1、The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedMarch 2023White Paper2March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)ContentsIntroduction 03Industry Organizations 04The

2、Global Landscape 05In Conclusion 193March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)IntroductionThe coronavirus pandemic put clinical trials in the spotlight or hot seat,depending on ones perspective.Around the globe pressure came from

3、 multiple fronts:regulatory agencies,the public,patients,advocates,pharmaceutical industry watchdogs and investors all clamored for increased clinical transparency.The push for accountability has not abated for study sponsors to publish results in a timely manner.However,just as there are numerous r

4、egulatory agencies and guidelines(approximately 90 countries have requirements related to the disclosure of clinical trial data made publicly available on over 30 clinical trial registries),enforcement of clinical trial disclosure requirements varies greatly.While study sponsors have come under fire

5、 for failure to disclose trial information,so too have regulatory agencies.The US National Institutes of Health(NIH)failed to ensure the timely reporting of results in roughly half of the clinical trials it funded in 2019 and 2020,according to areportreleased by the Department of Health and Human Se

6、rvices Office of Inspector General.In some cases,the agency allowed noncompliant researchers to launch new trials.A 2022 Health and Human Services inspector generals office audit of the NIH revealed that of 72 intramural and extramural trials,only 35 submitted results were on time,12 were submitted

7、late,and 25 never submitted.The report reads:“NIH did not have adequate procedures for ensuring that responsible parties submitted the results of clinical trials,took limited enforcement action when there was noncompliance,and continued to fund new research of responsible parties that had not submit

8、ted the results of their completed clinical trials.”Its recommendation included that the NIH“take enforcement actions against responsible parties that are late in submitting trial results or do not submit results.”The European Medicines Agency(EMA)refused to release major documents containing clinic

9、al data,including adverse effects,produced by pharmaceutical companies,according to a 2022 report.The report concluded:“The European Parliament and the European Commission,which are responsible for adherence to the institutional and regulatory principles of the EU,should also ensure that clinical st

10、udy reports are published in their entirety,as required by the Clinical Trials Regulation CTR.”That said,lack of transparency at a regulatory agency does not diminish the sponsors responsibility to comply with disclosure deadlines.By Darcy Grabenstein4March 2023 Copyright 2023 Pharma Intelligence UK

11、 Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedIndustry OrganizationsMany pharmaceutical industry groups have issued statements or developed policies regarding clinical

12、trial disclosure.Following are several organizations that have taken a stance on transparency.The International Committee of Medical Journal Editors(ICMJE)“requires,and recommends that all medical journal editors require,registration of clinical trials in a public trials registry at or before the ti

13、me of first patient enrollment as a condition of consideration for publication.”In addition,the ICMJE recommends that journals publish the trial registration number at the end of the abstract.The trade organization International Federation of Pharmaceutical Manufacturers&Associations(IFPMA)provided

14、this statement on disclosure:“The innovative pharmaceutical industry is committed to the transparency of clinical trials that are sponsored by our member companies.We therefore commit to a set of principles regarding the disclosure of information relating to clinical trials we sponsor and appeal to

15、all sponsors of clinical trials to commit to keeping these registries accurate and up to date.”The Pharmaceutical Research and Manufacturers of America(PhRMA),in response to a request for comment,released this statement:“PhRMA members are committed to enhancing public health and advancing the develo

16、pment of medicines by sponsoring and conducting clinical research that fully complies with all legal and regulatory requirements.Further,our Principles for Responsible Clinical Trial Data Sharing set forth PhRMA members commitment to enhancing public health through responsible sharing of clinical tr

17、ial data in a manner that safeguards the privacy of patients,respects the integrity of national regulatory systems,and maintains incentives for investment in biomedical research.”In May 2017,over 20 international regulatory agencies and related organizations signed a joint statement from the World H

18、ealth Organization(WHO)on public disclosure of results from clinical trials.The signatories agreed to the following:“Within 12 months of becoming a signatory of this statement,we each pledge to develop and implement a policy with mandated timeframes 12 months from primary study completion for prospe

19、ctive registration and public disclosure of the results of clinical trials that we fund,co-fund,sponsor or support.We each agree to monitor registration and endorse the development of systems to monitor results reporting on an ongoing basis.We agree to share challenges and progress in the monitoring

20、 of these policies.We agree that transparency is important and therefore the outputs from the monitoring process will be publicly available.”A 2022 paper co-authored by Till Bruckner,PhD,founder of TranspariMED,a nonprofit working to end evidence distortion in medicine,posed this question:Do Europea

21、n medical research funders require grantees to register and report clinical trials in line with WHO best practices?This cross-sectional study of the 21 largest nonmultilateral public and philanthropic funders in Europe found that funders implemented a mean of 36%of WHO best practices in clinical tri

22、al transparency.A total of 14 funders(66.7%)mandated prospective trial registration and six funders(28.6%)required that trial results be made public on trial registries within 12 months of trial completion.Less than half of funders actively monitored whether trials were registered(9 funders 42.9%)or

23、 whether results were made public(8 funders 38.1%).5March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedLets take a look at a

24、broad spectrum of global regulations,whether penalties exist for noncompliance and,if so,whether they are being enforced.Citeline reached out to all major regulatory agencies;those listed below provided requested updates.NORTH AMERICAThe USAs in all areas the FDA regulates,the agencys goal is to ach

25、ieve voluntary compliance with applicable legal requirements.The FDAs compliance activities related to the ClinicalTrials.gov requirements provide the opportunity for responsible parties to take voluntary corrective actions before the agency proceeds with a civil or criminal enforcement action.The a

26、gency uses a risk-based approach to compliance and enforcement to prioritize the greatest risks to public health and works with responsible parties to help them voluntarily comply.The FDA is authorized to seek civil money penalties for violations of the ClinicalTrials.gov requirements.Responsible pa

27、rties that fail to submit clinical trial results information for certain applicable clinical trials to the ClinicalTrials.gov databank could also be subject to an injunction and/or criminal prosecution.Penalties of$13,327(maximum adjusted penalty)are in place for all violations adjudicated in a sing

28、le proceeding and,if a violation is not corrected within 30 calendar days following notification of such violation,the law provides for an additional civil money penalty for each day the violation continues until it is corrected.The FDA is required by law to issue a Notice of Noncompliance to a resp

29、onsible party whom the FDA has determined has failed to comply with this requirement.To date,the FDA has issued 92 Pre-Notice Letters and four Notices of Noncompliance to encourage compliance with the ClinicalTrials.gov requirements.The four recipients of Notices of Noncompliance submitted the requi

30、red clinical trial information,a testament to the effectiveness of enforcement,and the agency did not pursue civil money penalties against them.The FDA has not yet pursued civil money penalties against any responsible parties.However,the FDA has defined a limited approach to identify violations.A vi

31、olation may be detected during a Bioresearch Monitoring(BIMO)inspection or based on an evaluation of complaints received by the agency.FDA enforcement to date is perceived as being extremely slow.Even though over 4,000 clinical trial results are missing in the US(24%of trials that require results un

32、der the Final Rule),the FDA is currently only sending out two notices per week.“Just put 10,000 letters in the mail,”advises TranspariMEDs Bruckner.“Sending out letters to people who break the law is not a difficult regulatory decision.”While the US may be one of the few countries taking baby steps

33、to enforce clinical trial disclosure,some say more enforcement is needed.The Global Landscape6March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and H

34、ow They Are EnforcedUS Academia Brings Up Its Grades,After Report Card Goes PublicNavya Dasari is a woman on a mission.A student at New York Universitys School of Law,she is a member of the North American Coordinating Committeefor Universities Allied for Essential Medicines(UAEM).The health justice

35、organization focuses on access to medications and drug pricing.She said the issue of clinical trial results reporting“struck me as something that shouldnt be controversial.”In 2019,UAEM,in conjunction with TranspariMED,published first report on clinical trials conducted by US universities.A key take

36、away,Dasari noted,was the significant lack of transparency in academia,even more so than at pharmaceutical companies.After UAEM members discussed the results with administrators at various universities,Dasari said some of the worst offenders became 100%compliant.UAEM conducted a follow-up report in

37、2021,which revealed that over half of the top 40 research universities were in violation of transparency regulations.In the wake of the report,Columbia University went from a 16.7%compliance rate in 2019 to 100%in 2021.And the number of institutions above an 80%compliance rate increased from 16 to 3

38、6.Dasari said FDA Commissioner Robert Califf has highlighted the need for better compliance:“I think with him at the head of the FDA were really excited to see greater enforcement.”Dasari isnt the only one who expressed her dissatisfaction in writing.In January 2023,Frank Pallone,ranking member of t

39、he House Energy&Commerce Committee,sent a six-page letter to the Food and Drug Administration(FDA)and National Institutes of Health(NIH),criticizing the organizations for not doing enough to enforce pharmaceutical companies disclosure compliance on ClinicalTrials.gov.“FDA and NIH both have a role in

40、 enforcement of ClinicalTrials.gov requirements,”the letter reads.Making a Case for Clinical Trial Transparency Bruckner,who founded the aforementioned TranspariMED in 2017,is a vocal advocate for clinical trial transparency.He is also a partner in Consilium Scientific,a nonprofit research and educa

41、tional organization dedicated to informing and enacting health policy change in the UK and around the world.“Failure to register and fully report clinical trials harms patients,wastes taxpayers money,and slows down the development of new treatments,vaccines and cures,”Bruckner said.Navya Dasari7Marc

42、h 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedTill BrucknerHe said one of his biggest accomplishments is getting a lot more

43、groups to understand the problem and push for policy solutions.He has brought together over 30 groups in over a dozen countries.He brought Transparency International on board because it is“outside the narrow medical scene;thats sustainable.”One of his biggest challenges is capacity/bandwidth to keep

44、 up with so many countries regulations.Bruckner said the UK is the only country that has addressed the transparency problem since 1980.He cited the UKs national clinical trial strategy as“the gold standard,”cutting unnecessary bureaucracy and paperwork.“Countries should really look to the UK for a w

45、ay to solve this problem in a way that doesnt aggravate sponsors,the industry,in a way thats efficient.Look to the UK model.”(See more on UK regulations below.)Figure 1:Potential Solution:UK ModelTrial DesignNationally ArchivedAutomatic RegistrationEthics ApprovalTrial RegistrationConduct of TrialRe

46、sults ReportingHealth Research AuthorityChecks if Results Reported8March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedCanada

47、In 2019,the Canadian government created a new online portal to access clinical study reports.However,according to a 2022 article in Citelines In Vivo,the Canadian regulator never passed regulations to build on a 2014 law stating there is a duty to publicize clinical trial information.New draft guide

48、lines on registration of trials and public disclosure of results were released in February 2023 and are out for public consultation until April 24.LATIN AMERICAArgentinaAccording to the book Clinical Trials in Latin America:Where Ethics and Business Clash(2014),in 85%of the protocols approved by ext

49、ernal private research ethics committees(RECs),the Institutional Council for the Review of Research Studies(CIREI)found a total of 92 infractions of The National Administration of Drugs,Foods and Medical Devices of Argentinas(ANMATs)standards and regulations.For example,42%of the protocols did not s

50、tate that results of the trial would be made public and 24%did not assume any obligation to participants following the conclusion of the study.Another study,focused on clinical trial registration,suggested that to increase compliance and promote clinical trial registration,national health authoritie

51、s,sponsors,and local investigators could implement a grassroots educational campaign to improve clinical trial regulation.MexicoMost industry-sponsored studies in Mexico aim to comply with FDA regulations,while national regulations are less strict compared to international standards.The agency respo

52、nsible for regulation in Mexico is the Federal Commission for the Protection against Sanitary Risks(COFEPRIS).In terms of registration,once an applicant has received an authorization letter from COFEPRIS,registration is mandatory and must be completed within five business days.Many trials are tracke

53、d on ClinicalTrials.gov,where Mexico currently has over 4,000 registered trials,many of which have yet to report results.According to the Clinical Trials in Latin America book,“No specific provisions exist to assure study participants that they will benefit from the results of the clinical trial.”TH

54、E UKThe timeframe for publishing summary results is within one year(six months for pediatric trials)of the end of trial,according to UKs Medicines and Healthcare products Regulatory Agency(MHRA).Where applicable,it advises sponsors to publish summary results within this timeframe in the public regis

55、ter(s)where the trial is registered.The UK government will introduce a legal requirement to make public the results of all clinical trials within 12 months of trial completion.Any company or university breaking the law will be refused permission to start new trials,the UK drug regulator announced on

56、 March 21.Sponsors do not need to submit the summary report to the MHRA,but must confirm via email once the result-related information has been uploaded to the public register.If a clinical trial is not on a public register or the results will not be published in the register(for example,an adult Ph

57、ase I study),summary results should be submitted via MHRA Submissions.Sponsors should also submit a final report to the Research Ethics Committee within the same timeframe 9March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of G

58、lobal Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are Enforcedfor reporting the summary of results.Sponsors of trials conducted in UK already registered in the EU Register are able to submit results to EudraCT.A spokesperson for the UKs Health Research Authority

59、said:“Transparency about what research is going on,and what its findings are,is important for patients,service users and the public.It builds trust and accountability,acknowledges their contribution and encourages participation in research.Being transparent also avoids duplication of effort and enab

60、les findings to be used to develop new and better treatments for patients and service users.“Our Make it Public campaign demonstrates our commitment to support and encourage the research sector to be transparent and open.”THE EUROPEAN UNION(EU)From July 2014 to Jan.31,2023,it was possible to registe

61、r a trial on EudraCT under the EU Clinical Trials Directive.While results were required under the directive,there was no enforcement mechanism and no penalties could be imposed.Since Jan.31,2022,trials posted on the Clinical Trials Information System(CTIS)under the EU Clinical Trials Regulation(mand

62、atory for new trials since Jan.31,2023),European Economic Area(EEA)member states have the regulatory framework to impose penalties,as described below.The regulation enables significant improvements concerning the public availability of information on clinical trials conducted in the EU/EEA,including

63、 summary of results,via the public CTIS website.Article 37(4)of the regulation provides a clear legal obligation to post clinical trial results,together with a plain language summary of the results,within one year from the end of the clinical trial.It allows member states to impose penalties applica

64、ble to infringements of the Regulation(Article 94),and to take all measures necessary to ensure that they are implemented.In January 2023,Pink Sheet reported that the EMA is working on restarting this landmark policy on publishing clinical trial data,with the first phase expected to start this year.

65、The EMA notes that it is important to make the distinction between the disclosure rules which have been applying in the context of the EudraCT website(and its public interface,the Clinical Trials Register),and those which apply now since the implementation of the Clinical Trial Regulation and the la

66、unch of the CTIS,which became mandatory for submissions as of Jan.31,2023.In a prepared response,the EMA said:“Together with the European Commission and the member states,the EMA is aware that there is still work to be done to improve the situation and have taken a number of actions to further impro

67、ve the reporting rate of summary of results in the Clinical Trial Register.Since September 2018,EMA has been regularly identifying trials with missing due results.EMA,together with the European Commission and the member states,have been working on a number of actions to further improve the reporting

68、 rate in the EU Clinical Trials Register.EMA has substantially improved the EudraCT website and its instructions in order to make results reporting easier for academia and for commercial sponsors.”The EMA concluded with this statement:“Transparency is an essential component of clinical research,and

69、clinical trial information and results need to be publicly available.”Following the June 2019 issuing of a jointletter reminding all sponsors ofclinical trialsconducted in the European Union of their obligation to make summaries of results of concluded trials publicly available,national competent au

70、thorities(NCAs)and the EMA have sent reminders to noncompliant sponsors,to 10March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are Enfor

71、cedincrease compliance with the transparency rules and their follow-up on reporting obligations.According to the EMA,due to these reminders,the percentage of posted results substantially increased.However,for some trials the reminders were not successful:Many sponsors could not be reached.A list of

72、trials for which sponsors could not be reached,or for which sponsors did not follow up on the request of results posting,is published on https:/www.clinicaltrialsregister.eu/.The posting and publication of summary results in the EU Clinical Trials Register is further set out in a European Commission

73、guideline.The publishing of results has been required since July 2014.However,there is no legal basis for EMA to impose penalties on sponsors who are not fulfilling the legal requirements to provide results in EudraCT.According to section 4.7(noncompliance,factual inaccuracy)on posting and publicati

74、on of result-related information on clinical trials,it is the responsibility of the member states to verify that,for clinical trials authorized by them,the result-related information is posted to the agency and therefore to decide on further actions.A study published in January 2023,“Towards full cl

75、inical trial registration and results publication:longitudinal meta-research study in Northwestern and Central Switzerland,”found that approximately 10%of clinical trials remained unregistered despite the legal obligations.“More support for investigators and stricter enforcement by regulators are ne

76、eded to improve the transparency of investigator-sponsored trials in particular.”Figure 2:Number of Missing Trial ResultsSingle-country trials approved up to 2016 only,estimateSource:TranspariMEDItalyNetherlandsSpainFranceSwedenAll othersDenmarkFinlandGermanyBelgiumNorwayAustria3635927927

77、32482372217774December 2020July 202011March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedNational medicines regulators in Eur

78、ope have failed to ensure the publication of at least 5,488 clinical trial results,the report states.On a more positive note,the star performer was Austria,which increased its reporting rate from 26%to A September 2022 report,the first of its kind,published by TranspariMED,Consilium Scientific and o

79、ther and other European health groups,found gaps in clinical trial disclosure regulations across Europe.Key findings of the report include:Regulators in at least five countries Austria,Belgium and Denmark are actively prompting trial sponsors to make the results of their past drug trials public.65%w

80、ithin less than two years.Germany and Austria also achieved high reporting rates,and Denmark and Belgium made substantial progress.Regulators in four countries France,Italy,Spain and Sweden appear to be taking little or no action on missing drug trial results.In January 2023,Italy released its Regis

81、ter of Observational Studies(RSO);registration is mandatory for new requests submitted for Ethics Committee review,and results are due within 12 months of study completion.Legal basis for the RSO is Article 6 of the Ministerial Decree of Nov.30,2021.Figure 3:Percentage of Trials with ResultsSingle-c

82、ountry trials approved up to 2015 onlySource:TranspariMEDUK*GermanyAustriaDenmarkBelgiumSpainSwedenFinlandFranceItalyNetherlandsNorway74646644652020 Baseline2022 Baseline264724171910176%with results December 2020%with results July 202012March 2023 Copyright 2023 Pharma Intellig

83、ence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are Enforced None of the countries covered have laws requiring the publication of clinical trial results that do not involve in

84、vestigative drugs or medical devices.Legislation for Austria,A month later,TranspariMED published another report on compliance in the EU.The report showed that the majority of unreported drug trial results in Europe were concentrated within just four countries:Italy,the Netherlands,Spain and France.

85、TranspariMEDs Bruckner commented:“We are seeing a clear willingness by many national regulators within the European Union to impose sanctions if clinical trial sponsors fail to comply with legal CTIS results reporting requirements.I think many regulators patience has run out.”Belgium Belgium was the

86、 first EU country to disclose specific details about its penalties.As of February 2022,the Federal Agency for Medicines and Health Products(FAMHP)has the authority to impose fines of 550 to 250,000 and a prison sentence of up to two years for failure to report results.Repeat offenders can face maxim

87、um penalties of a 500,000 fine and a three-year prison sentence.Whats more,a judge can ban repeat offenders Germany and Sweden is unclear whether regulations apply specifically to results reporting.from participating in clinical trials for three to 10 years.Its important to note that this law applie

88、s only to trials for drugs,not medical devices,and only covers drug trials registered on the new EU-CTIS trial registry since January 2022.An August 2021 notice from the Federal Agency for Medicines and Health Products calling for sponsors to publish clinical trial results begins:“The FAMHP reminds

89、all sponsors they are obligated to publish the results of their clinical trials in the European Clinical Trials Database(EudraCT)within one year after the end of trial date(or six months for a paediatric trial).Publication on external sources or the transmission of reports to national competent auth

90、orities is not sufficient.The guideline applies retrospectively.Results should be posted in the EudraCT database as soon as possible.”In terms of enforcement,the letter only states:“The FAMHP will contact all sponsors of clinical trials that have been conducted and completed in Belgium for which no

91、results have been uploaded in EudraCT.”EU member states that impose fines for failing to report the results of a drug trial*:*Updated to reflect current fines.CountryFinesAustria25,000-50,000Belgium550-250,000DenmarkTo be determinedFinlandTo be determinedGermany25,000 maximumNetherlands33,500SwedenT

92、o be determined13March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedIf a violation is found,a determination will be made by a

93、 GCP inspector of the FAMHP,who may then prepare a pharmacovigilance(PV)document of determinations.This PV document,together with the inspection report,will be transmitted to the violator and the FAMHP official-lawyer(being the head of the Division of Legislation and Disputes).The official-lawyer ca

94、n then,in consultation with the inspection,propose an amicable settlement to the offender for a minimum 4,000,the minimum amount of the fine multiplied by the applicable surcharges.The Czech RepublicThe requirements for clinical trials of medical products and everything related to them are specified

95、 in the national legislation which,although not currently aligned to EU regulations,refers to the 2003 EU directive(Act on Pharmaceuticals;Decrees).The Czech Republics first national law,Pharmaceutical Act,No.79/1997,was amended several times.In short,a study sponsor must submit a final report into

96、the EudraCT database(CTIS).The Act on Pharmaceuticals also lists misdemeanors and sanctions for noncompliance.Sanctions could be imposed by the Legal Department of SKL,the State Institute for Drug Control.For enforcement,officials rely on GCP inspections.However,GCP inspections typically only focus

97、on the conduct of the trial;it is unclear whether this would include clinical trial disclosure.DenmarkIn October 2020,the Danish Medicines Agency(DKMA)announced it was taking tougher action to ensure the publication of clinical trial results.It cited a 2019 survey showing that only 23.6%of the non-c

98、ommercial sponsors in Denmark fulfilled their obligation to publish the results from clinical trials of medicines.Sponsors are responsible for sending clinical trial results to EudraCT.Sponsors who fail to publish the results in alignment with CTIS requirements are liable to a fine or imprisonment o

99、f up to four months.Interpretation of Chapter 6 of the Act on Clinical Trials indicates that the DKMA will check for Article 37 of Regulation 536/2014(to submit results to CTIS rather than EudraCT in this context).The DKMA will send a reminder to noncompliant sponsors and then take further steps if

100、the results are not reported.The agency cannot itself issue a fine or sentence sponsors to imprisonment;it must go through the public prosecutor.EstoniaThe Estonian Medicines Agency is the regulatory body governing clinical trials in Estonia.All trials in Estonia are run according to the Medicinal P

101、roducts Act.Chapter 5 of the act regulates clinical trials in humans,stating:“The sponsor must submit an Estonian summary of the results of a clinical trial of a medicinal product aimed at an ordinary user to the database specified in Article 81 of Regulation(EU)No 536/2014 of the European Parliamen

102、t and of the Council in accordance with Article 37(4)of the same Regulation.”Estonia goes into great detail regarding various types of noncompliance.The sanction for noncompliance with the requirements of a clinical trial of a medicinal product,including provisions governing the submission of data o

103、r the safety of a trial subject,is a fine of up to 300 fine units.According to the European Commission,onefine unitequals 4,for a total fine up to 1,200.The sanction for the same act committed by a legal person is a fine of up to 32,000.FinlandIn Finland,no penalties have been established in legisla

104、tion for noncompliance of clinical trial results reporting,neither under the Clinical Trial Directive 2001/20/EC or Clinical Trials Regulation No 536/2014.14March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical T

105、rial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedSwedenAccording to Article 67b of Swedens Federal Act on Medicinal Products and Medical Devices,the Federal Council may,taking into account internationally recognized regulations,require publication of clinical trial

106、results.Chapter 14 section 3,referring to EU pediatric regulation and EU directives,and chapter 16 section 1 of the Medicinal Products Act(2015:315)(lkemedelslagen)provide the legal foundation for the Swedish Medical Products Agency(MPA)to issue injunctions and prohibitions necessary for compliance

107、with the EU-CTR in relation to clinical trials.Although the legislation does not specify clinical trial results,decisions on injunctions or prohibitions may be accompanied by a fine,the amount determined per the Act on fines(viteslagen).ASIA-PACIFICChinaThe Chinese Clinical Trial Registry(ChiCTR)is

108、a WHO International Clinical Trials Registry Platform(ICTRP)primary registry.As per its guidelines,after the completion of a trial,the statistical results should be uploaded to ResMan,a public management platform for clinical trials,and the results should be published one year later.Additionally,as

109、per the Provisions for Drug Registration(SAMR Order No.28)(managed by Drug Evaluation Center of China,NMPA),trial registration is required.The provisions were promulgated by the State Administration for Market Regulation(SAMR)and officially implemented July 1,2020:“The sponsor shall register the dru

110、g clinical trial protocol and other information on the drug clinical trial registration and information disclosure platform before carrying out the drug clinical trial.During the drug clinical trial,the sponsor should continuously update the registration information,and register the drug clinical tr

111、ial results and other information after the drug clinical trial is completed.The registration information is publicized on the platform,and the sponsor is responsible for the authenticity of the drug clinical trial registration information.”Sponsors found in violation of the following shall be order

112、ed to make corrections within a specified time limit.Failure to do so shall result in a fine of not less than 10,000 yuan but not more than 30,000 yuan:1.Failure to register on the platform as required before conducting drug clinical trials;2.Failure to submit a safety update report during research

113、and development as required;3.Information such as clinical trial results are not registered after the drug clinical trials are completed.Hong KongUnder Regulation 36B of the Pharmacy and Poisons Regulations(Cap.138A),a Certificate for Clinical trial/medicinal test(the certificate)is required for the

114、 purpose of conducting a clinical trial on human beings.The certificate application must include a copy of the protocol.Anyone violating this regulation is liable to a fine.The regulation only applies to pharmaceutical products.The regulation does not address disclosure of results.IndiaA 2018 study,

115、“Trial publication after registration in Clinical Trials Registry of India(CTRI):A cross-sectional analysis of randomized controlled trials,”is revealing about the lack of transparency in clinical trials in India.The study was conducted by the Campbell Collaboration,an international social science r

116、esearch network,and three other entities.It looked at trials from June 2009 to June 2015.15March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How

117、They Are EnforcedThe study found that none of the trial details were fully complete as per WHO criteria.Out of 2,938 trials,publication details of 78(2.6%)were mentioned in the Clinical Trials Registry-India(CTRI).From publication details of 676 trials,the average time to publication was 21.13 month

118、s.Sources of monetary support and government funding were found to be significant towards influencing publication status.Prospective registration on CTRI is mandatory per the“New Drugs and Clinical Trials Rules,”although results posting is not mentioned.Wording from the Central Drugs Standard Contro

119、l Organisation(CDSCO)indicates that“Failure to comply with any provision of the Act may result in one or more of following actions:i)written warning issued;ii)rejection of the results of the clinical trial;iii)suspension or cancellation of permissions;iv)barring of the investigator or sponsor from f

120、uture clinical research,for such period as considered appropriate by the DCGI Drugs Controller General of India.”JapanThe Japan Registry of Clinical Trials(jRCT)is a WHO ICTRP primary registry,funded by Ministry of Health,Labour and Welfare,while the Japan Medical Association,Center for Clinical Tri

121、als(JMACCT),JapanPharmaceutical Information Center(JAPIC),and University Hospital Medical Information Network (UMIN)are the partner registries.According to PFSB/ELD Notification No.0831-9,a trial should be registered before the first subject is enrolled,and the results should be registered within on

122、e year after the completion of the clinical trial,unless it conflicts with the laws and regulations of other countries or if it interferes with publication in peer-reviewed medical journals.KoreaIn Korea,pharmaceutical and biotech companies listed on the Korea Securities Dealers Association(KOSDAQ)i

123、ndex can be penalized if they do not properly disclose major information on clinical trials.They will be first designated publicly as dishonest disclosure companies and could be penalized such as paying fines.Such firms have the opportunity to discuss their positions during the process.Kospi-listed

124、firms,however,do not appear to have separate disclosure guidelines for biopharma companies.SingaporeAs with many countries,the regulatory obligations for sponsors are vague.The government does,however,state that it establishes and maintains arrangements to ensure compliance with the principles of GC

125、P.ICH guidelines regarding final reports read:“Upon completion of the trial,the investigator,where applicable,should inform the institution;the investigator/institution should provide the Institutional Review Board IRB/IEC with a summary of the trials outcome,and the regulatory authority(ies)with an

126、y reports required.”Very specific penalties are defined for lack of notification of trial status to the authorities.A person contravening Regulation 12 is considered guilty of an offense and is liable on conviction to a fine not exceeding$5,000 or to imprisonment for a term not exceeding two years o

127、r to both.However,this does not appear to extend to the public registry.CENTRAL AMERICACentral America has a common regulation called“Reglamento Tcnico Centroamericano-RTCA”(Central American Technical Regulation).These rules vary depending on the type of product.Costa RicaIn Costa Rica,the governmen

128、tal bodies setting regulations are the“Ley General de Salud”(General Law of Health),and the“Ley Orgnica del Ministerio de Salud”(Organic Law of the Ministry of Health).While the regulation does 16March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying pr

129、ohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are Enforcednot appear to directly address the responsibility for disclosure,it does outline research participants right to information,including:Access to the results of their analyses,when

130、 they have not undergone anonymization processes,if the study design allows it To be informed about the progress,the unexpected adverse events and overall results of the research All verbal and written information is provided in an understandable lexicon and in the language of the participants.Costa

131、 Rica maintains a national register of trials conducted in the country,but it is not considered a registry from a disclosure standpoint.GuatemalaHere,disclosure regulations fall under the General Directorate of Regulation,Surveillance and Control of Health through the Department of Regulation and Co

132、ntrol of Pharmaceutical and Related Products.The office provided the following statement regarding Article 15 of the Law on Access to Public Information:“Use and dissemination of information.The interested parties will have criminal and civil responsibility for the use,management or dissemination of

133、 public information to which they have access,in accordance with this law and other applicable laws.”Clinical trial regulations suggest that a summary of results must be available to citizens through the agency website,but no specific regulatory language supports this.SOUTH AMERICA ColombiaThe Natio

134、nal Institute for Food and Drug Surveillance(INVIMA,Colombias regulatory agency)manages different regulatory processes related to clinical trials.From the evaluation of the initial protocol proposal to the assessment of protocol amendments,follow-up of administrative changes,surveillance and control

135、 of the execution of trials at the approved sites,etc.,all of these procedures have different timelines.According to an INVIMA statement,“it is every stakeholders responsibility to ensure strict compliance.”The monitoring compliance of clinical trials is guided by international standards,such as ICH

136、,Colombian legal rules or regulations:Resolution 2378 of 2008,Resolution 8430 of 1993,and internal guidelines,among others.No specific language pertains to disclosure other than a broad statement defining that results should be relayed to the scientific community.OCEANIAAustralia The Australian clin

137、ical trial requirements are longstanding,with the ICH GCP Guidelines for Good Clinical Research Practice(GCRP)in Australia first adopted in 1991.Clinical trials are regulated at a number of levels under Commonwealth and state and territory legislation in Australia.The Therapeutic Goods Administratio

138、ns(TGAs)role in clinical trials is to regulate access to“unapproved”therapeutic goods(medicines,medical devices and biologicals)for use in clinical trials through the Clinical Trial Notification(CTN)and Clinical Trial Approval(CTA)schemes.Under the CTN scheme,trial proposals are submitted directly t

139、o the reviewing Human Research Ethics Committee/s(HRECs),which assume the primary responsibility for ethical and scientific review and approval.The CTA scheme involves TGA evaluation of scientific data for higher-risk trials in addition to the 17March 2023 Copyright 2023 Pharma Intelligence UK Limit

140、ed,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are Enforcedethical review and approval by the responsible HREC(s).The legislation underpinning the CTN and the CTA schemes requires that cl

141、inical trials involving the use of“unapproved”therapeutic goods be conducted in accordance with the GCP guidelines,the National Statement on Ethical Conduct in Human Research(National Statement),and the protocol approved by the applicable HREC.Trial sponsors are also required to comply with other re

142、levant When a clinical trial is conducted in breach of the conditions of the CTA scheme,the TGA has power to revoke approval of the trial.The TGA also has power,in specific circumstances,to direct that a clinical trial under the CTN scheme requirements of Commonwealth and/or state and territory legi

143、slation.The Australian clinical trial handbook provides further information on conducting clinical trials in Australia using unapproved therapeutic goods.In regard to compliance management,the TGAs approach is outlined in the Compliance management|Therapeutic Goods Administration(TGA)and Compliance

144、actions and outcomes|Therapeutic Goods Administration(TGA).not be conducted or be stopped.Continuation of a clinical trial after approval has been revoked or in breach of the conditions of the CTN scheme may amount to a criminal offense or a civil contravention under section Figure 4:Tools Used to A

145、ddress NoncomplianceSource:Australian Therapeutic Goods Administration(TGA)Low Compliance Risk High Compliance RiskEducation&GuidanceWarning LettersSuspensions from ARTGCancellations from ARTGEnforceable UndertakingsInjunctionsAdvertising Directions NoticesInfringement NoticesCivil PenaltiesCriminal

146、 Prosecutions18March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are Enforced19B or 19D of the Therapeutic Goods Act 1989.Section 21A of

147、 the act specifies the grounds for prosecuting offenses related to not complying with conditions of registration or listing.In relation to noncompliance identified in the GCP Inspection Program,the TGA adopted a pragmatic approach with its Corrective and Preventative Action Plan(CAPA).This allows th

148、e sites to amend their processes,procedures and systems,facilitating development of compliance strategy aligned with relevant legislation and guidelines.First,the TGA provides education and advice to the responsible entity.Next,a warning letter may be issued,identifying the noncompliance,what correc

149、tive action is needed,what other action the TGA may take if the noncompliance is not remedied within the specified timeframe,and education on how to remain compliant in the future.Civil penalties,if imposed,are 5,000 penalty units for an individual,or 50,000 penalty units for a corporation.A penalty

150、 unit is currently$275 for offenses committed on or after Jan.1,2023.Criminal penalties,if warranted,can include 57 years imprisonment and fines of up to 4,000 penalty units.It should be noted that the above guidance refers to clinical trial authorizations and conduct,not to trial registration in a

151、publicly accessible register.However,the National Statement on Ethical Conduct in Human Research(and Australian Code for theResponsible Conduct of Research)encourage sponsors to register on a publicly accessible register and publicly disseminate results.New ZealandMedsafe is New ZealandsMedicines an

152、d Medical Devices Safety Authority,operating under the Ministry of Health.Under the Medicines Act of 1981,sponsors should submit routine progress reports to Medsafe online,with the first report sent not more than six months after the trials approval date.Subsequent reports should be submitted at six

153、-month intervals throughout the duration of the trial.At the global end of the trial,a synopsis of the final report should be sent to Medsafe when available.While the penalties for specific violations were unclear,the law states:“Every person who commits an offense against these regulations is liabl

154、e onconviction to a fine not exceeding$500.”As per Australia,there is no legal mandate for clinical trial registration/results disclosure.However,the National Ethics Standards state that sponsors must register their clinical trials in a WHO-approved clinical trial registry prior to study start and m

155、ust provide results in the public database of the registry.19March 2023 Copyright 2023 Pharma Intelligence UK Limited,a Citeline company(Unauthorized photocopying prohibited)The State of Global Clinical Trial Disclosure:What Noncompliance Penalties Are in Place,and How They Are EnforcedNick Ide,form

156、erly with ClinicalTrials.gov,shared his predictions for the future of clinical trial disclosure in the US:There will be more public scrutiny of content.The FDA might focus not just on whether studies were submitted,but the quality of the data.Standardization and better structure for outcome measures

157、.Reaching agreement on key elements of eligibility criteria and how to specify them.Interpretation of penalties as defined in legislation is difficult.In many cases,it is unclear whether regulations strictly apply to disclosure activities(registration in a publicly accessible registry and results di

158、ssemination)or more specifically to the direct interaction with authorities and clinical trial authorization requirements,which are often distinct processes.While there has been movement toward greater enforcement of clinical trial reporting regulations across the globe,it is obvious that more needs

159、 to be done.Management of clinical trial disclosure is a complicated endeavor,and regulatory agencies should take steps to make compliance as easy as possible and to enforce strict penalties for noncompliance.Doing so will protect clinical trial participants and,ultimately,the patients who rely on t

160、hese life-saving treatments.In ConclusionCopyright 2023 Pharma Intelligence UK Limited,a Citeline company.Pharma Intelligence UK Limited is a company registered in England and Wales with company number 13787459 whose registered office is Suite 1,3rd Floor,11-12 St.Jamess Square,London,England,SW1Y 4

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162、ve clinical,commercial and regulatory-related decisions and create real-world opportunities for growth.Our global teams of analysts,journalists and consultants keep their fingers on the pulse of the pharmaceutical,biomedical and medtech industries,covering it all with expert insights:key diseases,clinical trials,drug R&D and approvals,market forecasts and more.For more information on one of the worlds most trusted life science partners,visit C