Prescription Medicines Registration Requirements in Australia

TGA regulates prescription medicines (drugs that are prescribed by a medical practitioner) and has provided many guidelines to meet the regulatory and legislative requirements. Section 9 D (applicable for variations) and section 23 (applicable for new registrations) of the Therapeutics Good Act 1989, provides legislative basis for the regulatory requirements for applications which requires non-clinical, clinical and/or bioequivalence data along with quality and other information to prove safety, efficacy and quality of prescription medicines. Such applications fall under category 1 and category 2 and will include new drugs as well as generics.

The process defined for prescription drugs have certain key elements: -

1)     Management by Milestones – TGA’s process includes 8 phases with 8 milestones and established timelines for each phase. These phases include pre-submission, submission, first and second round assessment phase, consolidated section 31 request (queries) after first round assessment, expert advisory reviews, and two decision-making phases. TGA’s guideline - ‘Prescription Medicines Registration Process’ provides details about the phases and timelines that help in proper planning of dossier submission/lodgement to meet the product launch timelines. A brief overview of some of the initial phases has been presented below for ease of understanding of the regulatory process.

2)     Quality of Application –TGA does not accept any application for evaluation which is not of high quality and compliant to their requirements. The dossiers should be prepared according to the CTD format and TGA’s regulatory requirements. To achieve this objective the TGA’s guideline – ‘Mandatory requirements for an effective application’ must be well-understood and information provided accordingly. The technical requirements are as per ICH and CHMP guidelines adopted by the TGA.

3)     A pre-submission planning phase – This is the first phase and in this phase, TGA requires the lodgement of a pre-submission planning form (PPF) through the electronic business services (eBS). For doing this, refer to the TGA guidelines – ‘Pre-submission planning form’ and ‘Information for applicants completing a pre-submission planning form’. Another key requirement is the submission of CTD Module 2 that provides a brief summary of the pre-clinical, clinical and quality data. This helps TGA to plan their resources and define timelines/ milestones of the regulatory process. A planning letter providing key dates is provided by the TGA if it considers the PPF to be complete and acceptable. An applicant should lodge their PPF form with complete details at least 2_1/4 months before the submission of complete dossier. The applicants should propose a dossier lodgement date in the PPF form and ensure that the dossier submission happens as per the date mentioned here. The applicant should have clear visibility of data required and its availability before deciding to provide a date in the PPF.

4)     Submission of the complete dossier – After receiving the planning letter from TGA, a complete dossier must be provided in the second phase, understanding well that there is no scope of submission of any additional data after this phase, except if requested by the TGA. As per the procedure, the applicant certifies in the PPF that the information provided in the PPF and the dossier is completely aligned. Any new additional information, except those related to the safety of the medicines, new/renewed/updated TGA clearance certificate, or revised trade names will be considered as unsolicited information and a justification is required for any such data submission after the complete dossier submission phase. It is important to understand that the complete dossier submission needs to happen as per the date noted in the planning letter of the TGA. At the end of this Phase, TGA sends a notification letter to the applicant stating whether the application has been accepted or not accepted for evaluation.

5)     Initial evaluation phase and request for information under section 31 – In this phase, a consolidated list of queries or any additional information, as applicable is sent by the TGA after the initial evaluation of the complete dossier.

TGA’s regulatory framework has provided additional pathways for prescription medicines such as ‘Priority Review Designated Applications’ for faster assessment and approval of life-saving medicines and ‘Provisional Approval Pathway’ for medicines which has the potential for substantial benefit for patients. The eligibility criteria, step by step guidelines, and registration process for both the above pathways have been provided in detail at the TGA website.

For complex medicine submissions or for better understanding of requirements concerning an Orphan drug (medicines developed for rare diseases to treat small number of patients with specific conditions) status or eligibility for priority reviews, a pre-submission meeting may be requested by manufacturers, sponsors or agents, as this provides an opportunity for a face to face discussion with the TGA. A pre-submission meeting can occur any time before the submission of a PPF, but before requesting for a meeting, the process needs to be well understood by referring to the guideline ‘Pre-submission meeting with the TGA’. As per this guideline, certain information needs to be provided upfront to the TGA by completing the meeting request form and preparing a briefing package which may include an agenda, list of question for the TGA, summaries of studies and other relevant information. The briefing package must be sent at least 2 weeks prior to the scheduled meeting. More information regarding this is available on the TGA website.

There are some pre-conditions that must be met before starting the PPF phase of an application. For example, Orphan drug designation must be applied and granted by the TGA before lodging the PPF for orphan drug applications. Applications for orphan designation should be done at least 2-3 months in advance. The fee waivers applicable for orphan drug applications would be granted only if the ‘Orphan designation application’ has been approved by the TGA before lodging of the PPF. Similarly, for literature-based submissions (submissions which are not based on conventional approach of conducting a study and clinical trials, but instead solely depends on bibliographic data to support safety and efficacy claims), the applicant must seek the TGA’s agreement on the method or strategy employed for the search of literature and database to be searched. Here again, all discussions with the TGA should happen at least 3 months ahead of a PPF submission.

Other cases wherein pre-conditions apply are mentioned below. Complete information about the requirements for each of the listed applications is available in the TGA guidance ‘Prescription Medicines Registration Process’. 

a) Fixed-dose combination applications

b) Applications for registration of any new ingredients to be included in TGAs database 

c) Applications that may contain Genetically Modified Organisms (GMOs)

d) Applications which require rescheduling of existing substance in the Poisons Standard and 

e) Concurrent applications

All applicants are liable to pay the application fee (except for orphan drugs) upon lodgement of the PPF that allows the TGA to recover the cost for the processing of the PPF and arranging the resources for evaluation of the application. Please note that if the PPF is not effective or the dossier is not accepted for evaluation by the TGA, the application fees will be forfeited. There is another fee called evaluation fee which must be paid when the application is accepted for evaluation. The notification letter will specify the amount that must be paid. These fees must be paid within 2 months from the date of the notification letter. The fees and payment section on the TGA website provides information about the fees associated with different types of applications of prescription medicines.

TGA accepts electronic submissions and requirements have been provided for both eCTD and non-eCTD (like NeeS) in the respective guidelines available on the TGA website. TGA accepts hard copy submissions as well. There is another requirement for lodgement of application of all new chemical entity, new fixed-dose combination and new generic medicine application, which requires electronically lodging the application through eBS (electronic business service) prior to sending the hard copy or electronic copies of the dossier.  This means that applicants must create an application in eBS, take a printout of this same application form and the electronic lodgement cover sheet and include it in Module 1 of the dossier.

The TGA guideline - ‘mandatory requirements for an effective application’ includes details of all requirements applicable for new registrations as well as variations. It provides information about the legislative requirements, technical and administrative requirements, CTD format requirements and establishing bioequivalence or therapeutic equivalence requirements. Additionally, requirements concerning prescribing information, evidence of GMP, pharmacovigilance information (including a risk management plan, as applicable), studies required specifically for a new chemical entity or a generic application has also been provided in detail.

While all the requirements are mandatory, some exceptions may be accepted by the TGA, but only after assessment of a very robust scientific justification (which must be provided well before lodging a PPF) for not complying with the requirements. A few examples are justification for a generic application where the salt/ester form of a generic product is different from Australian reference product or a justification for including preservatives for single-dose injections.

Justification is also required for not providing a biopharmaceutics study against an Australian sourced reference product when the data is provided against an overseas reference product.

TGA’s guideline on the General dossier requirements provides further information on the language, measurements, provisions of Module 1 specific for Australia, and electronic data requirements. Labelling requirements are provided in Therapeutic Good Order No. 91 (TGO 91). These also need to be referred and complied with while preparing dossiers.

There may be cases when an application does not meet the TGA requirements, hence considered not effective and hence not accepted for evaluation. In such cases , an applicant may resubmit the application after ensuring all requirements and deficient aspects are met, by lodging a new PPF, and submitting a new dossier. Sometimes an applicant may realise that they will not be able to meet the dossier submission date. In such cases, the applicant should contact the TGA at the earliest. This allows the TGA to reallocate resources. But here again, the applicant will forfeit the application fee. If the applicant wishes to submit the same application on another date, they will need to lodge a new PPF again.

After submission of the dossier, the TGA will complete its first and second round assessments, request for any additional information as deemed necessary and complete all activities as per their defined phases and milestones and finally send the applicant a decision letter for approval of a new registration. After receiving approval, the applicant must provide a patent certification/notice. At this stage, the TGA will check all product information and then convert the provisional ARTG record, originally provided by the applicant during lodgement of the dossier, to an ARTG Record of Registration. There are certain obligations and conditions outlined in the decision letter which the applicant must meet, such as they must notify the TGA about the actual first date of commercial marketing. The final approved Product Information (PI) must be lodged with the TGA within 2 weeks of the date of registration of the product. The Consumer Medicines Information (CMI) for new products should be lodged prior to the first commercial supply of the product.

Since December 2009, the TGA has started publishing the Australian Public Assessment Report (AUSPAR) on it’s website, which includes decisions relating to the evaluation of prescription medicines and rationale for approving (or not approving) the same.

At the end of this blog, I would emphasise on the fact that before initiating any dossier for registration of the prescription medicine in Australia, take time to understand the legislative and regulatory requirements. There is a gamut of information available at the resource link provided below. Understand what is applicable for your specific application and ensure compliance!!

For first time readers, pls read this blog along with my previous blog titled Drug Registration in Australia-An Overview of the Regulatory Framework. My previous blog includes some general information that are also applicable for registration of prescription medicines.

My next blog will be on registration of OTC medicines in Australia. See you soon!!

Resource:

TGA website, https://www.tga.gov.au/prescription-medicines

Fees and charges, https://www.tga.gov.au/book-page/prescription-medicines-4