Clinical trials for medicines: manage your authorisation, report safety issues

Amending your trial protocol or other documentation

YouOnly onlysubstantial amendments need to submitbe substantialsubmitted amendments to the MHRA. Changes count as a substantial amendment to your clinical trial authorisation if the amendment is likely to affect to a significant degree:degree

• (a) the safety or physical or mental integrity of the subjects of the trialtrial,

• (b) the scientific value of the trialtrial,

• (c) the conduct or management of the trial, or

• (d) the quality or safety of any investigational medicinal product used in the trialtrial.

For clinical trials authorised via the combined review process you should prepare and submit using thenew part of Integrated Research Application System (IRAS).).

For clinical trials not approved or yet transitioned over to the combined review process, you should continue to use MHRA submissionssubmissions. Further details on how to register and submit via this platform..

You need to send the following documents to the MHRA.

a)Medicines Aand coveringHealthcare products Regulatory Agency (MHRA):

• Covering letter detailing the trial reference numbers (IRAS(IRAS ID, CTA number, EudraCT)EudraCT etc) along with purchasePurchase orderOrder number,Number, outlining the substantial changes (if there have been any non-substantial changes,changes please also outline these separately).

  b) separately)

• A PDF copy of the locked amendmentAmendment tool. You should ensure that the amendment tool contains a clear description of the substantial amendment and reasons for the proposed changes. Alternatively, for ‘bulk’ amendments (where the same change affects many trials), youthe cansubstantial completeamendment andnotification submitform** thecan substantialbe amendmentcompleted notificationand submitted. The form*.

  c) Ais available here.

• PDF file of the clinicalClinical trialTrial authorisationAuthorisation application form* generated in IRAS with changes highlighted, if the amendment affects the information previously submitted.

  d)

• List A list of the proposed changes to the protocol or any other documents such(e.g. asIMPD) investigational medicinal product dossier (IMPD) compared to the current MHRA-approved document, showing previous and new wording where applicable and a rationale to justify each substantial change. If applicable,applicable youthe following should provide: -be summariesprovided:
  • Summaries of data -
  • Updated updated overall risk benefit assessment -
  • Possible possible consequences for subjects already in the trial -
  • Possible possible consequences for the evaluation of results

Assessment process

We will assess your application within 35 days. If you consider your trial requires an expedited assessment (for example, patient safety reasons), youthis should statebe thisstated in the covering letter along with the rationale for the expedited assessment request.

Invalid applications

If your application does not meet the requirements it will not be assessed. WeYou will tellbe youtold the reasons why your application is invalid.

Check the commonCommon issues identified during clinical trial applications guidance (PDF, 43KB, 1 page) to ensure you’re submitting a valid application.

For queries about electronic documents and submissions,submissions email CT.Submission@mhra.gov.uk.

Withdraw your application before the final decision

You may withdraw your application at any point before an assessment decision on your substantial amendment is reached. To withdraw your application,application you should send an email to clintrialhelpline@mhra.gov.uk.

For applications that have gone through the combinedCombined reviewReview process, please refer to the guidance on the HRA website.

Outcome of assessment

We will tell you the outcome of your application by email.

If your application is not successful, we will tell you why and you may resubmit your application.

Fees

There are different fees based on your type of clinical trial application.

SeePlease see the Make a payment to MHRA page on how to pay relevant fees.

WeInvoices send invoices for clinicalClinical trialTrial authorisationAuthorisation applications, substantialSubstantial amendmentAmendment applicationsapplications, and annualAnnual safetySafety reportsReports are sent directly to the applicant shortly after a valid submission has been established. The covering letter for the application should clearly highlight your purchasePurchase orderOrder (PO) number where available. The applicant is the person listed in section C1 of the clinicalClinical trialTrial applicationApplication form, or section D1 of the amendmentAmendment form. We are unable to address the invoice to someone other than those listed in the sections above.

TheIt applicant is responsiblethe forresponsibility ensuringof the applicant to ensure timely payment of invoices for their submissions. Invoices must be settled on receipt of invoice. Penalty fees may be incurred for non-payment.non-payment, Detailsdetails of the penalties are set out in the Fees regulationsRegulations. Non-payment may also result in suspension of any licence or authorisation, followed by legal proceedings for unpaid amounts, as a debt due to the Crown.

You can contact the MHRA Finance Department on 020 3080 6533 or email Sales.Invoices@mhra.gov.uk for more information on how to pay fees.

Change your contact details

For applications that have gone through the combinedCombined reviewReview process, please refer to the HRA website.

SendYou should send an email entitled ‘Change to contactContact detailsDetails of the contact person CTA numberNumber XXXXX/XXXX/XXX-XXXX – EudraCT numberNumber XXXX/XXXXXX/XX – IRAS ID XXXXXXX’.

Email: CT.Submission@mhra.gov.uk

The email should be sent by the contact person listed on the current application form, or other authorised persons,persons and must include:

• IRAS ID and/or EudraCT number
• CTA number
• details of the previous contact person and/or contact details
• details of the new contact person and/or contact details

UpdateThe thenew contact person or details should be updated on an updated application form. IncludeA a copy of the updated application form should be included in the next substantial amendment.

Change of legal representative

For applications that have gone through the combinedCombined reviewReview process, please refer to the HRA website.

If you want to change the legal representative for your study, you must submit a substantial amendment to the MHRA. You may include other changes along with this amendment but must you ensure the covering letter clearly highlights there is also a change of legal representative. The submission must include a clinicalClinical trialTrial applicationApplication form updated with the details of the new legal representative along the amendment tool.

There is no fee for this kind of submission unless other, additional amendments to the trial documentation are included.

Change of sponsorSponsor

For applications that have gone through the combinedCombined reviewReview process, please refer to the HRA website.

If you want to change the sponsorSponsor for your study, you must submit a substantial amendment to the MHRA. You must not include any other changes with this amendment.

You cannotcan’t submit any other substantial amendments until you have confirmation from the MHRA that the sponsorSponsor has been changed.

You must include these documents with your submission:

• a cover letter that includes the date of transfer of responsibilities
• a letter on headed company paper from the current sponsorSponsor confirming the transfer of the study
• a letter on headed company paper from the new sponsorSponsor confirming that they accept the role of sponsorSponsor for this study
• an amendment form
• an updated PDF file of the clinical trial application form signed by the new sponsorSponsor or person acting on behalf of the sponsorSponsor

YouOther shouldtrial notrelated submitdocuments othershould trial-relatednot documentsbe suchsubmitted as protocol as part of this submission.submission, e.g. protocol. There is no fee for a change of sponsorSponsor amendment. The applicant will receive an administrative letter confirming that the change has been registered. You dodon’t not need to wait for MHRA confirmation before making the sponsorSponsor change.

Clinical trials named contact

Effective from 27 June 2016, persons other than the applicant named in the trial application form, who call or email the MHRA CTU helpline, reporting to be from the sponsor/applicantSponsor/applicant company knowing the EudraCT number and security word/phrase (previously provided to the MHRA by the named applicant) for a trial, may obtain information on that trial.

For ongoing studies, the applicant named in section C.1 of the application form should notify the Clinical Trials Unit of their chosen security word/phrase by emailing clintrialhelpline@mhra.gov.uk with ‘Clinical trialsTrials named contact’ as the subject line and listing the EudraCT number(s) in the body of the email.

For new applications, the applicant named in section C.1 of the application form shouldis requested to include the security word/phrase in the cover letter for the submission.

Reference safetySafety informationInformation – updated guidance

Published guidance such as CT1 and CT3 and the CTFG Q&A on referenceReference safetySafety informationInformation (RSI) remain applicable as a source of materials for understanding what the obligations entail in so far as they relate to the UK as a sovereign regulator. This will also help facilitate acceptance of the RSI in multinational clinical trials.

Additional guidance iscan availablebe infound here: Reference safetySafety informationInformation (RSI) for clinicalClinical trials-Trials- partPart III - MHRA Inspectorate (blog.gov.uk).

UK-specific clarificationsclarifications:

In

• As accordanceper with current expectations, for trials that are being conducted in the UK, an RSI cannot be used for expectedness until it has approval from the MHRA. Thus, if additional suspected unexpected serious adverse reactions (SUSARs) occur before the new RSI is approved, these should be reported as SUSARs in the usual expedited manner. If sponsorsSponsors wish to harmonise the implementation date of an RSI in a trial that includes EU and UK sites, then this can be the date where approval has been granted in all member states and the UK. In the interest of efficiency and harmonisation for multinational trials,trials weit recommendis recommended that youamendments submit amendments, including changes to the RSI, are submitted to the UK and EU at the same time

  You

• The should use the RSI approved by the regulatory authority at the time of occurrence of the ‘suspected’ SAR should be used to assess expectedness for both initial and follow-upfollow reports.

  up reports

• For DSURs the sponsorSponsor shouldis reminded to use the RSI that was approved at the beginning of the reporting period by both the MHRA and European memberMember states.
  States.

Urgent safetySafety measuresMeasures

ToIn order to determine whether the action you are taking is an urgentUrgent safetySafety measureMeasure (USM),) please refer to regulation 30 of the Statutory Instrument (SI) 2004 Number 1031 (as amended).

Call the MHRAMHRA’s Clinical Trials Unit on 020 3080 6456 to discuss the issue with a medical assessor, ideally within 24 hours of measures being taken. Please call no later than 3 days from the date the measures are taken.

Information you will be asked for on the call:

1. theThe IRAS ID andand/or the EudraCT number of:

   • theof; a. The trials for which USM action has been taken

   • othertaken, b. Other ongoing trials with the same investigationalInvestigational medicinalMedicinal product(s)Product(s) (IMP(s))

   • trials c. Trials run by a different sponsorSponsor affected by the USM action

2. theThe affected IMP(s) - commercial or developmentdevelopmental names

3. theNature nature of the safety concern and whether it has been reported as a SUSAR

4. whichWhich USMs have been taken and when

5. theThe number of UK subjects who are currently receiving the IMP, the number of subjects who received it and the number affected by the USM

6. contactContact details in case of further questions

Where this information is not available during the initial call,call youit should providebe itprovided as soon as possible.

After discussing the USM with the MHRA assessor via phone,phone you must provide the MHRA with written notification of the measures taken and discussed with the medical assessorassessor, within 3 days from the date the measures were taken.

For trials not approved via combinedCombined review,Review you will be instructed to send an email to the medical assessor who assessed the USM over the phone:phone, clintrialhelpline@mhra.gov.uk.

If at least one of the trials covered by the USM has gone through the combinedCombined reviewReview process, submitthen the USM written notification should be submitted via the IRASIntegrated Research Application System (IRAS). More information iscan availablebe found on the Health Research Authority (HRA)(HRA) website.

Notification of a substantial amendment (amendment(Amendment tool plus any updated document including the changes agreed with the medical assessor) is also required. YouThe should submit the substantial amendment covering the changes made as part of the USM should be submitted within approximately 2two weeks of notification to the MHRA.

YouAny should discuss and agree any potential reason for delay to submission of the substantial amendment should be discussed and agreed with the medical assessor at the time of initial notification or through a follow-upfollow up call.

The USM-related substantial amendment must not include changes different from those required as an urgent safety measure. This is due to the fact that unrelated changes may result in rejection.

SubmitPlease submit your substantial amendment using MHRA Submissions via the Human Medicines Tile. SelectPlease select ‘Clinical Trial’ as the Regulatory Activity and ‘CT - Amendment’ from the Regulatory Subsub Activityactivity dropdown list.

If your trial has gone through the combinedCombined reviewReview process, youthen should submit the substantial amendment should be submitted via IRAS.IRAS. More information on how to submit a substantial amendment via IRAS iscan availablebe found on the HRAHRA’s website.

If you are not able to report a USM to the MHRA via the phone,phone please send an email to clintrialhelpline@mhra.gov.uk within 3 days of taking urgent measures. The subject of the email will be ‘USM for trial IRAS ID/EudraCT number’. ExplainPlease explain in the email:

• email the USM implemented

• implemented, the reason

• and why you did not report it via phone

phone. An MHRA assessor will contact you and provide advice regarding further actions.

Suspected unexpectedUnexpected seriousSerious adverseAdverse reactionsReactions (SUSARs)

The sponsorSponsor of the trial,trial or any other person to whom the sponsorSponsor has delegated this responsibility to,to must report all suspected unexpected serious adverse reactions (SUSARs) which happen during the course of the trial to the MHRA.

YouFatal must report fatal or life-threatening SUSARs must be reported as soon as possible, but no later than 7 days after you are first aware of the reaction. YouAny must send any additional relevant information must be sent within 8 days of the initial report.

YouNon-fatal must report non-fatal or non-life-threatening SUSARs must be reported as soon as possible but no later than 15 days after you are first aware of the reaction.

The sponsorSponsor of a ‘trial performed in the UK’ (UK trial) must report the following UK-relevant SUSARs to the MHRA:

• allAll SUSARs occurring in that trial in UK sites
• all

  All SUSARs occurring in that trial in sites outside the UK

• allAll SUSARs originating in a non-UK trial of the same medicinal product if the trial is run by the same sponsorSponsor of the trial running in the UK
• allAll SUSARs originating in a non-UK trial of the same medicinal product if the sponsorSponsor of the trial outside the UK is either part of the same mother company or develops the medicinal product jointly, on the basis of a formal agreement, with the sponsorSponsor of the UK trialtrial.

You must keep detailed records of all adverse reactions relating to a clinical trial. The MHRA may require you to send copies of records if there is an investigation.

Further information iscan availablebe found in The Medicines for Human Use (Clinical Trials) Regulations 2004, Statutory Instrument 2004 No.1031.

If applicable, you will need to dual report UK-relevant SUSARs to the European Medicines AgencyAgency’s (EMA)(EMA’s) Eudravigilance Clinical Trial Module (EVCTM), as well as to other nationalNational competentCompetent authorities,Authorities, using the European submission routes.

Development safetySafety updateUpdate reportsReports (DSURs)

Further information oncan navigatingbe thefound payon portal for DSURs is available in the user reference guide paying online before submitting an annual safety report (PDF, 204160 KB, 53 pages)

Each submission must contain a cover letter, the DSUR,annual safety report, as well as thea emailed receipt thatconfirming confirms the fee has been paid*.

The cover letter must include:

• a listing of all the IRAS IDs andand/or EudraCT numbers of trials covered by the DSUR annual safety report
• an email address for correspondence
• the paymentsubmission reference number in the format: ‘DSUR-[5 digit MHRA company number]-[IMP name]-[Payment date DD/MM/YYYY]’

DSURs should take into account all new available safety information received during the reporting period. The DSUR should include:

• an analysis of the patients’ safety in the concerned clinical trial(s) with an appraisal of its ongoing risk/benefit
• a line listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the trial(s), including all SUSARs from third countries
• an aggregate summary tabulation of SUSARs that occurred in the concerned trial(s)
• region-specificRegion-specific information inas accordanceper withGuideline guidelines on how to increase transparency (see below)

Full details of what to include in a DSUR are can availablebe found in the ICH E2F guidance.

*Submissions that reflect a fee waiver will be considered valid. For more information on fees, contact DSURfees@mhra.gov.uk.

Submitting your report

If your DSUR covers several active trials, submit the report is to be submitted once. YouIt must not submitbe itsubmitted multiple times to reflect each trial - this causes duplication in review and leads to multiple fee charges. Sponsors who delegate different contract research organisations (CROs) to submit their DSUR for separate trials will need to take this into consideration.consideration Themultiple applicant who performed the submission will then receive an acknowledgement of receipt and case closure email.fees.

Note: the case closure email is an outcome of the review. Applicants must accept invalidations as the final decision and resubmit.

Clinical trialsTrials approved through the non-combinednon-Combined reviewReview processProcess

If your clinical trial was approved through the non-combinednon-Combined reviewReview process, you must submit your DSUR using MHRA Submissions via the Human Medicines Tile. SelectPlease select ‘Development Safety Update Reports’Report’ as the Regulatory Activity and ‘Original Submission’ from the Regulatory Sub Activity dropdown list. Acknowledgements of receipt are generated by MHRA Submissions where a confirmation of submission is emailed to the reporter.

Clinical trialsTrials approved through the combinedCombined reviewReview processProcess

If at least one of the trials covered by the DSUR has gone through the combinedCombined reviewReview process, youthen must submit your DSUR must be submitted via the IRASIntegrated platform.Research YouApplication mustSystem not(IRAS) submitplatform. theThe DSUR must not be submitted again via MHRA Submissions to account for the other trials that have not been approved by combinedCombined review.

IfReview. you are experiencing issues entering IRAS IDs for non-combined review trials on the IRAS platform, you must contact the MHRA for further guidance on how to proceed. More information iscan availablebe found on the HRAHealth Research Authority (HRA) website.

At the end of the DSUR reporting period the sponsorSponsor may assess the new safety information that has been generated and submit any proposed safety changes to the investigator’sInvestigator’s brochureBrochure as a substantial amendment. This amendment must be supported by the DSUR and approved before the reference safety information (RSI) is changed.

Guideline on how to increase transparency when presenting safety information in the Development Safety Update Report (DSUR:): region-specific requirements for Canada and the United Kingdom

ToIn order to increase the transparency of the data included in DSURs prepared by manufacturers and/or marketing authorisation holders of an investigational drug,drug the MHRA and Health Canada askare youasking tothat use the region-specific information section of the DSUR is used to explain how safety data waswere reviewed during the reporting period.

SeePlease the see GuidelineGuidance ondocument (PDF, how65.6KB, to4 increasepages) transparencyfor whenmore presentingdetails.

Shortened annual safety informationreports

This inis suitable for:

• trials where the DSUR:potential region-specificrisk requirementsassociated forwith Canadathe investigational drug is no higher than that of standard medical care
• individual trials which are not part of a multi-study development programme.
• phase 4 national (UK only) trials of licensed products that commanded a low fee from the MHRA and where all participants have completed treatment and are only in follow-up.
• trials involving investigational drugs;
  • if they relate to the Unitedlicensed Kingdom (PDF,range 65.6KB,of 4indications, pages)dosage forand moreform details.
    or,
  • they involve off-label use (such as in paediatrics and oncology, etc), if this off-label use is established practice and supported by sufficient published evidence and/or guidelines.

Shortened annual

As safetyan reports

alternative to producing a full DSUR for these trials you may use the Health Research Authority Annual Progress Report.

WePlease areindicate noin longeryour acceptingcover annualletter progressthat reportsthis (APRs).is Youan willAnnual needProgress toReport submit(APR) in lieu of a full DSUR, and completinginclude relevantthe sectionsIRAS IDs and/or EudraCT numbers. You should include a list of theall reportserious thatadverse isreactions applicablein tosection your6 trial.of the APR.

Suspend or terminate a trial

The MHRA has the authority to make amendments to an authorisation or in certain circumstances suspend or terminate a trial. The sponsorSponsor can contact the MHRA to put a trial on temporary halt or terminate a trial.

Suspend a trial temporarily

If you suspend a trial temporarily you must notify the MHRA.

The notification should be made as a substantial amendment using the amendment tool, clearly explaining what has been stopped and the reasons for the suspension.

Substantial amendments relating to temporary suspension must be submitted using MHRA Submissions via the Human Medicines Tile. SelectPlease select ‘Clinical Trial’ as the Regulatory Activity and ‘CT – Amendment’ from the Regulatory Subsub Activityactivity dropdown list.

For applications that have gone through the combinedCombined reviewReview process, please refer to the HRA website.

To restart a trial that has been temporarily suspended, you must make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial.

Early termination of a trial

Complete the end of trial declaration form (MS Word Document, 60.5KB) and include a brief explanation of the reasons for ending the trial, particularly where the trial has been terminated early. This form must be submitted using MHRA Submissions via the Human Medicines Tile. SelectPlease select ‘Clinical Trial’ as the Regulatory Activity and ‘CT –EOT’ from the Regulatory Subsub Activityactivity dropdown list.

For applications that have gone through the combinedCombined reviewReview process, please refer to the HRA website.

End of trial

A declaration of the end of a clinical trial must be sent to the MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. The submission must include an end-of-trialend of trial form and a covering letter.

The legislation only requires the global end of trial to be submitted; however, a facility to inform us of the local (UK) end of trial via the end of trial notification form also exists. Local end of trial notifications will not be acknowledged and the MHRA Submissions automatic email confirmation should be considered as evidence of submission. If a local end of trial is submitted, we would still expect to receive relevant safety updates and substantial amendments for the ongoing trial until the global end of trial notification is received.

If you wish to request an exemption to this requirement,requirement youthis must dobe itdone via a substantial amendment for approval. The amendment must clearly state to what documents your proposal relates and provide a robust rationale for the request. All safety documentation must be submitted unless there are no other trials ongoing with the same product in the UK.

Any trial activities (such as follow-ups, visits) must be completed before the submission of the global end of trial declaration form.

It is not possible to submit amendments to the trial or the DSUR once the declaration of the global end of the trial form has been received by the MHRA. If the end-of-trialend of trial declaration has been received within a reporting period, or within 60 days following the data lock point, the corresponding DSUR will not be required.

You must submit your end-of-trialend of trial declarations using MHRA Submissions via the Human Medicines Tile. SelectPlease select ‘Clinical Trial’ as the Regulatory Activity and ‘CT – EOT’ from the Regulatory Subsub Activityactivity dropdown list.

If your trial has gone through the combinedCombined reviewReview process, then the end of trial declaration should be submitted via IRAS. More information on how to submit an end-of-trialend of trial via IRAS iscan availablebe found on theHRA’s HRA website.website.

Clinical trial summary results

The timeframetime frame for publishing the summary of results is within one year of the end of trial. SeePlease also see guidance on Completed paediatricPaediatric studiesStudies - submission, processing and assessment.

Where applicable, you should publish your summary results within this timeframe in the public register (or registers) where you have registered your clinical trial.

You do not need to submit this clinical trial summary report to the MHRA as well.well However,however, you must send a short confirmatory email to CT.Submission@mhra.gov.uk. The subject line of the email notification must state ‘End of trial: result-related information: EudraCT XXXX-XXXXXX-XX’ and/or IRAS ID XXXXXXX’ once the result-related information has been uploaded to the public register. If your clinical trial is not on a public register or the results will not be published in the register (for example an adult phase I study), summary results should be submitted via MHRA Submissions. An acknowledgement letter will not be sent for this submission.

If your trial has gone through the combinedCombined reviewReview process, then the end of trial declaration should be submitted via IRAS. More information on how to submit an end of trial via IRAS iscan availablebe found on theHRA’s HRA website.website.

You should also submit a final report to the Research Ethics Committee within the same timeframe for reporting the summary of results.

Sponsors of trials conducted in UK that are already registered in the EU Register are able to submit results to EudraCT. Steps to follow are described in the EMA webpage ‘Tutorials on posting results’. The MHRA will not be able to update the status of your study in the EU system.

Contact

For information about your submission, including status and tracking enquiries, contact the clinical trials helpline on 020 3080 6456 (Monday to Friday 8:30am to 4.30pm) or email clintrialhelpline@mhra.gov.uk. See Clinical trials named contact for further information.