- The Australian regulatory system ensures the safety, effectiveness and quality of biological medicines, including biosimilar medicines. The system addresses every step in medicine production and use.
- The Therapeutic Goods Administration (TGA) has adopted international guidelines from the European Medicines Agency that outline the quality, nonclinical and clinical data requirements for biosimilar medicines and the assessment of comparability.
- The TGA monitors the safety of all medicines, including biosimilar medicines, postmarket. Manufacturers are required to have a risk management plan in place before the medicine can be registered.
The Australian regulatory system ensures the safety, effectiveness and quality of all medicines, including biological and biosimilar medicines. The regulatory system is conducted by the Therapeutic Goods Administration (TGA), which is part of the Australian Government Department of Health.
The regulatory system addresses every step in medicine production and use:
- premarket assessment
- postmarket monitoring and enforcement of standards
- licensing of Australian manufacturers and verifying overseas manufacturers’ compliance with the same standards as their Australian counterparts.
Biological and biosimilar medicines are higher-risk medicines that are only supplied with a prescription. The TGA requires three types of data to assess prescription medicines:
- quality data
- composition of the drug substance
- batch consistency
- stability data
- sterility data (if applicable)
- the impurity content
- nonclinical data from laboratories
- pharmacology data
- toxicology data
- clinical data
- results from clinical trials.
These data, along with a plan to manage risk, are evaluated at the TGA by a group that includes doctors and other health professionals, scientists, and consumer representatives. The TGA is also able to seek advice from the Advisory Committee on the Safety of Medicines, which comprises experts in clinical medicine, pharmacoepidemiology, and pharmacy and consumer issues.
Once the TGA is satisfied that the benefits to patients outweigh any risks, the medicine can be registered for use in Australia.
As with all medicines in Australia, biosimilar medicines are rigorously evaluated by the TGA.
For a biosimilar medicine to be registered in Australia:
- the reference biological medicine must be a biological medicine that has been registered in Australia (or a similarly regulated country) based on full safety, effectiveness and quality data
- the reference biological medicine must have been marketed in Australia long enough for there to be a substantial body of acceptable data regarding its safety and effectiveness
- the similarity of the biosimilar medicine to the reference biological medicine need to be demonstrated through analytical, laboratory and clinical studies.
The scientific principles for establishing biosimilarity are the same as those for demonstrating comparability after a change in the manufacturing process of an already registered biological medicine.
The TGA has adopted international guidelines from the European Medicines Agency (EMA) that outline the quality, nonclinical and clinical data requirements for biosimilar medicines and the assessment of comparability. The European Union was the first region to set up a legal framework and regulatory pathway for the approval of biosimilar medicines, and the EMA assesses all applications for biological and biosimilar medicines. The EMA published its first regulatory guidelines in 2005, and has since developed overarching, product-specific, quality, clinical and nonclinical guidelines for biosimilar medicines, which are regularly updated.
On 16 December 2015, the TGA published on its website an updated version of the TGA guideline on biosimilars, the Regulation of biosimilar medicines. This guideline refers to a number of adopted European guidelines that outline the quality, nonclinical and clinical data requirements specific to biosimilar medicines.
The EMA guidelines used by the TGA include:
- quality guidelines
- Guideline on similar biological medicinal products, European Medicines Agency (2014)
- Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues, European Medicines Agency (2014)
- comparability guidelines
- clinical and nonclinical data guidelines
- Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: non-clinical and clinical issues, European Medicines Agency (2005)
- Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process: non-clinical and clinical issues, European Medicines Agency (2007)
- Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins, European Medicines Agency (2014)
- product-specific biosimilar guidelines
- Product-specific biosimilar guidelines detailing the clinical and safety data requirements, European Medicines Agency.
Once the TGA has approved a medicine, the pharmaceutical company may apply to the Pharmaceutical Benefits Advisory Committee (PBAC) to list their medicine on the Pharmaceutical Benefits Scheme (PBS). The PBS subsidises the costs of listed medicines to reduce the cost to patients. In deciding whether a medicine should be recommended for subsidy, the PBAC considers the patient benefits and cost-effectiveness of the medicine compared with alternative medicines
The PBAC will only recommend a biosimilar medicine for PBS listing if it is satisfied that it will deliver the same health outcomes as the reference biological medicine. The PBAC will also recommend to the Minister for Health whether a biosimilar medicine can be substituted for the reference biological medicine at the point of dispensing.
Further information about the PBAC process can be found on the PBS website.
Before any biological medicine is released to market, the manufacturer must develop a risk-management plan, which outlines how the manufacturer will further monitor and fill any gaps in the data regarding safety and efficacy once the medicine is released to market. This plan is assessed by the TGA as part of their approval assessment.
Once the medicine is on the market, the TGA continues to monitor its performance in terms of safety, effectiveness and quality, with a focus on adverse effects.
The TGA investigates all reports of adverse effects. Pharmaceutical companies are required to report any adverse events that they are aware of, and reports can also be made by health care professionals, consumers or carers.
The adverse reaction reports are placed in a database (the Australian Adverse Drug Reaction Reporting System), and the database is analysed regularly by scientific and medical staff at the TGA. TGA staff also analyse published literature. TGA reports are sent to the World Health Organization database of individual case safety reports (VigiBase®).
The TGA has several options if it discovers that there may be a risk to patients from any medicine. It can:
- require changes to product labelling, such as added warnings
- narrow the population in which the medicine can be used
- require the company to undertake postmarket studies
- take the medicine off the market.
The TGA sends out alerts and media articles to ensure that health professionals and the public are aware of any safety concerns and changes to the availability and recommended use of the medicine.
It is recommended that biological medicines including biosimilar medicines be prescribed and dispensed by both active ingredient name and the brand name.
-  Council of Australian Therapeutic Advisory Groups, Overseeing biosimilar use:www.catag.org.au/wp-content/uploads/2012/08/OKA10798-CATAG-Overseeing-biosimilar-use-Version-2-final.pdf
The TGA conducts ongoing monitoring of biological and biosimilar medicines after registration to ensure variability (drift) of the molecules is within the established acceptable ranges.
All newly registered biological medicines, including biosimilar medicines, will be placed on a batch or protocol release as a condition of registration. This includes:
- submitting release certification and shipping records for all batches
- submitting samples from batches for release that may be tested for compliance
- applying these conditions until satisfactory batch consistency has been demonstrated (usually at least five batches of unique medicine substance).
After the initial batch release phase is completed, the sponsor of the biological or biosimilar medicine is required to submit an annual report of all batches and provide samples to the TGA for testing in periodic product surveys
There are currently no consistent rules internationally around the naming of biological or biosimilar medicines. The current practice in Australia is similar to that of chemical medicines, in that the names of the various brands are different (e.g. Remicade®, Inflectra®) but the name of the active biological ingredient is the same (e.g. infliximab).
In 2014 World Health Organization’s International Nonproprietary Names (INN) for Biological and Biotechnological Substances guidelines indicated that nonglycosylated biosimilar medicines should have the same INN as the reference biological medicine, whereas glycosylated biosimilar medicines are noted with a Greek letter added to the INN. However, this naming system changed in 2015 when WHO put forward a proposal for a worldwide biosimilar medicine naming convention, which suggested that the nonproprietary name can be different between reference biological and biosimilar medicines, and that they are identified by a common suffix consisting of four random consonants and an optional two-digit checksum. Subsequently, in 2017 the WHO advised that the proposal would not proceed as no consensus was reached on its application.
In early 2017, the United States Food and Drug Administration issued guidance on nonproprietary naming for biological medicines, proposing that all reference and biosimilar medicines share a core, nonproprietary name accompanied by a unique meaningless suffix to distinguish them from one another.
These proposals are currently being considered by regulatory agencies, including the TGA. In 2018, the TGA advised of the Government’s decision to maintain the existing naming convention for biological and biosimilar medicines, continuing use of the Australian biological name (without a specific identifier suffix) together with strengthened adverse event reporting.