BioEntrepreneurship: Navigating the Global Regulatory Pathway

MaRS BioEntrepeneurship Lecture Series:

Navigating the Global
Regulatory Pathway

Anne Tomalin
President, 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 to
follow 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, the
Regulatory 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 in
particular about design of preclinical testing, particularly if
your 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 Nonclinical
!
Laboratory 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 reports
including 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 prior
!
to 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 in
!
preparation 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 be
!
conducted 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 to
!
requirements for Good Clinical Practice (GCP), IRB approval, and
informed 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 and
!
the Investigator that they agreed to comply with all relevant
regulations.
Clinical sites can be inspected by the FDA, and documentation
!
would need to be provided at that time.

Clinical Trials in the
United 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 days
have 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 significant

changes 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 level
which 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 a
process 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, it
is 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 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 volunteers
within 7 days.
• Except: Somatic cell therapies, xenografts, gene therapies,
prophylactic vaccines or reproductive and genetic technologies.

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

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 from
HPFB

TPD - CTAs Received + Outcome
(1999-2005)

2000

1500

1000

500

0
1999 2000 2001 2002 2003 2004 2005

# CTAs No Objection Not Satisfactory Withdrawn

BGTD - CTAs Received + Outcome
(1999-2005)

300
250
200
150
100

50
0
1999 2000 2001 2002 2003 2004 2005

# CTAs No Objection Not Satisfactory Withdrawn

Bioequivalence Studies - TPD

1200
1000
800
600
400

200
0
2002 2003 2004 2005

Bioequivalence

Phases of Other Studies - TPD

350
300
250
200
150
100
50
0
2002 2003 2004 2005

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

Phases of Other Studies - BGTD

140
120
100
80
60
40
20
0
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 provided
here.
! 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 and
Radiopharmaceuticals 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 notify
Health Canada within a 30 day period.

Labelling Requirements
Investigational Drug. To be used by Qualified
!
Investigator Only. Drogue de recherche. Reservée
uniquement 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 Directorate
!
in 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 be
inspected each year
• 80 inspections per year (approx 4000 trials)

How Will Compliance Be
Assessed?
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 at
discretion of Health Canada.

Clinical Trial Submissions In Europe

Like Canada, you submit your protocol, Investigator’s
!
Brochure, and summaries of the rest of the data.
• Full toxicology or clinical reports are not required, nor is full Quality
data.

Process for Ethics Committee
SPONSOR
ETHICS COMMITTEE
Obtains Eudra CT number
Response to Request
Valid Application Max +
Application 60 days

Single Request for additional information

Timelines for Ethics Committee

Maximum of 60 days
Standard Products

Gene therapy
+30 days
Somatic cell therapy
Genetically Modified Organisms

+90 days
External consultations

No time limit
Xenogenic cell therapy

Process for Competent Authority
Authorisation
SPONSOR
COMPETENT
AUTHORITY
Obtains EudraCT number
Amended Application
Max
Valid Application
60 Days
Application

Grounds for non-acceptance
No amendment
application rejected

Process for Competent Authority
Authorisation
Max 60 days
Standard Products
“tell and do”
Products defined in
Max 60 days,
Part A, 2309/93, or with
but written authorisation
special characteristics

Gene therapy
+30 days
Somatic cell therapy
Genetically modified organisms

+90 days
Committee Consultation

No time limit
Xenogenic Cell Therapy

Process for Clinical Trial Applications in
EU
Notification totoCA
Notification toCACA
Notification toCA
Notification to CA
Notification to CA
Notification to CA
Notification to CA CA
Notification
Authorisation from
Non acceptance
Proceed if
ethics committee
has given positive
Positive opinion and if no
Apply for
Sponsor grounds for
EUDRACT
non-acceptance
Number
Application from competent
Application
Ethics Application to
to ApplicationApplication to
authority
to Application Committees
Ethics Ethics
Application to CommitteesEthics Committees
to Application
Application to CommitteesEthics Committees
to Application
Ethics
Application to Committees Ethics Committees
to Application
Ethics
Committees to Committees Ethics Committees
Application to
Application
Application to to Application
Application to ApplicationApplication to
Ethics
Ethics
Ethics
Single request for Committees to Committees Ethics Committees
Application to
Application to ApplicationApplication to
Application Ethics
Ethics
Ethics
Application to
Committees
Application
Application
toApplication to to Ethics
Ethics
Ethics
Application
Ethics
Committees
Application
Application
Ethics
toApplication to to Ethics
Information (clock stopped Ethics
Committees
Ethics
Committees
Application Committees
Ethics
Committees
Ethics
Committees
to Ethics
Committees Committees
to Ethics
Ethics
Committees
Committees
to Ethics
until receipt of info.) Committees
Committees
Committees
Committees
Committees
Maximum 60 days

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

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


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


!
• 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


!
• 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-controlled
!

investigations by experts qualified by scientific training and
experience to evaluate the effectiveness of the drug involved, on
the basis of which it could be fairly stated and responsibly
concluded that the drug will have the effect if purports or is
represented 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 are
!
needed?
• 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 antibiotic
applications
– Format and content of the summary for new drug and antibiotic
applications
– Format and content of the nonclinical pharmacology/toxicology section of
new drug and antibiotic applications; also for Human PK and BA, Clinical
Microbiology, 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


!
• 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”.


!
• 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.


!
• 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.


!
• 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.


!
• 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


!
• 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)


!
• 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
!


!
• 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
!


!
• Post approval commitments
– There are defined requirements that are required after approval of a drug. These
include safety updates and annual reports, and apply to all applications
– There can also be specific agreements made between the FDA and sponsor to
conduct additional studies or follow-up as a Phase IV commitment; these
commitments are specific to a given NDA
– For example, to comply with pediatric rule, if studies have not already been
conducted in pediatrics, it is not uncommon for there to be an agreement to carry out
these 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 name
!
of your drug for “look alike / sound alike” problems.
! This will occur within 90 days of acceptance of your
submission.
! Another review of the names will occur within 90 days
of approval of your submission.

Legibility From slides by Dr. Lesar, NY

Unasyn or Vancomycin?

Protonix or Protamine?

Capoten or Cozaar?

The Review Process
Both the CMC and the Clinical portions of the
!
submission are reviewed by a primary reviewer.
! A second reviewer usually reviews the
submission 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 severely
!
debilitating disease for which no drug is available
or which is not currently adequately managed.
! Manufacturer submits a written request to
Director of Bureau (Pharmaceutical Assessment
or Biologics/Radiopharmaceuticals).
! Priority = all data available
! Conditional = promising data available
• Company commits to developing full data

NOC-c’s Approved to Date
Year HIV/AIDS Cancer Orphan CV Other

1998 2
1999 1 1 1 1
2000 1
2001 1 1
2002 3
2003 1 2
2004 1 1
2005 1 1
Total 5 8 3 1 2

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
Class Screen 1 Review 1 Screen 2 Review 2

Priority 25 180 25 90
NOC/c 25 200 25 90
NAS 45 300 45 150
Clin/C&M 45 300 45 150
Comp/C&M 45 180 45 150

C&M/Label 45 180 45 150
Label 7 60 0 0
Admin 45 0 0 0

Average Approval Time - Drugs - NDSs

1000

800

600

400

200

0
2001 2002 2003 2004 2005

Priority NAS NAS

Average Approval Time - Biologics - NDSs

1800
1600
1400
1200
1000
800
600
400
200
0
2001 2002 2003 2004 2005

Priority NAS NAS

Average Approval Time - ANDSs

700
600
500
400
300
200
100
0
2001 2002 2003 2004 2005

ANDS

Biologic and Genetic Therapies
Directorate
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
•

NDSs
Abbreviated 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
•

ANDSs
Canadian Reference Product
A drug which has an NOC and is marketed in
!
Canada by innovator.
! Another drug acceptable to the Minister where the
Canadian drug is no longer marketed.
! Another drug acceptable to the Minister, where it
can be proven that it is the same as the Canadian
drug.

ANDSs
Declaration of Equivalence

NOC for an ANDS states the Canadian reference
!
product and constitutes a “declaration of
equivalence” for the new product.
This is very important from a provincial perspective.
!
Provinces are moving to stop bioequivalence reviews
at a provincial level.

ANDS
Comprehensive 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 to
!
and would enter the market subsequent to an
approved innovator product.
! BGTD is working to develop a comprehensive
regulatory 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 minimum
!
period 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 a
!
pediatric 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 molecular
!
entities
Combinations of previously approved medicinal ingredients
!
are not eligible for an additional data protection period.
Biologic drugs are included within the scope of innovative
!
drugs.
Protection only applies if drug is marketed in Canada.
!

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

Pediatric Exclusivity

Additional 6 months for drug submissions filed within
!
the 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.

NDSs
Cost 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

NDSs
Cost For Review

CMC for drug substance: $11,500
!

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

Marketing Authorizations
in 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


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)


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 valid
!
application to CHMP.
! Timeline can be extended, if justified.

! Accelerated Assessment: time limit reduced to 150
days.
• 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 its
opinion in favour of granting authorization


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 days
!
after the “European Phase” has ended.


Covers all medicinal products not authorized in the EU
!
for 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 is
!
not possible.

Timetable in Decentralized Procedure

Discussion with RMS
Before Day -14 !
!

Submission to RMS & CMSs, validation
Day -14 !
!
of dossier
RMS starts procedure
Day 0 !
!
RMS forwards Preliminary Assessment
Day 70 !
!
Report (PAR) & draft SmPC, package
leaflet and labelling to CMSs.
CMSs send their comments
!
Until Day 100
!
Consultation between RMS, CMSs &
!
Until Day 105
!
applicant. If consensus, procedure
ends. Otherwise clock stop.


Restart of clock after receipt of final
Day 106 !
!
responses.
RMS sends Draft Assessment Report,
Before Day 120 !
!
SmPC, package leaflet and labelling to
CMSs.
End of procedure if consensus reached.
!
Day 120
!
National decision to be adopted.
!
Day 150
!


Start of Assessment Step II.
Day 120 !
!
CMSs send final comments to RMS
Day 145 !
!
Close of procedure if consensus
Day 150 !
!
reached. National approval within 30
days.
Day 180
!
If no consensus reached, RMS
!
communicates outstanding issues to
applicant and prepares report for
discussion at Coordinating Group.
Until Day 205 Break out group of involved member
! !
states reach consensus.
If consensus, closure of the procedure.
Until Day 210 !
!
National approvals within 30 days.

Disagreement Between RMP and CMPs

In case member state cannot agree on grounds of a
!
potential 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 question
!
relating to the marketing authorization of a medicinal
product 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 for
arbitration.
CHMP will provide opinion usually within 60 days, but
!
can extend period by up to 90 days.
! Member states that have approved the assessment
report and labelling of the RMS may, on request of the
applicant, grant an MA without waiting for the outcome
of the procedure.

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