introduction to regulatory affairs - pauwels consulting academy
TRANSCRIPT
Regulatory affairs Introduction
June 14 2016
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The presentersRegulatory affairs
Fiorenzo SavorettiRegulatory & Quality Consultant More than 10 years RA experience Working at Pfizer as Site Compliance Network MemberPreviously 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 DeschachtRegulatory and Quality ConsultantMore than 6 years RA experience Working at GSK as Global Regulatory Affairs CMC specialistPreviously worked at Pfizer and Zoetis
…will tell you about Drug Registration from a RA perspective
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DefinitionRegulatory affairs
Perceived definitionRegulatory Affairs (RA) is all about paper work
How the drugs are being approved, safety standard and information databasehttp://www.indeed.com
Comprehensive definitionRA 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
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HistoryRegulatory 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
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HistoryRegulatory 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 transparentEMA committee was developed for drug assessment in the EU
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ResponsibilitiesRegulatory 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 drugIn the design and monitoring of clinical studiesFor the marketing, the advertising and the communicationManufacturing, packaging and distributionDeveloping business strategy
Monitoring and analyzing regulatory issues for multiple nations and regions of the world
Part 1 The Drug Development
Fiorenzo Savoretti
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Drug DevelopmentA regulatory point of view
Develop and launch a new pharmaceutical product takes up to 15 years
ProblemsDuring the process of scientific development Changing regulatory environment
Includes Pre-clinical research on microorganisms and animalsClinical trials on humansObtaining regulatory approval to market the drug
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DiscoveryDesign phase
Stage 110.000 compounds may be potential candidates for development as a medical treatment
Stage 2After early testing, however, only a small number of compounds look promising and call for further study.
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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
DiscoveryDesign phase
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DevelopmentExperimental 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)
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Preclinical ResearchPrediction of effects
Before testing a drug in people potential to cause serious harm (toxicity)?
Two types of preclinical research
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Clinical ResearchStudies in human
Clinical research: trials that are done in peopleFollow a typical series
Phase I: early, small-scale
Phase III: late-stage, large scale
Phase ITest a new drug or treatment in a small group of people for the first timeEvaluate
Its safetyDetermine a safe dosage rangeIdentify side effects
20 - 100 volunteers: healthy or with disease/condition (safety and dosage)
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Clinical ResearchStudies in human
Phase IIDrug or treatment is given to a larger group of people Evaluate
EffectivenessFurther evaluate its safety
Up to several 100 people with the disease/condition
Phase IIIThe drug or treatment is given to large groups of people Confirm
Effectiveness,Monitor side effectsCompare it to commonly used treatmentsCollect information on the safety
300 - 3000 volunteers who have the disease
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RegistrationConclusion 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
CompanyFile 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
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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 DevelopmentEureka… but too early!
2006 receives FDA Fast Track DesignationTalactoferrin Alfa in Non-Small Cell Lung Cancer and Diabetic Foot Ulcers
OCT 5, 2006 http://www.prnewswire.com
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Example of Drug DevelopmentEureka… but too early!
2008 Talactoferrin AlfaMother’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 systemAgennix 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
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Example of Drug DevelopmentEureka… 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
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Drug DevelopmentWrap 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
End Part 1
Part 2 Registration and product life cycle
Nick Deschacht
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Drug DevelopmentWrap 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
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The path towards drug development does not always have a happy ending, but what if it does?
Drug developmentHappy endings?
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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!
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A medicinal product
Define what a medicine is!
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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!
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ClassificationControl based
Prescription drugs – OTC (over the counter) drugs
Route of administrationGastro intestinalEpidural Cerebralintradermal
Therapeutic effectPreventive vs treatment
Anatomical Therapeutic Chemical (ATC) Classification System
Define what a medicine is!
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ClassificationSmall molecule drug – Chemicals
Biopharmaceuticals – BiologicalsRecombinant proteinsVaccinesBlood products Gene therapyMonoclonal antibodies Cell therapy (stem cell therapies)
Define what a medicine is!
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The path towards drug development does not always have a happy ending, but what if it does?
Drug product registration Happy endings?
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Drugs are not ordinary consumers’ products! In most instances, consumers are not in a position to make decisions about
when to use drugswhich drugs to usehow 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?
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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 criteria1. Quality2. Safety3. Efficacy
General expectation of medicine
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U.S. Food and Drug administration (FDA) – 1906Center 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…
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CFDA
Pmda
TGA
ANVISA
Regulations made by…
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http://www.efpia.euWorldwide : 195 countries
Global market
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International Conference on Harmonisation of Technical Requirements (ICH) for Registration of Pharmaceuticals for Human Use – Established in 1990 by JP, US, EU
Quality guidelinesSafety guidelinesEfficacy guidelinesMultidisciplinary 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
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DossierCollection 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
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FilingUSA
New Drug application (NDA)Abbreviated New Drug Application (ANDA)Biologics License Application (BLA)
EuropeNational Procedure (NP)Decentralized Procedure (DCP)Mutual Recognition Procedure (MRP)Centralized Procedure (CP)
All routes lead to…. Registration?Different filings
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FilingUSA
New Drug application (NDA)Abbreviated New Drug Application (ANDA)Biologics License Application (BLA)
EuropeNational Procedure (NP)Decentralized Procedure (DCP)Mutual Recognition Procedure (MRP)Centralized Procedure (CP)
All routes lead to…. Registration?Different filings
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Filing Europe
Centralized Procedure (CP)
All routes lead to…. Registration?
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Filing Worldwide
Determined by authorities
All routes lead to…. Registration?
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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 professionalsEnsure 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 AffairsDefinition
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Currently represented by 2 main organisations
The Organisation for Professionals in Regulatory Affairs, TOPRA (UK)
The Regulatory Affairs Professionals Society, RAPS
Regulatory Affairs
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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 AffairsImportance
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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 AffairsNonsense of RA
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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.
ExamplesRegulatory Affairs
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Global Regulatory Affairs
Local Regulatory Affairs
Clinical Regulatory Affairs
Technical Regulatory Affairs (CMC)
Labeling Regulatory Affairs
Regulatory AffairsFunctions
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Knowledge of legislation
Regulatory Procedures
Timelines for Procedures
Content of Applications
Technical skills
Regulatory AffairsExpertise required for Regulatory
Negotiation skills
Flexibility
Insight into stakeholders interest
Language skills
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Regulatory AffairsRegulatory interactions
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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
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Mergers and acquisitionsOwner changeProduction site change
Marketing desireClaim extensionsLabelling changes
Technical changesChange in bacterial cultureChange in adjuvant
Daily routine, what do I do?Global Regulatory Affairs, CMC consultant
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Scientific and technical writings
Meetings
Information analysis (literature)
Read guidelines/documents
Quality review documents
Strategic guidance
Global Regulatory Affairs, CMC consultantDaily routine, what do I do?
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Regulatory requirements change
Regulations change
Guidelines rewritten
Experience based job
Technology keeps developing
Global Regulatory Affairs, CMC consultantDaily routine – always??
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Biosimilars
GenericsPatent basedPossible registration short cut
Company A
Company B
Current challenges
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BiosimilarsProperties 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
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Personalized medicinePersonalized stents
Lung stentExemption needed
Bioresorbable Airway Splint Created with a Three-Dimensional PrinterN Engl J Med 2013; 368:2043-2045 May 23, 2013 DOI: 10.1056/NEJMc1206319
Diagnostics coupled to treatment Breast cancer – Herceptin
Future/Current challenges
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Personalized medicine Cell therapy
Redesign clinical trialsDifferent production and quality standard
AntibioticsAntimicrobial resistanceNovel Antibiotics Decrease in requirements needed
Future challenges
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Future challenges
Personalized medicine Xenobiology (next generation biologicals)
http://www.complix.com
Genetic Modified organisms (actogenix-intrexon)
Actiobiotics
Part 2 The End