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1、ICON 2023Global agency meetings:A collaborative approach to drug developmentSponsors who take advantage of this collaborative approach to drug development can align their development plans with agency expectations and are in the best position to ensure that their licensing applications meet with app

2、roval following a smooth and timely assessment.Ultimately,of course,this benefits patients by ushering medicinal products to market faster.Each global region,however,has its own specific consultation offerings,procedural steps,and timelines.Here,we explain what types of agency meetings can be sought

3、 in the EU,the US,Japan,China,and Canada and provide details to guide sponsors in requesting and preparing for successful agency interactions.Regulatory authorities share sponsors goal of delivering safe and effective drugs to patients and of doing so as efficiently as possible.They,therefore,offer

4、a number of different opportunities for sponsors to seek their advice and direction at various stages of development.These range from early consultation services to scientific advice meetings on protocol designs to discussions of regulatory issues that arise in the course of development.ICON EU scie

5、ntific adviceThe European Medicines Agency(EMA)and the European Union(EU)national competent authorities(NCA)offer several opportunities for sponsors to engage and discuss scientific,technical,and regulatory topics with the agency(ies)at any stage of the development.Sponsors are encouraged to seek sc

6、ientific advice via the EMA,scientific advice working party(SAWP),or via NCA national or simultaneous national scientific advice(SNSA).Of note,national agency experts serve as members of the EMAs scientific committees,working parties,or in assessment teams.A list of NCAs can be found here.EMA scient

7、ific adviceScientific advice can be requested of the EMA at any stage of the products development,although the agency prefers to have information on the target indication so that its advice can be as accurate as possible.Discussions with NCAs should be held early in the development process,especiall

8、y if the developer plans to conduct the clinical development(e.g.,clinical trials)in one or several EU member states.Though this does not rule out the need for validation or the possibility of questions following the clinical trial application(CTA),it will enable the NCAs to be aware of the products

9、 development and upcoming CTA.This is particularly beneficial for cell and gene therapy products,for example.EU scientific advice processAt any stage of a medicines development,the developer can ask for scientific advice on the best methods and study designs.The EMA provides scientific advice to med

10、icine developers to support the timely and sound development of high-quality,effective,and safe medicines.The Committee for Medicinal Products for Human Use(CHMP)has established the SAWP as a standing working party with the remit of providing scientific advice and protocol assistance(the name given

11、to the scientific advice procedure for products with an Orphan Designation)to Applicants.The SAWP/CHMP is responsible for giving scientific advice to Applicants by answering questions based on the documentation provided by the Applicant in light of the current scientific knowledge.Any scientific adv

12、ice or protocol assistance given is not legally binding with regard to any future marketing authorisation.Scientific advice timelinesThe procedure is divided into two phases:1.A planning phase with/without a preparatory meeting,and 2.An evaluation phase without discussion meeting(40 day)OR with a di

13、scussion meeting(70 day)See European Medicines Agency Guidance for Applicants seeking scientific advice and protocol assistance EMA/4260/2001)dated 14 October 2022.Scientific advice questionsRegardless of the authorisation status,the question(s)posed to the SAWP/CHMP by the Applicant should address

14、scientific issues and may relate to the following:1.Any quality/manufacturing aspects e.g.,characterisation,specification,quality by design,and comparability 2.Any non-clinical development aspects e.g.,toxicology,pharmacology,and choice of animal model 3.Any clinical study design aspects e.g.,popula

15、tion,stratification factors,dose regimen,comparator including external control and real-world evidence,duration,cross-over,endpoints including digital endpoints,Patient Reported Outcomes(PROs)or other Clinical Outcome Assessment(COA)measures and use of biomarkers as surrogate endpoints,safety monito

16、ring plan;and for any type of clinical study(e.g.first-in-human,bioequivalence studies,dose-finding,development in special populations,clinical pharmacology,pivotal trials,post-approval trials and registry-based studies)4.Any methodological issues(e.g.,statistical analysis plan,type I error control,

17、adaptive designs,Bayesian approaches,extrapolation strategy,modelling,and simulation)5.Overall development strategy(e.g.,adequacy of development plan to support marketing authorisation application except in a pediatric population;conditional marketing authorisation or authorisation under exceptional

18、 circumstances;substitution of nonclinical/clinical trials by literature or real-world evidence;or bridging strategy to support applications relying on a reference medicinal product,safety database,or risk management plan)When developing a briefing document for SA,it is critical to ask clear,focused

19、 questions and to provide the company positions.Where guidelines already exist on a topic,that guidance is expected to be followed.ICON updatesRecent updates include the following:Scientific advice and protocol assistance guidance has been updated to rev.14,dated 14 October 2022.Further clarity is p

20、rovided regarding what aspects fall under the scope of scientific advice and protocol assistance,application,submission,and validation.The template for CHMP protocol assistance scientific advice briefing document has been updated.The IRIS guide for applicants(How to create and submit scientific appl

21、ications,for industry and individual applicants)has been updated with regards to Section 4,Scientific Advice.Updated guidance on parallel EMA/EUnetHTA 21 Joint Scientific Consultation has been issued on 06October 2022,along with an updated parallel consultation briefing document template.EU and US p

22、arallel scientific adviceSponsors may also engage EU and US agencies in parallel SA.Applicants considering using this procedure should contact both agencies as early as possible,taking into account the general principles as published in the document:General Principles EMA_FDA Parallel Scientific Adv

23、ice.Each agency will provide its independent advice to the Applicant.These requests should preferably coincide with:An End-of-Phase II or Pre-IND meeting at the Food and Drug Administration(FDA)Depending on the nature of the issues,the discussion between the agencies might take the form of an exchan

24、ge of documents,a teleconference,or a videoconference.A discussion meeting with the Applicant will always take place.EU scientific advice outcomeAdherence to EMA scientific advice on trial design results in higher success rates,shorter overall assessment time,and fewer major objections during assess

25、ment.Of note,compliance with scientific advice on clinical trial design was associated with a reduction in major objections raised by CHMP during the assessment of the Marketing AuthorisationApplication(MAA)and a 61-day shorter assessment procedure on average,indicating that these medicines may be a

26、vailable to patients earlier.Further details can be found on an EMA webpage:Scientific advice leads to stronger applications from industry.ICON FDA meetingsSponsors can solicit feedback from the FDA on both scientific and regulatory issues at critical junctures in their development program.The FDA o

27、ffers various options for such interactions,and taking advantage of these different opportunities to interact with the agency at different stages of development is hugely beneficial.FDA offers the following types of meetings:Type A,B,B(End-of-Phase(EOP),C,and D meetings.FDA encourages sponsors to re

28、quest critical milestone meetings and provides feedback to sponsors in three main formats:face-to-face meetings,teleconferences,and written response only(WRO).Meeting typesType A meetings are those necessary for an otherwise stalled product development program or to address an important safety issue

29、.Examples of Type A meetings include:Dispute resolution meetings as described in 21 CFR 10.75,312.48,and 314.103 and in the guidance Formal Dispute Resolution:Sponsor Appeals Above the Division Level Meetings to address clinical holds and devise a new path forward Special protocol assessment meeting

30、s that are requested by the sponsor after receipt of an FDA Nonagreement Special Protocol Assessment letter Post-action meetings requested within three months of an FDA regulatory action(other than approval)Meetings requested within 30 days of FDA issuance of a refuse-to-file letterBefore submitting

31、 a Type A meeting request,sponsors should contact the review division to discuss the appropriateness of the request.Type B meetings include:Pre-investigational new drug application (pre-IND)meetings Pre-emergency use authorisation meetings Pre-new drug application(pre-NDA)/pre-biologics license appl

32、ication(pre-BLA)meetings.Post-action meetings requested three or more months after an FDA regulatory action(other than approval)Meetings regarding risk evaluation and mitigation strategies or post-marketing requirements that occur outside the context of the review of a marketing application Meetings

33、 held to discuss the overall development program for products granted breakthrough therapy designation status.All subsequent meetings for breakthrough therapy designated products will be considered either Type B or possibly Type A meetings (if the meeting request meets the criteria for a Type A meet

34、ing)Type B(EOP)meetings include:End-of-Phase I(EOP1)meetingsfor drugs intended to treat life-threatening and severely debilitating illnesses(21 CFR 312 subpart E)and drugs under accelerated approval for serious or life-threatening illnesses(21 CFR 314 subpart H)End-of-Phase II(EOP2)or pre-Phase III

35、meetingsType C meetings are meetings other than Type A,Type B,or Type B(EOP)meeting regarding the development and review of a product.Type D meetings are meetings focused on a narrow set of issues(should be limited to no more than two focused topics)and should not require input from more than three

36、disciplines or divisions.Type D meetings were introduced by the FDA on 01 October 2022,as part of the Prescription Drug User Fee Act reauthorisation(PDUFA VII).Examples of such meetings include:A follow-up question that raises a new issue after a formal meeting A narrow issue on which the sponsor is

37、 seeking agency input with only a few associated questions A general question about an innovative development approach that does not require extensive,detailed advice.Meeting typeFDA response to request FDA receipt of meeting packageFDA scheduled meeting or WRO (from receipt of request)A14 daysWith

38、meeting requestWithin 30 days B21 daysNo later than 30 days before meetingWithin 60 daysB(EOP)14 daysNo later than 50 days before meetingWithin 70 daysC21 daysNo later than 47 days before meetingWithin 75 daysD14 daysWith meeting requestWithin 50 daysTimelinesFDA strongly encourages sponsors to cond

39、uct such meetings,particularly milestone meetings as these can be a valuable forum to discuss questions that may arise during product development.ICON agency meetingsThe Pharmaceuticals and Medical Devices Agency(PMDA)provides“face-to-face”consultation services regarding clinical trials and other as

40、pects of application dossiers covering all stages of development.Upon the receipt of applications from clinical trial sponsors,the PMDA ensures that the proposed clinical trial meets the requirements for approval applications.In doing so,the PMDA considers the ethical and scientific acceptability,re

41、liability,and safety for subjects for clinical trials of drugs,medical devices,cellular and tissue-based products,and other products under their review.To request a consultation,sponsors must provide an Application Form,Briefing Document,Protocol or Synopsis,and Investigators Brochure.All documents

42、should be submitted to PMDA on a Monday,five weeks prior to each consultation meeting.Suggestions and advice are provided and documented from experts inside and outside of PMDA in accordance with the level of international scientific knowledge at the time of the consultation.They are based on the do

43、cuments submitted by the Applicant and those independently collected by the PMDA.Official meeting minutes of the face-to-face consultation should be attached to the application for marketing approval.Meeting typesThe agency offers pre-consultations(free of charge)for the purpose of clarifying consul

44、tation items in advance of a smooth face-to-face consultation.A single pre-consultation is conducted in less than 20 minutes with five or fewer participants,and no meeting minutes are taken.Pre-consultations are highly recommended especially for new compounds/molecules planned to be developed in Jap

45、an.Consultation services*provided regarding clinical trials on new drugs/biological products include:1.Consultation before starting Phase I clinical trials:This meeting concerns whether the first administration of the investigational drug in humans can be justified and whether the design of the prop

46、osed Phase I study is acceptable.The PMDA provides its first suggestions and advice based on the information available at that time on the quality of the drug;the results of safety,pharmacological and pharmacokinetic studies;use of the drug in humans in other countries;drug approval(s)in other count

47、ries;information on existing similar drugs;and any other pertinent information that PMDA finds useful.2.Consultation before starting early Phase II clinical trials(dose-finding studies in a small number of patients):The PMDA provides suggestions and advice specifically on early Phase II clinical tri

48、als based on the results of Phase I trials and other studies available at the time of consultation.3.Consultation before starting late Phase II clinical trials:Applications for this type of consultation are received for the design of subsequent Phase II clinical trials before a recommended clinical

49、dose is decided and after completion of Phase I.The PMDA provides suggestions and advice based on the results of Phase I(and other studies available at that time),clinical experience,approval(s)in other countries,and information on existing similar drugs.Consultation services provided on the design

50、of late Phase II clinical trials are classified into this category if they are provided before starting a late Phase II trial.4.Consultation upon completion of Phase II clinical trials:This meeting is the first consultation service that is provided for the investigational product after the determina

51、tion of the recommended clinical dose.Suggestions and advice are provided on the study design of Phase III clinical trials based on the results of clinical studies available at that time point and the information available on existing,similar drugs.5.Pre-application consultation on drugs:Based on th

52、e results of the clinical trials available at the time of this meeting,the PMDA provides suggestions and advice on how to compile the dossiers and whether sufficient data and other required information are available for the New Drug Application.6.Follow-up consultation on drugs:Second and subsequent

53、 consultation services after each consultation.7.Post face-to-face consultation:Consultation is additionally provided on matters that were determined to be managed in a post-consultation which had been agreed upon by both PMDA and the applicant at a face-to-face consultation.Data evaluation,which is

54、 conducted in a preceding face-to-face consultation,is not subject to post face-to-face consultation.In addition to the above clinical trial consultations,other consultations regarding drug development are available,such as post-marketing,compliance and reliability,and product information(package in

55、sert).*Please note that these consultations are also for medical devices and regenerative products.ICON following flowchart shows the flow of face-to-face consultation procedures.The face-to-face consultation scheduling application form 1 needs to be submitted on the first day of the month,two month

56、s prior to the requested consultation date(e.g.,If the applicants request for a face-to-face consultation in April,the scheduling application form 1 shall be submitted to PMDA on 1st February and the Notice of the date of consultation 2 will be provided by the PMDA on 7th February).Applications for

57、product covered as priority review products will be accepted at any time(e.g.,Orphan drugs,SAKIGAKE-designated products,etc.).Flowchart for face-to-face consultationThe general timeline from the kick-off meeting to face-to-face consultation,including the pre-consultation meeting,is described in the

58、following chart.(Approximately five to seven months from kick-off meeting to receipt of meeting minutes,depending on the volume of documents to be prepared).Designated bank1)Application for face-to-face consultation2)Copy of remittance certifcateFace-to-face consultation scheduling application formA

59、pplication for face-to-face consultationNotice of consultationApplication for consultation scheduling1Notice of the date of consultation36Inquiries9Answers and comments10Return of reference documents16Delivery of reference documents for face-to-face consultation7Bank,etc.Remittance4Remittance of con

60、sultation fee5Remittance certificateConsultation11Advice12Participation14Confirmation15Delivery of reference minutes17Office of Review Management8Reference documents13 Participation2Time schedulingAppointed review officePMDAs expertsPMDAPreliminary meetingsMeeting for consultationDrafting of minutes

61、ApplicantPreliminary investigationCompletion of minutesICON typeCDE receipt of meeting packageCDE scheduled meeting or WRO(from receipt of meeting request)RemarkType IWith meeting request30 working daysWhen an official meeting is agreed by CDE,the meeting date will be further communicated with the A

62、pplicant.Generally,the meeting duration will be a maximum of 60 minutes.The meeting minutes shall be finalised no later than 30 working days after meeting completion if an official meeting is held.Type IIWith meeting request60 working daysType IIIWith meeting request75 working daysChina agency meeti

63、ngsThe regulatory environment in China is rapidly changing to encourage and support innovative product development.The information below outlines the current regulatory status regarding agency meetings for pharmaceutical products.During pharmaceutical product development and the registration applica

64、tion technical review process,the Center for Drug Evaluation(CDE)offers various options to Applicants for fulfilling advice needs,including three types of agency meetings for communication about key technology issues that havent been covered by the current regulatory guidelines.The forms of agency m

65、eetings include face-to-face meetings,video conferences,teleconferences,or WRO.Teleconferences are encouraged.Meeting typesType I meetings are generally held to address major safety issues encountered in drug clinical trials,critical technical issues encountered during the development of breakthroug

66、h therapeutic products,or other specific situations(e.g.,communication meeting applications purely for childrens clinical trial plans/protocols or results when meeting one of the four situations specified by CDE).Type II meetings are generally held in the critical stages of drug development.These ma

67、inly include,but are not limited to:Pre-IND meetingTo address major technical issues prior to the initial submission of clinical trial applications,discussions might include,but are not limited to sufficiency of existing research data for supporting the proposed clinical trial and risk controllabili

68、ty of the clinical trial for subjects/patients,etc.The pre-IND meeting package should include the clinical trial protocol(a draft version is acceptable,although the full protocol is highly recommended),the complete dossier of existing CMC and nonclinical study data,and other research data when appli

69、cable.End-of-Phase II(EOP2)or Pre-Phase III meetingTo address major technical issues after the completion of Phase II study and before the implementation of pivotal Phase III study,discussions might include,but are not limited to:Sufficiency of existing research data for supporting the proposed Phas

70、e III clinical trial,Evaluation of the Phase III protocol,etc.Pre-NDA meetingTo discuss whether the existing research data meets the technical requirements for drug marketing authorisation.Risk assessment and control meetingFor evaluating and controlling the post-marketing risks of drug product,the

71、discussion is performed before marketing authorisation and focus on sufficiency and controllability of the post-marketing risk control plan/measures.Other particular situations,e.g.,communication on conditional approval and/or application of priority review and approval procedures,Type II meeting mi

72、ght be considered.Type III meetings are applicable to the situations beyond the scope of Type I and II meetings,when necessary.Such situations might include,but are not limited to:Clinical trial application for adding a new indication,adding combination use with other drugs,etc.Critical technical is

73、sues in the development process of drugs that are in urgent need or for rare diseases.Design proposals for complex and important nonclinical studies(e.g.,carcinogenicity study)Communication applications for products in frontier technology field and during its R&D process.Communication applications d

74、uring clinical trial period regarding issues/questions exist in safety evaluation and risk control area.Post-marketing clinical trial design.Post-marketing amendments that are not covered by existing regulations and guidelines.Meeting timelinesICON points There are several key points that Applicants

75、 should note:The authorities do not charge for China CDE communication meetings.The pre-IND meeting is not mandatory especially for studies with specific guidelines and where the Applicant has experience in a related study.Nor is it necessary for multi-national clinical trials that have obtained cli

76、nical trial approvals in countries/regions with comprehensive regulatory administrations systems.However,Applicants are strongly encouraged to seek the pre-IND meeting given that there is no opportunity to submit/supplement any technical documents during the IND review stage.Therefore,there is a hig

77、h risk that the IND could be rejected if any technical deficiency is identified after IND submission.The CDE communication meeting package shall be submitted along with the application submission.The meeting package should include the application form,a briefing book(including questions,applicants p

78、ositions,and supportive documents),and a slide deck.Additional documents might be required by CDE based on an of the meeting request and documents received.Generally,the number of questions to be discussed in a meeting should not exceed 10.Canada agency meetingsA sponsor may request pre-submission/a

79、pplication meetings prior to filing a submission/application.These meetings may be conducted face to face or by teleconference.The meeting allows the sponsor to educate Health Canada on the product and the development process.Pre-submission meetings also provide an opportunity for sponsors to addres

80、s any potential concerns raised by Health Canada prior to filing the submission.A pre-submission meeting can be requested for the following type of submissions:Drug submissions/applications(e.g.,NDS,SNDS,ANDS,etc.)Request for Combination Product Classification Request for Priority Review Request for

81、 advanced consideration of a submission under the Notice of Compliance with Conditions (NOC/c)Policy Submissions for Extraordinary Use New Drugs(EUNDS)Submission/application relying on third party data,or Response to a Notice of Deficiency(NOD)or Notice of Non-Compliance(NON)Objectives of the meetin

82、gTypically,the primary goals of a pre-submission meeting are to:Discuss any questions or concerns that have been identified during the drug development process.Provide Health Canada with a high-level overview of the data to be included in the submission,to facilitate the review.Identify the pivotal

83、studies that support the filing,providing Health Canada the opportunity to discuss any concerns in design etc.Provide the opportunity to explore the most expedited regulatory pathway for the submission,such as Priority Review and NOC/c.Give the opportunity to optimise the submission data quality.Ena

84、ble the appropriate Directorate to plan resources and project timelines etc.Although meeting participants may discuss the data planned to be part of the submission,the acceptability of the data will only be considered during the scientific review of the submission/application.Requesting a pre-submis

85、sion meetingA request for a meeting must be made by the sponsor in writing.With the request,a sponsor should include:The specific details regarding the product to be discussed(e.g.,active ingredient,dosage form,and therapeutic classification,etc.,including whether the drug is first in class)Adequate

86、 information regarding the product to enable Health Canada to assess the utility of the meeting A list of preliminary questions to be addressed during the meeting Submission/application information(control number,product name,etc.)and a copy of the NOD/NON if the meeting is regarding a response to a

87、 NOD/NON Suggestion regarding the review expertise necessary to discuss the proposed issues(e.g.,clinical/chemistry/biopharmaceutics reviewers,biostatisticians,etc.),and If the drug submission will rely solely on third-party data If Health Canada agrees with the request,an acknowledgement letter wil

88、l be sent to the sponsor confirming the date and time of the meeting and an initial list of proposed Health Canada attendees.Should it be determined that a formal meeting is not required,a response and rationale will be provided to the sponsor.ICON packagesSponsors will be required to submit a pre-s

89、ubmission/application meeting package containing the following key information:A brief summary of the drug product Identification of the indication(s)for which approval is sought Proposed strengths and dosages A summary of the clinical development plan for the drug,including identification of clinic

90、al trials completed in Canada(if any)and confirmation of which trials are still on-going(if any)A summary of the product development leading up to a description of the manufacturing process for the product to be marketed;including,any changes in production process,dosage form,and testing methods Bri

91、ef summaries of the safety and efficacy data relating to the drug An overview of the market history of the product including the foreign regulatory status of the drug A list of specific issues or questions(grouped by discipline)the sponsor would like to discuss or have addressedTimelinesWhen plannin

92、g a pre-submission meeting,it is best to contact the appropriate Health Canada directorate and/or review division as early as possible to understand when the division is booking meetings.In some cases,this can be 3-6 months in the future.The pre-meeting package must be provided to Health Canada one

93、month in advance of the meeting.The sponsors slide presentation must be submitted one week prior to the meeting.It is common practice for sponsors to receive advance feedback from Health Canada within the last week before the meeting.This can often necessitate revisions to the meeting slides and may

94、 result in a change to the focus of the meeting.The sponsor is responsible for taking minutes of the meeting and submitting the draft minutes within two weeks of the meeting.Health Canada will review the minutes,provide any revisions,and advise when the minutes can be considered final.ConclusionAlth

95、ough requesting and attending a meeting with regulatory authorities to seek scientific advice takes time and requires specialised resources,the undertaking is well worth the investment.When approached properly that is,in a timely manner and according to the procedures laid out by agencies meeting wi

96、th regulators can prevent unhappy surprises later in the development and approval cycle.Indeed,it is often key to optimising a products path to approval.The types of meetings outlined here,the circumstances under which they can be sought,and the process for requesting them vary widely from region to

97、 region.Thus,pursuing input from the authorities demands attention to detail and a thorough understanding of how such exchanges are conducted.ICONs global regulatory consultants have extensive experience in orchestrating and conducting each type of SA meeting across therapy areas and geographies and

98、 for multiple sponsors.Our professionals are available to guide you and support you so that your agency interactions are constructive and proceed smoothly.For more information on how ICON may assist your team in preparing for and gaining the most out of SA meetings.Please contact us at:SRS-INFO 2023 ICON plc.Allrights reserved.