BioEntrepreneurship: Navigating the Global Regulatory Pathway

MaRS BioEntrepeneurship Lecture Series:

Navigating the GlobalRegulatory Pathway

Anne TomalinPresident, CanReg Inc.

January 15, 2007

CanReg Inc.

! Dedicated exclusively to global regulatory affairs

! Founded in 1996; based in Dundas, Ontario

! Approximately 100 in-house employees

Agenda

! Drug Development Overview

! Conducting Clinical Trials

• United States

• Canada

• Europe

! Marketing Applications

• United States

• Canada

• Europe

! Q&A

Drug Development

! Phases of Drug Development

• Exploratory research and Preclinical (animal) Pharmacology Studies

• Preclinical Toxicology Studies

• Phase I Clinical trials

• Phase II Clinical trials

• Phase III Clinical trials

Drug Development

! Exploratory Research• Identification of drug molecules, characterization of their biological

and pharmacological activity• May include preliminary toxicology screens• Decision on candidate drugs for further development• NOT subject to Regulatory approval, no requirements to tell the

Regulatory Authorities what you are doing EXCEPT:– studies that will eventually used in support of a New Drug

Application/Submission/Marketing Authorization may need tofollow Good Laboratory Practice (GLP) guidelines

Drug Development

! Animal Pharmacology

• Studies are usually conducted in animal models in support of the efficacy

of a product for a given indication (i.e. pharmacology tests).

• Many of these studies will ultimately fall under the requirements for GLP.

Drug Development

! Pre-clinical Toxicology Testing• Must be conducted under GLP if you are planning to use the study in support

of an IND/CTA or NDA/NDS/MA submission

OR, provide some justification for why GLP was not followed

• Once you reach a point where an IND/CTA is being submitted, theRegulatory Agency expects to see this data• No need to inform the Regulatory Agency of toxicology studies or results

prior to this stage

HOWEVER, it may be a good strategy to ask the FDA inparticular about design of preclinical testing, particularly ifyour product is unique e.g. recombinant proteins

Drug Development

! Pre-clinical Toxicology Testing

CASE STUDY:You are developing three candidate new chemical entities (NCEs) for

treatment of type II diabetes, and have conducted preliminary toxicology tests

as part of your screening process. Drug Candidate 1 shows major toxicity

problems in an animal toxicology study. The other two candidates do not

show these problems. Do you need to inform the FDA of Candidate 1’s

toxicity profile?

Drug Development

! Good Laboratory Practices (GLP) for NonclinicalLaboratory Studies• 21 CFR 58• Describes how animal studies should be conducted and documented.• Covers such items as organization and personnel, facilities,

equipment, test and control articles, protocols, records and reportsincluding sample and record retention.• Final study reports contain a certification where the laboratory

supervisor signs off that the study was conducted under GLP.• Facilities that carry out animal toxicology studies can be inspected by

the FDA.• Preliminary pharmacological screening, preliminary metabolism

studies, pilot studies (e.g. dose-ranging) do not have to follow GLP.

Drug Development

! Phase I studies

• First in man

• Healthy volunteers

• Cannot be done until an IND/CTA is in place

• This is the first point at which there is a legal requirement for the

Regulatory Agency’s involvement in the drug development process

Drug Development

! Phase I studies

• Protocols for Phase I studies, with the supporting animal data, will be

reviewed by the Regulatory Agency for safety aspects.

• The Regulatory Agency will decide if there is sufficient information

to ensure the there is a reasonably low risk to human subjects.

• There is a recognition of the need for flexibility in study design at

these early stages of development.

Drug Development

! Do all animal toxicology studies need to be completed priorto starting Phase I trials?

CASE STUDY:

You plan to initiate the first Phase I trial for a NCE in 24 healthy male

volunteers, age 18 to 35. You will be using a single dose of 100 mg

and collecting blood sample for out to 24 hours to measure

pharmacokinetic parameters. What animal toxicology studies do you

need to complete in order to support this trial?

Drug Development

! ICH Guideline that relates to timing of nonclinical studies inpreparation for clinical trials:

• M3 Nonclinical safety studies for the conduct of human clinical trials

for pharmaceuticals.

• Amount of information needed is decided on a case by case basis.

Drug Development

! Phase II and III Clinical Studies

• Studies in patients

• Involves efficacy as well as safety evaluation

• Increasing numbers of patients as drug development progresses

NOTE: The different “Phases” of development are used by Industry

and the Regulatory Agency as convenient terms to describe clinical

trials. There is considerable flexibility in the definitions of these

Phases within the regulations.

Drug Development

! Phase II and III studies

• During review, Phase II and III studies are scrutinized for efficacy as

well as safety aspects.

• These studies can be put on clinical hold if it is felt the study design is

flawed.

• By the time you reach Phase III, the clinical endpoints of your trial

will be used to determine the indication for your product. These are

often major points of discussion between the Agency and the sponsor.

Drug Development

! Do the different phases of drug development need to beconducted in order?

CASE STUDY:

Your company has just completed two large-scale Phase III studies in

support the safety and efficacy of a NCE for the treatment of asthma.

Your clinical team then comes to you to submit a Phase I Protocol for

this NCE.

– Is this allowed under the regulations?

– What kind of study might they be planning to do?

Drug Development

! Regulatory requirements for the conduct of clinical trials:

• Covered in Good Clinical Practice (GCP) Guidelines

• Also covered in US Regulations (21 CFR 312 Subpart D), Canadian

Regulations and European Regulations

– describes the responsibilities of those conducting clinical trials

INDs & Drug Development

! Details and documentation about how a Sponsor conforms torequirements for Good Clinical Practice (GCP), IRB approval, andinformed consent are not required to be submitted with an IND.

! For example, copies of signed informed consent forms,monitoring reports from study sites, etc.

! What is required is a certification on the part of the Sponsor andthe Investigator that they agreed to comply with all relevantregulations.

! Clinical sites can be inspected by the FDA, and documentationwould need to be provided at that time.

Conducting Clinical Trials

Clinical Trials in theUnited States


! Regulations and Guidelines that Relate to INDs

! 21 CFR:

! CFR 312 Investigational New Drug Application

! CFR 58 Good Laboratory Practices

! CFR 50 Institutional Review Boards (IRBs)

! CFR 56 Informed Consent

! CFR 320.31 Bioequivalence

! ICH Guidelines on Good Clinical Practice

! Guidelines on Clinical Trial Design and Nonclinical Testing (FDA and ICH)


! IND Application! The IND is essentially an exemption from the FD&C Act that allows an

unapproved drug to be shipped in interstate commerce

! In practice, you are submitting technical information on your

product to the FDA to allow them to assess the risks to human

subjects

! Once an IND is submitted, trials cannot begin until 30 dayshave passed

! INDs are not approved! If after 30 days the IND has not been put on “clinical hold”, the IND

“becomes effective” and the trial can begin.


! Exemptions:! Off label use of approved drugs by physicians (within the

practice of medicine)! Clinical investigations of approved drugs, provided that

! The information is not intended to support significantchanges in labeling or advertising

! The trial does not involve a change in the patient population,the route of administration, or a change in the dosage levelwhich might increase risk

! Certain bioavailability studies (generic drugs)


! CLINICAL HOLDS (21 CFR 312.42 )

! A clinical hold is an order issued by the FDA to the sponsor to delay a

proposed clinical investigation, or to suspend an on-going investigation

! The Agency can impose a clinical hold for a Phase I study if

! There is unreasonable risk to human subjects

! The Investigators are not qualified

! The Investigator Brochure is erroneous, misleading or materially

incomplete

! The IND does not contain sufficient information to assess risks

! The Agency can impose a clinical hold for a Phase II or III study if

! Any of the above conditions for Phase I Clinical holds applies

! If the study protocol or plan is clearly deficient in design to meet its

stated objectives


! In the US, the IND is a dynamic document, and is as much aprocess as a submission

! Associated with a drug development program rather than a specific protocol

! For example, once an IND is open for a particular drug and indication, multiple

protocols can be submitted to the same IND

! There is no “wait time” associated with protocols sent in to an already existing IND


! Reflects the dynamic nature of drug development

! Non-clinical investigation continues in parallel with clinical development

! Chemistry and Manufacturing changes from small scale to commercial scale

! IND requirements increase with increased clinical development

! The FDA expects to be informed of clinical progress and new information


! Common issues/questions that arise for US INDs

! What kind of supporting data do we need to submit a US IND for a Phase I

study?

! First in man

! Healthy volunteers


! Treatment INDs

! Emergency Use INDs


! How to put together an IND submission! Relevant Sections of the CFR:

! CFR 312 Investigational New Drug Applications 312.23 (original

submission), 312.30, 312.31, 312.32, 312.33

! Relevant Guidelines:

! Content and format of INDs for Phase I studies for drugs, including

well-characterized, therapeutic, biotechnology-derived products

! INDs for Phase 2 and 3 studies of drugs, including specified therapeutic

biotechnology-derived products. Chemistry, manufacturing and

controls content and format [DRAFT GUIDANCE]


! The IND Submission

! The key components are the Pharmacology and Toxicology

background information, the Study Protocol, and the Chemistry and

Manufacturing information


! The Submission Process

! Submission is placed in color-coded accupress binders; these are available

from the FDA for a fee

! The first submission is given a serial number 000; volumes are labeled 1.1,

1.2, 1.3 etc.

! Pages should be numbered sequentially starting with 001

! A typical submission for a Phase I study with supporting Pharm/Tox data

might be 5 to 10 volumes in length (versus 1 or 2 volumes for a Canadian

CTA).

! The application is sent to the FDA in triplicate.


! Once the IND arrives at the FDA:

! It will be assigned a 5-digit number such as 64,295. This number opens up

a file or docket for that product and indication.

! You will receive a letter that the IND has been received, with the date of

receipt.



! A review team will be assigned to the project

! Project Manager - non-reviewer, acts as a regulatory coordinator, your

main contact for the IND

! Medical Reviewer - usually acts as team leader

! Pharmacology/Toxicology

! CMC

! Biopharmaceutics - only if needed



! The team will review the package, and a consensus will be reached on the

acceptability of the IND

! Any comments/advice received are usually from individual review teams

! Example, comments from CMC reviewers


! The IND is a dynamic process

!Any further correspondence related to the IND goes in under that

number, and should be labeled as sequential serial numbers e.g.

Serial 001, Serial 002

!There are four main kinds of updates, or Amendments, which are

submitted to INDs


!Types of Amendments

! Protocol Amendments

! Information Amendments

! Safety Reports

!Annual Reports


! Meetings with the FDA during drug development

!The FDA is obligated to provide an opportunity for meeting with

Sponsors on request at specific stages during development

! Pre-IND meeting! End-of Phase II Meeting

! Pre-NDA Meeting


! By the time a product has reached the NDA stage, itis well-known by the review team

! In most cases, the same individuals will review your NDA

!An advantage for the FDA, since they are mandated to review

NDA applications within fixed timelines (target times 6-10

months)


! THINKING AHEAD

!How to position your product for an NDA

! Pose questions on requirements for certain animal and Phase I

studies

! Agree ahead of time with the FDA on clinical endpoints and

their relationship to the intended indication

! Be aware of how formulation changes will impact on the

acceptability of your animal and early phase human data - will

bridging studies be needed?


! THINKING AHEAD

!Maintain needed clinical trial documents (e.g. financial disclosure

forms) for filing and for review of NDA

!Develop labeling (i.e. package insert) as early in the process as

possible


! The US versus the rest of the world- What is harmonized and what is not?

! Harmonized:! GCP! Informed consent! ADR reporting! Many clinical trial and animal study guidelines

! Not harmonized:! Actual IND application packages! Concept of multiple protocols in one IND versus one application per

Protocol! Requirements for INDs at early stages of development (different for

different countries)

Clinical Trials and Canada

Clinical Trial Applications

! When required

• For clinical trials in Phases 1 through 3

• Includes trials involving marketed products where the

proposed use is outside of the NOC or DIN application

• Applies to companies and researchers/physicians

! When not required

• Phase IV

• Practice of Medicine

How Are Clinical Trials Approved?

! A Clinical Trial Application (CTA) must be filed.

! Approved or rejected within 30 days.

! Each study is its own CTA.

Phase I Studies! Target: review comparative bioavailability trials

and Phase I trials in healthy adult volunteerswithin 7 days.• Except: Somatic cell therapies, xenografts, gene therapies,

prophylactic vaccines or reproductive and genetic technologies.

! Trial must have a No Objection Letter (NOL) tostart.

Pre-CTA Consultation

! Can be requested at any time

! Particularly useful for NCEs or complex studies

! Also useful if you have not filed a study before

! Sponsor can present data and get input fromHPFB

TPD - CTAs Received + Outcome(1999-2005)

0

500

1000

1500

2000

1999 2000 2001 2002 2003 2004 2005

# CTAs No Objection Not Satisfactory Withdrawn

BGTD - CTAs Received + Outcome(1999-2005)

0

50

100

150

200

250

300

1999 2000 2001 2002 2003 2004 2005

# CTAs No Objection Not Satisfactory Withdrawn

Bioequivalence Studies - TPD

0

200

400

600

800

1000

1200

2002 2003 2004 2005

Bioequivalence

Phases of Other Studies - TPD

0

50

100

150

200

250

300

350

2002 2003 2004 2005

Phase 1 - 7 Phase 1 - 30 Phase 2 Phase 3

Phases of Other Studies - BGTD

0

20

40

60

80

100

120

140

2002 2003 2004 2005

Phase 1 - 30 Phase 2 Phase 3

Filing a CTA (cont’d)

! Module 1• 1.1 Table of Contents• 1.2 Application Information

– 1.2.1 Drug Submission Application Form & Appendices

– 1.2.2 Information on Prior-related Applications– 1.2.3 Investigator’s Brochure*– 1.2.4

! For Pharmaceuticals, Protocol Synopsis (PCERT)! For Biologicals, Submission Rationale/Brief Summary


! Module 1

• 1.2Application Information (con’t)

– 1.2.5 Study Protocol(s)*

– 1.2.6 Informed Consent Document(s)

– 1.2.7 Clinical Trial Site Information

– 1.2.8 Canadian Research Ethics Board(s) Refusals

– 1.2.9 Foreign Refusals

– 1.2.10 Letters of Access

– 1.2.11 Other Application-related Information


! Module 2

• For a CTA, this module reflects Quality (Chemistry &

Manufacturing) Information only.

• 2.1 CTD Table of Contents

• 2.2 CTD Introduction – N/A

• 2.3 Quality Overall Summary*


! Module 3• 3.1 Table of Contents• 3.2 Body of Data

– Any additional Quality information should be providedhere.! 3.2.R.1 Production Documentation

! 3.2.R.1.1 Executed Batch Records! These should be provided if possible.

• 3.3 Literature References – for Biologicals andRadiopharmaceuticals only.

CTA Amendments/Notifications! Sponsor proposes information to support changes

to a previously approved application.

! May involve

• Clinical trial supplies

• Changes to protocol

• Both

! Amendments require a 30 day review

! Notifications can be made immediately and notifyHealth Canada within a 30 day period.

Labelling Requirements

! Investigational Drug. To be used by QualifiedInvestigator Only. Drogue de recherche. Reservéeuniquement à l’usage de chercheurs competents.

! Name, number or identifying mark of drug

! Expiry date

! Storage conditions

! Lot number

! Name and address of sponsor

! Protocol Number

! Radiopharm requirement

Premature Discontinuation

! If trial is discontinued, must notify Directoratein 15 days.

! Notification must include:

• Rationale

• Impact on proposed trials in Canada

• Confirmation that distribution stopped

• Confirmation that unused drug returned

• Confirmation that investigators notified

Records

! Must be kept for 25 years.

Research Ethics Board

! Men and women

! At least 5 members

! Majority Canadians or Canadian residents

• 2 Scientific – 1 MD

• 1 Ethics

• 1 Canadian law

• 1 Community

• 1 Lay Person

Who Will Be Inspected?

! Sponsors

! Contract Research Organizations

! Site Management Organizations

! Up to 2% of all Canadian trial sites will beinspected each year

• 80 inspections per year (approx 4000 trials)

How Will Compliance BeAssessed?

! Measured against GCP in Division 5 and ICH.

! Average time of one week per inspection.

! Most inspections will be announced.

! Unannounced inspections will be conducted atdiscretion of Health Canada.

Clinical Trials in Europe

Clinical Trial Submissions In Europe

! Like Canada, you submit your protocol, Investigator’sBrochure, and summaries of the rest of the data.

• Full toxicology or clinical reports are not required, nor is full Quality

data.

SPONSOR

ETHICS COMMITTEE

Valid Application Max +

60 days

Response to Request

Application

Single Request for additional information

Obtains Eudra CT number

Process for Ethics Committee

Timelines for Ethics Committee

Standard Products Maximum of 60 days

Gene therapySomatic cell therapyGenetically Modified Organisms

+30 days

External consultations +90 days

Xenogenic cell therapy No time limit

Process for Competent AuthorityAuthorisation

COMPETENT

AUTHORITY

Valid Application Max

60 Days

Grounds for non-acceptance

Application

Amended Application

No amendment

application rejected

SPONSOR

Obtains EudraCT number

Process for Competent Authority

Authorisation

Standard Products

Products defined inPart A, 2309/93, or withspecial characteristics

Gene therapySomatic cell therapyGenetically modified organisms

Committee Consultation

Xenogenic Cell Therapy

Max 60 days“tell and do”

Max 60 days,but written authorisation

+30 days

+90 days

No time limit

Process for Clinical Trial Applications in

EU

Apply forEUDRACT

Number

Proceed if

ethics committee

has given positive

opinion and if no

grounds for

non-acceptance

from competent

authority

Sponsor

Notification to CANotification to CANotification to CANotification to CANotification to CANotification to CANotification to CANotification to CAAuthorisation from CANon acceptance

Single request for

Information (clock stopped

until receipt of info.)

Positive

Maximum 60 days

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Process for Clinical Trial Applications in EU

Fees are payable at national level

Procedures to get favorable opinion from Ethics Committee and

authorisation from Competent Authority can be run in parallel

Fees are not excessive but substantial costs due to general increase in

bureaucracy and the need for Investigational Medicinal Products to

comply with GMP requirements

Implications for Clinical Trials

Approval of all phases (incl. phase 1 and 4) of studies necessary

Request for Authorisation NOT Notification

Specific timescales for ethics review

IMPs (investigational medicinal products) to comply with GMP

requirements


Substantial protocol amendments require a positive opinion from

Ethics Committee and CA

Specific guidance on monitoring and reporting of ADRs


Information on content, commencement and termination of trial to be made

available to Member State (MS)

For multicentre trials carried out in more than one MS simultaneously, a

single opinion from each MS required

Inspections to assess compliance with GMP and GCP at sites

Sets out requirements for consent processes-focus on children and

incapacitated adults


GMP and IMPs

• Includes test products, placebos and active comparator products

• Authorisation is required for each manufacturing or importation site

by MS where manufacture or importation occurs

• Appointment of QP required


• QP ensures that each batch of IMP is manufactured and checked in

accordance with

- Principles and guidelines of GMP as derived from

Dir 91/356/EEC

- Product Specification file

- The clinical trial submission filed with CA (information notified pursuant

to Article 9(2) of the Directive)


GMP and IMPs

• IMPs manufactured in EU or third country require certification from QP

• Comparator product from third country require certification from QP

• Once product meets requirements, importation into another MS can be done

without further checks

• Labelling in at least national language (full details in GMP guidelines on

investigational products)

Directive 2001/83/EC

! Section A- General Requirements

! Section B - Conduct of Clinical Trials

! Section C- Presentation of Results

! Section D- Clinical Pharmacology

! Section E- Bioavailability/ Bioequivalence

Directive 2001/83/EC

! Section F - Clinical Efficacy and Safety

! Section G - Documentation for applications in exceptional

circumstance

! Section H - Post-marketing Experience

! Section I - Well-established Use

Marketing Applications

Marketing Applications

! Common Technical Document– Use of the Common Technical Document is mandatory in Europe

and Canada, and highly recommended in the US.! Module 1: Administrative and prescribing information (region

specific)! Module 2: Summaries and overview! Module 3: Information on Product Quality! Module 4: Nonclinical study reports! Module 5: Clinical study reports

New Drug Applications(NDAs) in the United States

New Drug Applications

! Types of Applications

• Biologic Licence Application (BLE)

• New Drug Application

– Three main types of applications are described in the FD&C Act under

Section 505

1. An application that contains full reports of investigations of

safety and effectiveness

!505 (b) 1

!Most new chemical entities would fall under this

category


! Types of Applications• New Drug Applications

2. An application that contains full reports of investigations of safety and

effectiveness, but where at least some of the information required

for approval comes from studies not conducted for or by the

applicant and for which the applicant does not have right of reference

! 505 (b) 2

! Use of published scientific studies or previous submissions in

support of an application

! Can be a modification such as different salt, different formulation,

different strength


! Types of Applications

• New Drug Applications

3. An application that contains information to show that the proposed

product is identical in active ingredient, dosage form, strength,

route of administration, labeling, quality, performance

characteristics and intended use to a previously approved product

! 505 (j)

! Abbreviated NDAs for generic drugs (ANDAs)


! PDUFA

– Prescription Drug User Fees Act 1992

– Renewed in the FDAMA of 1997, and is currently up for a further

5-year renewal

– Provides a mechanism for the FDA to collect fees to defray the

costs of review

– Tied to performance goals for review times by the Agency

(“PDUFA clock”)

! 10 months for standard review, 6 months for priority reviews, 4

months for manufacturing supplements


! PDUFA

• User fees required for review of

– NDAs

– Supplemental NDAs

• User fees not required for review of

– INDs

– ANDAs

– Medical Devices


! PDUFA

• Current fee structure (2001):

– Applications requiring clinical data: ~$700,000

– Applications not requiring clinical data: ~$300,000

– US dollars


! PDUFA

• NDAs that can be exempted from user fees

– Some 505 (b) 2 applications

– Orphan Drugs

– Small business waivers (less than 500 employees including affiliates) -

first application only


! Content - Do you have what you need?

– Many content issues are dealt with during drug development

! Some common gaps

– CMC Stability data

– Carcinogenicity studies

– Long-term clinical studies conducted as follow-ups for safety

– Number or adequacy of clinical studies in support of efficacy


! Adequacy of clinical trials• The FD&C Act requires that substantial evidence of effectiveness be provided

for approval of a new drug:

! “evidence consisting of adequate and well-controlledinvestigations by experts qualified by scientific training andexperience to evaluate the effectiveness of the drug involved, onthe basis of which it could be fairly stated and responsiblyconcluded that the drug will have the effect if purports or isrepresented to have under the conditions of use prescribed,recommended or suggested by the proposed labeling.” (505 (d))


! Adequate and well-controlled investigations• Described in 21 CFR 314.126• An adequate and well-controlled study has the following characteristics:

– Clear statement of objectives– Design allows for a valid comparison with a control to provide a

quantitative assessment of drug effect! Placebo concurrent control! Dose-comparison concurrent control! No treatment concurrent control! Active treatment concurrent control! Historical control


! Adequate and well-controlled investigations

• Method of selection of patients ensures they have the disease being studied

• Method of assigning patients to treatment and control groups minimizes bias

and is intended to assure comparability of groups (randomization)

• Adequate measures are taken to minimize bias on the part of subjects and

investigators(blinding)

• Methods of assessing subject’s response are well-defined and reliable

• Analysis methods are adequate


! How many adequate and well-controlled clinical trials areneeded?

• Historically, the term “investigations” has been interpreted to mean more than

one, and “adequate” has been interpreted to mean reproducible, which also

implies more than one

• FDA’s “Gold Standard” has been two adequate and well-controlled trials

(pivotal trials) for approval of new drugs


! FORMAT - how to put together your application• Described in 21 CFR 314.50• Several guidance documents available:

– Formatting, assembling and submitting new drug and antibioticapplications

– Format and content of the summary for new drug and antibioticapplications

– Format and content of the nonclinical pharmacology/toxicology section ofnew drug and antibiotic applications; also for Human PK and BA, ClinicalMicrobiology, Clinical and statistical sections, CMC

• CTD is the recommended format at this time.


! Application and Review Process

• Before sending in your application:

– Request an NDA number

! Unlike IND numbers that are assigned to the submission after it is sent

in, the NDA number is assigned ahead of time, and you can use this

number as an identifier throughout the application

! Request user fee number

– Send in User fee cheque to Mellon Bank, Pittsburgh


! Application and Review Process• Once submission arrives, it will be screened for completeness (60 days)

– FDA can refuse to file for reasons of incompleteness

• If accepted for review, you will receive a letter stating that the application has been

accepted for review.

• The log-in date is the reference date used for the “PDUFA clock”.


! Application and Review Process

• Transition from the IND

– If an IND is in place, usually the same review team will be

involved, including the project manager

– Already have a contact in place to ask about the status of the

submission

– Can inform them that the NDA is being submitted, and when.


! Application and Review Process• QUESTIONS FROM REVIEWERS

– During the review, the FDA will communicate with applicants about scientific,

medical and procedural issues. This communication can take the form of letter,

telephone calls or meetings

– It is the intent of the Agency to provide notification of easily correctable

deficiencies during the course of review

– Not as formalized in response time as the Canadian clarifaxes.


! Application and Review Process• AMENDMENTS

– If a revision, addition or change is sent to the NDA prior to approval, it is referred

to as an Amendment

– Amendments can be in response to requests from reviewers for more information

– If any amendment is substantial, the FDA can stop the PDUFA clock. For example,

there may be situations where additional studies may be agreed to, which would add

time to the review.


! Application and Review Process• Advisory Committee Meetings

– Sometimes, the Agency will make use of non-FDA employees to help in the review

process

– These are usually experts in the field (i.e. medical or scientific specialists)

– Usually, the involvement of an Advisory committee is decided at some point in the

drug development phase


! Application and Review Process• Advisory Committee Meetings

– These meetings are open forums, open to the public

! Including competitors and stockholders

– An Advisory Committee only has recommending power

– However, in practice, 98% of the time if a Committee recommends a course of

action, the FDA follows their recommendation

– Transcripts and tapes of these meetings are available (public information)


! Application and Review Process• Approval letter

– Can contain agreements for further work

• Approvable letter

– An indication that the NDA is basically approvable, providing that certain issues are

resolved

– Changes to labeling (package insert) a common requested change

– 10 days to respond

! Notify an intent to file an amendment to address the issues

! Withdraw application

! Request a hearing


! Application and Review Process• Not-approvable letter

– This letter will describe deficiencies in the application

– Can respond as for approvable letter:

! Notify an intent to file an amendment to address the issues

! Withdraw application

! Request a hearing


! Application and Review Process• Post approval commitments

– There are defined requirements that are required after approval of a drug. Theseinclude safety updates and annual reports, and apply to all applications

– There can also be specific agreements made between the FDA and sponsor toconduct additional studies or follow-up as a Phase IV commitment; thesecommitments are specific to a given NDA

– For example, to comply with pediatric rule, if studies have not already beenconducted in pediatrics, it is not uncommon for there to be an agreement to carry outthese studies post-approval

– These agreements are spelled out in the approval or approvable letter

New Drug Submissions(NDSs) in Canada

The Review Process

! Log in

• Takes 10 days.

• Everything received; No. given

! Screening

• The submission is screened to ensure the quality of the

submission is sufficient for review.

• Generally takes 45 days.

The Review Process! Documents Issued at Screening

• Clarifax– This is a document that clarifies minor questions.– Generally 10-15 days to respond.

• Screening Deficiency– This means that there is a major discrepancy in the data.– Company has 45 days to respond.– Submission then undergoes a further 45 day screen.

• Acceptance for Review• Submission Withdrawal

Name Review

! Health Canada will review the Brand and Generic nameof your drug for “look alike / sound alike” problems.

! This will occur within 90 days of acceptance of yoursubmission.

! Another review of the names will occur within 90 daysof approval of your submission.

Legibility From slides by Dr. Lesar, NY

Capoten or Cozaar?

Protonix or Protamine?

Unasyn or Vancomycin?

The Review Process

! Both the CMC and the Clinical portions of thesubmission are reviewed by a primary reviewer.

! A second reviewer usually reviews thesubmission to provide a second opinion.

The Review Process! Documents Issued During Review

• Clarifaxes

– These faxes are intended to deal with minor questions.

– Usually have 15 days to respond.

• Notice of Deficiency

– Intended to identify major missing data.

– Company has 90 days to respond.

– Clock stops and restarts when data is submitted.

The Review Process

! Documents issued at the end of review• Notice of Compliance

– This indicates that the submission is approved and sale of the product

can commence.

• Notice of Non-Compliance

– Company has 90 days to address major questions

– Submission goes back through screening and review.

– If issues not addressed at this stage, submission is withdrawn.

Priority Submissions / Conditional NOCs

! Applies to serious, life-threatening or severelydebilitating disease for which no drug is availableor which is not currently adequately managed.

! Manufacturer submits a written request toDirector of Bureau (Pharmaceutical Assessmentor Biologics/Radiopharmaceuticals).

! Priority = all data available

! Conditional = promising data available• Company commits to developing full data

NOC-c’s Approved to Date

112005

21385Total

112004

212003

32002

112001

12000

11111999

21998

OtherCVOrphanCancerHIV/AIDSYear

NOC-c’s Withdrawn

! 3 were withdrawn

• 2 were for cancer

– Casodex – for safety reasons

– Iressa – surrogate marker was not related to prolonged survival.

Product was not withdrawn. A subpopulation did respond

• 1 Cox II – Celebrex for prevention of recurrence of colorectal polyps

– DSMB stopped study

– Indication was withdrawn

NDS Targeted Time Frames

00045Admin

00607Label

1504518045C&M/Label

1504518045Comp/C&M

1504530045Clin/C&M

1504530045NAS

902520025NOC/c

902518025Priority

Review 2Screen 2Review 1Screen 1Class

Average Approval Time - Drugs - NDSs

0

200

400

600

800

1000

2001 2002 2003 2004 2005

Priority NAS NAS

Average Approval Time - Biologics - NDSs

0

200

400

600

800

1000

1200

1400

1600

1800

2001 2002 2003 2004 2005

Priority NAS NAS

Average Approval Time - ANDSs

0

100

200

300

400

500

600

700

2001 2002 2003 2004 2005

ANDS

Biologic and Genetic TherapiesDirectorate

! How are biologic submissions different?• Still NDS.• Require a pre-approval inspection.• Require information on manufacturing facility.• Require samples.• Will require some degree of post-approval release.• Reviewed by the BGTD• Sometimes require toxicity in primates (immune) issue• Require an annual report

NDSsAbbreviated New Drug Submission

! Applies to products that are

• Pharmaceutical equivalent

• Bioequivalent

• Given same route of administration

• Sold for the same conditions of use to Canadian Reference Product

ANDSsCanadian Reference Product

! A drug which has an NOC and is marketed inCanada by innovator.

! Another drug acceptable to the Minister where theCanadian drug is no longer marketed.

! Another drug acceptable to the Minister, where itcan be proven that it is the same as the Canadiandrug.

ANDSsDeclaration of Equivalence

! NOC for an ANDS states the Canadian referenceproduct and constitutes a “declaration ofequivalence” for the new product.

! This is very important from a provincial perspective.Provinces are moving to stop bioequivalence reviewsat a provincial level.

ANDSComprehensive Summary

! Physicochemical Characteristics

! Pharmacology

! Pharmacokinetics

! Drug Product Classification (conventional, etc.)

! Summary of Bioequivalence Studies

Subsequent Entry Biologics

! SEB means a biologic product that would be similar toand would enter the market subsequent to anapproved innovator product.

! BGTD is working to develop a comprehensiveregulatory framework for SEBs.


! SEBs are subject to all requirements for biologics

• File NDS

• Extent of the clinical data required may be different.

• Key factors

– Choice of the innovator product

– Design of comparability studies

– Details of the clinical data provided

• Less clinical data may be required for products that are shown clearly to be very

similar to the innovator


! Data Requirements• Complete CMC• Rational for choice of the innovator biologic• Sufficient characterization information to demonstrate both chemical and

biological comparability• Sufficient comparative animal toxicity data, where appropriate• Pharmacodynamic data to demonstrate comparable bioactivity• Pharmacokinetic data to demonstrate comparable bioavailability• Immunogenic profile of the SEB in humans• Clinical package

Exclusivity

! As of October 5, 2006, new drugs will have a minimumperiod of market exclusivity of 8 years.

• Includes a 6 year no filing provision for generic submissions.

! An additional 6 months of data protection is available as apediatric exclusivity.

! These regulations were published in draft form on June 17,2006

! Effective date is June 17, 2006.

Basic Exclusivity

! Only applies to “innovative drugs”, i.e., new molecularentities

! Combinations of previously approved medicinal ingredientsare not eligible for an additional data protection period.

! Biologic drugs are included within the scope of innovativedrugs.

! Protection only applies if drug is marketed in Canada.

! Registry of innovative drugs, similar to the Orange book, willbe established.

Pediatric Exclusivity

! Additional 6 months for drug submissions filed withinthe first 5 years of the 8 year protection period, if

• Clinical trials were designed and conducted with the purpose of

increasing knowledge about the use of the drug in pediatric populations.

NDSsCost For Review

! Preclinical/Clinical Fee

• Preclinical & Clinical data: $117,000

• Clinical only: $52,900

• Clinical with supplementary preclinical: $52,900

• Comparative clinical, PD or PK: $17,200

• Published clinical references: $2,200

! Additional

• Additional route, dosage form or indication

– Supported by additional clinical: $52,900

– Supported by comparative clinical, PD or PK: $17,200

NDSsCost For Review

! CMC for drug substance: $11,500

! CMC for dosage form: $15,300 for each dosage form

Marketing Authorizationsin Europe

Types of Marketing Applications

! Centralized Procedure

! Decentralized Procedure

! National Procedure*

EMEA & Centralized Procedure

! EMEA = European Medicines Agency

• CHMP – Committee for Medicinal Products for Human Use

– One member per member state

• Committee for Orphan Medicinal Products

Centralized Procedure

! Obligatory for

• Biotech products

• Orphan medicinal products

• New Active Substances for

– AIDS

– Cancer

– Neurodegenerative disorders

– Diabetes

– Auto-immune diseases & other immune dysfunctions (as of May

20/08)

– Viral diseases (as of May 20/08)

Centralized Procedure

! Optional

• If the medicinal product is a significant therapeutic, scientific or

technical innovation

• If the granting of a centralized Marketing Application is of interest at

the Community level to patients health (e.g., completely new OTC

product)

• Other New Active Substances

Timelines in the Centralized Procedure

! Opinion issued 210 days from receipt of validapplication to CHMP.

! Timeline can be extended, if justified.

! Accelerated Assessment: time limit reduced to 150days.

• Decision making process shortened from 3-4 months to around 2

months.

Transparency in Centralized Procedure

! Publication of withdrawal

! Publication of refusal

! Publication of Assessment Report, reasons for itsopinion in favour of granting authorization

Decentralized Procedure

! European Phase

• Report is issued within 90 days of receipt of valid application.

• Report, Summary of Product Characteristics (SmPC), labelling and

package leaflet sent to Concerned Member States (CMSs) and the

applicant.

• CMSs have 90 days to approve the assessment report, SmPC, etc.

! The national decision has to be adopted within 30 daysafter the “European Phase” has ended.

Decentralized Procedure

! Covers all medicinal products not authorized in the EUfor which the Centralized Procedure does not apply.

! Applicant can select the Reference Member State(RMS) and lists CMSs.

• The RMS is the state that will be the primary reviewer of the

submission.

! Once selected, withdrawal from selected countries isnot possible.

Timetable in Decentralized Procedure

! Before Day -14

! Day -14

! Day 0

! Day 70

! Until Day 100

! Until Day 105

! Discussion with RMS

! Submission to RMS & CMSs, validationof dossier

! RMS starts procedure

! RMS forwards Preliminary AssessmentReport (PAR) & draft SmPC, packageleaflet and labelling to CMSs.

! CMSs send their comments

! Consultation between RMS, CMSs &applicant. If consensus, procedureends. Otherwise clock stop.


! Day 106

! Before Day 120

! Day 120

! Day 150

! Restart of clock after receipt of finalresponses.

! RMS sends Draft Assessment Report,SmPC, package leaflet and labelling toCMSs.

! End of procedure if consensus reached.

! National decision to be adopted.


! Day 120

! Day 145

! Day 150

! Day 180

! Until Day 205

! Until Day 210

! Start of Assessment Step II.

! CMSs send final comments to RMS

! Close of procedure if consensusreached. National approval within 30days.

! If no consensus reached, RMScommunicates outstanding issues toapplicant and prepares report fordiscussion at Coordinating Group.

! Break out group of involved memberstates reach consensus.

! If consensus, closure of the procedure.National approvals within 30 days.

Disagreement Between RMP and CMPs

! In case member state cannot agree on grounds of apotential serious risk to human health

• Detailed statement of the reasons shall be provided to RMS, other

CMSs and applicant.

• Points of disagreement shall be referred without delay to the

Coordination Group.

Coordination Group

! Responsible for the examination of any questionrelating to the marketing authorization of a medicinalproduct in two or more member states.

! Secretariat provided by EMEA

! One representative per member state

! Renewable period of 3 years.

Procedure in Case of Disagreement

! Until Day 210• Referral to Coordination Group

! Until Day 270• If consensus reached, procedure will be closed. National approvals

within 30 days. If no consensus reached, referral to CHMP forarbitration.

! CHMP will provide opinion usually within 60 days, butcan extend period by up to 90 days.

! Member states that have approved the assessmentreport and labelling of the RMS may, on request of theapplicant, grant an MA without waiting for the outcomeof the procedure.

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