From start to outcome of clinical trials

Definitions

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

Sponsor’s responsibilities

Articles 36-39 of the CTR describe the sponsor’s obligations in relation to the start, end, possible temporary halt, early termination and reporting of final results of a clinical trial. The articles specify the timelines within which the sponsor, via CTIS, shall notify these events to each Member State of Concern (MSC).

Events to be reported, among others, are:

• When a clinical trial starts.
• When the first visit of the first subject takes place in each Member State.
  • Important to note that if no subject has been included in a MSC within two years, the authorisation expires in that MSC. The status for the trial will automatically change to “expired” in CTIS 2 years and 15 days after the authorisation of the trial if the sponsor does not include a date under, what today is named, “Recruitment start date”.
• When recruitment is completed in each Member State.
• When a clinical trial has been completed in all Member States and also in the third countries concerned.
• If the trial is temporarily halted in all Member States for reasons that do not affect the risk/benefit balance (e.g. a shortage of investigational medicinal product) and when the trial may be resumed in all MSCs.
• A clinical trial that has been temporarily halted and is not resumed within two years.
• If the trial is temporarily halted or prematurely terminated due to a change in the risk/benefit balance (e.g. related to safety, lack of efficacy or quality problems with the investigational medicinal product). In some cases, this may be related to Urgent Safety Measures (USMs). The resumption of such a clinical trial constitutes a substantial modification.

Within one (1) year of the end of the clinical trial in all MSCs, the following shall be submitted:

• a summary of the results of the clinical trial in accordance with Annex IV to the CTR
• a summary written for laypersons in accordance with Annex V to the CTR.

This applies irrespective of the outcome of the trial.

The time limit for reporting results from a clinical trial on children where the medicinal product is approved and the sponsor of the trial is the marketing authorisation holder of the medicinal product is 6 months. This is stated in Article 46 of EU Regulation 1901/2006.

Conduct of the trial

The Swedish Medical Products Agency receives many questions relating to different aspects of clinical trials on medicinal products and Good Clinical Practice (GCP). Below, we have collated some important aspects to consider.

The information is not comprehensive but covers and clarifies some of the areas relating to clinical trials on medicinal products and GCP where questions often arise.

More information can also be found on the EMA website.

Screening log

A screening log (ICH GCP, 8.3.20) has several purposes. One aim is to ensure that there was no selection bias in the inclusion of subjects into the clinical trial. The screening log is also a tool for the sponsor to verify whether any of the inclusion or exclusion criteria complicate the inclusion of subjects in the trial.

The screening log shall include information on which subjects have been screened and reasons for those who have not been included in the trial. As the screening data is available to the sponsor, the identity of the subjects should not be stated.

An example of a screening log is available (in English) on the Swedish Pharmaceutical Society website.

Patient identification log

The purpose of the log is, if necessary, to be able to quickly identify the subjects who have received investigational medicinal products. In Sweden, the log must therefore include names and social security numbers (in Swedish fullständigt personnummer) or equivalent.

An example of a patient identification log is available (in English) on the Swedish Pharmaceutical Society website.

Investigator’s clinical trial master file

When conducting a clinical trial, the investigator is responsible for ensuring that all relevant documentation in accordance with ICH GCP and regulatory frameworks is available at the trial site. The regulatory frameworks do not require documentation to be set out according to the sponsor’s templates. If the trial site has its own procedures and templates for documenting relevant information, they may alternatively use these. The company's internal procedures (Standard Operating Procedures, SOP) apply to the sponsor’s staff, but not to the staff at the trial site.

Investigational New Drug trials in Sweden

All clinical trials conducted in Sweden must be carried out in accordance with current legislation in Sweden. By signing Form FDA 1572, the investigator also undertakes to conduct the trial in accordance with US legislation (21 CFR part 312). It should then be ensured that these legislations are compatible.

There is no requirement from the U.S. Food and Drug Administration (FDA) for clinical trials outside the USA to be carried out under an Investigational New Drug (IND) programme, which is clearly described in their regulatory framework. It is also described what the FDA expects if IND trials are nevertheless conducted outside the USA.

The FDA's standpoint on these issues is described in Frequently Asked Questions – Statement of Investigator (Form FDA 1572) and in the regulations regarding 21 CRF 312.120.

Information in the patient medical record

For subjects who are cared for within the framework of a clinical trial, the Patient Data Act (2008:355) must be followed. The content of the patient medical record is clearly defined in Chapter 3, Article 6 (translated to English):

‘A patient medical record shall include the information that is needed for good and safe care of the patient. If the information is available, a patient medical record must always include:

1. information on the patient’s identity
2. essential information on care background
3. information on diagnosis and the reason for more significant measures
4. essential information on adopted and planned measures and
5. details regarding the information provided to the patient and on the decisions taken regarding the choice of treatment options and the possibility of a renewed medical assessment.

The patient medical record must also state who has made a certain entry in the record and when the entry was added.’

It must be clear that the patient is participating in a clinical trial and what the trial entails in terms of treatment, doses and treatment period. Furthermore, it must be clear that the patient has been informed and given their written consent to take part in the trial. Information that is collected solely for a clinical trial, that has no relevance for the patient’s normal healthcare, may be noted in another source data document, for example in the CRF or worksheet.

In accordance with Chapter 3, Article 7 of the Patient Data Act, the patient medical record must also contain information required according to other laws.

Source data

Source data is defined in ICH GCP 1.51 and 4.9.0. The Swedish MPA expects the investigator/clinic to collect source data in source data documents that meet the requirements in ICH GCP(R2). This means that source data must be documented in such a way that it is possible to confirm who has documented it and when, it must be legible and correct/complete, in original form and collected contemporaneously. Additionally, source data must be permanent, and amendments to source data must be traceable (amendments must not obscure what was originally there and must be explained if necessary).
A description of source data can also be found on the EMA website, Q&A GCP, ‘GCP matters’, Question 3: How and where should source data be defined?

CRF as source data

Data in the Case Report Form may be source data in the event of data being registered directly in the CRF, and where it is indicated in the trial protocol that the CRF may contain source data (ICH GCP 6.4.9). As the procedures may vary between trial sites, a separate document should be made for each trial site clarifying where different types of source data are registered. The principal investigator and the sponsor’s representative sign and date the source data location agreement before the trial start, e.g. at the time of the site initiation visit. If the process is changed during the course of the trial, the source data location agreement must be updated.

An example of a source data location agreement is available on the Swedish Pharmaceutical Society website.

Copies of source data documents

If a copy is made of a source data document, with the intention to replace an original document/data/record, it must be verified to fulfil the definition of a certified copy in ICH GCP 1.63.

Monitoring frequency and nature of monitoring

For each individual clinical trial, the sponsor must decide on the extent and nature of monitoring. The Addendum to ICH GCP E6 (R2) explains that the decision must be based on a risk-based approach and that the sponsor must document the rationale for the chosen monitoring strategy, e.g. in a monitoring plan. The type and structure of the trial, previous knowledge of the investigational medicinal product and the trial site’s experience of trials are examples of important factors in determining the frequency and nature of monitoring to be used. The sponsor is also responsible for identifying and rectifying what is discovered by the monitoring during the course of the trial, and updating the plan as needed based on this.

ICH GCP specifies two types of monitoring, on-site and central monitoring. The concept of central monitoring was also used in the original version of ICH GCP but was clarified in R2 (Addendum), where it is defined as ‘a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g. data managers, biostatisticians)’.

ICH GCP 5.18.4 lists the many different activities (including source data verification) included in the monitor's job to ensure that the trial is conducted and documented in a correct manner. An important reason for the need for source data verification and monitoring at the trial site is the responsibility to safeguard and protect confidentiality, and not to risk violating the integrity of the patients.

Both the EMA and FDA have published ‘reflection papers’ on their respective websites as a guide for risk-based monitoring.

Guidance can also be found in this document from the EU Commission which refers to the CTR and covers, among other things, risk-based monitoring.

Secrecy agreement

In accordance with the Patient Data Act (SFS 2008:355), only staff who play an active role in the subject’s treatment have access to the relevant medical record. The person responsible for medical records at the respective clinics is responsible for ensuring that the monitor's access to medical records complies with relevant laws and internal procedures.

A secrecy agreement must be signed by those who have access to the patient medical records and by the person responsible for them at the clinic, which often is the head of the clinic/institution at the clinical trial site (in Swedish “verksamhetschef”). In line with common practice, this is done even if the monitor is employed at the same hospital.

An example of a secrecy agreement form is available on the Swedish Pharmaceutical Society website.

If the trial is conducted within the public healthcare, reference must be made to the Public Access to Information and Secrecy Act (SFS 2009:400, Chapter 25, Article 1), while for private services, reference must be made to the Patient Safety Act (SFS 2010:659, Chapter 6, Article 16).

Site initiation report in the investigator’s file

The site initiation report is an essential document that must be included in the investigator’s file in accordance with ICH GCP 8.2.20. The purpose of the report is to document the verification that the trial site is ready to start including subjects in the trial. This includes, among other things:

• all authorisations are in place
• all documentation and material are on site
• the procedures of the trial have been discussed with the investigator and other employees.

The report is the monitor’s quality stamp on the trial site and should therefore not just contain a number of multiple-choice questions, but actually document what has been discussed and agreed.

Source data review of patient medical records in electronic systems

The person responsible for medical records at the respective clinics is responsible for ensuring that the monitor's access to medical records complies with relevant laws and internal procedures.

At many trial sites, the monitor may not have direct access to the electronic patient medical records via their own login in order to carry out a review of source data in a clinical trial. The main reason for this is that in certain systems it is not possible to limit access to only include subjects included in the current trial.

In practice, the monitor’s review of source data at the trial site is therefore often carried out with the help of printouts of relevant medical notes. These printouts are not aimed at replacing the source, i.e. the full electronic medical records, and therefore need not be signed and dated by the investigator. The printouts may be stored at the trial site during the course of the trial and destroyed after the end of the trial. The monitor should at some point during the course of the trial, together with trial staff, ensure that all relevant medical notes have been made available to the monitor. It may be useful to document what has been source data verified in the monitoring report.

Distribution of investigational medicinal products

The provisions in the law regarding the trade of medicinal products means that different requirements apply to the distribution of investigational medicinal products to trial sites within hospitals, and trial sites outside hospitals, respectively.

For trial sites outside hospitals, the concept of ‘primary healthcare providers’ is used here. It should be noted that this may also include trial sites physically located at a hospital but which do not belong to the hospital organisation.

According to the Swedish MPA’s interpretation of the legal situation, investigational medicinal products may be distributed to hospital clinics by the functions or activities that constitute hospital pharmacies within the meaning of the law, and to primary healthcare providers by pharmacies that have outpatient pharmacy authorisation, or by those who have wholesale distribution authorisation.

Furthermore, the Swedish MPA's regulations (LVFS 2014:8) on the wholesale and distribution of medicinal products stipulate that those who have authorisation to manufacture medicinal products are also entitled to operate wholesale distribution of such medicinal products included in the authorisation, i.e. supplying investigational medicinal products to primary healthcare providers. In such specific cases, a sponsor who has a relevant manufacturing authorisation in Sweden may supply investigational medicinal products directly to trial sites outside hospitals.

Requirements for handling of investigational medicinal products in connection with distribution are stated in HSLF-FS 2021:109.

Storage of investigational medicinal products

Investigational medicinal products must be stored in accordance with the directions stated on the label of the investigational medicinal product, in a locked area, and without granting access to unauthorised persons. Returned medicinal products and medicinal products that have not been supplied to a subject must be stored clearly separated from each other (risk of mix-up). Similarly, investigational medicinal products from different clinical trials must be stored clearly separated from each other. If medicinal products are to be stored under special conditions, for example in a refrigerator, temperature control covering the entire storage period is required (Medical Products Act (2015:315)).

An example of a temperature log is available on the Swedish Pharmaceutical Society website.

Stock record for investigational medicinal products at the trial site

ICH GCP 4.6.3 states that ‘The investigator/institution and/or a pharmacist or other appropriate individual […] should maintain records of the product’s delivery to the trial site, the inventory at the site, the use by each subject […]’.

There is thus a requirement for a stock record to be kept where the investigational medicinal product is stored, at the pharmacy and/or trial site, which shows current stock balance. Certain IRT (Interactive Response Technology) may offer such reports. If this is to replace a manual stock record, the person responsible for the stock must have access to extract such reports from the system when needed during the trial and a complete stock record must be archived in the investigator’s file when the trial ends.

Requisition of investigational medicinal products

Persons with the right to requisition must be identified in the pharmacy agreement or other equivalent agreement with wholesale distributors. They must also be included in the delegation list with associated CVs.

Handling of investigational medicinal products at pharmacies and wholesale distributors

The requirements of handling investigational medicinal products at pharmacies and wholesale distributors are included in HSLF-FS 2021:109. It states that pharmacies or wholesalers who supply investigational medicinal products must, among other things, check that the labeling is correct. This means that the labeling corresponds to the labeling approved in the clinical trial authorisation. If the approved label includes a dedicated space for the investigator's name ("Prövare: XX"), this is expected to be filled in when the investigational medicinal product is delivered to the trial site. Pharmacists at a hospital pharmacy function, without the requirement of manufacturing authorisation, may add additional labeling with the investigator name. This must then be covered by the agreement between the sponsor and the pharmacy.

Handling of medicinal products at trial site

For the handling of medicinal products at a trial site, the National Board of Health and Welfare’s regulations (HSLF-FS 2017:37) on the handling of medicinal products in healthcare must be followed in addition to regulatory frameworks surrounding clinical trials. This means, among other things, that the same regulations apply to the prescription, preparation and administration of medicinal products and to documentation in the patient’s medical record, as to healthcare in all other respects.

Documentation for laboratories

An accreditation certificate or other documentation which validates that the laboratory used for the analysis of samples is qualified to do this, must be available in the investigator's documentation. This applies even if the samples in, for example, a kinetic study are to be analysed in the company's internal laboratory where accreditation is usually lacking. In these cases, at least a QA statement (Quality Assurance) must be available (ICH GCP 8.2.12).