An Introduction to Regulatory Affairsc3c69610-733f-49a0-8164-7850d3bbf065... · Let’s bring...

Let’s bring medicines to the world ©NDA Group 2016 | 1Confidential. This presentation is for the sole use of the intended recipient

An Introduction to Regulatory Affairs

Dr. rer. medic Stephanie Krumholz, General Manager, NDA Regulatory Service Switzerland GmbH

26 November 2018


Content

Regulatory affairs for medicinal products• What is regulatory affairs?

– What is the role of regulatory affairs? Why are there regulations in the first place?

– Why do we need regulatory agencies?– And why different ones?

• What is driving the development of a medicinal product?

– What does this all mean for me – if I found a company?

– Recommended Do`s – Where to find more information?

• Key messages/summary

Regulatory affairs for medical devices (a brief intro)• What are medical devices?• How are they regulated?• What`s new?


Stephanie Krumholz - Who am I? What do I do?

• Headquarters: Stockholm, Sweden• Leadership: Johan Strömquist, Chief

Executive Officer and Laurie Smaldone Alsup , MD Chief Operating and Chief Scientific Officer

• Regions: United States and Europe• Locations: Boston, Princeton, San

Francisco, London, Munich, Paris, Stockholm, and Zurich

• Employees: 150+ worldwide• Expert network and Advisory board:

1000 +• Legacy of Leadership: 20+ years.

NDA Group at a Glance


Statistics Showcase

Trusted Partner for Success

1000+ Clients Served

100+ Major Submissions Managed including 50 Rare Disease Programs

80% success rate with Advisory Committee Meetings

80% of the top 20 pharma and 65% of the top 20 biotech companies have contracted with us

45% of all new medicinal products approved in the EU over the last three years


Where NDA Provides Help

TRANSLATIONAL SCIENCE

EARLY DEVELOPMENT

LATE DEVELOPMENT

POST SUBMISSION /

APPROVAL

LIFE CYCLE SUPPORT /

OPPORTUNITIES

SubmissionCTAs/IND

Pre-IND/ SA

Fit to purpose

pre clinical programs

Phase 1Breakthrough

PRIMEAcceleration

strategies

EMA or National Sci. Adv

FDA EOP2HTA meetings

Phase 2Dose SelectionPhase III design

Integrated Regulatory/MA plan

Pediatric Plans

Pre-submission Agency MeetingsNDA/MAA

Phase 3Confirmatory

Clinical studiesIntegrated

Regulatory/MA plan

Line ExtensionsImplement RMPs/

REMsPediatric studiesNew indications

Reviews/ LOQs

Ad Com PrepOE

Final LabelingRisk ManagementPricing Negotiaion

Training

MarketAccess


When do clients come to us?

• Help, I am not sure which animal studies to use.

• I have a new MOA and there is no FDA / EMA guidance which tells me what kind of endpoint, number of patients etc I need to use. What should I do?

• Our investors wants us to go to FDA – what do I need to do? What data do I need to compile?

• Am I subject to any fast track or accelerated procedures?

Our Mission:

- To streamline the global development process

- To accelerate patient access to important medical therapies


What is Regulatory Affairs?

- Who has heard about «regulatory affairs»?

- Why do we have regulations in the first place?

- Is it a strategic or operational function?

- Do you think it`s an important function? What is the ultimate goal?

- What kind of people work there?

- What are major health authorities there? And why do we have different health authorities and not one for the whole world?

- Why can I just not provide the same information (for clinical trial start for example) to all health authorities?

- Why does it matter – even for start ups? I will exit anyhow not get the medicinal product on the market


Why do we have Regulatory Agencies?

FDA (Food and Drug Administration`s)Mission Statements

1. Protecting the public health

-> safe AND efficacious medicinal products with a

positive benefit / risk profile

2. Advancing the public health

-> speed innovation, provide for affordable medicinal products

3. Respond to public health threats

-> key role in counterterrorism

capability


Why do we have regulations in the first place?

• Major incidences drive updates to regulation e.g. • FDA

– Elixir of Sulfanianmide ->1906 Pure Food and Drugs Act

– Thalidomide - > 1962 Kefauver- Harris Amendment• EU

– Tegenero - >Guideline on Requirements for First-in-Man Clinical Trials for Potential High-Risk Medicinal Products


Regulatory Affairs –Operational / Strategic / Key

Keep up to date with regulations in a country / region

• conduct of preclinical / clinical trials

Submit regulatory dossiers to health authorities to enable

• For medicinal products to be sold in pharmacies

Submit marketing authorisation applications to regulatory authorities (MAAs)

• E.g. Patient populations, number of patients required based on precedents, indication, number of studies required, clinical endpoints required for clinical studies and / or MAA submissions depending on the phase of development

Provide strategic guidance to internal stakeholderes to advise on


Introduction to the major health agencies

FDA:Covering the US

EMA:Covering the EU

Health Canada:Covering Canada

TGA:Covering Australia

Swissmedic:Covering Switzerland

https://www.google.ch/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwi_rdmV3r7bAhUL8RQKHWBsDFQQjRx6BAgBEAU&url=https://commons.wikimedia.org/wiki/File:Food_and_Drug_Administration_logo.svg&psig=AOvVaw2OZX8bCx9YsI94U3NvRIFd&ust=1528364075465453

http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000221.jsp&mid=WC0b01ac058097a27a

http://www.google.ch/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjMn-G73r7bAhUFVRQKHQM5COkQjRx6BAgBEAU&url=http://disch.ch/quality-management/&psig=AOvVaw0_OTsgP2O3mrmWoT03uHVA&ust=1528364195761622

https://www.google.ch/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjox8zr3r7bAhXHWRQKHfRbDYsQjRx6BAgBEAU&url=https://www.thepharmaletter.com/article/health-canada-warns-on-tecentriq-myocarditis-risk&psig=AOvVaw056627zidNRo-EsJkk1GZP&ust=1528364286147866


Overview of FDA and EMA: One Agency – Multiple Agencies

FDA Headquarter in Maryland

2017: approximately 18.000 FTEs

Office of the Commissioner and 4 directorates overseeing core agency functions

1 Language

Website: www.fda.gov

EMA will re-locate to Amsterdam (Brexit consequence)

Staffed by temporary and contract agents (587/143)

Executive Director as legal representative. 7 scientific committees responsible for evaluation and life cycle management from early stages of development through MA to safety monitoring

25 Languages (incl Icelandic and Norwegian)

Website: http://www.ema.europa.eu/ema/


What about Swissmedic?

• About 360 FTE• Clinical studies: have to be approved by Swissmedic

and an Ethic Committee• Scientific advice: No separate scientific guidance

provided by Swissmedic, Swissmedic refers to ICH, EMA / FDA guidance

• Do`s: for complex regulatory questions, it is advisable to reach out to FDA / EMA / EU national agencies with the «acual knowhow» in the therapeutic area

• Swissmedic typically provides written feedback, vs F2F meetings with EMA / FDA, EU national authorities more common

• Marketing Authorisation Applications: For certain medicinal products, Swissmedic will not perform an assessment on their own, but approve based on an FDA / EMA approval if certain requirements are met (e.g. Biosimilars, Orphan Drugs can be approved through Article 13 TPA) - new legislation coming into effect 1.1.2019


A snapshot of regulations

which need to be considered

in the development process…..

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004134.pdf


The take away...

- Regulatory Affairs is a key function to support ultimately the registration of a medicinal product

- It also supports the development of a medicinal product before the registration e.g. by enabling clinical trials to test the medicinal product

- The regulatory system is complex and requires an in-depth knowledge in order to navigate appropriately

You need to start thinking about your regulatory strategy early, at the time, when your plan is to set up your own company


Moving into drug development…..

How to get started/what to consider?


It`s long and expensive to get a drug developed

• Return on investment is declining – Increase the success rate – Decrease the costs related to failures

• Development and regulatory strategies:– Reduce the development time and

speed up market access– Early engagement with regulators

likely to increase the success rate• Think ahead and use “core dossier” plus

updates required for each national market


Overview of pre-clinical Studies

Source: https://www.researchgate.net/figure/Steps-of-non-clinical-studies-in-drug-development-process-GLP-Good-laboratory-practice_fig1_311567021


Clinical Development - Objectives

• Develop an effective and safe medicine which has a place on the market with the possibility for re-imbursement

• The conduct of clinical trials must be GCP compliant Highly regulated Strict reporting requirements

• Compliant with current legislation and with input from the regulators Important the ensure that the clinical development program is in line with the marketing expectations Input from regulators recommended

• Meets the patients expectations The patient voice is carrying more weight than in the past and should be considered


Clinical Trial Phases

Phase No of participatns Population Purpose Length Success Rate

I 20 to 100 Healthy volunteers or people with the disease/condition.

Safety and dosage Several months Approximately 70% of drugs move to the next phase

II Up to several hundred people

Patients with the disease/condition.

Efficacy and side effects

Several months to 2 years

33% of drugs move to the next phase

III 300 to 3,000 Volunteers who have the disease or condition

Efficacy and monitoring of adverse reactions

1 to 4 years Approximately 25-30% of drugs move to the next phase

IV Several thousand Volunteers who have the disease/condition

Safety and efficacy

Source: https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm

Scientifically controlled studies undertaken in humans to establish or confirm the safety and effectiveness of investigational medicinal products


Multiple opportunities for interactions with Agencies

R&D Proof of concept Phase 1 Phase 2 Phase 3 Phase 4

IND

Pre-IND Meeting

Pre-Pre IND

Meeting EOP 1 Meeting

EOP 2 Meeting

Pre BLA Meeting

NDA/BLA

R&D Proof of concept Phase 1 Phase 2 Phase 3 Phase 4

• National or pan- European Advice (EMA)• Scientific Advice possible during the entire development process

• Either 40 days or 70 days procedure (the day 70 procedure allows for a meeting)


What do I need to do to get feedback about my development path from a regulatory agency?

Interactions with FDA (at milestones) / Scientific Advice with EMA, national agencies or SwissmedicA briefing package, consisting e.g. of- Formal documentation (e.g. Application form)- (Investigator Broschure)- A (non-)Clinical Protocol, i.e. what you want to test (typically

you would start with a study in healthy volunteers with a single dose)

- Questions to the regulatory authorities about the development program and company position e.g.

- Nonclinical: e.g. Does the Agency agree with the species selection, the dose and the design of the study?

- Clinical: e.g. Does the Agency agree with the patient population, the inclusion and exclusion criteria given the planned indication in xxxx

- CMC

Don`t go and ask, if you are not

ready to take the Agency`s advice !


Overview of medicinal product development, incentives & opportunities for dialogue with EMA

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004134.pdf

Interact early!

Start duringPreclinical phase


Financial incentives for SMEs (small, medium- sized enterprise)

http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2011/03/WC500104237.pdf

SME status, qualification• be established in the European

Economic Area (EEA) • employ less than 250 employees

and have an annual turnover of not more than €50 million or an annual balance-sheet total of not more than €43 million.

Application process to receive SME status


Orphan Drug Designation is a huge opportunity

US EUOrphan Drug Designation

• Fewer than 200.000• No return on investment

Incentive• 7-year marketing exclusivity • Tax credits • Exemption/Waiver of application (filing) fees • OOPD assistance during the development process • Research grants funded by the OOPD

• Life-threatening or chronically debilitating

• Prevalence less than 5 in 10.000

• Significant benefit

Incentive• Protocol assistance• Eligible for the

CentralisedProcedure

• 10 years of market exclusivity


Pediatric plan (PIP)

PIP Application• Basis for development and authorisation of a medicinal product for

all paediatric population subsets. • Includes details of the timing and the measures proposed, to

demonstrate: – Quality – Safety Marketing Authorisation– Efficacy

• To be agreed upon and/or amended by the PDCO • Binding on company -> compliance check (but modifications

possible, at the company’s request)• Certain products exempt from PIP (e.g. Well established use,

biosimilar, generic, traditional herbal medicines)• No MAA filing possible, if PIP is not agreed and procedure

finalized before MAA submission as well as agreements adhered to

PIP Waiver• Exemption• No pediatric

development needed or not appropriate

• Not default, needs good rationale

PIP Deferral• Initiation or

completion of some or all studies after the MAA filing in adults

Peds plan is also required in US (PSP) and CH (PPK)


Different incentives will need to be considered carefully

Orphan SME status

PIP ATMP Adaptive Pathway

PRIME Certain drugs

Fee reductions **

Market exclusivity

SPC extension

Pre- MAA certification

Excemption from paediatric legislation

*

Use of real world data

Conditional approval ( )

Accelerated assessment

Briefing meeting

Dedicated contact pointAssigned CHMP / CAT RapporteurProduct translation by EMAInnovation task force

* e.g. Well - established use, generic, biosimlar, homoeopathic and traditional, herbal products, ** for SME


Opportunities for early access to the market

USA

• Fast Track• Breakthrough Therapy• Priority Review• Accelerated Approval

EU

• PRIME• Accelerated assessment• Conditional MA• Approval under Exceptional

Circumstances

Patient access programs not covered


In EU, there are several filing procedures

Centralised procedure (EMA)

• Single Marketing Authorisation for all EU- countries

• Mandatory for certain medicinal product submissions

Mutual Recognition(EU Member State)

• First Step – 1 national license

• Second step –Mutual agreement in selected MSs

• A Marketing Authorisation in more than 1 country

DecentralisedProcedure

(EU Member State)

• All MSs included in the initial assessment

• A Marketing Authorisation in more than 1 country

National License (one EU Member

State)

• A Marketing Authorisation in one country e.g in Germany


Useful links

• EMA: https://www.ema.europa.eu/

• FDA: https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/OCE/default.htm

• Swissmedic:https://www.swissmedic.ch/swissmedic/de/home.html

• EMA / SME status: https://www.ema.europa.eu/human-regulatory/overview/supporting-smes/applying-sme-status

https://www.ema.europa.eu/

https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/OCE/default.htm

https://www.swissmedic.ch/swissmedic/de/home.html

https://www.ema.europa.eu/human-regulatory/overview/supporting-smes/applying-sme-status


So, what does this all mean for me? Do`s

- Start thinking about your regulatory strategy when you found your company.

- Put a regulatory budget in your plans to allow getting the right experts to help you.

- Think ahead- what drug develompent / regulatory information / documentation may you need at your planned exit and why is it important for a potential byer.

- Carefully consider an early dialoge with regulatory agencies starting in the preclinical stage / EOP I to benefit from incentives, rewards and understand obligations.

You need to understand the incentives, rewards and obligations (e.g. PIP) early on to avoid delays in the development of a medicinal product and in order to have an adequate package for your exit


Content

Regulatory affairs for medicinal products• What is regulatory affairs?

– What is the role of regulatory affairs? Why are there regulations in the first place?

– Why do we need regulatory agencies?– And why different ones?

• What is driving the development of a medicinal product?

– What does this all mean for me – if I found a company?

– Recommended Do`s – Where to find more information?

• Key messages/summary

Regulatory affairs for medical devices (a brief intro)• What are medical devices?• How are they regulated?• What`s new?


What are medical devices?Definition*: ‘Medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings.

Examples: • dental and surgical instruments • bandages and splints• treatment chairs and hospital beds

*A full definition can be found in Article 2(1) of the MDR.


What are in vitro diagnostics?Definition*: ‘In vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, piece of equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body.

Examples: • pregnancy tests • blood glucose monitors

*A full definition can be found in Article 2(2) of the IVDR


New regulation – what`s coming when?

New: Medical Devices Regulation (2017/745/EU) (MDR) and the In-vitro Diagnostic Medical Devices Regulation (2017/746/EU) (IVDR)

• Bring EU legislation into line with technical advances, changes in medical science, and progress in law making.

• The MDR will replace the existing Medical Devices Directive (93/42/EEC) (MDD) and the Active Implantable Medical Devices Directive (90/385/EEC) (AIMDD).

• The MDR was published in May 2017• A transition period is in place

Regulations do not need to be transposed into national law. • The MDR and the IVDR will reduce the risks of discrepancies in interpretation across the EU

market.• New Regulations will create a robust, transparent, and sustainable regulatory framework,

recognised internationally, that improves clinical safety and creates fair market access for manufacturers.

https://ec.europa.eu/docsroom/documents/31201


What`s different to medicinal products?• No official authorisation procedure in Switzerland. EU system:

compliance assessment and certification (based on bilateral agreements)

• Compliance with internationally valid norms is evaluated by private entities.

• Medical devices are attributed to various categories that require varying assessment procedures. - > CE Mark

• Based on treaties: permit direct distribution from Switzerland to all EU and EFTA Member States and Turkey, without an authorised representative with registered offices in the said countries. In return, companies with registered offices in the countries concerned can distribute compliant medical devices directly to Switzerland. However, country-specific requirements relating to medical devices remain valid

• Swissmedic's focus is on effective market surveillance.• FDA – regulates medical devices• EMA – does not regulate medical devices, they are regulated in

Europe by notified bodies


Classification of a medical device

• Classification is based on risk, as set out in Annex VIII of the MDR and Annex VII of the IVDR.

• Manufacturers need to demonstrate that their medical device meets the requirements in the MRD or IVDR by carrying out a conformity assessment.

• The assessment route depends on the classification of the device. • Manufacturers can place a CE mark on the product to show that the

medical device has met the requirements when it has passed the conformity assessment.

• The risk class determines whether or not a conformity assessment would be required (which is done by a Notified Body).


What requirements do I need to meet for a conformity assessment?

1. General Safety and Performance Requirements (Annex I of the MDR and IVDR):

• Benefits > risks and achieve the claimed performance - This must be proven with supporting clinical evidence and investigation

• Chemical, physical and biological properties for medical devices• Performance characteristics for in vitro diagnostic medical devices• Information supplied by the manufacturer with the device - For example, instructions for

use. It is important that devices are labelled correctly

2. Technical documentation (Annex II of the MDR and IVDR)

3. Harmonised standards / common specifications (Articles 8 and 9 of the MDR and IVDR)

Please see Annex IX, X and XI of the MDR and the IVDR for more information.


Useful links (please consult those links)

• Factsheet for manufacturers of medical devices: https://ec.europa.eu/docsroom/documents/31201

• Swissmedic / EU information on medical devices (classification process, requirements): https://www.swissmedic.ch/swissmedic/en/home/medical-devices/regulation-of-medical-devices/medical-device-regulation_online-guide.html

• https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/640404/MDR_IVDR_guidance_Print_13.pdf

https://ec.europa.eu/docsroom/documents/31201

https://www.swissmedic.ch/swissmedic/en/home/medical-devices/regulation-of-medical-devices/medical-device-regulation_online-guide.html

An Introduction to Regulatory Affairsc3c69610-733f-49a0-8164-7850d3bbf065... · Let’s bring...

Documents

Transcript of An Introduction to Regulatory Affairsc3c69610-733f-49a0-8164-7850d3bbf065... · Let’s bring...