Download The advisory process for anticancer drug regulation: a global

Annals of Oncology 17: 889–896, 2006
doi:10.1093/annonc/mdj099
Published online 15 December 2005
review
The advisory process for anticancer drug
regulation: a global perspective
A. T. Farrell1*, I. Papadouli2, A. Hori3, M. Harczy4, B. Harrison5, W. Asakura3, M. Marty6,
R. Dagher1 & R. Pazdur1
1
United States Food and Drug Administration, Center for Drug Evaluation and Research Office of New Drugs, Office of Oncology Drug Products, Division of Drug
Oncology Products, Silver Spring, MD, USA; 2European Medicines Agency, London, UK; 3Pharmaceuticals and Medical Devices Agency, Tokyo, Japan; 4Division of
Antineoplastic Drugs, Bureau of Metabolism, Oncology and Reproductive Sciences, Therapeutic Products Directorate, Ottawa, ON, Canada; 5Therapeutic Goods
Administration, Symonston, Australia; 6Saint Louis Hospital, Paris, France
Received 22 August 2005; revised 4 November 2005; accepted 7 November 2005
Purpose: This paper summarizes the role of external advisors in oncology drug development and regulation from
Agency, the Japanese Pharmaceuticals and Medical Devices Agency, the Australian Therapeutic Goods
Administration and Health Canada held a meeting in conjunction with the American Society of Clinical Oncology
meeting. The role of external advisors in oncology drug development and regulation in each of these jurisdictions was
presented and discussed.
Results: All regulatory bodies described have experience with two forms of outside expertise: advice from individual
experts and advice from a group of experts assembled as an advisory group. Regulatory jurisdictions use individual
experts variably. In some regions, individual experts provide advice based on knowledge and experience during the
drug development phase or in the planning phase for the submission of a drug registration package. In other regions,
these individuals serve as external evaluators with the primary responsibility for the review of a clinical trials package
submitted for drug registration. Advisory boards have been formalized in all jurisdictions discussed. Advisory boards
have a role in discussing specific applications as well as broad policy issues. A common theme is a composition of
a core panel of experts with augmentation by additional expertise as needed for consideration of specific scientific
questions. In all jurisdictions, advisory board recommendations are not binding on the regulatory body.
Conclusions: Global oncology drug development and registration involves the use of experts by regulatory
authorities. The types of experts needed, the expert’s role and the transparency of the advisory process reflect the
individual needs in different regions.
Key words: advisory process, drug regulation, oncology
introduction
An annual meeting of oncology drug international regulators
has been held in conjunction with the American Society of
Clinical Oncology meeting since 2001. Recently, representatives
from the United States Food and Drug Administration
(USFDA), the European Medicines Agency (EMEA), Health
Canada, the Japanese Pharmaceuticals and Medical Devices
Agency (PMDA) and the Australian Therapeutic Goods
Administration (TGA) presented and discussed the role of
external advisors in drug regulation. The following five sections
are authored by the individual participants and approved by
*Correspondence to: Dr A. T. Farrell, United States Food and Drug Administration,
Center for Drug Evaluation and Research, Office of New Drugs, Office of Oncology Drug
Products, Division of Drug Oncology Products, 10903 New Hampshire Avenue,
Building #22, Room 2106, Silver Spring, MD 20993, USA. Tel: +1-301-796-2330;
Fax: +1-301-796-9867; E-mail: [email protected]
ª 2005 European Society for Medical Oncology
their respective regulatory bodies. Following these sections, the
Discussion section highlights the similarities and differences in
the advisory process for the regulation of oncology drugs
between different regulatory agencies.
United States: USFDA
The United States Food and Drug Administration (USFDA)
employs a staff of medical oncologists/hematologists who
perform multiple functions, including review of new drug
applications (NDAs) for oncology products. However, oncology
applications may require expertise not found in the Agency.
The USFDA utilizes external expert consultants primarily to
provide independent scientific advice during the evaluation of
regulated products and to aid the Agency in making decisions
based on reasoned application of good science. Consultants also
review
a global perspective.
Design: Recently, representatives from the United States Food and Drug Administration, European Medicines
review
advise the Agency on general criteria for evaluation and on
broad scientific issues unrelated to specific products. All
consultants are Special Government Employees (SGEs) or
Federal Employees who must undergo a clearance process for
conflict of interest for each project. The external consultants are
paid for their time. The Office of Oncology Products utilizes
consultants for the Oncologic Drugs Advisory Committee
(ODAC) meetings and for review of some protocols submitted
under the Special Protocol Assessment (SPA) mechanism. The
SPA mechanism, described in the Food, Drug and
Modernization Act (FDAMA), provides a binding agreement
between the sponsor and USFDA regarding the design of
a clinical study potentially leading to drug approval. Thus,
external consultants are used in both the drug development
phase (investigational new drug phase) and during the
regulatory approval phase (NDA phase).
Consultants must undergo a screening process for conflict of
interest for each application. The clearance process prohibits
participation in any official action in which the consultant has
a financial interest. This financial interest can include those
interests of a consultant’s employing organization. One example
of a potential conflict of interest is if the employing organization
has sizeable grants. The possible outcomes of the clearance
process are as follows: a consultant is cleared, the consultant
receives a waiver, or the consultant is excluded. A decision
about whether a waiver could be granted is based on the amount
of financial interest, percentage of the consultant’s net worth
and the impact on the firm/organization if the product is
approved/disapproved. A waiver to participate is permitted if
the USFDA’s need outweighs the conflict. If the waiver involves
a participant at an ODAC meeting, that information is disclosed
to the public.
Advisory committees (ACs) are the primary means by which
the USFDA obtains independent scientific advice [1]. Four
main assumptions exist with regard to ACs. First, ACs are
independent with respect to influence by either the product
sponsor or by the USFDA. Secondly, ACs provide ‘expert
scientific advice’, because the committee members are
acknowledged experts in their respective fields. Thirdly, the
AC advises the USFDA; however, it lacks the authority to
make decisions to obligate the Agency. Fourthly, the AC
often addresses specific questions drafted by the Agency’s
professional staff.
Starting in 1962 and prior to the passage of formal
legislation, the USFDA had used panels of outside experts. In
1972, Congress passed the Federal Advisory Committee Act
Public Law 92-963, which prescribed the formal use of ACs.
The Act required that the USFDA renew these committees every
2 years or the committee automatically expires. The
Government in Sunshine Act of 1977 required that when
possible, AC meetings be open to the public. Portions of the
meeting may be closed if there are privacy concerns or
confidentiality issues including discussion of commercial or
trade secrets or law enforcement investigations. AC meetings
must provide a minimum of 60 minutes for an open public
hearing. The open public hearing allows the public to participate
in the AC through oral presentations or written submissions.
With the passage of the 1997 FDAMA, a number of new
changes involving ACs were made: a provision was added that
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Annals of Oncology
the AC must meet within 60 days of when a subject is ready for
review, it was stated that the Agency must take an action
within 90 days of a committee recommendation, two new AC
members (consumer representative, industry representative)
were added, a requirement was added that at least two members
on the AC must be specialists or have expertise in the particular
indication under consideration, and new conflict of interest
limits on voting were introduced. FDAMA specifically
prohibited AC members from voting on their own scientific
work, and new member training became mandatory prior to
the initial AC meeting.
The composition of each AC must be ‘fairly balanced’
meaning that membership must be as open and inclusive as
possible [2]. Committee membership should include recognized
clinicians and researchers for the specific field while maintaining
a goal of ethnic, gender, geographic and racial diversity.
Nominations for AC are solicited by means of a Notice in the
Federal Register [3]. Individuals can be referred by scientific or
medical societies, academic medical institutions, government
agencies, consumer or patient groups, and former or current
AC members. In addition, self-nominations are allowed.
The Agency has three ACs where oncology products and
issues have usually been discussed: ODAC, the Pediatric
Subcommittee of the Oncologic Drugs Advisory Committee,
and the Biologic Response Modifiers Committee, recently
renamed the Cellular, Tissue, and Gene Therapies Advisory
Comittee. For most oncology products and issues, the ODAC
meeting is the most visible use of external advisors. Typically
ACs have 10–15 members. The ODAC includes a chairperson
and 13 members. Currently, 11 clinicians each with a 4-year
term serve on ODAC. Additional experts can be added for
a particular ODAC meeting if needed. Typically, one statistician
serves on the committee for a 4-year term. The one industry
representative is non-voting and serves a 4-year term. The
industry representative addresses general issues for the
pharmaceutical industry and does not represent a specific
commercial sponsor. The patient representative, a voting
consultant on the panel (unless refused for conflict of interest),
is identified on a case by case basis depending on the product(s)
and subject of the meeting. The consumer representative,
a voting member, serves a 4-year term. The consumer
representative must have worked with potential consumers of
the product under discussion, allowing the consumer
representative to address the impact of decisions on consumers.
The AC provides an opportunity for patients and patient
advocates to voice their opinions on the potential impact of the
issues under discussion. Three or four ODAC members
complete their term every year and are replaced. This staggered
replacement schedule provides for continuity.
The Federal Register publishes a notice of tentatively
scheduled meeting dates a year in advance of each meeting, with
meetings planned on a quarterly basis. Meetings can be canceled
and others added as needed. A number of issues may arise
necessitating an ODAC meeting. An ODAC may be convened to
discuss a new drug application or a new indication for
a marketed drug, borderline evidence of efficacy for a drug or
use of a new efficacy end point for use in clinical trials (e.g.
discussions about the use of progression-free survival as an end
point instead of survival for comparative efficacy trials for solid
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tumors). Significant safety issues or special regulatory issues
such as whether a marketed drug should receive a boxed
warning or its distribution restricted are also potential subjects
of an ODAC discussion.
Once a decision is made that an ODAC meeting is necessary,
the review team must complete a number of tasks. First, the
team must inform the pharmaceutical sponsor. The Agency
subsequently publishes a Federal Register Notice inviting the
public. The oncology staff writes a briefing document which is
published on the web at http://www.fda.gov/ohrms/dockets/ac/
cder05.html#OncologicDrug/ prior to the meeting [4]. At the
ODAC meeting, the committee members listen to presentations
by the pharmaceutical sponsor and the USFDA review staff.
Following the presentations and the open public hearing, the
AC discusses the questions drafted by the Agency staff on
issues such as study design, methodology, adequacy of data,
assessment and interpretation of risks and effectiveness, and
provides recommendations.
Advice may also be sought from individual consultants or
ODAC members who serve as SGEs. In addition to the SPA
mechanism mentioned previously, this form of advice is
sometimes sought in preparation for end-of-phase-II meetings,
where sponsors discuss their plans for the latter stages of drug
development and the relevant trial designs. In the Office of
Oncology Products, we have also made an effort to include
patient consultants in these deliberations. When the USFDA is
considering taking an action without convening an ODAC
meeting, an effort is made to obtain input from individual
consultants, ODAC members and patient consultants.
Crucial to understanding the role of ACs and consultants is
the understanding that the advisory process is not binding.
Although an ODAC member or consultant may recommend
a course of action, the USFDA is not obligated to follow that
advice. The regulatory decision regarding UFT is an example
where the AC recommended approval and the Agency declined
to follow that advice.
Europe: EMEA
The European Medicines Agency (EMEA) coordinates
a network of 42 national agencies and has undergone significant
legislative and institutional changes concurrent with the
enlargement of the European Union (EU). These changes
address the challenges of enlargement while focusing on
providing timely access to new therapies, providing public
access to information in a transparent fashion, and maintaining
a high level of scientific assessment. The Agency aims to provide
a high level of scientific advice, providing a particular emphasis
on continuous monitoring of medicines through
pharmacovigilance, transparency in communications, and
provision of information to patients and Good Manufacturning
Practices/Good Clinical Practices. The EMEA structure is
outlined in Figure 1. Changes to be discussed include
a requirement that all new oncology drugs submitted starting
in 2005 must be submitted through the centralized procedure
(i.e. through the EMEA without the possibility of submission
to a selection of individual countries) and introduction
EXECUTIVE DIRECTOR
Executive support
Integrated quality
management and audit
Legal support
PRE-AUTHORIZATION
EVALUATION OF
MEDICINES FOR
HUMAN USE
POST-AUTHORIZATION
EVALUATION OF
MEDICINES FOR
HUMAN USE
VETERINARY
MEDICINES
AND INSPECTIONS
COMMUNICATIONS
AND NETWORKING
ADMINISTRATION
Scientific advice and
orphan drugs
Regulatory affairs and
organizational support
Veterinary marketing
authorization procedures
Document management
and publishing
Personnel and budget
Quality of medicines
Pharmacovigilance and
post-authorization safely
and efficacy of medicines
Safety of veterinary
medicines
Meeting management
and conference
Infrastructure services
Safety and efficacy
of medicines
Medical information
Inspections
Project management
Accounting
Information technology
Figure 1. European Medicines Agency structure.
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doi:10.1093/annonc/mdj099 | 891
review
(since 2003) of formal scientific advisory groups, including
a scientific advisory group (SAG) for oncology (SAG-O) [5].
Previously, anticancer development strategies in Europe
could approach applications for regulatory approval from two
perspectives. One option is known as the mutual recognition
procedure, whereby a marketing application is submitted to
individual countries within Europe. Another option, known as
the centralized procedure, consists of a single authorization by
the EU based on EMEA review which, if granted, applies to all
member states. Starting in November 2005, applications for
marketing authorization for certain indications will require
submission exclusively through the centralized procedure. These
indications include diabetes, AIDS, cancer, neurodegenerative
disorders and products with orphan designation. This
requirement will also be extended to products for viral and
auto-immune diseases in 2008.
In Europe, the level of involvement for external experts varies
depending on the level at which the review process is being
conducted. At the national level, involvement varies by country
but can range from one advisor to specialized working groups
such as those available in France that include clinicians,
pharmacologists, pharmacists and statisticians. Current
scientific expertise at the EMEA relies on the EMEA scientific
committees, working party members, assessors from national
regulatory authorities (‘internal assessors’) and experts from
scientific societies and academic institutions (‘external experts’).
Internal assessors and external experts are complementary:
internal assessors, in addition to their own scientific and clinical
expertise have regulatory expertise and are responsible for
writing assessment reports and notes for guidance. External
experts are mainly clinicians, having recognized expertise in
a specialized scientific area. In the EU, experts play a number of
advisory roles such as contributing to scientific advice,
providing input on post-authorization commitments and
variations to introduce new indications (analogous to
supplemental NDA’s in the USA) and providing advice on
pharmacovigilance. External assessors are not paid by the
EMEA for providing their expertise.
As part of the initiatives taken by the EMEA to increase the
transparency of its operations, the list of experts has been made
available on the website. Other information, including full
declarations of interests and details about the specific fields of
expertise is available upon request to the EMEA.
SAGs (previously known as Therapeutic Advisory Groups)
are created by the CHMP (Committee for Medicinal Products
for Human Use within the EMEA) on a consultative basis to
address questions posed by the CHMP. SAG meetings are closed
to the industry and the public; the applicant can be invited to
give an oral explanation and answer questions from the SAG.
The response is a consensus by the deliberation of the members
on the question rather than by voting. The CHMP, while taking
into account the position expressed by an advisory group,
remains ultimately responsible for its final opinion. The SAGs
can be consulted on centralized applications for a Marketing
Authorization or a new indication for an already authorized
product, on scientific advice/protocol assistance and on
guidelines or other specific issues.
From a logistical point of view, membership of the SAGs
comprises both a core panel of nine experts and other individual
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members who may be called upon to participate in a given
meeting. Core members are external experts and should reflect
a balanced composition of expertise. In that respect, an expert in
clinical trials methodology should always be part of the core
group. Moreover, the composition of the core group should as
far as possible reflect different ‘schools of thinking’ or EU
therapeutic practices. Individual members invited on a case by
case basis are experts in the particular condition for which the
product under consideration is indicated or in specific issues.
All members should be independent from the pharmaceutical
industry (without conflicts of interest). In addition,
participation of representatives of consumer or patient interests
can be considered. The applicant company is often invited to
give a presentation.
Where consensus cannot be reached on an answer to the
CHMP list of questions, the conclusion reached by the majority
together with any divergent positions within the SAG-O will be
noted in the ‘SAG Answers and Comments to the CHMP’. The
answers and comments of the SAG-O on a specific medicinal
product are included in the scientific discussion of European
Public Assessment Report of the product, which is published at
the EMEA website as soon as Marketing Authorization is
granted by the European Commission.
The preliminary experience of SAG-O can be summarized as
follows. Some of the questions addressed have included the
clinically relevant risk/benefit determination in the absence of
randomized clinical trials, the relevance of composite response
definitions, the impact of inspections on conclusions reached
based on clinical studies and post-marketing commitments.
SAG-O meetings have been convened to discuss revision of the
Note for Guidance in evaluation of the anticancer products.
It is expected that the advisory process in Europe will evolve
based on accumulating experience with advisory groups
including the SAG-O and the new regulatory framework
requiring a centralized review process for anticancer drugs.
Canada: Health Canada
The Division of Antineoplastic Drugs (DAD) reviews new drug
submissions for the indication of cancer. DAD is part of the
Bureau of Metabolism, Oncology and Reproductive Sciences of
the Therapeutic Products Directorate of Health Canada.
The Scientific Advisory Committee on Oncology Therapies
(SAC-OT) was established in 2003. It provides Health Canada
with expert advice ‘on the safety and effectiveness of drugs used
for the treatment of cancer’.
Although the advisory process in Canada shares some
similarities with that of the USA, which will be outlined, it has
its own unique features that will be discussed.
General features of the advisory process that are similar to
that in the USA include the role of the advisory process as an
independent aid in the regulatory process and the focus on
issues pertaining to the safety and efficacy of drugs for cancer
therapy. The terms of reference of SAC-OT are posted on Health
Canada’s website, which details the mandate, reporting
structure, membership, tenure, security clearance, legal
assistance and administration issues related to the committee
[6]. Particular similarities are: (i) committee members are
required to declare any associations they may have with
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The regulatory framework in Japan has undergone recent
restructuring. Previously, several bodies had oversight over
different aspects of the review process. The Organization of
Pharmaceutical Safety and Research (OPSR/KIKO) was
responsible for equivalency reviews, clinical trial consultation,
compliance audits and drug safety. The Pharmaceuticals and
Medical Devices Evaluation Center (PMDEC) was responsible
for substantial review of new drug applications. The Japan
Association for the Advancement of Medical Equipment was
Volume 17 | No. 6 | June 2006
Non-Clinical
Test
(Synthesis)
(Preparation)
(Pharmacology)
(Toxicity Test)
Sngl. & Rept. Dose
Clinical Test
30
days
2~10 years (Ave. 5 years)
Phase I
Phase II
Pre P- II Consltn.
Phase III
End of P- II Consltn.
Pre P- I Consltn.
Follow-up Consltn.
New Drug Appl.
Japan: PMDA
responsible for device equivalency reviews. As of 1 April 2004,
these activities have been integrated into the newly established
Pharmaceuticals and Medical Devices Agency (PMDA) [8]. The
PMDA is authorized by the Ministry of Health, Labor and
Welfare (MHLW) and includes a staff of approximately 250
personnel including reviewers. The PMDA is comprised of
four offices: Office of Relief Funds, Office of Review, Office of
Safety and Office of Research and Development Promotion.
The advisory process in Japan has two major elements;
clinical trial consultation where the PMDA gives advice to the
applicant and the NDA review process including AC where
PMDA has discussions with external experts.
From 1997 to 2004, OPSR provided clinical trial consultation.
Discussions related to trial design sometimes involved the
PMDEC team, as well as the MHLW. As of April 2004, clinical
trial consultation has been clearly established as a responsibility
of the NDA review team within the PMDA. Whether
consultation involves development of oncology drugs or drugs
for other indications, the process has several characteristic
features including discussion based on scientific data,
consultation with senior advisors and external experts
appointed from the PMDA, discussion of the feasibility of the
proposed protocol and the realities of clinical practice, and
recording and filing of the proceedings. A schedule for
consultation is summarized in Figure 2. Consultation may be
provided at different stages of the review process as summarized
in Figure 3 [9]. The PMDA pays external experts for their
consultation.
Clin.Tri.Notif.
regulated industry; (ii) recommendations are not binding to the
regulatory agency; (iii) the similarity in expertise sought such as
in medical oncology, radiation oncology, biostatistics,
immunology and patient representation; and (iv) records of
proceedings are published on the website of the respective
regulatory agencies.
The main differences currently in the advisory process are
that: (i) the SAC-OT does not meet as often as the USFDA’s
ODAC; (ii) members do not customarily review data of
a concrete new drug submission, but rather answer questions
prepared specifically for them by the review staff of the Division;
(iii) the nature of questions presented in most cases is general,
affecting more than one future or current submission addressing
the acceptability of a surrogate for regulatory approval or
methodological issues; and (iv) the response is achieved through
consensus among the members on the question rather than
by voting, although voting was employed to finalize
recommendations at the meeting in 2005.
Those with declared associations with industry may still
participate at the discretion of the chair on issues but may not
vote or participate in the final assessment of any consensus.
Committee members are not paid for their work.
The first session of the SAC-OT took place in January, 2004
on the issue of ‘Regulatory Requirements for Approval of
Submissions for Adjuvant Therapy of Hormone Responsive
early Breast Cancer’. A closed meeting was held for 2 days in
which observer status was granted to some interested
companies. Day 1 was open only to sponsors, observers and
other regulatory agencies. During this time, Health Canada
presented the issue analysis and interested/competing sponsors
had the opportunity to present their standpoint on issues
outlined in the analysis in front of the committee and other
sponsors. Individual companies were allowed to present their
proprietary information in a closed ‘in camera’ session with the
committee in the presence of the reviewer staff. Day 2 was
devoted to Committee discussions and consensus, with Health
Canada staff present as observers. For the SAC-OT,
recommendations were reached by consensus. A record of the
proceedings was prepared based on consensus rather than word
for word, which are posted on the Health Canada website [7].
A second session took place on 19 May 2005. During this one
session several issues were discussed. These issues were general
at large but each issue was illustrated by a specific application.
The final record of proceedings will be posted on Health
Canada’s website in a redacted version to protect proprietary
information. The Advisory Committee on Oncology Therapies
is a new evolving committee.
Review
Pre-NDA Consltn.
Figure 2. Drug research and development stage and clinical trial
consultation in Japan.
Submit Questions and
Background
(investigator’s Brochure ,
Protocol, etc)
Application for
Consultation
-2~4 months
-3 weeks
Appx. 1 month
Meeting
Coordinate Meeting Day
-7~10 days
Present the
Meeting Report
Review Team Premeeting (including
senior advisors)
Figure 3. Summary of schedule for clinical trial consultation in Japan.
doi:10.1093/annonc/mdj099 | 893
review
During the NDA review process, discussions are held at the
PMDA with medical experts appointed from the PMDA. The
number of clinical external experts are approximately three to
five for each application. These discussions are not open to the
public or to the applicant. The PMDA always makes the final
decision in all applications including those where there may
have been a conflict in the recommended regulatory decision
between external experts and the PMDA.
After completion of the team review, applications are subject
to closed review by the Second Committee as well as the
Executive Committee, although the minutes are available to the
public. These committees are the advisory board for the MHLW
and provide advice on new drug applications. The current
number of members of the Second Committee and the
Executive Committee are 16 and 23, respectively, and the
members of these committees are paid for their time.
The external experts undergo a screening process for conflict
of interest. Any expert cannot attend a meeting as a consultant
during the clinical trial consultation and evaluation phase for
each application if the expert had a financial interest or took
part in the development of each drug.
Future plans at the PMDA include a desire for qualitative
improvement in the clinical trial consultation and review
process based on high expertise, a more transparent
management through a more transparent process and disclosure
of outcomes, and reinforcement of priority review and
priority clinical trial consultation, also known as the Japanese
‘Fast Track’ system.
Australia: TGA
In Australia, the Therapeutic Goods Administration (TGA) has
authority in the regulation of a number of products, including
prescription medicines, non-prescription medicines, medical
devices and gene technology products. As a part of this, it also
includes a unit that deals with adverse drug reactions. The TGA
website, http://www.tga.gov.au/, provides information on drug
regulation in Australia. Most of the work involving oncology
drugs is handled by the Prescription Medicines Branch. For
further information, the following links at http://www.tga.gov.
au/pmeds/pmeds.htm are recommended:
• Medicines Regulation and the TGA;
• Australian Regulation of Prescription Medicinal
Products; and
• Australian Regulatory Guidelines for Prescription Medicines.
The TGA guidelines are aligned with those of the EU and the
International Conference on Harmonisation of drug regulatory
activities (ICH). The TGA had input in the development of
those guidelines, and has adopted most EU/ICH guidelines
without change. For information on EC guidelines adopted by
TGA, see http://www.tga.gov.au/docs/html/euguideh.htm.
The process to register a new drug in Australia usually begins
with a presubmission meeting. Presubmission meetings are
designed to provide advice to industry on product development
and submission. These may be conducted in person, by video
conference or by teleconference. A clear purpose and agenda is
identified in advance. This process should help reduce the
894 | Farrell et al.
Annals of Oncology
number of questions during the evaluation process.
Presubmission meetings are strongly recommended for
literature-based submissions to discuss search strategies
including unpublished data. Topics may include availability of
evaluation reports from other regulatory agencies and the
possibility of shared evaluations with other agencies. The
sponsor should not seek formal agreement for development
plans or assurances that the data package will be adequate. TGA
suggestions or comments should not be taken as binding as
circumstances may change following completion of the
evaluation.
Evaluation of marketing applications involves several steps.
First, there is a review of the pharmaceutical chemistry or
molecular biology, a review of the preclinical trials and a review
by medical officers of the clinical trials.
Evaluation of the clinical trial package is mostly done by
external evaluators who are medical specialists in the relevant
field. Evaluators enter a contract to carry out the evaluation and
must declare there is no conflict of interest. Any conflict would
exclude an evaluator from doing a particular evaluation.
Evaluators are paid at the rate of a senior medical officer within
the Australian public service. Evaluators follow a standard TGA
guideline and also receive guidance from senior TGA medical
officers to ensure evaluations are of an acceptable standard. In
addition to the standard TGA guideline, specific EU or ICH
guidelines may also be relevant for a particular evaluation.
Evaluators of oncology drugs follow the EU guideline, Note for
Guidance on the Evaluation of Anti-Cancer Medicinal Products in
Man (CPMP/EWP/205/95) and the Addendum on Paediatric
Oncology (CPMP/EWP/569/02). Companies are sent
evaluations reports and, within 5 days of receipt, may request
a meeting to discuss any problems and whether they can be
rectified. New data may be submitted as a result of this.
Secondly, there is a review by a delegate of the Secretary of
the Australian Government Department of Health and Aging.
Delegates are senior medical officers within the TGA. The
industry has the opportunity to comment.
Independent advice may be sought from an AC, the
Australian Drug Evaluation Committee (ADEC). The ADEC,
is a committee of up to 24 medical and scientific experts
nominated by medical professionals and the Australian
Government. ADEC currently has six core members and 14
associate members. Core members attend every meeting,
whereas associate members attend as required depending on
the meeting agenda. Core members can serve for up to three
consecutive 3-year terms or a total of five 3-year terms and
associates for up to two 5-year terms. At the present time, the
Committee Chair (a core member) and one of the associate
members are practicing oncologists. However, it is not
a requirement for an oncologist to be a core member. The
committee meets every 2 months and provides advice on
a variety of topics including new chemical entities, new routes
of administration and new dosing regimens, new fixed
combinations, new indications and patient groups, and
proposed TGA rejections of other types of applications such
as generics, new dosage forms, new strengths and significant
safety issues.
Before each meeting, members must declare any conflicts
of interest in writing for agenda items. In the case of a conflict,
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Annals of Oncology
the meeting decides if the conflict is serious enough to exclude
the member from discussion and decision-making on the
particular item. For example, a member who had participated
in the development of a drug under discussion would be
excluded. Members also complete an annual declaration of
pecuniary and other interests. The holding of shares in
pharmaceutical companies would exclude a person from being
a member of the Committee. Members are paid at standard
Government rates for committee members.
ADEC meetings are closed to the industry and the public,
although industry comments on evaluations are included in
agenda papers. In a pilot fashion, the Australian Consumers
Association has provided input on some items. For more
information on ADEC, see http://www.tga.gov.au/docs/html/
adec/adec.htm.
The final step is approval or rejection of the application by
the delegate. Decisions are required to be made within 255
working days of the application. The delegate is not bound by
the ADEC advice.
If there is dissatisfaction with a decision, sponsors may
contact the delegate to see whether there is room for
negotiation. If necessary, an appeals process can be followed
by submission of a letter of appeal to the Minister of Health
within 90 days of the decision. A subsequent appeal is possible to
the Administrative Appeals Tribunal. These are merits review
processes. If there is a concern about the legality of a decision,
an affected party may also go to the Federal Court.
In the post-marketing phase, it is worth noting several
features of the Australian system. Australia does not have fasttrack review or conditional registration though registration is
subject to conditions, including those related to
pharmacovigilance. Companies submit Periodic Safety Update
Reports for 3 years following registration. Adverse events are
reported through a spontaneous reporting system known as the
‘Blue Card’. Additionally, there is an expert committee, the
Adverse Drug Reactions Advisory Committee (ADRAC), that
provides advice on adverse event reports. Information on
ADRAC is obtainable from http://www.tga.gov.au/adr/
adrac.htm. Possible outcomes of an adverse event review
include review of the drug, sponsor comment, other external
comment, preparation of a Bulletin item, or international
discussion. The ADRAC Bulletin is published six times a year.
Previous issues can be obtained from http://www.tga.gov.au/
adr/aadrb.htm.
Input on drug safety issues is sought internationally through
several activities. These include participation in the WHO
network, video conferencing with USFDA, Health Canada and
New Zealand every 2 months, teleconferencing with authorities
in Singapore and New Zealand every 2 months, and
participation in the WHO annual National Centres meeting.
discussion
Anticancer drug development is a complex process involving
interactions between industry, academia, government
regulatory bodies, patient advocacy groups and other
stakeholders. Furthermore, oncology patient care is
a multidisciplinary task involving medical and radiation
oncologists, surgeons, nurses, pharmacists, physician assistants
Volume 17 | No. 6 | June 2006
and other health care professionals. Finally, drug discovery,
development and interpretation of clinical trial results involve
the above disciplines as well as other scientists including
chemists, pharmacologists, toxicologists and statisticians.
Because of these multiple interactions, regulatory bodies will
often seek advice on broad policy and scientific issues, as well as
advice regarding specific drug products and marketing
applications.
The experiences described above from regulatory bodies in
the United States, Canada, Europe, Japan and Australia can be
summarized as experiences with two forms of outside expertise:
advice from individual experts and advice from a group of
experts assembled as an advisory group. The following
discussion of similarities and differences between the
approaches taken by these regulatory bodies focus on these two
forms of advice: individual experts and committees.
Starting with advice from individual experts, regulatory
agencies from all regions utilize this form of outside expertise to
varying degrees. These individual experts may be involved in
both the drug development process (presubmission) or during
the evaluation of a registration package, as seen in Table 1. In
some regions such as in the United States, external experts are
not responsible for the primary review, but provide advice based
on knowledge and experience in a certain field. In other regions
such as in Europe and Australia, external evaluators are given
primary responsibility in the review of a clinical trials package
for registration. In all cases, conflict of interest issues are
addressed prior to discussions with outside consultants. Finally,
none of the advice is binding, and all regulatory bodies
reserve the primary right and responsibility for ultimate
decision-making.
For eliciting advice and feedback from a group of experts, all
regulatory bodies discussed above have mechanisms involving
the establishment and convening of ACs. There are differences
and similarities between regulatory agencies in terms of the
structure of their ACs and in the nature of the interactions
between ACs and members of the regulatory agencies. Table 2
outlines some basic features of ACs established in different parts
of the world. It is interesting to note that in both the United
States and Australia, advisory boards were initially convened in
the early 1960s to address concerns regarding thalidomide.
Subsequently, ACs were formalized and began to address
a variety of subjects.
Table 1. Individual expert utilization in different regions
Region or
country agency
Drug development
phase (prior to
submission of
registration data)
Registration
phase
Primary reviewer
for registration
package
PMDA Japan
USFDA
TGA Australia
EMEA
Health Canada
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
PMDA, Pharmaceuticals and Medical Devices Agency; USFDA, United
States Food and Drug Administration; TGA, Therapeutic Goods
Administration; EMEA, European Medicines Agency.
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Annals of Oncology
Table 2. Oncology advisory committees from different regions
Region or
country
agency
Advisory
committee
title
Year of
establishment
PMDA Japan
USFDA
Second
Committee
ODAC
TGA Australia
EMEA
ADEC
SAG-O
1963
2003
Health Canada
SAC-OT
2003
1961
1962, 1972
Member composition
Deliberations
public
Public availability of
deliberations
Scientific experts
No
Yes.
11 clinical; 1 statistical;
1 industry; 1 patient;
1 consumer representative;
can add other experts
6 core and 14 associate
9 core + other individual
members (may include
consumer and patient
representatives)
Up to 13 core members
+ ad hoc (includes
patient representative)
Yes, unless commercial
secrets or law enforcement
issues involved
Yes, transcript of
meeting and summary
available on website
No
No
Yes, in summary form
Yes, scientific report
available on web
No
Yes, record of
proceedings
available on web
PMDA, Pharmaceuticals and Medical Devices Agency, USFDA, United States Food and Drug Administration; ODAC, Oncology Drugs Advisory Committee;
TGA, Therapeutic Goods Administration; ADEC, Australian Drug Evaluation Committee; EMEA, European Medicines Agency; SAG-O, Scientific Advisory
Group—Oncology; SAC-OT, Scientific Advisory Committee on Oncology Therapeutics.
A common theme in the composition of these committees
is the existence of a ‘core’ panel of experts with expertise
in clinical and statistical issues, with augmentation by
additional experts as needed for specific meetings. Some
committees may have patient representation. In most
jurisdictions, sponsors are invited to address the committee
at some point. In addition, the position of the committee is
non-binding in most regions, although the stance of the
Committee in Japan appears to have a significant impact on the
ultimate decision.
One apparent difference between the USFDA mechanism and
the others is the public nature of all aspects of the ODAC’s
deliberations. In all other regions, deliberations are not open to
the public. This difference may be explained by some historical
and cultural factors, where formalization of the current format
of the USFDA advisory process in the 1970s was in part
a reaction to a perceived lack of transparency in government
deliberations. Another element driving the move to public
deliberations was and continues to be the active participation of
patient advocacy groups in the debates surrounding health care
issues. Although the degree of transparency during regulatory
deliberations differs between regulatory bodies, most publish
either a summary or transcript.
acknowledgements
The views expressed are the result of independent work and do
not necessarily represent the views or findings of individual
regulatory authorities. The authors would like to thank the
following individuals for their review of the manuscript:
K. Mori, PhD and T. Urano, PhD, Pharmaceuticals and Medical
896 | Farrell et al.
Devices Agency, Japan; Dr Francesco Pignatti, European
Medicines Agency; Simonetta Yagnik (technical assistance),
European Medicines Agency; Drs Leonie Hunt and Jamie
McGinness, Therapeutic Goods Administration, Australia;
Igor Cerny, PhD, Johanna Clifford MS, RN, BSN, and Justina
Molzon MS Pharm, JD, United States Food and Drug
Administration; and Eric Ormsby, Office of Science Therapeutic
Products Directorate, Health Canada.
references
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Administration Advisory Committees. Washington, DC: National Academy
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3. A Committee Member Guide to FDA Advisory Committees. United States
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5. Pignatti F, Boone H, Moulon I. Overview of the European regulatory approval
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Iyakuhin Kenkyu 2004; 35: 487–499.
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