTELLIGENCE - Objective 2 RAD should – • comment on new draft guidelines / draft legislation and take an active role in participating in the outcome of final regulatory comments. • for this purpose preferably join pharmaceutical associations to represent the needs of pharmaceutical industry on a higher level.

37. Good Regulatory Practice (GRP) Problem today: • Insufficient quality submissions to the Regulatory Authority • Industry and Regulator perceive each other as opponents rather than partners • We are like opposite sides of the same coin -neither side detracts from the value of the coin but rather together give it its character and identity.

38. Good Regulatory Practice (GRP) • Present system based on mutual mistrust • Involves high cost i.t.o. time, manpower, rejects on both sides • Quality cannot be added by regulations, guidelines, etc. • Without any real dossier quality improvement timelines cannot improve

39. Good Regulatory Practice (GRP) Could GRP be the solution to the problem?

40. Good Regulatory Practice (GRP) What is GRP? • Establishment of a quality system • Involves both industry and Regulator • About trying to achieve quality by less rather than more control • About producing quality in the first place • Based on sound science, coupled with organisational ability

41. Good Regulatory Practice (GRP) What are the goals of GRP? • Efficiency: quick and qualified decisions on Q/S/E of products • Effectiveness/productivity: effective use of resources, cost-effectiveness • Results: achieve and preserve an image of high standing

42. Good Regulatory Practice What are the advantages of GRP? • Quality medicines available to patients in timely fashion • Because global picture is seen and • Entire process is designed to produce quality

43. Good Regulatory Practice How? • Decide on goals • What must be done by whom and how • Write it down • Adhere to it • Watch the results and if necessary modify the system

44. Good Regulatory Practice(GRP) • A pre-requisite to GRP - the communication of all relevant information, including its evaluation and relevance for the existing product, to ALL interested parties within the organisation • Pivotal to GRP is the need to keep abreast of world-wide legislation including potential changes and • The interpretation of possible consequences in the event of failure to meet requirements

45. Good Regulatory Practice(GRP) • The involvement of GRP in the concept of Total Quality Management (TQM) is essential from initial development phase of the product and continues for its entire life • Efficient RAD organisation and working methods are mandatory • RAD skills for communication and communicating information to other departments - a key parameter to ensure compliance with regulatory requirements

46. Good Regulatory Practice (GRP) • Implementation of GRP essentially contributes towards continuous Total Quality Assessment of all aspects of regulatory affairs and is • The essential link between each discipline in Total Quality Management • Increasing complexity of regulatory requirements especially as RADs operate numerous interfaces within a pharmaceutical company

47. Good Regulatory Practice (GRP) • GRP Guidelines define the role and position of the RAD within the organisation • Appropriate and effective management of the regulatory process is mandatory for: • Bringing a medicinal product to the market and keeping it there • In compliance with legal, scientific, ethical and administrative requirements • To ensure the compliance of the relevant company’s activities to the local and global regulations in terms of official and company regulations

48. PERSONNEL There should be sufficient personnel at all levels within the organisation with the: • Ability • Education • Training • Experience and • Appropriate professional skills to perform the tasks assigned to them • All personnel should be trained regularly in their skills to ensure they possess sufficient skill and knowledge of the procedures and policies of the organisation • Ideally, all graduate personnel should have a multidisciplinary background

49. PERSONNEL • Ideally, all graduate personnel should have: • multidisciplinary background • scientific expertise • communication and negotiation skills • regulatory knowledge • planning capacity • be able to work in teams • to organize multidimensional projects • to work in a multidimensional manner • Standard operating procedures should be designed to deal with communication and flow of information

50. PERSONNEL • The responsibilities of the Responsible Pharmacist (RP) and the Qualified Person for Pharmacovigilance (QPPV) in relation to the RAD should be clearly defined • These responsibilities should be explained and written into the job description for each person together with any training and education required on product registration • Key personnel in responsible positions should be accountable for: • authorizing procedures and tasks and • having adequate supporting staff • persons should be designated to deputise for them in their absence