Insights | Bulgaria – ‘How To’ Guide for Non-Interventional Studies
June 2021 – Our three (3) step ‘How To’ guide for conducting prospective voluntary NIS in Bulgaria:
- Study Classification – Clinical Trial or Non-Interventional Study?
- Submission Requirements – Approvals, Notifications and Registration
- Submission Documents – Initial Application and Substantial Amendments
Definition: A non-interventional study shall be conducted with medicinal products authorised for use in the Republic of Bulgaria where these are studied in order to obtain additional information about the product prescribed in the usual manner in compliance with the conditions determined in the marketing authorisation. No additional diagnostic or monitoring procedures, different from the usual practices shall be applied to the patients in non-interventional studies, and epidemiological methods should be used for the analysis of the collected data (as per Article 145(1) of the Medicinal Products in Human Medicine Act)[1].
Regulatory Consideration 1: Study Classification – Is your study a non-interventional study or a clinical trial?
Use the following simple decision tree to determine whether your proposed clinical study is a clinical trial or a non-interventional study
Regulatory Consideration 2: Approvals, Notifications and Registration
Bulgaria is one of the few European countries where the competent authority for medicinal products (Bulgarian Drug Agency)[2] must approve non-interventional studies (see below).
Approvals:
Notifications: Not Applicable
Registration: EU PAS Register (Optional)
Fee: BGN 400
Regulatory Consideration 3: Submission Documents
Initial Application[4]:
1. Administrative documentation
. Administrative documentation
– Application form^
– Cover letter
– List of the regulatory bodies to which an application has been submitted and their decision
– List of all planned centers, principal investigators and research teams for the territory of the Republic of Bulgaria
– Copy of the recommendations of the Scientific Committee of the European Medicines Agency for consultation on trial planning (if applicable)
– Assignment letter or contract for authorization of the person who submits the application on behalf of the sponsor, when the applicant is not the sponsor
– Document for current registration, issued by a competent authority, to the contracting authority and the applicant on the territory of the European Union
– Declaration that the documentation submitted to the BDA and the Ethics Commission contains the same information.
2. Information for Participant:
– Information about the patient / participant and a form of informed consent – original and in Bulgarian
– Description of the procedures for recruiting patients / participants
– Description of the procedures for obtaining informed consent from a legal representative, where foreseen
– Ethical justification in case of recruitment of participants who are not able to give informed consent
– Any other information that will be used to recruit participants and / or provide to a participant before or during the non-interventional study.
3. The protocol documentation:
– Protocol of the study with all current changes
– Summary of the protocol in Bulgarian
– Assessment of the scientific value of the study by a specialist in the relevant field, when available
– Ethical evaluation of the protocol by the principal or coordinating researcher, when it is not part of the protocol
– A page of the protocol, signed by the sponsor and the principal investigator for each of the proposed centers
4. Documentation for the Medicinal Product:
– Current brief description of the product (SmPC)
5. The Documentation for the Technical Requirements and the Personnel:
– Description of the necessary equipment and / or technical requirements for implementation of the protocol
– Documents certifying the available technical possibilities for implementation of the protocol
– Permit for carrying out medical activity under Art. 47, para. 1 of the PPA / registration certificate under Art. 40, para. 1 of the Health Insurance Act for the medical institution – center of the non-interventional research.
6. Financing and Administrative Organization of the Study:
– Insurance
– Contract between the sponsor and the medical institution
– Contract between the sponsor and the researcher
– Data on the source of funding of the study, when the contracting authority is a non-profit legal entity
– Documentation that the fee has been paid = 400 BGN
Substantial Amendments[5][*]:
1. Application form^^
2. Cover letter
3. Summary of the planned change
4. List of the updated documents
5. The updated documentation reflecting the changes
6. Pages from the documentation with marked changes, comparing the current and the new texts
7. Justification of the changes
8. Documentation that the fee has been paid = 120 BGN
9. A copy of the positive opinion of the ethics committee, when it becomes available.
* Both the BDA and ECKI need to approve any substantial amendments: https://iisda.government.bg/adm_services/services/service_provision/6858
^ NIS Application Form: https://iisda.government.bg/adm_services/service_sample_file/6844_76240
^^ NIS Substantial Amendment Application Form: https://iisda.government.bg/adm_services/service_sample_file/6858_76336
References
1. Article 145(1) of the Medicinal Products in Human Medicine Act (ZLPHM)
Link: https://www.bda.bg/images/stories/documents/legal_acts/20210208_ZLPHM_English.pdf
2. Bulgarian Drug Agency (BDA)
Link: https://www.bda.bg/bg/
3. Ethical Commission for Clinical Trials (ECKI)
Link: https://www.bda.bg/bg/%d0%b7%d0%b0-%d0%b8%d0%b0%d0%bb/%d0%b4%d1%80%d1%83%d0%b3%d0%b8-%d0%ba%d0%be%d0%bc%d0%b8%d1%81%d0%b8%d0%b8/67-cemi
4. BDA/ECKI – Approval of a Non-Interventional Study of a Medicinal Product
Link: https://iisda.government.bg/adm_services/services/service_provision/6844
5. BDA – Issuance of Approval for a Significant Change in a Non-Interventional Study
Link: https://iisda.government.bg/adm_services/services/service_provision/6858
Useful Resources:
ECKI – Issuance of an Opinion by the Ethics Committee for Clinical Trials for Making a Significant Change in a Clinical Trial or Non-Interventional Study
Link: https://iisda.government.bg/adm_services/services/service_provision/92971
NIS Ordinance – Ordinance № 8 of March 31, 2021 on the terms and conditions for conducting non-interventional studies of medicinal products on the territory of the Republic of Bulgaria
Link [Bulgarian]: https://www.bda.bg/images/stories/documents/regulations/naredbi/20210415/%D0%9D%D0%90%D0%A0%D0%95%D0%94%D0%91%D0%90%20%E2%84%96%208%20%D0%9E%D0%A2%2031%20%D0%9C%D0%90%D0%A0%D0%A2%202021%20%D0%93..pdf
Link [English]: https://nis-regs.com/wp-content/uploads/2021/06/NIS-Ordinance-2021.pdf
Medicinal Products in Human Medicine Act (ZLPHM)
Link: https://www.bda.bg/images/stories/documents/legal_acts/20210208_ZLPHM_English.pdf
Note1: Articles 81 to 144 = Clinical Trials
Note2: Article 145 = Non-interventional Studies.
Note3: Articles 183 to 194 = Pharmacovigilance
Guideline on good pharmacovigilance practices (GVP) – Module VIII Addendum I – Requirements and recommendations for the submission of information on non-interventional post-authorisation safety studies (Rev 3) (EMA/395730/2012 Rev 3; 15 June 2020)
Link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-addendum-i-requirements-recommendations_en-1.pdf
Insights | Real World Research in Mental Health
June 2021 – Mental health disorders remain the highest unmet medical need, surpassing cancer. One in four of us is affected by mental illness. That’s a friend, a partner, a child or maybe even you. Fortunately, health crises this prevalent attract large budgets and significant awareness campaigns.
Usually
In 2019, $3.7 billion was spent around the world researching mental health, which sounds big, but that is only 4% of total global health research. It’s too little, unchanging over time, and disproportionate to the burden of suffering attributable to mental health disorders globally.
It is also too inequitable, with less than 10% of funding being spent in countries that have 90% of global health problems. And more importantly it is too skewed, with more than 50% devoted to biological and aetiological research, and about 7% allocated to health services research, clinical research, and prevention[1]. We continue to chase a pharmaceutical solution to a human problem, with little sign of the kind of success seen in virtually any other disease.
And then came COVID-19. We now have a pandemic within a pandemic. Everywhere you look there is evidence of the massive impact on mental health that lockdowns, loss of loved ones, loss of jobs or just being on the front line of healthcare has had. In 2019, 8% of the US population thought mental health was the most important health issue, 13% thought it was cancer. In 2020 that flipped on its head – 13% now say it’s mental health and 9% say it’s cancer[2].
So, being realistic, mental health will never get the kind of funding that it deserves, so how can we make the most of what funding is available?
Researchers and scientists are expanding current approved therapeutics in new indications as well as looking at non-traditional technologies to help patients dealing with mental health issues and they are increasingly doing this by turning to real-world research (RWR) data. There is a significant opportunity to generate insights from real-world data on mental health disorders to get a much better understanding of the issues facing individuals on a day-to-day level and then to develop novel, scalable solutions to address this increasing burden.
RWR, when done properly, is a low-cost / high-quality alternative to traditional research. Improving mental health across the board needs to focus not just on pharmaceutical interventions. Strengthening the implementation of research evidence and good practice into a range of settings where people seek support is equally important.
A key part of enabling this will be to support mental health delivery staff to be research literate, encourage RWR at the front line and then making research findings accessible and relevant for local implementation. Unfortunately, within the clinical research world the experience and expertise required to deliver high quality real-world research lags behind randomised clinical trials in the same way mental health is the poor cousin to oncology. Developing systems and processes to ensure that money spent on RWR data in mental health carries the same reliability as randomised controlled trials (RCTs) will be equally important.
Although RCTs remain crucial for coverage and reimbursement decisions by payers, RWR can be employed to assess clinically meaningful endpoints, gauge the impact of interventions on the quality of healthcare, and help payers make appropriate data-driven decisions.
The future for mental health research may well be Real.
References:
1. Vikram Patel. Mental Health Research Funding: Too little, too inequitable, too skewed
Lancet, Volume 8, Issue 3, P171-172, March 01, 2021
Link: https://www.thelancet.com/journals/lancet/article/PIIS2215-0366(20)30471-5/fulltext
2. America Speaks – Survey data reflecting the views of Americans on medical, health, and scientific research. Poll Data Summary, Volume 20.
Link: https://www.researchamerica.org/sites/default/files/PollDataSummary_vol20.pdf
Insights | EU – Quality Standards for Registry Studies
31 AUGUST 2021 – According to a recent US FDA presentation (May 2021)[1]:
“Quality RWE can’t be Built without Quality RWD”
As noted in the National Guidelines for Data Quality in Surveys[2] published in August 2021 by the ICMR-National Institute of Medical Statistics (ICMR-NIMS)[3]:
“There is an impending need…for data quality guidelines to improve the quality of data that promotes evidence-based decision making”
In September 2020, the EMA published a [draft] checklist[4] for evaluating the suitability of registries for registry-based studies. The list is adapted from the REQueST[5] tool published by EUnetHTA[6].
Why is this important?
This is one of the first quality standards [data quality guidelines] published by the EMA that specifically addresses the quality expectations of real world data sources (i.e., disease registries) used to generate real world evidence (RWE) for regulatory purposes.
According to the EMA[7], the use of a registry-based study for a regulatory purpose depends on many factors related to its relevance to answer a specific research question, the characteristics of the concerned registry, the quality of the data collected and the design and analytical plan of the proposed study.
The tool has been developed to be a comprehensive resource that covers all important aspects relating to the quality of registries. The standards set out in the tool are universal and essential elements of good practice and evidence quality that are, therefore, relevant for different types of registries.
Examples of where registry-based studies may be useful for evidence generation[7]:
- To supplement the evidence generated in the pre-authorisation phase
- To provide data sources or infrastructure for post-authorisation evidence generation
- To evaluate the effects of medications received during pregnancy
Things to assess, be aware of, or consider when assessing the suitability of a patient registry for a registry-based study, include:
1. Administrative information
1.1. Governance for collaborations
– Publicly available documentation (with website) of key registry characteristics
– Single contact point for information
– Publicly available policy for collaborations with external organisations
– Governance structure for decision-making on requests for collaboration
– Supportive scientific and technical function
– Supportive function for ethical and legal aspects
– Template for research contracts between the registry and external organisations
1.2. Data privacy
– Status of implementation of GDPR
– Informed consent form and its validity for registry-based studies (or need for re-consent)
1.3. Funding
– Funding sources and impact on short, long-term sustainability and possible conflicts of interest for a specific registry-based study
2. Methods
2.1. Objectives
Purpose of the data collection system, which may influence the main characteristics of the registry population and the data collected
2.2. Data providers
– Adequate description of data providers, such as patients, carers or health care professionals (with different specialties), their geographical area and any selection process (inclusion and exclusion criteria) that may be applied for their acceptance as data providers
2.3. Patient population covered
– Adequate description of the type of patient registry (disease, condition, time period covered, procedure), which defines the criteria for patient eligibility
– Relevance of setting and catchment area
– Clarity on patients’ inclusion and exclusion criteria
– Methods applied to minimise selection bias and loss to follow-up
– Numbers of patients available in the registry (total number and number of eligible patients if applicable), numbers of new patients entering the registry per year, numbers of patients lost per year (with reasons for exit)
– Mean/median duration of follow-up per patient, person-time of exposure in defined categories, if applicable
2.4. Data elements
– Core data set collected from patients by all centres; optional data set
– Definition, dictionary and format of data elements
– Standards and terminologies applied
– Capabilities and plans for amendments of data elements
2.5. Infrastructure
– Systems for data collection, recording and reporting, including timelines
– Capability (and experience) for expedited reporting and evaluation (at physician or registry level) of severe suspected adverse reactions in primary data collection
– Capability (and experience) for periodic reporting of clinical outcomes and adverse events reported by physicians, at individual-patient level and aggregated data level
– Capability (and experience) for data cleaning, extraction, transformation and analysis
– Capability (and experience) for data transfer to external organisations
– Capabilities for amendment of safety reporting processes
2.6. Quality requirements
– Processes in place for quality planning, control, assurance and improvement
– Data verification (method and frequency of verification)
– Missing data (statistics, trends, variables affected, management)
– Auditing practice
What’s Next?
The 2021-2023 HMA-EMA joint Big Data Steering Group (BDSG) have published their ‘2021 – 2023 Workplan’.
Milestones to be aware of, include:
- Publication of Registries Guidance (November 2021)
- Roadmap for RWE Guidance Agreed (April 2022)
- EMA Draft Q&A on Secondary Use of Health Care Data and Data Protection (December 2021)
References
1. The FDA Real-World Evidence (RWE) Framework and Considerations for Use in Regulatory Decision-Making. Jacqueline Corrigan-Curay, JD, MD. Meeting of the Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee May 12, 2021
Link: https://www.fda.gov/media/148543/download
2. ICMR-National Institute of Medical Statistics (ICMR-NIMS)
Link: http://icmr-nims.nic.in/
3. National Guidelines for Data Quality in Surveys. ICMR-National Institute of Medical Statistics, New Delhi. July 2021
Link: https://main.icmr.nic.in/sites/default/files/upload_documents/National_Guidelines_for_DATA_QUALITY_in_Surveys.pdf
4. Appendix 3 of [DRAFT] EMA Guideline on Registry-Based Studies (EMA/502388/2020) (24 September 2020)
Link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-registry-based-studies_en.pdf
5. REQueST = Registry Evaluation and Quality Standards Tool (REQueST)
Link: https://www.eunethta.eu/request-tool-and-its-vision-paper/
6. EUnetHTA – European Network for Health Technology Assessment
Link: https://www.eunethta.eu/
7. Section 3.1 of [DRAFT] EMA Guideline on Registry-Based Studies (EMA/502388/2020) (24 September 2020)
Link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-registry-based-studies_en.pdf
8. Section 1 of the [DRAFT] EMA Guideline on Registry-Based Studies (EMA/502388/2020) (24 September 2020)
Link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-registry-based-studies_en.pdf
