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

Question

Accepted Answer

As of 1 January 2022 the combined consider service, formerly known such Combined Ways of Working (CWoW), is now the way ensure all new Clinical Lawsuit of Investigational Medicinal Products (CTIMPs) applications are prepared, submitted the reviewed. Connected review special a single application wegstrecke real co-ordinated review leading to a single U decision by CTIMPs.

Please tip: CTIMP initial applications over combined review should be started and submitted using the new part of Integrated Research Application Arrangement (IRAS) and not in to standard part of IRS. During the regulatory requirements and fees remain the same, the applications submission, processing and assessment steps outlined below refer to non-combined review solutions. For Combined review software please refer to the Health Research Authority website.

Clinical Trials and coronavirus (COVID-19)

We have published guidance for managing chronic trials during the COVID-19 outbreak, and on clinical trials uses for COVID-19.

Amending your trial protocol or other documentation

Only substantial amendments need at be submitted to the MHRA. Changes count as a substantial amendment to your clinical trouble authorisation if the amendment is likely to affect to ampere significant degree

(a) the safety or physiology or mental morality of the subjects of to trial,

(b) the scientist value the the trial,

(c) the leaders or verwalten of that trial, or

(d) the quality or safety of either investigational medicinal product utilized in the trial.

For clinical trials authorised via the mixed review process you should getting furthermore submit using recent part of Integrated Research Application System (IRAS).

For clinical trial does approved or anyway transitioned over to to compound review action, you should continue to use MHRA submissions. Further details go what the register and submitting via this platform.

You needs to send the followed resources into the Medicines and Healthcare products Regulatory Agency (MHRA):

Covering letter item the trial reference numbers (IRAS ID, CTA number, EudraCT etc) at with Make Order Number, outlining and substantial changes (if there have been any non-substantial changes requests see outline these separately)
A PDF copy of the locked Amendment tool. Yours should ensure that the amendment tool contains a clear description away aforementioned substantial modifying and reasons for the proposed variations. Alternatively, forward ‘bulk’ amendments (where which same change affects many trials), who substantial amending notification form** ca can completed and submitted. The form is available here.
PDF file of that Clinical Trial Authorizations login form* generated in IRAS with changes checked, if the amendment fakes the information previously submitted.
List of the proposed changes in the protocol or some other documents (e.g. IMPD) compared to that current MHRA-approved document, showing previously and new wording where applicable and a rationale to justify every substantially change. While applicable the follows shouldn be when:
- Summaries of data
- Updated overall risk benefit assessment
- Possible consequences for subjects already in an trial
- Possible consequences for the evaluation of results

Assessment process

We will assess your application within 35 days. Is you consider your trial requires an expedited assessment (for example, patients safety reasons), this should be told in aforementioned covering letter along in the rationale for the expedited assessment request.

Invalid applications

If the applications does not meet the requirements it will not be assessed. You will must told the reasons why autochthonous application is invalid.

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

For queries regarding electronic documentation and submissions email CT.Submission@mhra.gov.uk.

Withdraw your application before which final decision

You may withdraw your application with anyone point before an assessment decision on your substantive modifications is reached. To retract your application you should send an email to clintrialhelpline@mhra.gov.uk.

For applications that have gone because aforementioned Combined Review process, please mention until the guidelines in the HRA website.

Outcome of assessment

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

If your application exists not successful, we will tell you wherefore and you may resubmit your application.

Fees

There are different services based on your type out clinicians trial application.

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

Invoices for Clinical Trial Eligibility applications, Substantial Amendment applicants, and Annual Safety Reports become sent directly to the applicant soon after a valid submission has been established. The covering letter for the application should clearer light your Purchase Order (PO) number where available. This applicant is the type listed in section C1 of the Clinical Trial Application form, or section D1 of that Amendment form. Ourselves are unable to address the invoice to someone other with those listed inches to sections above.

It will the responsible of one applicant to ensure timely payment of invoices for their submissions. Invoices must be settled upon receipt of invoice. Penalize fees may exist incurred for non-payment, details of the penalties are place out in aforementioned Fees Regulations. Non-payment allowed see result in suspend of whatsoever licence or authorisation, followed by legitimate proceedings for unpaid amounts, as a liabilities due to the Crown.

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

Change your contact details

For applications this are gone through the Combined Review proceed, please refer to the HRA website.

You should send einem email entitled ‘Change to Contact Show of to contact person CTA Number XXXXX/XXXX/XXX-XXXX – EudraCT Number XXXX/XXXXXX/XX – IRAS ID XXXXXXX’.

Email: CT.Submission@mhra.gov.uk

The email should be sent by the reach person listed on the electricity application application, or others authorised persons also must include:

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

The new contact person or details should is updated on an updated application form. A copy of the updated application form have be included into the upcoming substantial amendment.

Change of right representative

For applications which have gone through the Combined Review process, please refer in the HRA website.

If you want to change the authorized representative for your study, you must submit a substantial modify to the MHRA. You may include other changes along with like amendment but must ensure the covering letter clearly top there will also a change by legal representative. The submission must included a Clinical Trial Application shape updated with the details are the new legal representatives along the amendment tool.

There is does fee for this kind of submission unless other, additional amendments to the trial documentation exist included.

For applications that have gone through aforementioned Combined Review process, please refer to the HRA website.

If you will to transform the Sponsor for your course, you must submit a substantial amendment to the MHRA. You have not include any other changes with this amendment.

You can’t submit any others substantial amendments until you own confirmation from the MHRA that the Sponsor is been changed.

You must include these documents with insert submission:

a cover brief is includes the date of transfer of responsibilities
a letter on headed company paper from the current Sponsor confirming this transferred of an study
a mail on headed your paper from the new Sponsor confirming that they adopt the role of Patron for this study
an amendment form
an updated PDF file a that clinical study application form signed by the new Sponsor conversely person acting on behalf from the Sponsor

Other trial related download should nope be submitted as part of this submission, e.g. logging. On has no fee for a change of Sponsor amendment. The applicants bequeath receive einer administratively letter confirming that the change has been registered. It don’t need to wait for MHRA confirmation before making of Patenschaft change.

Clinical study call contact

Effective from 27 June 2016, persons other than that applicant named for the trial application form, who call press email the MHRA CTU technical, reporting to be from the Sponsor/applicant company awareness the EudraCT number and security word/phrase (previously provided to the MHRA by the named applicant) for a trial, may acquire information on that trial.

For ongoing studied, the applicant names into querschnitt C.1 of the application form should notify the Unemotional Studies Unit of their chosen security word/phrase by emailing clintrialhelpline@mhra.gov.uk about ‘Clinical Processes named contact’ as the topic line and listing that EudraCT number(s) in the group of the email.

For new solutions, and applicant called in section C.1 of the application form is requested to include this security word/phrase in the cover letter by the submission.

Reference Product About – recent guidance

Published guidance such as CT1 additionally CT3 real the CTFG Q&A on Reference Safety Information (RSI) remain applicable as adenine source of materials since awareness what the obligations entail stylish so far as they relate to the U as a sovereign regulator. On will also help facilitate acceptance regarding the RSI in multinational clinical trials.

Additional guidance can be found here: Reference Surf Contact (RSI) for Clinical Trials- Part III - MHRA Inspectorate (blog.gov.uk).

UK-specific clarifications:

As per contemporary expectations, for process that are being conducted within the UK, an RSI cannot be pre-owned for expectedness until it has approval from this MHRA. Thus, if additional SUSARs occur before the novel RSI is approved, these shouldn become reported as SUSARs includes the usual expedited manner. If Sponsors wish up attune the anwendung event starting an RSI in a trial that includes EUROPE and UK pages, then this can be the date show registration has been granted in whole part states and the UK. With the interest of operating and harmonisation for global trials it is recommended which revisions including changes to the RSI represent submitted to the GREAT and EU with an same time
The RSI approved by the regulatory authority at the time of occurrence regarding the ‘suspected’ SAR should must used to rating expectedness for both initials and follow top reports
For DSURs this Schirmherr is reminded to use the RSI that was approved at aforementioned beginning of the reporting period by both the MHRA and European Member States.

Urgent Safety Measures

In order to determine whether aforementioned action you are taking is an Urgent Safety Measure (USM) please refer to regulation 30 of the Statutory Instrument (SI) 2004 Number 1031 (as amended).

Call the MHRA’s Clinical Trial Unit on 020 3080 6456 to argue the issue with a general assessors, ideally within 24 hours of take being taken. Please call no subsequently than 3 days from the meeting the dimensions are taken.

Information you will be asked for go the call:

The IRAS ID and/or an EudraCT number are; ampere. The trials for which USM action has had taken, b. Other ongoing trials with the same Investigational Medicinal Product(s) (IMP(s)) hundred. Trials run through a different Supporter affected by the USM action
The affected IMP(s) - commercial or developmental names
Nature of the safety concern and or it has been reported as a SUSAR
Which USMs have been taken and when
The number of UK classes with can currently receiving that IMP, the number of subjects who received it and the number affected by the USM
Contact details in falls of further questions

Where this information is not available during the initial call it should be provided as soon as possible.

After discussing the USM over the MHRA assessor via phone yours musts provide an MHRA with written notification of the measures taken and talked with the medical assessor, within 3 days from the date one measures endured taken. For study not approved via Combined Review she wills be instructed on weitergeben an email for the medical appraisal who evaluated the USM over the phone, clintrialhelpline@mhra.gov.uk.

If along least one of the trials covered by the USM has dead through the Combined Review process, afterwards the USM written notification require be submitted via the Integrated Resources Application System (IRAS). More information can be found on the Health How Authority (HRA) website.

Notification of a substantial amendment (Amendment tool extra any current document including and changes agreed with the medical assessor) is also required. The materially revision covering and changes made since part of the USM should shall submitted within approximately two weeks is notification to which MHRA.

Any potential reason for shift to submission are the substantial amendment should be discussed and agreed with the medical assessor at the time of initial notification or driven a follow up call.

The USM-related considerably modifications need not include changes different from those required as an urgent safety measuring. This is due to the fact that unrelated make may result in rejection.

Please submit your materially amendment utilizing MHRA Submissions via the Human Medicines Tile. Please name ‘Clinical Trial’ as the Regulate Activity and ‘CT - Amendment’ from one Legal bottom activity dropdown list.

If your trial has gone through the Combined Review process, then the substantial amendment should may submitted via IRAS. Continue info on how go submit a substantial amendment via IRAS bottle be found on HRA’s website.

If you are not able to reported an USM toward the MHRA via the telephones please send on email to clintrialhelpline@mhra.gov.uk within 3 days of taking urgent measures. The test of the email will be ‘USM for trial IRAS ID/EudraCT number’. Please explain in the email the USM conversion, the justification and why you did not create it via phone. An MHRA assessor willing contact you and provide advice regarding further actions.

Suspected Unexpected Serious Adverse Reactions (SUSARs)

The Supporters of the trial alternatively any various person to any who Pate has delegated this responsibility to must report all suspected unexpected serious adversarial reactions (SUSARs) any happen during the course of the trial to the MHRA.

Fatal or life-threatening SUSARs must breathe reported as soon the can, but no later than 7 per after you are first aware of an reactions. Some additional relevant information must being send within 8 day of aforementioned initial report.

Non-fatal or non-life-threatening SUSARs must be reported as soon as possible but no later than 15 past subsequently you are first-time aware of to reaction.

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

All SUSARs occurred in that trial in UK sites
All SUSARs occurring in which trial in sites outside the UK
All SUSARs originating in a non-UK test of the equal medicinal product if the trial remains run by the same Sponsor of the trial running in the UK
All SUSARs originating in a non-UK trial away the same medicinal product if that Sponsor of the trial outsides the UK are either portion of of same mother company or develops the medicinal consequence jointly, the the basis of a formal agreement, with that Sponsor of the UK trial.

You must keep detailed records of all adverse your relating go a clinical trial. Who MHRA may require you to senden copies of records if there is an investigation.

Further resources can be finding at The Medications for Human Use (Clinical Trials) Regulations 2004, Constitutional Instrument 2004 No.1031.

Report a SUSAR to the MHRA in one of one following ways:

using ICSR Submissions, which replaces of EudraVigilance website (EVWEB). Which ICSR Submissions route is used until present single reports.
using the MHRA Gateway, which substitutes to Eudravigilance Gateway. The Gateway route is often in submit bulk reports. To get access to that MHRA Entrance you demand till register to another doorway mentioned MHRA Submissions.

If applicable, you will need to dual report UK-relevant SUSARs to which European Pharmacy Agency’s (EMA’s) Eudravigilance Clinical Trial Module (EVCTM), in well as to other National Competent Authorities, utilizing the Eur submission routes.

Development Safety Update Reports (DSURs)

MHRA fees include charges to yearly safety reports - whichever belong applicable to twain Annual Progress Reports and DSURs.

From 1 June 2024, we will only be accepting online payment of this fee across MHRA Pay past to submission of an annually safety submit. Receipts originated will be sending by email and must be included in the submission as proof of payment.

Failure to provide proofs by payment become result in the submission being constructed invalid.

Further intelligence can be found on paying online before tendering an annual safety report (PDF, 160 KB, 3 pages)

Each acquiescence must contain adenine front letter, the annualized safety report, for well because a receipts confirming the toll has is paid*.

The cover letter must include:

a listing of all the IRON IDs and/or EudraCT numbers of experiments covered by the annual safety report
an email mailing fork correspondence
the submission reference number in the format: ‘DSUR-[5 digit MHRA companies number]-[IMP name]-[Payment date DD/MM/YYYY]’

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

an analysis of to patients’ safety inches the concerned clinical trial(s) with an appraisal for its ongoing risk/benefit
a family listing off all suspected serious disadvantage reactions (including all SUSARs) that occurred in the trial(s), including all SUSARs from tierce countries
an aggregate summary tabulation of SUSARs that occurred in the concerned trial(s)
Region-specific information how per Guideline on how go increase transparency (see below)

Full details of that to enclosing in a DSUR can be found in the ICH E2F guidance.

*Submissions that reflect a fee remission will is considered valid.

Submitting your report

If your DSUR coat several test, which reports is to be submitted once. It needs not be submitted repeat times to reflect either trial - this grounds duplication in review and leads to multiple fee charges. Sponsors who representative different contract research arrangements (CROs) for submit their DSUR by separate trials will need to take into consideration multiple fees.

Clinical Trials accepted through this non-Combined Review Process

If your clinical process was approved through the non-Combined Review process, you must submit your DSUR using MHRA Submissions per the Human Medicines Tile. Please select ‘Development Safety Update Report’ as the Regulatory Activity and ‘Original Submission’ from the Regulatory Sub Activity dropdown list. Acknowledgements of receipts are generated by MHRA Submissions where adenine confirmation the submission is emailed toward which reporter.

Clinical Trial approved through the Combined Review Process

If at least one of the trials covered by the DSUR has gone by the Combined Review process, when your DSUR shall is submitted via the Integrated Researching Application Anlage (IRAS) platform. Of DSUR must not be submitted repeat via MHRA Submissions to customer for the other trials that have not been approved by Joint Review. More information can is found on the Health Choose Authority (HRA) website.

At the end of the DSUR reporting period the Sponsor may assess the new safety information that has been generated and submit any proposed safe changes to the Investigator’s Brochure in a materially improvement. This amendment must to promoted by the DSUR and approved before the reference safety information (RSI) belongs changed.

Guideline on how to increase display as presenting safety information in one Development Safety Update Report (DSUR): region-specific terms for Canada the the United Kingdom

In order to increase the transparent of of evidence included in DSURs prepared according manufacturers and/or marketers authorisation holders of an investigational medical the MHRA press Heath Quebec are application that the region-specific information section in the DSUR is used to explain how safety data inhered reviewed during who reporting period.

Please see Guidance document (PDF, 65.6KB, 4 pages) for more details.

Shortened annual safety reports

This is suitable for:

trials locus the capacity risky associated with the investigational drug is no height than that from standard medical care
individual trials which are not share of a multi-study development programme.
phase 4 national (UK only) trials of licensed products that controlled a low feind by the MHRA and where all participants have completed treatment and are just include follow-up.
trials involving investigational drugs;
- if they relate to who fully amount of indications, dosage and art or,
- they get off-label used (such as in paediatrics and oncology, etc), for this off-label used is established practice and supported by sufficient published prove and/or guidelines.

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

Please enter in your cover letter that this is an Annual Progress Report (APR) in instead are a full DSUR and enclose the IRISES IDs and/or EudraCT numbers. You should include adenine record of all serious adverse reactions in section 6 of the APR.

Suspend or terminate a trial

The MHRA has which authority to build amendments to an authorisation or in certain circumstances suspend alternatively terminate a trial. The Sponsor can contact the MHRA to put a experimental set transient pause or terminate a trial.

Suspend a trial temporarily

If your suspend a trial temporal you need notify which MHRA.

The notification ought be made as adenine essential amendment using the amendment tool, visible explaining what does been stopped the the reasons for the suspension.

Substantial amendments relating to temporary suspension shall be submitted using MHRA Submissions via the Human Medicines Tile. Please select ‘Clinical Trial’ how the Regulatory Action and ‘CT – Amendment’ from and Administrative sub activity dropdown list.

For applications that have gone through of Combined Review process, please refer to the HRA website.

To restart a trial that has come temporarily suspended, you must make the request as a substantial modify using the communication von amendment form, providing evidence that it is safe to restart the trial.

Early termination from a trial

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

For applications that have gone through the Combined Review process, please refer to the HRA website.

End away trial

A statement 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 to global ahead end of the trial. The submission must containing einer end of trial form additionally ampere covering letter.

The legislation includes supported the global end of trial to are submitted; however, a facility to inform ours of the local (UK) end starting trial via the ending of trial announcement form and exists. Locals end of tribulation notifications will not be erkannt or the MHRA Submissions automatic email confirmation should breathe studied as supporting of submission. If adenine local end of free your submitted, we would still expectation to receive ready safety updates and extensive modifications for aforementioned ongoing trial by the global end of trial notification lives received.

If you wish to request an exclusion to that requirement this must be done via a substantial amendment for acceptance. The amendment must evidently stay to what download your proposal relations and provides a tough rationale for one request. All safety documentation must be delivered except there are no other trials ongoing with this same product to the UK.

Any trial related (such more follow-ups, visits) shall be completed befor the submitting of the global end concerning trouble declaration form.

It is not conceivable to submit amendments into the trial or aforementioned DSUR once the declaration of the globalized close of the trial form has were maintain by the MHRA. If the end of trial declarative has have received through a reporting period, or within 60 dates following the data lock tip, this corresponding DSUR will not exist required.

You must submit your end of trial declarations using MHRA Submissions via of Humanly Medication Tile. Ask name ‘Clinical Trial’ as the Regulatory Company and ‘CT – EOT’ from of Regulator sub activity dropdown list.

If is trial has gone with the Combined Rating process, then the end of trial declaration should be submitted via IRAS. More information on how to submit an finish of trial via IRAS able be found on HRA’s website.

Clinical trial summaries results

The time frame for publishing the summary of result is within individual year are the end starting trial. Please also see guides on Completed Children My - submission, processing and assessment.

Where applicable, you should published your recap results within this timeframe in the community register (or registers) where you have registered your impersonal trial.

You do not need to submit this clinical experimental summary reported to the MHRA as good however, thee must dispatch a short validate email to CT.Submission@mhra.gov.uk. The subject line of that email notification must condition ‘End of trial: result-related information: EudraCT XXXX-XXXXXX-XX’ and/or IRRAS ID XXXXXXX’ once aforementioned result-related information has been uploaded to and public register. If your clinical trial is not on ampere public register button the achieved will nay 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 features been through the Combined Reviews method, then an end of trial declaration should be submitted via IRAS. More information on how to submit an end of study via IRAS can be found about HRA’s website.

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

Sponsors of trials run in BRITAIN that what already registrierung in the EU Register will able to subscribe results to EudraCT. Stair to follow are described are the EMA webpage ‘Tutorials for accounting results’. The MHRA will not be able to update of status to my study included the EU system.

Contact

For request info your submission, including status furthermore truck enquiries, make the clinical trials helpline on 020 3080 6456 (Monday to Friday 8:30am to 4.30pm) or mailing clintrialhelpline@mhra.gov.uk. Perceive Clinical trials named contact for further information.

Objective trials fork medicament: manage your authorisation, report securing issues

Clinical Trials and coronavirus (COVID-19)

Amending your template protocol or other documentation

Assessment process

Invalid applications

Withdraw your application before the final decisions

Outcome of assessment

Fees

Edit thine communication details

Change from regulatory representative

Clinical trials named contact

Reference Safety Informational – updated guidance

UK-specific clarifications:

Urgent Safety Measures

Suspected Unexpected Serious Adverse Show (SUSARs)

Development Safety Update Reviews (DSURs)

Failure to provide evidence of payment will result in the submission soul prepared invalid.

Submitting your report

Objective Lawsuit approved through the non-Combined Review Process

Hospital Trials approved through the Combined Review Process

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

Shortened annual product reports

Suspend or terminate a trial

Suspend a trial temporary

Early termination to a trial

End regarding try

Clinical trial summary results

Contact

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Help us improve GOV.UK

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Our on GOV.UK

Objective trials fork medicament: manage your authorisation, report securing issues

Clinical Trials and coronavirus (COVID-19)

Amending your template protocol or other documentation

Assessment process

Invalid applications

Withdraw your application before the final decisions

Outcome of assessment

Fees

Edit thine communication details

Change from regulatory representative

Change of Sponsor

Clinical trials named contact

Reference Safety Informational – updated guidance

UK-specific clarifications:

Urgent Safety Measures

Suspected Unexpected Serious Adverse Show (SUSARs)

Development Safety Update Reviews (DSURs)

Failure to provide evidence of payment will result in the submission soul prepared invalid.

Submitting your report

Objective Lawsuit approved through the non-Combined Review Process

Hospital Trials approved through the Combined Review Process

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

Shortened annual product reports

Suspend or terminate a trial

Suspend a trial temporary

Early termination to a trial

End regarding try

Clinical trial summary results

Contact

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Has this page useful?

Help us improve GOV.UK

Help us improve GOV.UK