Introduction to Regulatory Affairs - Pauwels Consulting Academy
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On Tuesday, June 14, our colleagues Fiorenzo Savoretti, Senior Regulatory and Quality Consultant at Pfizer and Nick Deschacht, Senior RA Consultant at GSK, gave an interesting “Introduction to Regulatory Affairs”. Fiorenzo and Nick talked about RA and their projects, each from their unique angle. They delivered their presentations for ## attendees at our Brussels office at the Lambroekstraat 5a in Diegem.
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Introduction to Regulatory Affairs - Pauwels Consulting Academy
- 1. Regulatory affairs Introduction June 14 2016
- 2. 22 The presenters Regulatory affairs Fiorenzo Savoretti Regulatory & Quality Consultant More than 10 years RA experience Working at Pfizer as Site Compliance Network Member Previously worked at Quintiles, SGS (consultant for Janssen) and Archemin … will tell you about Drug Development and give a short introduction from a RA perspective Nick Deschacht Regulatory and Quality Consultant More than 6 years RA experience Working at GSK as Global Regulatory Affairs CMC specialist Previously worked at Pfizer and Zoetis …will tell you about Drug Registration from a RA perspective
- 3. 33 Definition Regulatory affairs Perceived definition Regulatory Affairs (RA) is all about paper work How the drugs are being approved, safety standard and information database http://www.indeed.com Comprehensive definition RA is a comparatively new profession which developed from the desire of governments to protect public health by controlling the safety and efficacy of products in areas including pharmaceuticals, veterinary medicines, medical devices, pesticides, agrochemicals, cosmetics and complementary medicines. https://www.topra.org
- 4. 44 History Regulatory affairs USA – “Cutter Incident” Live Poliovirus instead of attenuated vaccine was inoculated to patients (new polio infection, 200 children with paralysis and 10 people killed) more effective regulation Circumstances faced by Health Authority (HA) drug regulations and pharmaceutical industry
- 5. 55 History Regulatory affairs Europe - Thalidomide tragedy Drug used as sedative and anti-cancer drug was negatively impacting the foetus development (infants with malformation of the limbs) 65/65/EEC, mandating marketing authorization Pharmaceutical legislations become clear and transparent EMA committee was developed for drug assessment in the EU
- 6. 66 Responsibilities Regulatory affairs RA professionals: involved in all aspects of drug development processes Address issues raised in the regulatory review process Involvement During the research and development phases of drug In the design and monitoring of clinical studies For the marketing, the advertising and the communication Manufacturing, packaging and distribution Developing business strategy Monitoring and analyzing regulatory issues for multiple nations and regions of the world
- 7. Part 1 The Drug Development Fiorenzo Savoretti
- 8. 88 Drug Development A regulatory point of view Develop and launch a new pharmaceutical product takes up to 15 years Problems During the process of scientific development Changing regulatory environment Includes Pre-clinical research on microorganisms and animals Clinical trials on humans Obtaining regulatory approval to market the drug
- 9. 99 Discovery Design phase Stage 1 10.000 compounds may be potential candidates for development as a medical treatment Stage 2 After early testing, however, only a small number of compounds look promising and call for further study.
- 10. 1010 Researchers discover new drugs through New insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease Many tests of molecular compounds to find possible beneficial effects against any of a large number of diseases Existing treatments that have unanticipated effects New technologies, such as those that provide new ways to target medical products to specific sites within the body or to manipulate genetic material Discovery Design phase
- 11. 1111 Development Experimental phase Once researchers identify a promising compound for development conduct experiments to gather information on How it is absorbed, distributed, metabolized, and excreted The potential benefits and mechanisms of action The best dosage The best way to give the drug (such as by mouth or injection) Side effects (often referred to as toxicity)
- 12. 1212 Preclinical Research Prediction of effects Before testing a drug in people potential to cause serious harm (toxicity)? Two types of preclinical research
- 13. 1313 Clinical Research Studies in human Clinical research: trials that are done in people Follow a typical series Phase I: early, small-scale Phase III: late-stage, large scale Phase I Test a new drug or treatment in a small group of people for the first time Evaluate Its safety Determine a safe dosage range Identify side effects 20 - 100 volunteers: healthy or with disease/condition (safety and dosage)
- 14. 1414 Clinical Research Studies in human Phase II Drug or treatment is given to a larger group of people Evaluate Effectiveness Further evaluate its safety Up to several 100 people with the disease/condition Phase III The drug or treatment is given to large groups of people Confirm Effectiveness, Monitor side effects Compare it to commonly used treatments Collect information on the safety 300 - 3000 volunteers who have the disease
- 15. 1515 Registration Conclusion of the R&D phase Drug developer Evidence from its early tests and preclinical/clinical research that drug is safe and effective for its intended use Company File an application to market the drug Regulator Examines all submitted data on the drug and makes a decision to approve or not to approve it
- 16. 1616 2005 received $22 million in venture capital Testing a gel that features a protein derived from human milk to make the wound unfriendly to bacterial growth AUG. 5, 2005 http://www.nytimes.com Example of Drug Development Eureka… but too early! 2006 receives FDA Fast Track Designation Talactoferrin Alfa in Non-Small Cell Lung Cancer and Diabetic Foot Ulcers OCT 5, 2006 http://www.prnewswire.com
- 17. 1717 Example of Drug Development Eureka… but too early! 2008 Talactoferrin Alfa Mother’s Milk Becomes Cancer Treatment JAN 26, 2008 http://cancergrace.org 2008 Hopes to raise $40 million in a late-stage round to fund clinical trials Developing a bioengineered version of a human protein called talactoferrin that plays an important role in regulating the immune system Agennix plans to use the funding to fund two late-stage, phase III trials of the drug in lung cancer FEB 28, 2008 http://venturebeat.com
- 18. 1818 Example of Drug Development Eureka… but too early! 2009 Completes merger with GPC Biotech $20 million (approximately €15 million) loan to Agennix in the form of a senior secured convertible promissory note, bearing an interest rate of 12% per annum, to support the funding of the clinical development of talactoferrin DEC 27, 2009 http://www.bizjournals.com 2012 Stock plunged nearly 80% Revealed that a Phase III trial assessing its key drug talactoferrin in patients with non-small cell lung cancer (NSCLC) did not meet its primary endpoint in demonstrating an overall survival benefit AUG 8, 2012 http://www.pharmatimes.com
- 19. 1919 Drug Development Wrap up Expensive and time consuming process Potential drugs are screened by regulators during the entire development process RA guide and advise pharmaceutical companies through the development phase the drug and formulate advice based on their experience and the available regulation The path towards drug development does not always have a happy ending
- 20. End Part 1
- 21. Part 2 Registration and product life cycle Nick Deschacht
- 22. 2222 Drug Development Wrap up Expensive and time consuming process Potential drugs are screened by regulators during the entire development process RA guide and advise pharmaceutical companies through the development phase the drug and formulate advice based on their experience and the available regulation The path towards drug development does not always have a happy ending
- 23. 2323 The path towards drug development does not always have a happy ending, but what if it does? Drug development Happy endings?
- 24. 2424 A medicinal product Any substance or combination of substances presented as having properties of preventing or treating disease in human beings Any substance or combination of substances that may be used by or administered to human beings with a view to restoring, correcting or modifying a physiological function by exerting a pharmacological, immunological or metabolic action, or making a medical diagnosis http://www.gov.uk/ - The Medicines and Healthcare Products Regulatory Agency Define what a medicine is!
- 25. 2525 A medicinal product Define what a medicine is!
- 26. 2626 Borderline products – categories Cosmetics (Botox, cream) Food products, including, in particular, food supplements (vitamin) Herbal products (Saint John’s Wort tea ( NL: Sintjanskruid, FR:Millepertuis Perforé) Medical devices (stents, pacemaker, app) Machinery/laboratory equipment Define what a medicine is!
- 27. 2727 Classification Control based Prescription drugs – OTC (over the counter) drugs Route of administration Gastro intestinal Epidural Cerebral intradermal Therapeutic effect Preventive vs treatment Anatomical Therapeutic Chemical (ATC) Classification System Define what a medicine is!
- 28. 2828 Classification Small molecule drug – Chemicals Biopharmaceuticals – Biologicals Recombinant proteins Vaccines Blood products Gene therapy Monoclonal antibodies Cell therapy (stem cell therapies) Define what a medicine is!
- 29. 2929 The path towards drug development does not always have a happy ending, but what if it does? Drug product registration Happy endings?
- 30. 3030 Drugs are not ordinary consumers’ products! In most instances, consumers are not in a position to make decisions about when to use drugs which drugs to use how to use them to weigh potential benefits against risks as no medicine is completely safe 1937 – Elixir Sulfanilamide 71 adults and 34 children died 1957 – Thalidomide/Softenon Estimate 10.000 to 20.000 – 40% died/malformation of limbs 1990 – 2001 – Cerivastatin (Baycol) – cholesterol treatment Reported to have impacted 100.000’s – 52 reported death … Why regulating drugs?
- 31. 3131
- 32. 3232 Regulations thus protect public health by controlling the safety and efficacy of products in areas including pharmaceuticals, veterinary medicines, medical devices, pesticides, agrochemicals, cosmetics and complementary medicines. In summary, all medicines must meet three criteria 1. Quality 2. Safety 3. Efficacy General expectation of medicine
- 33. 3333 U.S. Food and Drug administration (FDA) – 1906 Center for Drug Evaluation and research (CDER) Center for Biologics evaluation and research (CBER) World Health Organization (WHO) – 1948 European Medicines Agency (EMA) – 1995 European Directorate for the Quality of Medicines (EDQM) Regulations made by…
- 35. 3535 http://www.efpia.euWorldwide : 195 countries Global market
- 36. 3636 International Conference on Harmonisation of Technical Requirements (ICH) for Registration of Pharmaceuticals for Human Use – Established in 1990 by JP, US, EU Quality guidelines Safety guidelines Efficacy guidelines Multidisciplinary guidelines http://www.ich.org Development of (electronic) common technical document ((e)CTD) Standard structure for the dossier used when applying for marketing approval of a pharmaceutical product in the EU, the US and Japan ICH international standard
- 37. 3737 Dossier Collection of documents that contain all technical/scientific data of pharmaceutical product to be approved/registered/marketed Common technical document (CTD) All routes lead to…. Registration? ICH international standard
- 38. 3838 Filing USA New Drug application (NDA) Abbreviated New Drug Application (ANDA) Biologics License Application (BLA) Europe National Procedure (NP) Decentralized Procedure (DCP) Mutual Recognition Procedure (MRP) Centralized Procedure (CP) All routes lead to…. Registration? Different filings
- 39. 3939 Filing USA New Drug application (NDA) Abbreviated New Drug Application (ANDA) Biologics License Application (BLA) Europe National Procedure (NP) Decentralized Procedure (DCP) Mutual Recognition Procedure (MRP) Centralized Procedure (CP) All routes lead to…. Registration? Different filings
- 40. 4040 Filing Europe Centralized Procedure (CP) All routes lead to…. Registration?
- 41. 4141 Filing Worldwide Determined by authorities All routes lead to…. Registration?
- 43. 4343 Regulatory affairs (RA), also called government affairs, is a profession within regulated industries, such as pharmaceuticals, medical devices, energy, banking, telecom, … Regulatory affairs also has a very specific meaning within the healthcare industries. Regulatory affairs professionals Ensure that their companies comply with all of the regulations and laws pertaining to their business. Working with federal, state, and local regulatory agencies and staff on specific issues affecting the business Regulatory Affairs Definition
- 44. 4444 Currently represented by 2 main organisations The Organisation for Professionals in Regulatory Affairs, TOPRA (UK) The Regulatory Affairs Professionals Society, RAPS Regulatory Affairs
- 45. 4545 Continuous changing regulatory environment, increasing regulatory requirements, increasing development costs and commercial pressure RA play integral roles throughout the healthcare product lifecycle – at every stage of the development, distribution, marketing and post-market surveillance Healthcare products sector is global, landscape riddled with complexity, requiring a special set of skills and expertise Regulatory Affairs Importance
- 46. 4646 Administrative impact, check the box exercises in countries lacking the required standards and lack trained scientific staff. (South Africa – lead times to up 3 years) Regulation of the regulators, obsolete, overly-complicated or unnecessary regulations. “Politically motivated delays" in regulatory decision-making. Industries can-and often do-lobby for legislation and regulations favourable to their own interests. Regulatory Affairs Nonsense of RA
- 47. 4747 Guidance in the various regulatory options for drug development (clinical). Strategic guidance concerning ‘time to market’. Involvement in manufacturing site changes. Portfolio utilization and optimisation. Merger, Acquisition and divestment activities. Examples Regulatory Affairs
- 48. 4848 Global Regulatory Affairs Local Regulatory Affairs Clinical Regulatory Affairs Technical Regulatory Affairs (CMC) Labeling Regulatory Affairs Regulatory Affairs Functions
- 49. 4949 Knowledge of legislation Regulatory Procedures Timelines for Procedures Content of Applications Technical skills Regulatory Affairs Expertise required for Regulatory Negotiation skills Flexibility Insight into stakeholders interest Language skills
- 51. 5151 Global Regulatory Affairs Technical Regulatory Affairs (CMC) Clinical Regulatory Affairs Most of the work is post marketing (post approval work) Daily routine, what do I do? Global Regulatory Affairs, CMC consultant
- 52. 5252 Mergers and acquisitions Owner change Production site change Marketing desire Claim extensions Labelling changes Technical changes Change in bacterial culture Change in adjuvant Daily routine, what do I do? Global Regulatory Affairs, CMC consultant
- 53. 5353 Scientific and technical writings Meetings Information analysis (literature) Read guidelines/documents Quality review documents Strategic guidance Global Regulatory Affairs, CMC consultant Daily routine, what do I do?
- 54. 5454 Regulatory requirements change Regulations change Guidelines rewritten Experience based job Technology keeps developing Global Regulatory Affairs, CMC consultant Daily routine – always??
- 55. 5555 Biosimilars Generics Patent based Possible registration short cut Company A Company B Current challenges
- 56. 5656 Biosimilars Properties Generics Biosimilars Size Small (car) Large (Jumbo jet) Molecular weight <500-900 Daltons 4000 to >140,000 Daltons Structure Simple and well-defined Complex with potential structural variations Manufacturing Predictable chemical process to make identical copy Specialized biological process to make similar copy Complexity Easy to fully characterize Difficult to characterize due to heterogeneity Stability Relatively stable Sensitive to storage and handling conditions Adverse immune reaction Lower potential Higher potential Manufacturing quality test ≤ 50 ≥ 250 Approval requirements Small clinical trials in healthy volunteers Large clinical trials in patients Current challenges
- 57. 5757 Personalized medicine Personalized stents Lung stent Exemption needed Bioresorbable Airway Splint Created with a Three-Dimensional Printer N Engl J Med 2013; 368:2043-2045 May 23, 2013 DOI: 10.1056/NEJMc1206319 Diagnostics coupled to treatment Breast cancer – Herceptin Future/Current challenges
- 58. 5858 Personalized medicine Cell therapy Redesign clinical trials Different production and quality standard Antibiotics Antimicrobial resistance Novel Antibiotics Decrease in requirements needed Future challenges
- 59. 5959 Future challenges Personalized medicine Xenobiology (next generation biologicals) http://www.complix.com Genetic Modified organisms (actogenix-intrexon) Actiobiotics
- 60. Part 2 The End
Editor's Notes
- Is there any specific reason for you why you have decided to follow this training? What is the link in your daily work with RA?
- In the beginning more experience in clinical development
- First day at SGS and paper binders with EU guidelines and regultation Perceived definition of the RA work is all about administration (writing letters, filling forms, database), this is in part true but the RA profession is rapidly evolving with the change in the pharmaceutical environment, the scientific development (biotech products) and increasing complexity of products Safety is a playing a major role in defining and shaping the RA work now. Guidelines are issued for new products introducing regulation from previously unregulated fields ( for example gene therapy, biosimilars) and the contribution of the RA professional in implementing this new guidance and way of thinking is fundamental
- Controls being not effective (deficencies, lack of controls) New laws were the result (crisis-led change) Public demand to the adoption of more restrictive legislation (response to the perceived problems or perceived needs of society) In some countries there is even today not a structure for regulating drugs (no control possible)
- EU Directive 65/65/EECThe directive aimed to harmonise standards for the approval of medicines within the then EU Requirements for marketing authorization procedure
- Test amount and the dose, check the endpoint and outcome of clinical trials The choice of the most appropiate animal model, how trial should be conducted what should be checked Advertising and promotion of drugs strictly regulated Choice of excipients, primary packaging (interaction drug and primary container), shipping and transport (cold storage) Understand the regulatory landscape, evaluate potential hurdles, and create a plan to proactively address issues
- Problems encountered during scientific development the drug does not behave in the same way in the animal models and in humans. Mechanism of action might be different Time from Trial Approval to Trial Site Activation Difficulties in patient recruitment - During 15 years regulation might change (become more stringent, more clear, eliminating space for interpretation)
- The likelihood that a drug entering clinical testing will eventually be approved is estimated to be less than 12% (approval succes). Requires immense resources: the best scientific set, sophisticated technologies, evolving manufacturing processes, and complex project management. It also takes persistence and, sometimes, luck. Nowadays with personalized medicine (intra-and inter-individual variability physicians could divide patients into subgroups and treat them differently based on their genetic profile) and the better understanding of human genoma to create drugs that specifically act on the molecular profile and genetic makeup of each patient. Compounds that survive the initial screening are then “optimized,” or altered to make them more effective and safer
- Historically drugs were discovered by hazard (eg. penicillin accidentally discovered by Flemming) or developing traditional remedies Screening of large compounds libraries against isolated biological targets - Computer guide drug design
- Successful drugs must be: - Absorbed into the bloodstream, - Distributed to the proper site of action in the body, - Metabolized efficiently and effectively, - Successfully excreted from the body, and - Demonstrate to be not toxic in the tests performed.
- In vitro tests are experiments conducted in the lab (“vitro” is “glass” in Latin) In vivo studies are conducted in living cell and tissue cultures and animal models (“vivo” is “life” in Latin) During this phase not only potential side effects are screened, in parallel upscaling of the manufacturing process is attempted
- - Study types: experimental (more in the pre clinical fase) and observational (observing occurance in patients) Cohort studies (compare groups/treatment and outcome) Randomized controlled (planned experiments that introduce a treatment or exposure) Case control studies (patients are compared with people who do not have the condition) Phase I: Testing of drug on healthy volunteers for dose-ranging/determines whether drug is safe to check for efficacy (explore their safety and potential clinical benefit in humans) - Safety, Pharmacokinetics (absorbtion, metabolization, excretion) and pharmacodynamics (side effects)
- Phase II: - Testing of drug on patients to assess efficacy and safety / therapeutic dose in smaller group of patients - The drug is compared with patients receiving a different treatment or placebo when no other treatment is available Phase III: -Testing of drug on patients to assess efficacy, effectiveness and safety in larger group of patients / presumed to have some effect - Costliest and longest trials involving a lot of site sometime worldwide
- Submission of clinical information occurs during each phase of the clinical trials. - Submission to Health authorities and to the Ethics committees
- Venture capital is a type of equity financing that addresses the funding needs of entrepreneurial companies that for reasons of size, assets, and stage of development cannot seek capital from more traditional sources Fast track is a procedure used for promising new drugs
- - Proteins are very similar to human milk, this offers several advantages (almost non toxic and easily to assimilate and well tolerated by the human body)
- Involved as RA responsible leading the submission worldwide of the clinical studies to the countries for the late stage clinical trials Unfortunately not always what is promised turns to be the truth
- 2 to 3 billion is the average cost to develop new drugs “go/no go” decision at least in Phase 2 would reduce costs (misleading information collected in Phase 2) Regulators should not be seen as the ‘enemy’ but their input might often save clinical program from failure Because the stakes and resources involved and the pressure on the management and personnel is so high sometimes irrational and not scientifically based decision can be taken. Patient safety can even be ignored and this could end in failure! Promise the impossible generally it does not have an happy ending
- Cream: depends on claims and
- Cream: depends on claims and
- Cream: depends on claims and
- Elixir sulfanilamide was an improperly prepared sulfanilamide medicine that caused mass poisoning in the United States in 1937. It caused the deaths of more than 100 people. The public outcry caused by this incident and other similar disasters led to the passing of the 1938 Federal Food, Drug, and Cosmetic Act.[1][2] In 1937, S. E. Massengill Company, a pharmaceutical manufacturer, created a preparation of sulfanilamide using diethylene glycol (DEG) as a solvent, and called the preparation "Elixir Sulfanilamide".[3] DEG is poisonous to humans and other mammals, but Harold Watkins, the company's chief pharmacist and chemist, was not aware of this. (Though the first case of a fatality from ethylene glycol occurred in 1930 and studies had been published in medical journals stating DEG could cause kidney damage or failure, its toxicity was not widely known prior to the incident.)[1][4] Watkins simply added raspberry flavoring to the sulfa drug which he had dissolved in DEG and the company then marketed the product. Although animal testing should[clarification needed] have been routine in most drug company operations, Massengill performed none and there were no regulations requiring premarket safety testing of new drugs. Thalidomide first entered the German market in 1957 as an over-the-counter remedy, based on the maker’s safety claims. They advertised their product as “completely safe” for everyone, including mother and child, “even during pregnancy,” as its developers “could not find a dose high enough to kill a rat.” By 1960, thalidomide was marketed in 46 countries, with sales nearly matching those of aspirin.
- Share The Committee for Medicinal Products for Human Use (CHMP) is the committee at the European Medicines Agency that is responsible for preparing opinions on questions concerning medicines for human use. The CHMP replaced the former Committee for Proprietary Medicinal Products (CPMP). See the full overview of the CHMP's role Composition The members and alternates of the CHMP are nominated by European Union Member States in consultation with the Agency's Management Board. They are chosen on the strength of their qualifications and expertise with regard to the evaluation of medicines. They serve on the Committee for a renewable period of three years. The CHMP is composed of: a chair, elected by serving CHMP members; one member and an alternate nominated by each of the 28 Member States; one member and an alternate nominated by Iceland and by Norway; up to five co-opted members, chosen among experts nominated by Member States or the Agency and recruited, when necessary, to provide additional expertise in a particular scientific area.
- Share The Committee for Medicinal Products for Human Use (CHMP) is the committee at the European Medicines Agency that is responsible for preparing opinions on questions concerning medicines for human use. The CHMP replaced the former Committee for Proprietary Medicinal Products (CPMP). See the full overview of the CHMP's role Composition The members and alternates of the CHMP are nominated by European Union Member States in consultation with the Agency's Management Board. They are chosen on the strength of their qualifications and expertise with regard to the evaluation of medicines. They serve on the Committee for a renewable period of three years. The CHMP is composed of: a chair, elected by serving CHMP members; one member and an alternate nominated by each of the 28 Member States; one member and an alternate nominated by Iceland and by Norway; up to five co-opted members, chosen among experts nominated by Member States or the Agency and recruited, when necessary, to provide additional expertise in a particular scientific area.
- Herceptin The original studies of trastuzumab showed that it improved overall survival in late-stage (metastatic) HER2-positive breast cancer from 20.3 to 25.1 months.[2] In early stage HER2-positive breast cancer, it reduces the risk of cancer returning after surgery. The absolute reduction in the risk of cancer returning within 3 years was 9.5%, and the absolute reduction in the risk of death within 3 years was reduced by 3%. However, it increases serious heart problems by an absolute risk of 2.1%, though the problems may resolve if treatment is stopped.[8] Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer doesn't overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm). Doctors use laboratory tests to discover whether HER2 is overexpressed. In the routine clinical laboratory, the most commonly employed methods for this are immunohistochemistry (IHC) and either silver, chromogenic or fluorescent in situ hybridisation (SISH/CISH/FISH). HER2 amplification can be detected by virtual karyotyping of formalin-fixed paraffin embedded tumor. Virtual karyotyping has the added advantage of assessing copy number changes throughout the genome, in addition to detecting HER-2 amplification (but not overexpression). Numerous PCR-based methodologies have also been described in the literature.[34] It is also possible to estimate HER2 copy number from microarray data.