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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 890 | Farrell et al. 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 Volume 17 | No. 6 | June 2006 review Annals of Oncology 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. Volume 17 | No. 6 | June 2006 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 892 | Farrell et al. Annals of Oncology 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 Volume 17 | No. 6 | June 2006 review Annals of Oncology 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, Volume 17 | No. 6 | June 2006 review 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. doi:10.1093/annonc/mdj099 | 895 review 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 1. Rettig RA, Earley LE, Merrill RA (eds). Institute of Medicine: Food and Drug Administration Advisory Committees. Washington, DC: National Academy Press 1992. 2. Rados C. Advisory Committees: Critical to the USFDA’s Product Review Process. USFDA Consumer Magazine, January–February 2004. 3. A Committee Member Guide to FDA Advisory Committees. United States Government Printing Office 1994. Washington, DC. 4. Vaccari LA. The role of the Oncology Drug Advisory Committee in the FDA review process for oncologic drugs. In Teicher BA, Andrews PA (eds): Cancer Drug Discovery and Development: Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, 2nd edition. Totowa, NJ: Humana Press Inc.; 2004; 421–427. 5. Pignatti F, Boone H, Moulon I. Overview of the European regulatory approval system. J Ambul Care Manage 2004; 27: 89–97. 6. Health Canada. http://hc-sc.gc.ca/dhp-mps/prodpharma/activat/sci-com/onco/ index_e.html 7. Health Canada. http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/sac_ot_ati_2004-0114_rop_e.html 8. Pharmaceuticals and medical Devices (Japan). http://www.pmda.go.jp/ index-e.html 9. Sato T. Clinical trial consultation in pharmaceuticals and medical devices agency. Iyakuhin Kenkyu 2004; 35: 487–499. Volume 17 | No. 6 | June 2006