avoiding pitfalls in the regulatory path - mars best practices

Avoiding Pitfalls in the Regulatory Path Sonia Sanhueza September 30, 2011

Avoiding Pi*alls in the Regulatory Path

Best Prac7ce Sessions MaRS Discovery District

30 SEP 2011

Sonia Sanhueza, PhD Prac7ce Lead & Advisor, Life Science & Healthcare

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Avoiding Pi*alls in the Regulatory Path

1.   Pharma / Biotech / Medical Device Product Life Cycle

2. Regulatory and Quality Requirements

3. Common Pi*alls and Consequences

4. Avoiding Pi*alls

5. US FDA 483 / Warning LeRer

6. Summary

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Product Life Cycle

concept POC Pre-‐clin clinical approval

Quality / Regulatory requirements

$$$$

Drugs / biotech /biologics

Claims IFU

The Interna'onal Conference on Harmonisa'on (ICH) of Technical Requirements for Registra7on of Pharmaceu7cals for Human Use

US FDA European Medicine Agency

Health Canada

Japan’s Pharmaceu7cal and Medical

Devices Agency (PMDA)

concept prototype Tes7ng valida7on approval


$$$$

Medical devices Claims IFU

Product Life Cycle

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US FDA Competent Authority in

the MS

Health Canada



Drugs / Biotech / Biologics

concept POC Pre-‐clin clinical approval $$$$

GO /

NO-‐GO

R&D

Drugs / Biotech / Biologics Quality and Regulatory Requirements


•  Legal – IP / Trademark •  Raw materials •  CRO – pre-‐clin •  Suppliers qualifica7on •  SOPs •  Tes7ng > valida7on •  Reference standards •  Processes •  Procedures •  Personnel •  Facility •  Documenta7on

GO /

NO-‐GO


GO /

NO-‐GO

cGLP

GDP

cGMP



•  Legal – IP / Trademark •  Raw materials •  CRO – pre-‐clin •  Suppliers qualifica7on •  SOPs •  Tes7ng > valida7on •  Reference standards •  Processes •  Procedures •  Personnel •  Facility •  Documenta7on

GO / NO-‐GO

•  Protocols •  Reports •  Document control •  Process valida7on •  Environmental monitoring

•  cGMP/GCP/GLP/GDP •  Sta7s7cal analysis •  CMOs •  CROs – clin •  Audits


•  General provisions of current Good Manufacturing •  Responsibility of management. •  Conduc=ng audits, taking correc=ve ac=on and documen=ng results. •  Crea=ng design controls: input, output, valida=on, transfer, changes and

documenta=on. •  Purchasing and the evalua=on of suppliers. •  Iden=fica=on and traceability of products. •  Dealing with produc=on and process changes. •  Inspec=on, measuring and tes=ng equipment. •  Acceptance ac=vi=es. •  What to do with non-‐conforming products. •  Correc=ve and Preven=ve Ac=ons (CAPA). •  Labeling, storage, distribu=on and installa=on. •  Records and servicing of products.

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Legal The US Patent and Trademark Office (USPTO) is not the only checkpoint for pharmaceu=cal trademarks.

The trademark clearance process for pharma companies consists of both a legal and regulatory process

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Drugs / Biotech / Biologics Trademark Regulatory Requirement

In most cases the legal process consist of:

•  branding concept conceived by pharmaceu=cal branding specialists •  pool of poten=al brand-‐name candidates submiUed for considera=on by the marke=ng or trademark development department

•  candidates are typically priori=zed •  forwarded to the company’s trademark legal department or law firm for ini=al screening (e.g. Trademark db plaXorms) in key jurisdic=ons to weed out poten=ally problema=c candidates

•  Candidates proceed to a full trademark legal clearance search (trademark aUorney)

•  providing a legal opinion as to a trademark’s poten=al availability for use and registra=on in connec=on with a par=cular product (or service in the case of service marks)

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Specialized trademark research report -‐ assists a trademark aUorney in formula=ng a well-‐supported opinion on availability of a pharmaceu=cal trademark. It should mirror FDA review process •  Should have a name safety component •  Include a selec=on of sources that are reviewed by the FDA

o  Orange Book (FDA-‐approved drugs) o  U.S. Adopted Names, USAN, (generic-‐drug names) o  include informaEon derived using known FDA methods, such as the FDA’s Phone=c and Orthographic Computer Analysis algorithm.

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Health Canada •  4. DEFINITIONS •  Brand name (or proprietary drug name): C.01.001.(1) of the Food and Drug RegulaEons

•  Chemical name: The chemical name of a drug provides an unambiguous picture of a molecule so that a trained chemist can use it to draw its structure if required

•  Common name: C.01.001.(1) of the Food and Drug RegulaEons states that a "common name" means, with reference to a drug, the name in English or French by which the drug is (a) commonly known and (b) designated in scienEfic or technical journals, other than the publicaEons referred to in Schedule B to the Act.

•  Generic name: The generic or non-‐proprietary name describes the drug substance.

•  Health product: Health products include pharmaceu=cals, biologicals, vaccines, medical devices, natural health products, radiopharmaceu=cals and veterinary drug products.

•  Interna7onal Nonproprietary Name (INN): INNs iden=fy a drug substance by a unique, universally applicable and accepted generic name. It is noted that chemicals that do not have a defined chemical composi=on or structure or that cannot adequately be described cannot be assigned INNs (i.e., mixtures of substances).

•  Look-‐alike Sound-‐alike (LA/SA) Health Product Names: Health products that have a similar wriUen name or similar phone=cs to those of another health product.

•  Product line extension: A product line extension results when a drug is named by using the brand name of another drug with the addi=on of a modifying prefix or suffix that is intended to dis=nguish the new product from the original

•  Proper name: C.01.001.(1) of the Food and Drug RegulaEons states

•  Trade-‐mark: Sec=on 2 of the Trade-‐marks Act states that a trade-‐mark is (a) a mark that is used by a person for the purpose of disEnguishing or so as to disEnguish wares or services manufactured, sold, leased, hired or performed by him from those manufactured, sold leased, hired or performed by others, (b) a cerEficaEon mark, c) a disEnguishing guise, or (d) a proposed trade mark.

•  Trade-‐name: Sec=on 2 of the Trade-‐marks Act states that a trade name is the name under which any business is carried on, whether or not it is the name of a corporaEon, a partnership or individual.

•  United States Adopted Name (USAN): USANs iden=fies nonproprietary names for drugs by establishing simple, logical nomenclature based on pharmacological and/or chemical rela=onship.

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GO / NO-‐GO

Regulatory Agency

inspec7ons

•  Clinical sites •  Facili=es •  Pre-‐clinical data


•  SOPs -‐ dra`ed documents, no signatures of responsible person, originals not in place only photocopies, not enough detail for operators to follow procedures

•  Personnel o  lack of appropriate educa=on o  Lack of appropriate training o  Training not documented

•  Facili7es o  Lack of environmental monitoring program or unreliable o  Cleaning procedures not validated o  Airflow velocity inside cri=cal areas not well defined

Drugs / Biotech / Biologics Common Pi*alls

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Tes7ng procedures •  Acceptance criteria not established •  Specifica=ons not in place •  Inappropriate reference standard •  Tests not validated •  Results not documented

Raw materials •  Sourcing material with undefined impuri=es •  Supplier not qualified

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Clinical •  Conduct of clinical trial – lack of appropriate personnel supervision •  Enrolment of subjects that did not meet eligibility criteria •  Failure to no=fy IRB on protocol changes •  Protocol not signed by inves=gator •  Failed to obtain informed consent Customer Complains •  Parameters against which to assess adequacy of ac=ons not established •  SOP not in place

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concept prototype Tes7ng valida7on approval


$$$$

Medical devices Claims IFU

Product Life Cycle

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US FDA Competent Authority in

the MS

Health Canada



GO /

NO-‐GO

R&D

MEDICAL DEVICES

concept prototype Tes7ng valida7on approval $$$$

•  Legal – IP / Trademark •  Raw materials •  Suppliers qualifica7on •  SOPs •  Tes7ng > valida7on •  Processes •  Procedures •  Personnel •  Facility •  Documenta7on •  Design process

GO /

NO-‐GO

R&D

MEDICAL DEVICES


QS

ISO 13485

MEDICAL DEVICES

Design planning

Design verifica7on

Design transfer

QS

ISO 13485

inputs

outputs

Reviews

Change control


GO / NO-‐GO

•  Protocols •  Reports •  Document control •  Process valida7on •  Environmental monitoring

•  Sta7s7cal analysis •  CMOs •  CROs – clin •  Audits

MEDICAL DEVICES

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•  Gap analysis audit -‐ Audit in which the current level of compliance with the appropriate quality regula=ons including FDA GMP, ISO 13485, Japan PAL, Brazilian GMP and/or CMDR is determined for the company. The gap analysis is typically conducted before a system is implemented to iden=fy areas of deficiency.

•  Pre-‐assessment audit – It is highly recommend that a pre-‐assessment audit be conducted several weeks prior to a cer=fica=on audit.

MEDICAL DEVICES -‐ Quality Requirements

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•  Full or par7al internal audit -‐ ISO and FDA QSR (GMP) require that manufacturers conduct regular internal audits of their quality management systems. Par=al audits can be conducted in which the auditor focuses on specific areas of the quality system where you suspect non-‐compliance occurs or have occurred, or focus on areas where audits cannot be conducted by your in-‐house internal auditor due to possible conflicts of interest.

•  Subcontractor or supplier audit -‐ Cri=cal suppliers must be "controlled." This is not only a good business prac=ce, but o`en also a regulatory requirement. For example, if your device is manufactured by a subcontractor, it is your responsibility to ensure their manufacturing processes meet the appropriate standards and regula=ons.

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•  ISO 13485:2003, FDA Good Manufacturing Prac=ces (GMP), CE Marking and Canadian Medical Device Regula=ons (CMDR).

•  Management responsibili=es to customers, to quality policy, and to employees.

•  Resource management: personnel, materials, infrastructure and facili=es.

•  Product realiza=on from the planning stages through design development through interac=on with customers.

•  Ways to measure, evaluate, and improve performance within the organiza=on.

•  Requirements for incident repor=ng, technical files, and risk analysis.

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•  Procedures for implemen=ng CAPA and document CAPA ac=vi=es are inadequate or non-‐existent

•  Results are not documented or not verified

•  Procedures not in place for the valida=on of the device design, design requirements and document control

•  Acceptance criteria for tes=ng not in place

•  Lack of maintenance of quality requirements in regards to suppliers, contractors, consultants

MEDICAL DEVICES – Common pi*alls

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•  Device history records (DHR) for each batch, lot, unit are not maintained

•  Procedures used by operators to manufacture product are not maintained in Device master records (DMR)

•  Lack of compliance with established quality system requirements

•  Companies implement changes before performing iden=fica=on, documenta=on, valida=on, verifica=on, review, and approval of design

•  Acceptance of specifica=ons not established


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•  Risk process and analysis not in place

•  Design History File (DHF) – user needs and intended uses not defined

•  Design valida=on procedures for system integra=on tes=ng for the device so`ware not established and documenta=on not in place

•  Personnel – training records not in place


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•  Regulated companies -‐ opportunity to engage with healthcare consumers and healthcare professionals who are increasingly using the internet to find health informa=on

•  To avoid regulatory piXalls it is important to have expert counsel to: o  address product risk informa=on o  consumer-‐generated discussion of off-‐label uses o  online communica=ons o  interac=on between consumers and healthcare providers about

health topics that have an impact on pa=ent health

•  The team tasked with overseeing the design and execu=on of a social media campaign should be mul=disciplinary: marke=ng, corporate, regulatory, medical affairs, legal & other relevant internal par=es

ROL OF SOCIAL MEDIA in REGULATED COMPANIES

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Guidelines US FDA – no official guideline, release informa=on expected soon EU – only internet communica=on in general It is important to know the boundaries of what will and will not be permiUed

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ROL OF SOCIAL MEDIA in REGULATED COMPANIES

TIME IS MONEY = REVENUES LACK OF CREDIBILITY = INVESTORS

LOST MARKET = COMPETITIVE POSITION

Common pi*alls – Consequences / Impact

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US FDA will: •  Request prompt ac=on with consequences for lack of ac=on:

o  Seizure o  Injunc=ons o  Civil money penal=es

•  Address leUer within 15 business days

•  Withhold approval of any new applica=on or supplements lis=ng the firm as a drug manufacturer

•  Refusal by FDA of product manufactured at foreign facility to entry into the USA

•  Be aware: Not intended to be an all-‐inclusive list of viola=ons

Common pi*alls -‐ Consequences

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US FDA WARNING LETTERS

Drugs / Biotech / Biologics

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US FDA Form 483 and / or Warning LeRer

•  FDA Form 483 is referred to as "No=ce of Inspec=onal

Observa=ons."

•  The 483 is issued by the FDA field inves=gator a`er an on-‐site inspec=on

•  It lists deficiencies in your quality system.

•  The observa=ons are based on the inspector's interpreta=on of the regula=ons as they relate to your opera=onal GMP quality system.

•  The field inspector will submit the finalized 483 to his/her superiors; based on the severity of the findings, an FDA Warning LeUer may be issued to your firm.

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•  You must respond to the 483 promptly within a =meframe specified by the FDA.

•  Analyze the findings of the FDA Form 483 and/or Warning LeUer

•  Chart a course of ac=on for your company

•  Propose "Correc=ve Ac=ons“ (CA) to be made to your quality system.

•  Provide a detailed response for each item addressed in the 483. The quality and promptness of your response to this leUer are extremely important

•  Suggest an appropriate =meline to sa=sfy the FDA

•  Assist in implemen=ng correc=ve ac=ons in response to FDA Form 483.

•  Be available to answer all ques=ons from you or the FDA during your efforts to correct the noted deficiencies

US FDA Form 483 and / or Warning LeRer (cont’d)

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GCP compliance

Clinical inves=gato

r

Document control

safety and

validity of data

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compliance CAPA

15 bus. days

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procedures

Drug cGMP

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personnel

Dras=c consequences

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QS

Medical devices

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Doc. Procedures Controls

QS DHR

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QSR: DMR

procedures

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-‐Specs -‐Risk

-‐Valid’n -‐Intended

use -‐DHF

-‐ Process

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Process CAPA

Complains

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Hospital Post-‐

approval inspec=on

documenta=on

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Dras=c consequences

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Summary •  Start with the end in mind -‐ what is your claim?

•  Don’t cut corners

•  Get exper=se to help you prepare the Regulatory Requirements & Quality System –  audit your quality system on a regular basis to ensure compliance with the appropriate

regula=ons and standards in compliance with the FDA Quality System Regula=on, European Device Direc=ves, Japan's PAL, Brazilian GMP and Canadian Medical Device Regula=ons (CMDR).

–  Failure to do so can result in poor product quality, loss of cer=fica=on or lack of process improvement.

•  Key elements to have in place: processes, procedures, documenta=on, controls, training

•  Plan for tomorrow 51

THANK YOU FOR YOUR ATTENTION

Q&A

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