Sponsor and investigator

Definitions 

Regulation (EU) No 536/2014 (the Clinical Trials Regulation, CTR) provides, among other things, definitions for:

One or more sponsors

According to the CTR, a clinical trial may have one or more sponsors. If a clinical trial has more than one sponsor (co-sponsors), all sponsors are covered by sponsor liability, i.e. all sponsors have the same liability for the clinical trial. If the responsibility is to be divided, this shall be described in a written contract. If no liability is mentioned in the contract, all sponsors are responsible for this.

The co-sponsors shall jointly establish:

• a sponsor responsible for compliance with the obligations of a sponsor set out in Chapters II and III of the CTR
• a sponsor responsible for being a contact point for receiving all questions from subjects, investigators or any Member State concerned (MSC) in which the trial is being conducted
• a sponsor responsible for implementing corrective measures under Article 77 of the CTR.

The sponsor and the principal investigator may be the same person. A sponsor may delegate any or all of its tasks to an individual, a company or an institution, or an organisation. This shall be documented in a written contract. However, the sponsor is still responsible for the trial, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial.

Sponsors outside the EU

Article 74 of the CTR stipulates that where a sponsor is not established in the EU, this sponsor shall appoint a natural or legal person established in the EU as its legal representative. This legal representative will be responsible for ensuring compliance with the sponsor’s obligations pursuant to the CTR. All communications with the sponsor provided for in the CTR shall be sent to the legal representative.

Pursuant to Chapter 4, Section 3 of the Medicinal Products Ordinance (Läkemedelsförordningen), the Swedish Medical Products Agency (MPA) may decide that the sponsor does not need to appoint a legal representative, but instead at least one contact person who shall receive all communications provided for within the framwork of CTR. According to Article 74(2) of the CTR, this contact person shall be in Swedeen if Sweden is the only EU Member State in which the clinical trial is to be conducted. If the clinical trial is to be conducted in more than one Member State, this contact person shall be within the EU, as pursuant to Article 74(3).

Sponsor and investigator – responsibilities

The sponsor shall:

• when submitting a trial application to CTIS, indicate which Member States concerned (MSCs) are intended to be included in the trial, and propose one of these Member States concerned as the reporting Member State (RMS);
• translate application documents into languages to be determined by each MSC.

In Sweden, the application may be written in Swedish or English.

Note that a synopsis of the trial protocol must be submitted in Swedish. The synopsis shall be understandable to a layperson and should not exceed two A4 pages in length.

In Sweden, labelling documents for investigational medicinal products and auxiliary medicinal products, as well as the application dossier for Part II (national part) shall be submitted in Swedish. Where the information on biological samples referred to in point 17(s) of Annex I to the CTR is submitted in a separate document, that information shall be written in Swedish.

The sponsor and the investigator are responsible for:

• ensuring that the clinical trial is conducted in accordance with good clinical practice and the protocol
• ensuring that the premises are suitable for conducting the clinical trial
• ensuring that all information relating to the clinical trial is recorded, processed, handled, and stored in such a way that it can be accurately reported, interpreted and verified
• protecting the subjects’ records, other personal data and the information processed, from unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss, in particular if the processing involves the transmission of data over a network
• preparing and maintaining a clinical trial master file (TMF), which shall contain key documents relating to the trial and allow for verification of the conduct and data quality, taking into account the characteristics of the clinical trial, including if it is a low-intervention clinical trial. The TMF shall be readily available to Member States on request
• archiving the contents of the TMF for at least 25 years after the end of the clinical trial and on a medium that is complete and legible for the entire archiving period. Any changes to the TMF shall be traceable. Additional requirements are described in Articles 57 and 58 of the CTR.
  In the case of trials involving tissues and cells, further information on archiving can be found in the Swedish MPA's regulations (LVFS 2008:12) on the handling of human tissues and cells intended for manufacturing of medicinal products.
  If the investigator cannot personally be responsible for archiving documentation from the trial site, this can be regulated in the contract with the sponsor. However, the sponsor must not have access to the investigator’s documentation from the trial, which means that archiving must not physically take place with the sponsor.
  If electronic CRFs are used, the investigator must have an independent copy of his or her reported data, rather than a copy that has been retrieved from the company database – the sponsor must never have exclusive control over this data.

The sponsor is responsible for the quality control (monitoring) of the clinical trial.

The sponsor has reporting obligations for:

• serious breaches – within 7 days
• unexpected events that may affect the benefit-risk balance of the clinical trial but are not suspected unexpected serious adverse reactions – within 15 days
• urgent safety measures (USM) – within 7 days. 

The sponsor shall provide the investigator with an investigator’s brochure (IB), which shall be updated as new and relevant safety information becomes available and reviewed by the sponsor at least once a year. Since the investigator is required to have a good knowledge of the investigational medicinal product, the investigator must review the current IB before study start. This could, for example, be verified by an acknowledgement of receipt which the investigator signs. The acknowledgement of receipt should state which version was sent out and when the investigator received it. When an updated version of the IB is sent to the investigator, the previous version may be withdrawn by the sponsor. The documentation at the trial site must show which versions were on site during the course of the trial and during what time intervals (ICH GCP 8.2.1, 8.3.1).

Investigator – suitability and GCP

Under Chapter 7, Section 1 of the Medicinal Products Act (läkemedelslagen) (2015:315), a clinical trial may only be conducted on humans by a qualified medical doctor (physician licensed by the Swedish National Board of Health and Welfare) or qualified dental practitioner (dentist licensed by the Swedish National Board of Health and Welfare). The investigator shall possess sufficient competence in the area that the trial concerns.

Staff performing tasks in a clinical trial at the clinical trial site shall have the training and experience necessary to perform their respective tasks. In addition, the principal investigator, other investigators, and other staff to whom tasks in the trial have been delegated, shall have documented knowledge of good clinical practice and sound knowledge of the investigational medicinal product.

The investigator is responsible for ensuring that there is access to appropriate facilities as well as competent and suitable staff for proper and safe conduct of the trial.

The principal investigator is expected to allocate trial-related tasks in a trial to delegated co-investigators and other staff, such as research nurses, in a way that does not compromise the safety of subjects or the reliability and robustness of the data generated in the trial.

If the investigator delegates some of the duties to other staff at the clinical trial site, this shall be done in writing, and it shall be clear which duties are included and who is to carry them out. A delegation shall be signed both by the person delegating and the person who receives the delegation.
A combined signature and delegation list is often used (ICH GCP 4.1.5, 8.3.24). An example of such a list is available on the Swedish Pharmaceutical Society website.

Duties may only be delegated to someone who has adequate training and experience in carrying out the tasks, and who has had relevant trial-specific training. It should be noted that qualified medical doctors or qualified dental practitioner are always responsible for medical decisions and for the provision of medical care, e.g. decisions concerning inclusion in the trial and assessment of adverse events/reactions.

The Swedish MPA normally expects the persons to whom the investigator has delegated study-related duties to be included in the delegation list. Study-related duties may mean study-specific performance and/or study-specific assessment and documentation, for example on trial-specific worksheets or in the case report form (CRF).

However, the investigator does not need to delegate duties which are carried out according to normal clinical practice, i.e. when the person who carries out the task does not need study-specific training in order to either perform the task or document/report the outcome.

The investigator also does not need to delegate duties that are regulated in an agreement between the sponsor and the performer, if the sponsor for example has an agreement with the pharmacy for the handling of medicinal products, or with a radiology department for study-specific radiology examinations.

Basic provisions for delegation in healthcare can be found in the Patient Safety Act (patientsäkerhetslagen) (2010:659) and the National Board of Health and Welfare’s regulations and general guidance SOSFS (1997:14) on the delegation of duties within healthcare and dental care.