# Guidances for statistics in regulatory affairs

Guidances for statistics in regulatory affairs refers to specific documents or guidelines that provide instructions, recommendations, and standards pertaining to the application of statistical methodologies and practices within the regulatory framework of industries such as pharmaceuticals and medical devices. These guidances serve as a reference for statisticians, researchers, and professionals involved in designing, conducting, analyzing, and reporting studies and trials in compliance with regulatory requirements. These documents embody the prevailing perspectives of regulatory agencies on specific subjects. In the United States, the term "Guidances" is used, while in Europe, the term "Guidelines" is employed.
Regulatory affairs, alternatively referred to as government affairs, constitutes a profession within regulated sectors like pharmaceuticals and medical devices. Professionals, including statisticians, in these fields are expected to incorporate regulatory guidance into their work practices.
Statisticians operating in regulated environments, such as the pharmaceutical and healthcare industries, are required to possess a comprehensive understanding of the regulatory requirements influencing the design, execution, analysis, and reporting of their studies.
Regulatory guidance pertinent to the pharmaceutical and medical devices industries can be found at both international and regional/national levels. Examples of regulatory bodies include the European Medicines Agency (EMA) in Europe, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom, the Institute for Quality and Efficiency in Health Care (IQWiG) in Germany, the Food and Drug Administration (FDA) in the United States, and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.
Additionally, statistical regulatory guidance is available for general topics such as Good Clinical Practice (ICH E6(R2)), as well as specific areas explicitly related to statistics, such as Statistical Principles for Clinical Trials (ICH E9), and some indirectly related areas like Special Populations: Geriatrics (ICH E7) or Clinical Trial Endpoints in Oncology (FDA). The extensive array of regulatory guidance, encompassing both draft and final versions, undergoes periodic revisions. Consequently, users of these guidance documents are advised to consult the original websites to access the most up-to-date versions.

## History

Regulation in the United States had its origins in 1906 with the enactment of the Food and Drugs Act. This initial step towards regulatory oversight was further strengthened in 1938 with the implementation of the Federal Food, Drug, and Cosmetic Act, prompted by the tragic incident involving Elixir sulfanilamide in 1937, which led to numerous fatalities.
Another pivotal event that underscored the need for stricter regulations was the Thalidomide catastrophe. In 1957, Thalidomide was introduced in Germany without undergoing adequate testing, resulting in significant harm. This incident heightened regulatory pressures, prompting the United States to pass the Kefauver Harris Amendment in 1962 as an amendment to the Federal Food, Drug, and Cosmetic Act. Simultaneously, the United Kingdom introduced the "Medicines Act 1968" as a response within the European region.
These developments marked the emergence of a substantial body of regulatory guidelines. In the United States, the Food and Drug Administration (FDA) issued a multitude of regulatory "guidances," while the European Medicines Agency (EMA) released corresponding "guidelines" for Europe. Other regions of the world, such as Japan, also established their own regulatory guidance through institutions like the Pharmaceuticals and Medical Devices Agency (PMDA).
Recognizing the importance of harmonization across different regulatory systems, a plan was initiated in 1989 to align guidance standards in Europe, Japan, and the United States. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) held its inaugural meeting in 1990 in Brussels, representing a significant step towards international collaboration and standardization.
In the realm of Health Technology Assessment (HTA), numerous national guidance papers have been produced by respective HTA organizations across different countries. Notable examples include the Institute for Quality and Efficiency in Health Care (IQWiG) in Germany, the National Institute for Health and Care Excellence (NICE) in the United Kingdom, the Agency for Healthcare Research and Quality (AHRQ) in the United States, and the Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada. These organizations have provided valuable guidance to assist in evaluating the applications of health technologies.
In Europe, a collaborative effort led to the establishment of the European Network for Health Technology Assessment (EUnetHTA) in 2005. The primary objective of EUnetHTA is to create an efficient and sustainable network among European HTA organizations, fostering collaboration and knowledge sharing. As part of their work, EUnetHTA has developed guidelines known as EUnetHTA Guidelines. These guidelines serve as a resource to aid assessors in the processing, analysis, and interpretation of relevant data in HTA assessments.

## General Guidance

General guidance covers statistical topics that relate to good clinical practice: study design, monitoring and reporting, and market authorization of medical products or medical devices.

### Good Clinical Practice

Good Clinical Practice (GCP) is a globally recognized standard that upholds ethical principles and scientific rigor in the design, conduct, documentation, and reporting of clinical trials involving human subjects. It was developed and issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) under the Good Clinical Practice Directive (Directive 2005/28/EC) on April 8, 2005. This directive provides guidelines for ensuring the highest standards of quality and integrity in clinical research.
In the European Union, a parallel guideline exists for clinical trials involving medical devices. This guideline is known as the international standard ISO 14155, and it serves as a harmonized standard within the European Union. It aligns with GCP principles and provides guidance specific to clinical trials involving medical devices.
Adherence to the GCP standard offers reassurance to the public by ensuring the protection of the rights, safety, and well-being of individuals participating in clinical trials. It also ensures that the clinical trial data generated are credible and reliable. These principles are rooted in the Declaration of Helsinki, which forms the foundation for ethical considerations in medical research.
By adhering to GCP, researchers, sponsors, and regulatory bodies demonstrate their commitment to conducting clinical trials in an ethical manner and generating reliable data. This adherence promotes public trust and confidence in the research process and contributes to the advancement of medical knowledge and the development of safe and effective treatments.