5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?

The Sponsor is usually expected to be the employer of the chief investigator (CI) in the case of non-commercial research, or the funder in the case of commercial research. The Sponsor has overall responsibility for the research.

The employer or funder is not automatically the Sponsor; they explicitly accept the responsibilities of being the Sponsor.

The definition of the Chief Investigator and Investigator is provided under the “MHRA and HRA Position on who can act as Chief Investigator”.

Chief Investigator (CI)

The chief investigator is the overall lead researcher for a research project - (outside the UK, the term Coordinating Investigator or Investigator may be used). In addition to their responsibilities, if they are members of a research team, chief investigators are responsible for the overall conduct of a research project. The chief Investigator’s responsibilities are set out in more detail in the UK Policy Framework for Health and Social Care Research.

Principal Investigator (PI)

The PI is an individual responsible for the conduct of the research at a research site. There should be one PI for each research site. In the case of a single-site study, the CI and PI will normally be the same person.

It is not stated if PI/CI is to be approved/registered by any regulatory authority. However, their qualification and related experience does define if they could be assigned roles and responsibilities of PI/CI.

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

No, PI and CI must be based within the country.

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

Yes, consent can be documented electronically or in writing. A physical or electronic copy of the signed consent form will still need to be provided to the participant. To record consent electronically, electronic signatures will be needed. Because there are different forms and classifications of electronic signatures, the researcher should determine what is appropriate for the particular study. 

The HRA & MHRA joint statement on seeking and documenting consent using electronic methods sets out the legal and ethical requirements for seeking and documenting consent using electronic methods (also known as eConsent in the UK), as well as expectations regarding the use of electronic signatures. eConsent enables potential research participants to be provided with the information they need to make a decision via a tablet, smartphone, or digital multimedia. It also enables their informed consent to be documented using electronic signatures. 

This approach can supplement the traditional paper-based approach or, where appropriate, replace it. Albeit true, currently, there must still be interaction and a consent interview with an Investigator which could be in-person, over the phone, or via telemedicine and this discussion must be documented in the source notes.

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

Not as such. In the UK, ‘electronic methods for seeking informed consent’ and ‘eConsent’ refer to the use of any electronic media (such as text, graphics, audio, video, podcasts, or websites) to convey information related to the study and to seek and/or document informed consent via an electronic device such as a smartphone, tablet, or computer. Please note that DCT Guidance is currently under review by the MHRA.

A helpful example of a toolkit has been developed with the HRA (Health Research Authority) and RECs (Research Ethics Committees) and reflects accepted good practices for communicating with participants. 

Joint statement on seeking consent by electronic methods 2018

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

The UK GDPR and the Data Protection Act 2018 (DPA) contain provisions for processing personal data for research purposes in the United Kingdom.

The MHRA “GXP” Data Integrity Guidance and Definitions-March 2018” provides the MHRA’s position on data integrity and the minimum expectations to achieve compliance.

5.6 If a clinical study involves the study product as OTC and this is provided via pharmacy/amazon, etc., are there any specific regulations for IP management that need to be followed?

In the UK, an investigational medicinal product (IMP) is any medicinal product that is being tested within a trial or any product, including a placebo, used as a reference in a clinical trial. This includes products with a marketing authorization where the product is:

• used in a different form from the marketing authorization;
• used for an indication not included in the summary of product characteristics for that product; or
• used to gain further information about the product as authorized in the clinical trial authorization.

Therefore, any OTC product used as part of the study would be considered IMP.

5.7 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

Art. 28- 3 (b) of the Medicines for Human Use (Clinical Trial) Regulations 2004 indicates the following:

3) Subject to paragraphs (4) and (5), the sponsor of a clinical trial shall ensure that— 

1. the investigational medicinal products used in the trial, and 
2. any devices used for the administration of such products

are made available to the subjects of the trial free of charge.

5.8 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

The HRA has published guidance related to “Payments and Incentives in Research”.

It is acceptable for the reimbursement of expenses to be provided to study participants.

Any other “payments” will depend on the type of study, the expected benefit, and the risks for the participants, and will ultimately require REC approval.

5.9 Specific labeling requirements for clinical study product

Labeling for investigational products (IPs) (known as investigational medicinal products (IMPs) in the UK must comply with the requirements set forth in Part 1 (2) and Part 7, and Schedule 3, Part 2 (12) of the Medicines for Human Use (Clinical Trials) Regulation 2004, its amendments (Amendment Regulations 2006), Eudralex- Volume 4- Good Manufacturing Practice (GMP) Guidelines- Annex 13, and the International Council for Harmonization's Guideline for Good Clinical Practice E6(R2).

Labeling for IMPs must ensure the protection of the participant and traceability to enable identification of the product and trial, and to facilitate proper use of the IMP. For an IMP to be used in a clinical trial, it must be properly labeled in the official language of the country where the trial is being conducted.

As set forth in Annex 13, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

1. Name, address, and telephone number of the Sponsor, contract research organization (CRO), or investigator
2. Pharmaceutical dosage form, route of administration, quantity of dosage units, and, in the case of open trials, the name/identifier and strength/concentration
3. Batch and/or code number to identify the contents and packaging operation
4. Trial reference code allowing identification of the trial, site, investigator, and Sponsor (if not given elsewhere)
5. Trial participant identification number/treatment number and where relevant, the visit number
6. Investigator name (if not already included above)
7. Instructions for use (reference may be made to a leaflet or other explanatory document intended for the trial participant or person administering the product)
8. “For clinical trial use only” or similar wording indicating the IP is clinical trial material
9. Storage conditions
10. Expiration date (use by date, expiration date, or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity
11. “Keep Out of Reach of Children” except when the product is not going to be taken home by participants

A sample of the labeling is required as part of the clinical trial application submission. The IMP must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

5.10 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

The Qualified Person (QP) named on the UK MIA(IMP) should have the following documentation available as part of the oversight process for the import of IMP to Great Britain from listed countries:

1. Details of the manufacturing and distribution supply chain.
2. The UK Clinical Trial Application form, plus amendments. This should be used to confirm the site responsible for the final certification of the finished IMP.
3. The UK Clinical Trial Application and any amendment approval records (including any post-approval commitment requirements).
4. Evidence that the certifying site in the listed country is appropriately licensed and holds a current GMP certificate for the IMP dosage form(s) and associated activities (e.g. manufacture, packaging, testing, and/or import from a third country).
5. Details of the approved Great Britain trial sites from the ethics application, plus any updates or amendments.
6. Details of each shipment of IMP to Great Britain including the addressees’ information. This should be verified against the ethics approvals.
7. Details of any excursions from the stated storage conditions during shipment, along with any decisions taken by the Sponsor and certifying QP, and the rationale for those decisions.
8. Details of the responsibilities described in the written agreement between the Sponsor and the listed country MIA(IMP) holder.

This is not an exclusive or exhaustive list because importation requirements may vary depending on the responsibilities of each organization in the supply chain.

Written evidence should be available to demonstrate that each batch of IMP imported from a listed country has been QP-certified for use in the specified UK trial. This should be verified prior to the first shipment of IMP from each batch to the Great Britain trial site(s).

Not all options listed below may be suitable for different supply chain relationships. However, just one of these pieces of evidence is sufficient to satisfy the requirements of the Regulations. Other evidence may be acceptable provided it confirms that QP certification has taken place for the batch in question. 

Batch certification by a Qualified Person may be confirmed using evidence such as:

1. A batch certificate confirming QP certification in accordance with Article 13.3 of Directive 2001/20/EC.
2. Statement of certification (ad-hoc, confirming certification in accordance with Article 13.3 of Directive 2001/20/EC).
3. Access to the certifying MIA(IMP) holder’s internal systems (e.g. global Enterprise Resource Planning system) that confirm batch certification.

Until the QP named on the UK MIA(IMP) confirms that the batch of IMP has been appropriately certified by the listed country QP, the IMP should not be made available for use by the Great Britain trial sites. This is in addition to the two-step release procedure described in EU GMP (Annex 13). Regulatory release of the IMP may be given to some countries at different times. Therefore, the Sponsor should ensure the regulatory release is in place for the UK prior to IMP being made available for use in the trial.

You can import authorized or unauthorized products for use in a UK clinical trial in Great Britain that are:

• non-investigational medicinal products
• unmodified comparators to be labeled in Great Britain prior to QP certification and release to the clinical trial.

Importation from a listed country should use a wholesale dealer’s license (WDA(H)). A Responsible Person for import (RPi) may be required. Guidance is available on the importation of medicines from an approved country for import and the requirements for RPi. Importation from a country that is not a listed country will require a manufacturer's license. Obtaining non-investigational medicinal products from Northern Ireland will require a WDA(H) unless you are the Sponsor of the clinical trial.

There are two routes for IMPs to be received in Great Britain from a listed country for use in UK clinical trials following QP certification by the listed country MIA(IMP) holder:

1. Directly to the Great Britain clinical trial site, or
2. Via a Great Britain storage and distribution ‘hub’.

Both require the oversight of a UK MIA(IMP) holder and QP, with systems in place to ensure that:

• IMPs are not made available for use in Great Britain clinical trial sites until appropriate QP certification in a listed country has been verified by the QP named on the UK MIA(IMP).
• IMPs are only shipped to appropriate Great Britain trial sites detailed within the UK trial application.
• Up-to-date information and documentation relating to the clinical trial and associated Product Specification File are made available by the Sponsor to the QP named on the UK MIA(IMP).
• The clinical trial is authorized by the MHRA before IMP is made available to the Investigator.

Additional background information

Summary/Overview

According to the MHCTR, the MHCTR2006, the MHRA is responsible for authorizing the manufacture and import of IMPs in the UK to be used in a trial. A Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture or importation of any IP to be used in the trial. The Sponsor or his/her designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. The applicant must complete the form listed in “Medicines: application forms for a manufacturer license” to obtain an MIA(IMP) from the MHRA.

As per the MHCTR, the MHCTR2006, the MHRA Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP), Eudralex V4- GMP Guidelines, and the International Council for Harmonization’s Guideline for Good Clinical Practice E6(R2), the MIA(IMP) holder must also comply with the GMP guidelines and provide an IMP Certificate of Analysis. In addition, the MHCTR, the MHCTR2006, and the G-GMP-GDP specify that the holder of an MIA(IMP) must always have the services of at least one (1) QP at his/her disposal. The QP must satisfy the qualification and experience requirements delineated in the aforementioned sources. The QP’s primary legal responsibility is to certify batches of IPs prior to use in a clinical trial, or prior to releasing for sale and placing on the market. See Part 6 and Schedule 6 of the MHCTR for detailed applicant requirements.

In accordance with the MHRA guidance, IMPs that have been QP-certified in countries on the list of approved countries (initially, EU and European Economic Area (EEA) countries per G-CTApprovedCountries) do not need to be re-certified when importing to the UK. However, the Sponsor must require the MIA(IMP) holder to put in place an assurance system to check these IMPs have been certified by a QP in a listed country, before release to the trial. A Sponsor may perform verification of QP certification in a listed country themselves if they are the holder of a UK MIA(IMP). Alternatively, they may outsource this verification to a third party who holds a UK MIA(IMP).

IPs coming directly to the UK from third-party countries that are not on the list of approved countries will continue to require import and QP certification in the UK by the MIA(IMP) holder as per the existing requirements. Per the MHRA- “Authorization and procedures required for importing Investigational Medicinal Products to Great Britain from approved countries”, the verification process described above started on January 1st, 2022. See the MHRA page for additional details on the authorizations and procedures.

MHRA will assess variations and new MIA(IMP) applications within 90 days of submission.

5.11 What is the turn-around time to get an import permit?

Please refer to Section 5.10 above.

5.12 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

Current guidance does not go into the details of the place of destruction of clinical supplies.

The Sponsor must ensure IMP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation, and destruction of the unused IP, retrieval of unused IP(s), and return of unused IP(s) to the Sponsor.

According to Annex 13, sections 53, 54, and 55 indicate the following:

“53. The Sponsor is responsible for the destruction of unused and/or returned investigational medicinal products. Investigational medicinal products should therefore not be destroyed without prior written authorization by the Sponsor.

 54. The delivered, used and recovered quantities of product should be recorded, reconciled and verified by or on behalf of the Sponsor for each trial site and each trial period. Destruction of unused investigational medicinal products should be carried out for a given trial site or a given trial period only after any discrepancies have been investigated and satisfactorily explained and the reconciliation has been accepted. Recording of destruction operations should be carried out in such a manner that all operations may be accounted for. The records should be kept by the Sponsor.

 55. When destruction of investigational medicinal products takes place a dated certificate of, or receipt for destruction, should be provided to the Sponsor. These documents should clearly identify, or allow traceability to, the batches and/or patient numbers involved, and the actual quantities destroyed.”