Prescription medicines registration process

1. Introduction

The TGA registration process for prescription medicine applications, that need to be supported by nonclinical, clinical and/or bioequivalence data (category 1 and category 2). This regulatory process is designed to improve the efficiency and timeliness of the registration of prescription medicines without compromising the scientific rigour of the evaluation process, thus ensuring the maintenance of appropriate standards of quality, safety, and efficacy. This document describes this process and outlines the relevant regulatory requirements.

The key elements of this process are:

• management by milestones
• an improved quality of dossiers prepared in accordance with common technical document (CTD) format and other TGA regulatory requirements
• a pre-submission planning phase where applicants lodge details of a proposed application at least 2¼ months prior to lodgement of the dossier allowing the TGA to identify milestone dates and plan resource requirements (this is not required for submissions lodged in eCTD format if the sponsor selects the PPF-only option)
• a submission phase where the applicant must lodge a complete dossier, there being no opportunity to deliver new data after the submission date except as required by the Therapeutic Goods Act 1989 (the Act)
• requests for information under section 31 of the Act are consolidated and issued at the end of the initial evaluation phase.

Legislative instruments made under section 9D and section 23 of the Act support this process. These instruments provide the legislative basis for the documents that specify the regulatory requirements for applications lodged under this process.

2. Overview

2.1 Scope

This document provides an overview of the TGA's registration process for applications that need to be supported by nonclinical, clinical and/or bioequivalence data (category 1 and category 2).

Applications to vary a product registration (section 9D of the Act) and not supported by nonclinical, clinical and/or bioequivalence data are outside the scope of this document.

2.2 Regulatory and supporting documents

Category 1 and 2 applications for new registrations are made under section 23 of the Act. Section 23 requires that applications are made in a form approved by the Secretary. The currently approved form is the CTD format.

Category 1 and 2 requests to vary the entry in the Australian Register of Therapeutic Goods (ARTG) of registered therapeutic goods are made under section 9D of the Act. Section 9D requires that applications are made in a manner approved by the Secretary. The currently approved manner is the CTD format.

The CTD format is described in the following documents:

• CTD Module 1: Administrative information and prescribing information for Australia
• ICH M4Q Common technical document for the registration of pharmaceuticals for human use - Quality (CPMP/ICH/2887/99 Rev 1 Quality)
• ICH M4S Common technical document for the registration of pharmaceuticals for human use - Safety (CPMP/ICH/2997/99 Rev 1 Safety)
• ICH M4E Common technical document for the registration of pharmaceuticals for human use - Efficacy (CPMP/ICH/2887/99 Rev 1 Efficacy).

For category 1 and 2 applications, other than applications solely for an additional trade name, the section 23 and section 9D instruments specify applications must comply with the following regulatory documents:

• Mandatory requirements for an effective application
• Pre-submission planning form
• prescription medicines (PREMIER) electronic lodgement facility (for applications to register a new chemical entity, new fixed combination, similar biological medicinal product or a new generic medicine)

or

• the form Application for the registration, or to vary the conditions of registration, of prescription medicines (all other applications)

In addition to the documents specified by the section 9D and section 23 instruments, the TGA has produced other documents which provide further assistance for applicants who are lodging a PPF or dossier. These include:

• Prescription medicine registration process (this document)
• Information for applicants completing a pre-submission planning form
• Electronic format requirements for industry for providing regulatory information: Non eCTD electronic submissions (NeeS) for human medicinal products

2.3 Terminology

Application

• Application refers to the regulatory activity required in respect of a product (a specific set of formulations, strengths and presentations) as requested by the applicant of the product.
• It is the specific set of information on the product submitted for review.
• Examples include:
  • an application for the registration of a new medicine
  • registration of a new indication.

Application category

• Application category is identified by a number, for example, category 1 and category 2 applications, and refers to the overall legislated time-frames for decisions about applications.

Application type

• Application type relates to the fees associated with an application and is identified by a letter, for example, A, B or C application types.
• Examples include:
  • new chemical entity
  • new indication or major variation.

Dossier

• A dossier contains and/or references the necessary data to demonstrate the quality, safety and efficacy of a prescription medicine.
• The supporting data consists of:
  • the dossier lodged in the first instance
  • any dossiers provided to the TGA previously that are referenced by the application
  • any other data to support the application that is lodged following initial lodgement of the application (for example, section 31 responses, further safety data).

Submission

A submission is a collection of one or more applications that are grouped together for fee purposes, and is specific to a particular active ingredient and applicant.

2.4 Key regulatory requirements

2.4.1 Management by milestones

The registration process consists of eight phases with eight milestones, allowing effective planning and tracking by the TGA and applicants. Each phase has established timeframes.

To facilitate management by milestones, all applications received in a given intake will proceed as a group through the phases and milestones, a process known as 'batch processing'.

2.4.2 Quality of applications

For the TGA to ensure that planned and target timeframes are met, it is critical that applicants lodge well-planned, high quality applications. Should a dossier not meet the regulatory requirements, it will be considered 'not effective' and will not be accepted for evaluation.

It is not possible for applicants who submit incomplete, delayed, or poor quality applications to provide unsolicited information during the regulatory process to rectify these deficiencies.

2.4.3 Pre-submission phase

Under the registration process, applicants provide the TGA with planning data in the Pre-submission planning form (PPF) at the pre-submission phase. Planning data include general submission information as well as information about the proposed application type and details of the quality, nonclinical and clinical evidence that will be provided in the dossier. The PPF provides the TGA with the necessary information for effective resource planning.

If the TGA considers a PPF complete and acceptable, the applicant will receive a Planning letter that provides key dates for the phases and milestones of the regulatory process for the application.

2.4.4 Submission phase

Applicants provide a dossier for evaluation at the submission phase. Applicants must ensure applications meet TGA regulatory requirements for format and content or the application will be considered 'not effective' and will not be accepted for evaluation. There will be no requests for information or documents under section 31 of the Act at the submission phase to address deficiencies in applications that do not meet TGA requirements.

Applications must be received by the date noted in the Planning letter to allow the TGA to complete the necessary administrative activities by the end of the same month.

At the end of the submission phase, the TGA will send the applicant a Notification letter advising that the application has either:

• been considered effective and is accepted for evaluation

or

• been considered 'not effective' and is not accepted for evaluation.

2.4.5 Priority review designated applications

TGA now has a formal Priority review pathway for faster assessment of vital and life-saving prescription medicines for which a complete data dossier is available. The target timeframe of 150 working days is up to three months shorter than the standard prescription medicines registration process. A valid Priority review designation must be held in order to access the Priority review pathway. More information on Priority review is available at:

• Priority review designation: A step-by-step guide for prescription medicines
• Priority review designation eligibility criteria: Including supporting documentation
• Priority review registration process

2.4.6. Provisional approval pathway

The TGA now has a formal Provisional approval pathway for the provisional registration of prescription medicines on the basis of preliminary clinical data, where there is the potential for a substantial benefit to Australian patients. A valid Provisional determination must be held in order to access this pathway.

More information on Provisional approval is available at:

• Provisional approval determination: A step-by-step guide for prescription medicines
• Provisional approval determination eligibility criteria: Including supporting documentation
• Provisional registration process: a step-by step guide for prescription medicines
• Provisional registration extension and transition to full registration

2.5 Information

Applications must contain all the information and material required for purposes of section 9D or section 23 of the Act and the documentation presented at submission will be taken as the complete application.

The applicant certifies in the PPF that the content of the complete dossier aligns with the information provided in the PPF and that the dossier, as received by the TGA, will be considered to be the full and complete dossier notwithstanding any further data requested by the TGA (including under section 31 of the Act) and/or new safety related data, which the applicant is obliged to bring to the TGA's attention. Applicants are strongly advised not to lodge a PPF before the full extent of the supporting data necessary for the application to be evaluated is known to be available.

To assist applicants prepare a complete application, TGA has published numerous documents and guidelines on the preparation and submission of prescription medicine applications. Applicants of prescription medicine applications should refer regularly to the TGA web site for those guidelines and policies relating to a particular application type of interest. Where a relevant guideline is not met, an appropriate justification must be provided in the dossier.

Once an applicant has submitted the dossier to TGA any data received by TGA without being requested by TGA will be considered 'unsolicited information'.

Data submitted after submission of the dossier must be accompanied by a covering letter which includes the submission number of the relevant application, the purpose of the correspondence and whether the information and material is 'solicited' or 'unsolicited'.

2.5.1 Solicited information

TGA considers the following to be solicited information:

• information and documents sent in response to the consolidated section 31 request following the first round assessment phase. The request will be sent on the date identified in the Notification letter allowing applicants time to conduct any necessary preparation activities.
• responses to informal requests from TGA staff for information or documents (for minor issues and clarifications). These requests may occur throughout the evaluation process and are intended only to maintain efficiency in the evaluation process, not to rectify deficiencies in incomplete or poor quality applications.

All solicited information in response to questions should be submitted in a question and answer format which is cross-referenced to replacement volumes where appropriate.

Applicants will also be able to:

• comment on the evaluation reports to highlight any errors of fact or major omissions
• comment (pre-ACM/ACV response) on the delegate’s request for advice from the independent Advisory Committee on Medicines (ACM) or Advisory Committee on Vaccines (ACV) when such advice is sought.

2.5.2 Unsolicited information

TGA will accept the following unsolicited information for evaluation:

• safety data (see 2.5.3 for the definition of safety data). Applicants are obligated to inform the TGA as soon as new safety data becomes available.
• new/renewed/updated TGA manufacturing licences (for Australian manufacturing sites) and good manufacturing practice (GMP) clearances (for overseas sites) issued for those sites identified in the application.
• revised trade names. An applicant may change, but not add, a trade name at any time prior to the end of the second round assessment phase.

In the event that the TGA receives other unsolicited information from an applicant, the applicant should be aware that there is a likelihood that the TGA will not evaluate the data. Applicants must, therefore, ensure that their dossier contains the full data set that they wish the TGA to evaluate and that the mandatory requirements (as applicable to the nature of the medicine and application type) are met.

The TGA will work with applicants of medicines of critical importance to the Australian community in emergency situations to ensure this policy does not adversely affect the timely evaluation of such medicines. Applicants of such medicines are encouraged to discuss arrangements with the TGA at a pre-submission meeting and in any case, as early as possible.

2.5.3 Safety data

For the purposes of the registration process, new safety data refers to information that might negatively influence the benefit-risk assessment of a medicinal product. Examples include but are not limited to:

1. an increase in the rate of occurrence of an 'expected,' serious adverse drug reaction which is judged to be clinically important
2. a significant hazard to the patient population, such as emergent lack of efficacy with a medicinal product used in treating a life-threatening disease, or a spate of unlisted reports of an uncommon or rare but serious adverse event
3. a major safety finding from a newly completed animal study (such as an increased incidence of tumours in treated animals)
4. pooled analyses of clinical studies that suggest significant dose or time dependent adverse effects that were neither apparent nor available at the time of lodging the application
5. safety data associated with regulatory action in the event of, or to prevent risk to public health associated with use of the product in countries where it is already registered.

Safety data in this context do not include, for example:

1. studies which only confirm information previously submitted to the TGA, including extension studies of submitted nonclinical or clinical studies (i.e. a, b and c above do not apply)
2. studies or other data which support the use of the medicine in accordance with the proposed recommendations but which do not identify a new unexpected adverse drug event or an increased incidence of an expected adverse drug event
3. pharmaceutic data
4. nonclinical studies to justify proposed impurity limits.

3. Planning and tracking of applications

3.1 Regulatory phases

The regulatory process for evaluation of prescription medicines consists of eight phases. Each phase has a milestone that must be completed before commencement of the following phase. This approach allows effective and transparent management of resources and timelines for all applications.

Appendix 2 contains a pictorial representation of the regulatory phases. Section 5 of this document provides details about each of the phases.

3.2 Regulatory timelines

Depending on the type of application, different phases will be required which will affect the overall timeframe for the regulatory process. For initial planning purposes, applications are categorised into four distinct groups that are covered by some or all regulatory phases.

The registration process introduces planning timeframes into each of the phases, as indicated in appendix 4 and section 5 of this document. While the legislated TGA commitment of 40 working days between receipt of an application and notification of acceptance or rejection of that application remains, under the registration process this phase (the submission phase) will typically be completed in 15 or 21 calendar days, unless otherwise advised in the Planning letter.

The legislated TGA commitment of 255 working days between acceptance for evaluation through to the delegate's decision will also remain but will not be used for planning or for target times. The registration process is designed to take, on average, 330 calendar days (11 months), including the time for applicant activities.

Examples of timelines showing target milestone timeframes is provided in Appendix 1.

3.3 Submission planning

Planning for the evaluation process occurs during the pre-submission phase where the application type, the product, the scope and scale of the application, and the date of proposed dossier lodgement are identified. The information provided in the PPF allows the TGA to identify the resources required, including the specific areas of expertise, to evaluate an application. This phase also allows for the identification of any circumstances that may require the standard timeframe to be altered. Applicants will be notified of any alterations to the target timeframes.

Under the registration process, the TGA begins allocating resources for the evaluation phase when the PPF is lodged. These resources are based on the expected date of dossier lodgement. If a dossier does not arrive by the expected date, the TGA will reallocate the resources for that application and the applicant must re-commence the regulatory process from the beginning by lodging another PPF.

3.4 Submission tracking

Once the PPF is lodged, the TGA will track the application through the regulatory process. Each phase of the regulatory process concludes with the completion of a milestone.

At key points in the registration process TGA will notify the applicant of the evaluation plan milestone dates: an evaluation plan is included in the Planning letter at Milestone 1, the Notification letter at Milestone 2 and the Milestone 3 letter at Milestone 3. As target timeframes may change, applicants should always consult the most recent letter.

To facilitate tracking, the TGA has implemented a single email address for the applicant through which formal correspondence will be coordinated. The TGA point of contact should be the PMAB Case Manager of the relevant clinical evaluation unit. Information on the areas of responsibility for the clinical units is included in Clinical evaluation sections for prescription medicines.

4. Pre-process activities

4.1 Pre-submission meetings

Applicants may wish to discuss scientific or procedural issues with the TGA in a pre-submission meeting prior to preparing a PPF or dossier. Such discussions should occur well in advance of PPF and dossier lodgement. The TGA strongly recommends that applicants organise a pre-submission meeting for complex applications. Meetings between TGA and applicants are conducted according to the processes described in the guideline Pre-submission meetings with the TGA. Applicants will need to provide details in the PPF and the dossier (Module 1.8.1) of any meetings conducted with the TGA.

4.2 Availability of dossier

The PPF requires applicants to identify a proposed dossier lodgement date. Applicants should not lodge a PPF until they are confident all the data necessary for the evaluation of the application will be ready for delivery on the proposed dossier lodgement date.

A dossier that was lodged previously with the TGA but not accepted for evaluation may be re-used in certain circumstances.

4.3 Pre-conditions

Applicants may need to fulfil a number of pre-conditions before lodging a PPF. In some cases, evidence is required in the PPF that the approval process has commenced on related activities. These are described below.

4.3.1 Orphan drug applications

For designated orphan drugs, the Secretary waives application and evaluation fees for the evaluation of a medicine for the purposes of registration. For fees to be waived, the applicant must apply for, and be granted by the TGA, orphan drug designation before lodging the PPF. Further information about making such a request can be found in:

• Applications for orphan drug designation.

Discussions with the TGA regarding orphan drug applications should commence well before the pre-submission phase. Applications for orphan drug designation should be lodged with the TGA two to three months before the intended start of the pre-submission phase. If an applicant has not received approval for the designation but chooses to proceed with the application, they become liable for the relevant application and evaluation fees.

4.3.2 Literature-based submissions

For applications using literature references as all or part of the supporting data set, the applicant must seek the TGA's agreement on the following before lodging the PPF:

• the search strategy employed
• the databases to be searched
• the criteria for determining which papers identified by the search results are to be included/excluded from the dossier.

These requirements are necessary because the data provided in the dossier is dependent on the search strategy. Applicants should plan to discuss these issues with the TGA at least three months prior to the pre-submission phase. Further information on literature-based submissions is provided in Literature-based submissions.

4.3.3 Fixed combination applications

For a new fixed combination product the applicant must justify, prior to lodging a PPF, the particular combination and the type and extent of data to be provided in the dossier. This is done by preparing and lodging with the TGA a 'justification for fixed combination'. This is a letter to the TGA that presents the case for the fixed combination, prepared according to the following EU guidelines that have been adopted in Australia:

• CHMP/EWP/240/95 Rev. 1 - Guideline on clinical development of fixed combination medicinal products
• EMEA/CHMP/SWP/258498/2005 - Guideline on the non-clinical development of fixed combinations of medicinal products

If one or more of the component active ingredients of the fixed combination product is/are not registered, the justification must include the proposed dossier lodgement dates for the unregistered components and the fixed combination product.

4.3.4 Ingredients

The TGA maintains databases of proprietary and non-proprietary ingredients which can be accessed from the TGA's eBS portal. Where an applicant wishes to register a new product that contains a new ingredient (one that is not on the databases), the applicant must commence, before lodging the PPF, the process for approval of a new ingredient for inclusion on the relevant databases.

For each new ingredient, the following forms must be lodged:

• a Notification of a New Proprietary Ingredient for each new proprietary ingredient
• an application form for proposing a new chemical name (AAN), biological name (ABN) and/or herbal name (AHN) for each new non-proprietary ingredient. See Forms for new ingredient names and proprietary ingredients.

Refer to part 2.1 of Information for applicants completing a pre-submission planning form for details on accessing the ingredient databases and the location of forms.

4.3.5 Genetically modified organisms (GMOs)

It is likely that approval from the Office of the Gene Technology Regulator (OGTR) is required for medicines that:

• contain GMO(s)
• consist of GMO(s)
• are manufactured in Australia and are derived from GMOs.

In such circumstances, applicants must apply to the OGTR for a licence, an exemption, or a Notifiable Low Risk Dealing approval, before lodging the PPF. Any OGTR advice (for example, OGTR licence, acknowledgement of receipt of licence application, other record of consent) must be provided to the TGA with the PPF.

4.3.6 Medicines scheduling

Where a proposed application relies upon the rescheduling of an existing substance in the Poisons Standard, applicants must lodge an application for rescheduling prior to lodging the PPF:

• Application to Amend the Poisons Standard

4.3.7 Concurrent applications

Applications to amend any details for a product cannot be lodged until the product is listed on the ARTG. If an applicant wishes to make changes to a proposed product, the application cannot be lodged until the registration process is finalised. The same requirement applies to a new chemical entity application currently under evaluation and a proposed new combination application (where the product contains the new chemical entity under evaluation).

Where a product is already registered and there is an existing application (variation or registration) currently with the TGA, it is acceptable to lodge a concurrent application in certain circumstances, provided that the changes proposed in the applications are unrelated. The following table indicates when it may be appropriate to lodge concurrent applications.

¹A new registration (or new Register entry) is one that requires a new ARTG entry by reason of being 'separate and distinct goods' under s.16 of the Therapeutic Goods Act 1989. This includes new chemical entities, new strengths, new dosage forms, different directions for use, formulation changes, changes in trade name, extensions of indication. However, not all new registrations will result in a new AUST R number being allocated if they are taken to be grouped by reason of the Therapeutic Goods (Groups) Order 2001.

If unsure of regulatory requirements where a related application is under consideration, applicants should contact the TGA before lodging a PPF for an application. Where there is a potential relationship between an application currently under evaluation and the proposed application, this must be indicated in the PPF.

Where the proposed application seeks changes to an entry in the Register under section 9D of the Act and would result in changes to the product information document currently under evaluation, such changes to the document currently under evaluation must be identified, either in the product information document or the letter of application of the proposed application.

• the outcome of the initial application is negative
• the evaluation on the initial application has not progressed sufficiently.

5. Registration process phases

Click a link to find out more about each phase in the registration process. For a diagram of the registration process, see Appendix 2 - Registration process regulatory phases.

• Phase 1: Pre-submission
• Phase 2: Submission
• Phase 3: First round assessment
• Phase 4: Consolidated section 31 request response
• Phase 5: Second round assessment
• Phase 6: Expert advisory review
• Phase 7: Decision
• Phase 8: Post-decision

Appendix 1 - Sample timelines

*Where the target date falls on a weekend or public holiday, the actual target date will be the next working day.

*Where the target date falls on a weekend or public holiday, the actual target date will be the next working day.

Appendix 2 - Registration process regulatory phases

The following diagram shows the phases and milestones of the registration process. To view a larger, printable version, click on the image.