Regulatory Guidance for Literature Based Support of Efficacy and Safety of Medicines

​​API   Active Pharmaceutical Ingredient

eCTD   electronic Common Technical Document

EMA   European Medicines Agency

FDA   Food and Drug Administration

GCC   Gulf Cooperation Council 

GRADE   Grading of Recommendations, Assessment, Development, and Evaluations

KAS   Known active substance

LBS   Literature-based submission 

MeSH   Medical Subject Headings

MHRA   Medicines and Healthcare products Regulatory Agency

NCE   New Chemical Entity 

PMDA  Pharmaceuticals and Medical Devices Agency

SFDA  Saudi Food & Drug Authority

SRA  Stringent Regulatory Authority

Swissmedic  Swiss Agency for Therapeutic Products

TGA  Therapeutic Goods Administration​

Active Pharmaceutical Ingredient (API)   A substance in a drug that is responsible for its therapeutic effect.

Applicant   Drug applicant refers to an individual, organization, or entity that submits the drug application to SFDA for approval to market a new drug or a drug with a new indication.

Common Technical Document (CTD)   An international harmonized format for submissions for approval of pharmaceuticals. The CTD provides a standardization of the presentation of the content.

Generic product   A product created to be equivalent to the innovative / brand name product in dosage form, strength, route of administration, quality, performance characteristics and therapeutic indication(s). A drug application will be considered as generic if the innovative product is registered in one of the SRA irrespective of whether the innovative product is registered or not at SFDA.

Grading of Recommendations, Assessment, Development, and Evaluations (GRADE)    A systematic approach is used to assess the quality of evidence and strength of recommendations in clinical practice guidelines and systematic reviews. It ensures that recommendations are based on the best available evidence and presented in a transparent and consistent manner.

Inquiry    A questions or clarifications submitted through the SDR system to be answered by the applicant.

Known active substance    A new dosage form, strength, route of administration or indication of an active ingredient already marketed in Saudi Arabia.

Literature review or literature-based submission   It is a scholarly assessment of existing research and publications on a specific topic or research question. It involves systematically gathering, evaluating, and synthesizing relevant studies, theories, and findings to offer a comprehensive overview of the current understanding in the field.

Medical Subject Headings (MeSH)   It is a controlled vocabulary system used by the National Library of Medicine (NLM) to index and catalog biomedical and health-related information. index and catalog biomedical and health-related information. It is designed to facilitate the effective searching and retrieval of relevant information from databases such as PubMed.

Marketing Authorization Applications (MAAs)  A formal submission made by pharmaceutical companies to regulatory authorities seeking approval to market a new medicinal product. 

New chemical entity (NCE)  A product that includes new chemical entity and introduced by the innovator company (or the partner).

Reference product An approved drug product that serves as the standard for comparison when assessing new drug products. It provides a benchmark to ensure that new drugs, such as generics, are equivalent in terms of safety, efficacy, and quality.

Stringent Regulatory Authority (SRA)  A regulatory body that enforces stringent requirements for the approval and monitoring of medical products and practices USFDA, EMA, MHRA (UK), Swissmedic, Health Canada, TGA (Australia), and PMDA (Japan).​

The evaluation process for marketing authorization applications (MAAs) relies on the quality of the submitted clinical data. Upon receiving the MAA, the SFDA conducts an initial validation to ensure the completeness of the application and its adherence to regulatory requirements. The application then undergoes a thorough review by regulatory reviewers, who analyze the scientific data and documentation to assess the product's safety, efficacy, and quality. To obtain marketing authorization for new medicines, it is required to demonstrate a favorable benefit-risk profile through clinical studies, as outlined by SFDA related documents. Typically, these studies are sponsored by the applicant. However, in cases where applicant-sponsored trials are unavailable, the SFDA may accept literature references to these trials. This applies to:

• New generic applications when the reference product is not registered by the SFDA.

• New drug applications for known active substance (KAS).

If the submission is incomplete or requires further clarification, the applicant is expected to thoroughly analyze any literature-based inquiries that arise and address all aspects clearly, concisely, accurately, and ensuring that the required data is incorporated into the appropriate eCTD application. Meeting regulatory requirements helps avoid unnecessary delays and facilitates better regulatory decisions. 

1.1. Purpose

This guidance aims to standardize and improve the quality of clinical data for literature review-based submissions.

1.2. Scope

This guidance assists applicant on the required clinical data for generic (multisource) products and known active substance, when the reference innovator is not registered by the SFDA. It also encompasses the need for applicants to provide justification for any technical claims made in their clinical development program.

1.3. Related documents

This document should be read in conjunction with the following Drug Sector documents:

- Data Requirements for Human Drugs Submission

- Clinical Considerations for Efficacy and Safety

- Regulatory Framework for Drugs Approval

- Guidelines for Bioequivalence ​

​2.1. Pre-submission meeting [1]

The applicant is advised to request a meeting three months prior to submission to discuss the literature-based submission in term of: 

- Rational behind submitting this application:

o Objective of the submission; new drug approval, new indication … etc

o Outline the anticipated benefits; improvements in patient outcomes, advancements in treatment, address unmet medical needs

- Type of medicinal product (new, generic, known active substance) 

- Clinical data requirements 

- Literature search methodology

2.2. Clinical data requirements 

The data must be submitted in accordance with the eCTD structure. The clinical data requirements for each application varies based on the product type: 

2.2.1. Generic products (whether active pharmaceutical ingredient (API) is registered or not, the applicant must refer to SFDA bioequivalence guideline).

- For new generic product of an SFDA registered reference product: refer to the SFDA bioequivalence guideline on the SFDA website.  

- For new generic product of a non-SFDA registered reference product: The required data for literature-based submissions (LBS) varies depending on the worldwide registration status of the reference and/or generic products, as detailed in Table 1: 

2.2.2. Known active substance product (known as active pharmaceutical ingredients) is a drug product containing active pharmaceutical product that is already marketed in Saudi Arabia in a different dosage form, strength or therapeutic indication, the data requirements for these products may vary based on several factors. Therefore, the SFDA will assess each case individually and determine whether literature-based submission is sufficient to confirm the medicinal product's efficacy and safety or if additional clinical data (e.g. company sponsored trials) are necessary. 

The applicants must fill the table in Appendix 1, which should include a summary report of the Clinical Overview that encompasses:

* Clinical development program (if any) 

* Literature search methodology 

* Tabular listing of recent studies 

* Efficacy and safety study results 

* List of relevant literature references.

[1] To schedule a formal meeting with the Drug Sector, please adhere to the outlined 'Requirements for Formal Meeting between Drug Sector and Applicants'​

​literature search strategy involves a structured approach to finding relevant research and information on a specific topic. 

The key components of a literature search strategy are:

3.1. Formulate the question

* Using PICO which is a specialized framework to formulate a research question and to facilitate literature review. It consists of four components:

* P: Patients, Populations or Problems. What are the characteristics of patient or population? 

* I: Intervention. Is it therapeutic, diagnostic, or experimental intervention?

* C: Comparison. What is the alternative to intervention?

* O: Outcome. What are the relevant outcomes?

3.2. Search the literature

* Identify relevant database using PubMed (a free online search engine which support the search and retrieval of literature from MEDLINE)

* Subject searching/MeSH terms using ANDOR (also known as Boolean operators). Use limits/filters provided

* Keep a record of the keywords and methods used in searching (for describing how the search was conducted) 

3.3. Screen for inclusion

* Review abstracts to decide their relevance to the research question then obtain the full-text article for quality assessment.

3.4. Assess quality of evidence

* Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) Working Group which is a set of evidence-based criteria to grade the quality of evidence. GRADE considers study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias. For more details, see Appendix 2.

3.5. Extract, analyze and report data

* The Cochrane Handbook for Systematic Reviews of Interventions is a comprehensive guide designed to assist in the process of conducting systematic reviews, including data extraction, analysis, and reporting. 

A. Data extraction: it involves systematically gathering relevant information from included studies to ensure accurate and consistent data collection. 

* Steps for data extraction:

* Create a standardized form to collect necessary data from each study.

- Document information such as the study design, participant demographics, details of the intervention and comparator, and outcome measures.

- Extract data on primary and secondary outcomes, including effect sizes, confidence intervals, and any measures of variability or heterogeneity.

- Identify any reported biases in the studies and gather pertinent information on bias assessments.

- Ensure that at least two reviewers independently extract the data to reduce errors, and address any discrepancies through discussion.

B. Data analysis: it involves synthesizing and interpreting the extracted data to provide evidence that supports decision-making.

- Steps for data analysis:

* Assess risk of bias by apply tools such as the Cochrane Risk of Bias Tool 2 for randomized controlled trials and the Robinson tool for non-randomized controlled trials. 

* Conduct meta-analysis if appropriate, using statistical methods to combine data from multiple studies. If not applicable (due to reasons such as a limited number of studies reporting the same outcome, low study quality, etc.), then the data may be systematically summarized.

C. Reporting data: it involves presenting the findings of the systematic review in a clear and structured manner to enhance comprehension and practical application.

- Steps for reporting:

* Structure the literature review to include introduction, methods, results, discussion, and conclusion.

* Arrange the identified literature with their citations in a tabular listing as follows: 

o Start with the key clinical studies (e.g. confirmatory studies).

o Prioritize well-designed studies that are adequately powered and, ideally, multicenter. If a meta-analysis was performed, please complete the table in Appendix 3.

o Include studies with registered protocols or those listed in clinical trials registries (indicate their registration status)

o Place evidence from non-randomized controlled trials in a separate section of the table.

o Clinical study reports for each identified study, if possible.

​​To be completed in case of meta-analysis provided by the applicant: ​

• 1. ICH E3 Structure and content of clinical study reports

• 2. ICH guideline M4 (R4) on common technical document (CTD) for the registration of pharmaceuticals for human use

• 3. Pre-submission guidance for literature-based submissions (LBS) | Therapeutic Goods Administration (TGA)

• 4. Dossier requirements for literature based submissions | Therapeutic Goods Administration (TGA)

• 5. Systematic literature searches for literature based submissions | Therapeutic Goods Administration (TGA)

• 6. Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). Health Canada

• 7. Guidance Document: Authorization of human medicinal product with known active substance \ SwissMedic

• 8. Guidance on Conducting a Systematic Literature Review - Yu Xiao, Maria Watson, 2019 (sagepub.com)

• 9. GRADE handbook (gradepro.org)

• 10. Cochrane Handbook for Systematic Reviews of Interventions | Cochrane Training

• 11. RoB 2: A revised Cochrane risk-of-bias tool for randomized trials | Cochrane Bias

• 12. ​ROBINS-I | Cochrane Bias​