Regulation of Human Medicines

The purpose of this page is to give an overview of the regulatory landscape for human medicines in Australia and other countries with which Australia closely aligns its regulatory approach. It is not intended as legal advice and is intended solely to provide guidance materials to aid the human medicine industry to replace or reduce the use of animals in the regulatory setting. For specific regulatory questions, please contact the regulator in your country of operation.  Please note that this is a rapidly evolving field and this page compiles information relevant at the point of publication. 

Background key points: 

• The Therapeutic Goods Administration (TGA) is the regulator in Australia.  
• The TGA is part of the Health Products Regulation Group (HPRG), which comprises the TGA and the Office of Drug Control. 
• Australia aligns primarily its regulatory approach with the European Union (EU), the International Committee on Harmonization (ICH), and the United States Food and Drug Administration (US FDA) through the adoption of its international guidelines.  
• The TGA has mutual recognition agreements with Europe, the United Kingdom, Canada, New Zealand, and Singapore.
• Australia has a cooperative agreement with the US FDA 
• The TGA is an observer of the ICH. 
• The TGA is legislated primarily through the Therapeutic Goods Act (1989), Therapeutic Goods Regulations (1990), and through Therapeutic Goods Orders, via the Therapeutic Goods Act 1989 (Chapter 3, Part 3-1, 10 Determination of Standards, (1)).
• International scientific guidelines are adopted by the TGA

Legislation in Australia surrounding the use of animals in regulatory settings:

Whilst the TGA Act (1989) does not mandate animal testing, animal test data may be a condition of approval as implied by guidelines falling under this Act. Whilst most guidelines are subordinate to the Act, the M4 (safety) guidance sets a legislative requirement for mandatory requirements for an effective application.

This means applicants must “include such information as will allow the determination (preliminary assessment) of the application” and;

“Applications referred to in regulation 16C of the Regulations (including, Category 1 and Comparable Overseas Regulator (COR) report-based applications for new registrations, other than applications for an additional trade name) must comply with the following regulatory documents”

The M4 (safety) guideline states that “If alternatives to whole-animal experiments are employed, their scientific validity should be discussed.” This implies that whole animals should be used, and scientifically valid alternatives will be considered.

Guidelines that discuss scientific validity of alternative approaches that have been accepted by the TGA include:

PBPK guidelines

Guidelines

Guidelines (other than the M4) are not legislated but they are strongly encouraged to be followed. 

Guidelines may explicitly state that alternatives can be considered, for example:

ICH guideline S6 (R1) – preclinical safety evaluation of
biotechnology-derived pharmaceutica

In the above guideline, section 4.1 (Safety Pharmacology), it states that “investigations may also include the use of isolated organs or other test systems not involving intact animals.”

Australia and the Australian Therapeutic Goods Administration have the following facilities and strategies which can decrease the use of animals and support the use of alternatives to animal use:

1. The ability to adopt international guidelines.
   – International guidelines which the TGA have adopted can be found generally here though the search function: 
   – Guidelines which the TGA could adopt to reduce or replace the use of animals in alignment with the EMA review are here (please note some may already be adopted).  Additionally, some are recommended through the European Federation of Pharmaceutical Industries and Associations in their webinar.
2. The publication of AusPars through the transparency agreement in the Therapeutic Goods Act (1989). An AusPar is an overview of the drug sponsors application which can provide insight into which non-animal models were used, or which animal tests were not justified.
3. AusPar falls under the TGA Act (1989), Volume 2, Chapter 7, section 61, 5A section 61 “release of information”. The Secretary may release to the public therapeutic goods information relating to any decision or action taken under this Act or the regulations.”
4. A regulatory science strategy published by the Health Products Regulation Group (HPRG): 
   a. The strategy focused on four key areas:
   i. Maintain and build skills in regulatory science
   ii. Improve domestic and international collaboration with other government agencies, scientific organisations and regulators
   iii. Increase responsiveness to emerging technologies
   iv. Improve communication and engagement with stakeholders about regulatory science.
5. A non-animal models strategy published by the Commonwealth Scientific and Industrial Research Organisation (CSIRO) making the following recommendations: 1) Establish a national consortium that coordinates and promotes Australia’s non-animal model capabilities, 2) Develop national data collection standards on the use of animals in scientific research, teaching, and testing, 3) Align TGA processes and industry guidance with new FDA procedures for accepting non-animal model data, 4) Develop a national biobanking and tissue collection network, 5) Integrate outputs from NCRIS platforms into a coordinated pipeline for non-animal models, 6) Facilitate IP (intellectual property) management and material access for research and industry collaborations, 7) Enhance commercial skillsets across the non-animal model sector, 8) Update biomedical R&D infrastructure to support non-animal model capabilities, 9) Conduct retrospective studies that compare animal and non-animal model predictivity, 10) Conduct systematic reviews of locally and internationally developed non-animal models

The Australian Government Department of Health and Aged Care also published a Scoping Report Towards alternatives to animal testing of industrial chemicals in Australia which has some crossover with medical products. 

Background Key Points 

• The European Medicines Agency (EMA) is an agency of the European Union (EU) and is the main regulator in Europe
• The European Commission is the executive of the European Union and the European Commission is a founding regulatory member of the International Committee for Harmonization
• EU pharmaceutical legislation comprises directives, regulations, and non-legislative acts.
• The legislation is supported by guidelines 
• The European Commission has established the European Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM). EURL ECVAM is an integral part of the Joint Research Centre (JRC), the science and knowledge service of the European Commission. 
• EURL ECVAM has established the Scientific Advisory Committee (ESAC)  
• ECVAM has launched a series of studies to review available and emerging non-animal models being used for research in seven disease areas
• EURL ECVAM is part of the International Cooperation on Alternative Test Methods (ICATM)

The European Union and the European Medicines Agency have taken the following actions which can reduce the use of animals and support the use of alternatives to animal use: 

1. Published an EU regulatory strategy to 2025.
2. Conducted a review of all international guidelines so that EMA documents should not make reference to animal testing that is no longer considered appropriate.   
3. Enacted a supportive legislation motion
4. Enacted Directive 2010/63. Particularly: “(10) While it is desirable to replace the use of live animals in procedures by other methods not entailing the use of live animals, the use of live animals continues to be necessary to protect human and animal health and the environment. However, this Directive represents an important step towards achieving the final goal of full replacement of procedures on live animals for scientific and educational purposes as soon as it is scientifically possible to do so. To that end, it seeks to facilitate and promote the advancement of alternative approaches. It also seeks to ensure a high level of protection for animals that still need to be used in procedures. This Directive should be reviewed regularly in light of evolving science and animal-protection measures”  
5. Established an Innovation Task Force in 2014  
6. Established a Tracking System for Alternative methods towards Regulatory acceptance 
7. Provision of guidelines for regulatory acceptance of 3Rs testing approaches: and concept paper in development 

Background Key Points 

• The United States Food and Drug Administration (FDA) is the regulator in the United States  
• The FDA is a founding regulatory member of the International Council on Harmonization (ICH)   
• US pharmaceutical legislation includes the FDA Re-authorization Act (2017) and the 21st Century Cures Act (2021).
• The Interagency Coordinating Committee on the Validation of Alternative Methods (ICVAAM) was set up with the ICVAAM Authorization Act 2000, whose aim is: “To establish, wherever feasible, guidelines, recommendations, and regulations that promote the regulatory acceptance of new or revised scientifically valid toxicological tests that protect human and animal health and the environment while reducing, refining, or replacing animal tests and ensuring human safety and product effectiveness” 
• ICVAAM is supported by the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) 
• ICVAAM has established a Scientific Advisory Committee (SACTM)  
• ICVAAM has established working groups
• The FDA is a member agency of ICVAAM
• ICVAAM is part of the International Cooperation on Alternative Test Methods (ICATM)   

The United States and the United States Food and Drug Administration have taken the following actions which can decrease the use of animals and support the use of alternatives to animal use:

• Published A Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of Chemicals and Medical Products in the United States   
• Through this process, a registry of alternative methods that have been accepted is available.  
• Established the “Innovative Science and Technology Approaches for New Drugs (ISTAND)” program for the inclusion of new approach methods and digital technologies in sponsor applications.   
• Through ISTAND the drug development tool search is available for successful applications;   
• Enacted supportive legislation through the FDA Modernization Act 2.0. In Section 3209 (Animal Testing Alternatives) of the Consolidated Appropriations Act 2023, the FDA Modernization Act 2.0 amends Section 505 of the Federal Food, Drug, and Cosmetic Act, which mandates animal toxicity testing of novel drugs prior to their deployment in human subjects in the course of clinical trials. Specifically, changes include, 1) substituting the term “nonclinical tests” for the current “preclinical tests” (including tests on animals), 2) substituting the term “animal” for “nonclinical tests” and, 3) adding a new section defining “nonclinical tests” where “the term ‘nonclinical test’ means a test conducted in vitro, in silico, or in chemico, or a nonhuman in vivo test, that occurs before or during the clinical trial phase of the investigation of the safety and effectiveness of a drug. Such tests may include the following:(1) Cell-based assays.(2) Organ chips and microphysiological systems.(3) Computer modeling.(4) Other nonhuman or human biology-based test methods, such as bioprinting.(5) Animal tests.”
• Provided the Medical Device Development Tools (MDDT) program: “a way for the FDA to qualify tools that medical device sponsors can choose to use in the development and evaluation of medical devices” 

• The US Environmental Protection Agency has published a New Approaches Work Methods Work Plan which has some crossover with medical products. 

New Drugs and Clinical Trial Rules (2023) has been passed by the Government of India which aims to replace the use of animals in research, especially in drug testing.

The amendment authorises researchers to instead use non-animal and human-relevant methods, including technologies like 3D organoids, organs-on-chip, and advanced computational methods, to test the safety and efficacy of new drugs.
These rules mandate that any CRO conducting a clinical trial or bioavailability/bioequivalence study of new drugs or investigational drugs in human subjects must obtain registration from the Central Licensing Authority before conducting any such studies.

In South Korea, two bills were introduced at the National Assembly; the Act on the Promotion of Development, Dissemination and Use of Alternatives to Animal Testing Methods (PAAM Act), sponsored by Assembly member In-Soon Nam in 2020, and the Act on the Vitalization of Development, Dissemination, and Use of Alternatives to Animal Testing Methods (VAAM Act), sponsored by Assembly member Jeoung Ae Han in 2022.

The Korean Center for the Validation of Alternative Methods (KoCVAM) has been operated within the Ministry of Food and Drug Safety (MFDS) since 2009 in order to introduce alternative test methods or new approach methodologies (NAMs) in safety assessment and to support the promotion and utilisation of NAMs. Read the MFDS NAMs report here. 

Specific testing guidelines or agreements that are required in the regulatory setting:

• The OECD Guidelines are the internationally agreed testing methods that are primarily used in regulatory safety testing and subsequent chemical notification and registration 
• Under Mutual Acceptance of Data principle, OECD countries and full adherents have agreed that a safety test carried out in accordance with the OECD Test Guidelines and Principles of Good Laboratory Practice in one OECD country must be accepted by other OECD countries for assessment purposes.
• OECD supports Integrated approaches to testing and assessment (IATA).
• IATA combine multiple sources of information to conclude on the toxicity of chemicals, and this information is generated by new technologies and methods, such as in silico, in chemico and in vitro approaches, that reduce the need for animal testing, enabling toxicity testing that is faster, less expensive, and more relevant to human responses than traditional toxicity testing methods
• IATAs are increasingly based on methods that measure or predict key events from Adverse outcome pathways (AOPs) relevant to the biological effect of interest
• AOPs are “an analytical construct that describes a sequential chain of causally linked events at different levels of biological organisation that lead to an adverse health or ecotoxicological effect. AOPs are the central element of a toxicological knowledge framework being built to support chemical risk assessment based on mechanistic reasoning.” 
• The OECD  knowledge base and tools such as the AOP wikipedia which is a collaborative effort between the EU JRC and the US Environmental Protection Agency
• The OECD has a series of educational webinars to promote knowledge sharing on emerging science to chemical safety testing 
• The international Council for Animal Protection in OECD programs publishes a list of all globally harmonised non-animal methods
• WHO Guidelines for Biologicals are available here.
• Read a NCRSs Review of animal use requirements in WHO biologics guidelines | NC3Rs

ISO Standards

ISO Standards for Medical Devices can be viewed here. 

The following are New Approach Methods, technologies, or guidance’s that can help reduce or replace animal use and have been considered at the regulatory level:

EMA

1. Methods available on the TSAR – Tracking System for Alternative methods towards Regulatory acceptance
2. Computational methods such as Quantitative Structure Activity Relationship, Grouping and read-across and Physiologically Based Pharmacokinetics (PBK). The Virtual second species is an example of the use of PBPK modelling that can reduce the use of animals in testing.
3. PBPK guidance for industry has been developed by the EMA.

US FDA

• The USA FDA uses the TSAR – Tracking System for Alternative methods towards Regulatory acceptance 
• Other computational methods and approaches are evaluated here 
• PBPK guidance has been reported by the FDA: 
• Computer modelling and simulation guidance has been provided for industry

The FDA has issued draft guidance to inform individuals and organizations interested in qualifying a Drug Development Tool (DDT) about the qualification process as outlined in the 21st Century Cures Act. For more information on FDA’s current thinking on the DDT qualification process please see here. Guidelines for the qualification process are here. 

Other methods/strategies that are commonly used which reduce animal studies:

• Preclinical systematic reviews 
• Integrated approaches to Testing and Assessment 
• Adverse Outcome Pathways approach 

The following resources have been produced by organisations which work to reduce animal testing in the regulatory setting:

• Webinar recording on how the pharmaceutical industry is working to avoid and replace the use of animals for scientific purposes
• Physicians Committee for Responsible Medicine (PCRM) New Approach Methodology (NAM) Use for Regulatory Application (NURA) education program 
• PCRM Dynamic discussions workshop recording
• Roche Institute of Human Biology
• Recordings from NC3Rs workshop on increasing confidence in NAMS for regulatory decision making. 

Drugs or therapeutics approved or advanced to clinical trials without reliance on animal test data:

• In January 2019, the regulator approved in-human clinical trials for a cancer therapy developed by Achilles Therapeutics whose application had not been supported by animal data. The therapy involved using a patients’ own immune cells to treat the cancer, rendering animal data particularly irrelevant
• French pharmaceutical group Sanofi receive approval from the US Food and Drug Administration for a clinical trial to extend approval of an existing drug to a new disease, a rare autoimmune condition, chronic inflammatory demyelinating polyneuropathy, or CIDP, on the basis of organ chip data alone.

• Israelis create cancer drug without animal tests, by using human-simulating chip | The Times of Israel

• CN Bio PhysioMimix Organ-on-a-Chip data supports Inipharm’s INI-822 for metabolic liver disease treatment now in clinical testing.

• Read case studies of new drug and biologic approvals by the FDA aided by PBBK. 

Further reading:

AI assisted medicine development 

A history of animal use in regulatory science what can we learn?

Medical Devices and regulatory testing

Replacing Animal Tests to Improve Safety for Humans
Kathy Archibald, Robert Coleman, Tamara Drake
Animal Experimentation: Working Towards a Paradigm Change, 2019, pp. 417-442 

Replacing Animal Tests to Improve Safety for Humans

Guidance Snapshot Pilot | FDA

UK Government confirms no legal requirement for animal testing in medical research – Animal Free Research UK and written response from UK Health Department.

Publications Co-authored by FDA on Alternative Methods | FDA

Legislation and Regulation – FRAME 

In addition to implementing the recommendations and key points of the CSIRO non-animal strategy and the MHRA regulatory strategy, Australia could:

• Establish the equivalent of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICVAAM) or European Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) and relevant scientific advisory committees
• Become an observer or member of the international cooperation on alternative test methods (ICATM)
• Create the equivalent of the innovation task force (EU) or the Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program (US)
• Enact supportive legislation where necessary
• Adopt supportive guidelines both to reduce the number of animals used and to increase the uptake of alternative methods with guidances for credibility or validity of method