Cutaquig

Source: Australian Therapeutic Goods Administration

Replacement therapy should be initiated under the supervision of a healthcare professional experienced in the treatment of immunodeficiency.

In replacement therapy the dosage may need to be individualised for each patient dependent on the pharmacokinetic and clinical response.

For further information refer to the Product Information.

Consultation: Proposed improvements to the Therapeutic Goods Advertising Code

Source: Australian Therapeutic Goods Administration

This consultation closes on 18 June 2021.

The Therapeutic Goods Administration (TGA) is conducting a public consultation seeking feedback on options to improve the Therapeutic Goods Advertising Code (No.2) 2018 (the Code).

The Code has been in force since January 2019 and stakeholders have identified opportunities for improvements to increase clarity for advertisers and other users of the Code. The TGA’s own experience in administering the Code has also indicated opportunities for clarification and improvement.

For more information on the proposals, and to participate in the consultation, please visit the consultation hub.

The consultation opens on Friday 7 May 2021. Interested parties should respond by close of business Friday 18 June 2021.

Enquiries

For enquiries relating to the consultation paper or your submission please email advertising.consultation@tga.gov.au.

Clonidine – importance of dosing compliance and safe storage

Source: Australian Therapeutic Goods Administration

Health professionals are reminded that serious adverse events can occur in children who are accidentally overdosed with clonidine either when receiving treatment for behavioural disorders, or obtaining access to a family member’s medication. Even relatively minor overdoses (for example, double dosing) can result in toxicity, particularly in young children. You are advised to counsel patients and their parents/carers to pay close attention to dosing and remind them of the need for safe storage and other safety precautions.

Clonidine, marketed in Australia under the brand name Catapres and various generic brands, is approved for indications relating to the cardiovascular effects of the drug (for example, high blood pressure, migraine and menopausal flushing).

Clonidine is also being prescribed off-label under careful medical supervision for behavioural disorders in children, including attention deficit hyperactivity disorder (ADHD), tic disorders and sleep disturbances. Clonidine is not approved for the treatment of these conditions in children and the Product Information (PI) does not recommend its use in children due to the lack of supporting evidence in this population. The PI also advises against using clonidine off-label in combination with methylphenidate for this indication due to the risk of serious adverse reactions.

Accidental overdoses

The TGA and the NSW Poisons Information Centre have received reports of clonidine overdose involving children relating to accidental poisoning and dosing errors, including unintentional double-dosing. Many of these events required medical intervention and/or hospitalisation. The number of reports of poisoning has increased in recent years and similar trends have been observed overseas.

To 23 April 2021, there are 43 adverse drug reaction reports included on the TGA Database of Adverse Event Notifications (DAEN) relating to overdose, incorrect dose, or off-label use of clonidine in children. Of these, 27 reports were received in 2020, which is a significant increase from eight reports received in 2019. Accidental administration of a double-dose of clonidine to a child who subsequently required medical intervention has been reported in five cases. Adverse events in these cases include slow heart rate, low blood pressure and reduced level of consciousness. There have also been 11 reports confirming accidental ingestion of clonidine by a sibling for whom it had not been prescribed.

A publication by the NSW Poisons Information Centre states that during 2018, 415 cases of clonidine poisoning in children under 6 years of age were recorded by the NSW Poisons Information Centre. This represented a 50% increase over the previous four years. Off-label prescription of clonidine to the poisoning victim was noted in 28% of those cases. The authors note that clonidine has a narrow therapeutic window, meaning that relatively minor dosing errors (including double-dosing) can lead to toxicity.

In cases of accidental poisoning, clonidine may have been prescribed to the child, or other members of the household (including older siblings treated for ADHD, or adults with high blood pressure).

Clonidine poisoning presents with acute toxicity as early as 30 minutes and up to three hours after ingestion. Symptoms include coma, respiratory depression, bradycardia, hypotension and hypothermia. Milder side effects include constricted pupils, dry mouth, drowsiness, gastrointestinal upsets and dizziness.

The risk of poisoning is greater for younger children with low bodyweight where the low toxic threshold of the drug can be easily exceeded. Significant overdose can occur with ingestion of a single tablet.

Information for health professionals

When you are prescribing clonidine, you are advised to counsel patients and their caregivers about the importance of following dosing instructions carefully and precisely, and ensuring that the medicines are stored safely and out of reach from children. Extra vigilance is recommended when administering clonidine to ensure double-dosing does not occur.

Off-label prescribing should only be considered when other options are unavailable, exhausted, not tolerated or unsuitable, and you should always discuss the risks and benefits of the proposed treatment with the patient and/or their parents/carers so that they are capable of providing informed consent. Additionally, the treatment should be monitored and any adverse events should be reported to the TGA.


What to report? You don’t need to be certain, just suspicious!

The TGA encourages the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.

We particularly request reports of:

  • all suspected reactions to new medicines (look for the Black Triangle in PI and CMI documents – this symbol identifies medicines that are new or being used differently)
  • all suspected medicines interactions
  • suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.

Reports may be submitted:

For more information about reporting, visit www.tga.gov.au or contact the TGA’s Pharmacovigilance and Special Access Branch ADR.Reports@tga.gov.au.

Disclaimer

Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional’s judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.

© Commonwealth of Australia 2021

This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to tga.copyright@tga.gov.au.

For the latest safety information from the TGA, subscribe to the TGA Safety Information email list via the TGA website.

For correspondence or further information about Medicines Safety Update, contact the TGA’s Pharmacovigilance and Special Access Branch at .

Medicines Safety Update is written by staff from the Pharmacovigilance and Special Access Branch.

Acting Editor: Dr Catherine Brogan

Deputy Editor: Mr Michael Pittman

Contributor: Dr Neillan Nandapalan and Dr Margaret Wilson

Consultation: Proposed amendments to the Poisons Standard – ACMS #34, June 2021

Source: Australian Therapeutic Goods Administration

Scheduling amendments referred to expert advisory committee

Subdivision 3D.2 of the Therapeutic Goods Regulations 1990 (the Regulations) sets out the procedure to be followed where the Secretary receives an application under section 52EAA of the Therapeutic Goods Act 1989 (the Act) to amend the current Poisons Standard or decides to amend the Poisons Standard on his or her own initiative and decides to refer the proposed amendment to an expert advisory committee. These include, under regulation 42ZCZK, that the Secretary publish (in a manner the Secretary considers appropriate) the proposed amendment to be referred to an expert advisory committee, the committee to which the proposed amendment will be referred, and the date of the committee meeting. The Secretary must also invite public submissions to be made to the expert advisory committee by a date mentioned in the notice as the closing date, allowing at least 20 business days after publication of the notice.

In accordance with regulation 42ZCZK of the Regulations, the Secretary invites public submissions on scheduling proposals referred to the June 2021 meeting of the Advisory Committee on Medicines Scheduling (ACMS #34). Submissions must be received by close of business 27 May 2021.

Consultation documents

Contents

  • 1 Proposed amendments referred for scheduling advice to ACMS #34
    • 1.1 Amygdalin and hydrocyanic acid
    • 1.2 Bufexamac
    • 1.3 Ibuprofen
  • 2 How to respond
  • 3 What will happen
  • 4 Enquiries

Consultation: Proposed amendments to the Poisons Standard (oral contraceptives) – ACMS #34, June 2021

Source: Australian Therapeutic Goods Administration

Oral contraceptive proposals and substances referred to ACMS #34

Subdivision 3D.2 of the Therapeutic Goods Regulations 1990 (the Regulations) sets out the procedure to be followed where the Secretary receives an application under section 52EAA of the Therapeutic Goods Act 1989 (the Act) to amend the current Poisons Standard or decides to amend the Poisons Standard on his or her own initiative and decides to refer the proposed amendment to an expert advisory committee. These include, under regulation 42ZCZK, that the Secretary publish (in a manner the Secretary considers appropriate) the proposed amendment to be referred to an expert advisory committee, the committee to which the proposed amendment will be referred, and the date of the committee meeting. The Secretary must also invite public submissions to be made to the expert advisory committee by a date mentioned in the notice as the closing date, allowing at least 20 business days after publication of the notice.

In accordance with regulation 42ZCZK of the Regulations, the Secretary invites public submissions on scheduling proposals referred to the June 2021 meetings of the Advisory Committee on Medicines Scheduling (ACMS #34). Submissions must be received by close of business 27 May 2021.

Consultation documents

Contents

  • Oral contraceptive proposals and substances referred to ACMS #34
  • 1. Applications
    • 1.1 Application A: ethinylestradiol, levonorgestrel and norethisterone
    • 1.2 Application B: ethinylestradiol, levonorgestrel, norethisterone, cyproterone, desogestrel, dienogest, drospirenone, estradiol, gestodene, mestranol and nomegestrol
  • 2. Substances
    • 2.1 Ethinylestradiol
    • 2.2 Levonorgestrel
    • 2.3 Norethisterone
    • 2.4 Cyproterone
    • 2.5 Desogestrel
    • 2.6 Dienogest
    • 2.7 Drospirenone
    • 2.8 Estradiol
    • 2.9 Gestodene
    • 2.10 Mestranol
    • 2.11 Nomegestrol
  • 3. Additional requirements for pharmacy supply
    • 3.1 Appendix M entry proposed in Application A
    • 3.2 Appendix M entry proposed in Application B
  • 4 How to respond
  • 5 What will happen

Consultation: Proposed amendments to the Poisons Standard (sodium nitrite) – Joint ACMS/ACCS #28, June 2021

Source: Australian Therapeutic Goods Administration

3 Proposed amendments referred for scheduling advice to the Joint ACMS-ACCS #28

3.3 Sodium nitrite

The Department of Health (the ‘Department’) recognises that each of the numbers reported represents an individual. The Department acknowledges the devastating effects associated with acts of self-harm on individuals, their families, friends and communities. A list of support services and information sources is provided below.

The information below contains details of self-poisonings some people may find distressing. If you or someone you know is in need of additional support, please contact any of the below crisis support helplines:

Support services and information sources

Adult
Youth

Consultation documents

Contents

  • 3 Proposed amendments referred for scheduling advice to the Joint ACMS-ACCS #28
    • 3.3 Sodium nitrite
      • Support services and information sources
      • Alternative names
      • CAS Number
      • Applicant
      • Current scheduling
      • Proposed scheduling
      • Key uses / expected use
      • Reasons for proposal
      • Australian regulations
      • International regulations
  • 4 How to respond
  • 5 What will happen
  • 6 Enquiries

TGA issues warning about unlawful advertising of listed medicines

Source: Australian Therapeutic Goods Administration

The Therapeutic Goods Administration (TGA) is warning sponsors not to advertise listed medicines that are not included in the Australian Register of Therapeutic Goods (ARTG) with permitted indications.

Listed medicines that were not transitioned to use permitted indications were cancelled from the ARTG, effective 6 March 2021. If you are the sponsor of a listed medicine, you should be aware that this puts your medicines at risk of being unlawfully advertised.

Advertising medicines for indications not included in the ARTG

If you have transitioned your medicine to permitted indications, this effectively cancelled the medicine that included specific (free text) or coded indications in the ARTG with the old medicine being replaced by the new medicine using permitted indications

Only permitted indications included in the ARTG entry may be advertised, and it is unlawful to advertise any medicines for free text or coded indications that were previously included in the ARTG.

All sponsors must ensure that the therapeutic use, as described by the permitted indications in the ARTG entry, is of the same intent and meaning as the therapeutic use described on the label and in other advertising. Failure to do so provides grounds for regulatory action.

If you are the sponsor of a listed medicine, you are reminded that:

  • the name of a medicine, claims made and overall presentation of the indications on the label and in other advertising material have the potential to imply a therapeutic use that is not of the same intent and meaning as the indications included in the ARTG entry—which is likely to result in the advertising of a medicine for indications not included in the ARTG entry
  • the TGA has published guidance to assist sponsors with understanding legal requirements that apply to the advertising of listed medicines including the Permitted indications for listed medicines guidance and Advertising to the public: Complying with the Therapeutic Goods Advertising Code
  • the TGA is actively monitoring for non-compliance, particularly in relation to the advertising of medicines for indications that are not included in the ARTG entry and/or not permitted for listed medicines

Consequences of breaking the law

There are criminal offences under the Therapeutic Goods Act 1989 (the Act) for the unlawful advertising of listed medicines. This includes circumstances where medicines are advertised for indications other than those included in the ARTG entry.

The legislation also provides for the imposition of civil penalties in the same circumstances which means that the TGA can issue infringement notices and take court action for alleged breaches of advertising laws.

In a recent case, a sponsor of listed medicines has paid penalties of $119,880 in relation to alleged contraventions of conditions of listing and provisions relating to advertising under the Act.

Reminder about supply

If you are the sponsor of a listed medicine, you are reminded that it is a criminal offence to import, export, manufacture or supply a therapeutic good in Australia if it is not included in the ARTG. It is also an offence for a wholesaler to supply therapeutic goods that are not included on the ARTG, to another person who is not the ultimate consumer of the goods. As such, if you supply a listed medicine that has been cancelled as a result of being transitioned to include permitted indications in the ARTG, you may be committing an offence under the Act.

The TGA does not intend to take regulatory action in relation to products that are still available for supply carrying specific (free text) or coded indications providing these were compliant prior to their release for supply. However, you must ensure that you review relevant state and territory laws carefully to ensure that you do not commit offences relating to retail supply of therapeutic goods.

Global Therapeutics fined $119,880 for alleged unlawful advertising of complementary medicines

Source: Australian Therapeutic Goods Administration

Global Therapeutics Pty Ltd (Global Therapeutics) has paid penalties of $119,880 in response to nine infringement notices issued by the Therapeutic Goods Administration (TGA), part of the Department of Health. The infringement notices related to five listed complementary medicines sponsored by Global Therapeutics.

The advertising of these medicines was alleged to:

  • refer to serious conditions without approval or permission of the TGA
  • contravene requirements of the Therapeutic Goods Advertising Code (the Code)
  • include therapeutic uses that were not accepted as indications for the medicines.

In particular, the Global Therapeutics’ website allegedly contained unapproved references to ‘serious’ conditions such as upper respiratory tract infections, bronchitis, influenza, and viral and bacterial infections. The Code provides that representations about conditions requiring diagnosis, treatment or supervision by a suitably qualified health professional are ‘serious’, the use of which in advertising is restricted and not permitted for listed medicines.

Listed medicines are permitted to be supplied and advertised without full pre-market evaluation by the TGA as long as certain fundamental conditions are met to ensure the medicines are low-risk and suitable for self-selection by consumers. The onus is on sponsors to ensure compliance with these ‘conditions of listing’ and all other relevant requirements under the Therapeutic Goods Act 1989 (the Act). Contravening a condition of listing is behaviour that undermines the integrity of the trust-based listed medicines framework. Global Therapeutics allegedly breached one of these conditions by advertising their medicines for indications that were not accepted in the Australian Register of Therapeutic Goods (ARTG).

Sponsors of listed medicines must comply with relevant legislative requirements

Sponsors are reminded that at the time of listing a medicine on the ARTG, they certify that their medicine complies with all relevant requirements under the Act, which includes those in the Code. Sponsors also have an ongoing obligation to ensure that advertising for their medicine is compliant with all relevant legislative requirements and conditions of listing at all times, which include that all advertising material does not promote the medicine for therapeutic uses that are not accepted as indications in the ARTG entry.

The TGA is actively monitoring for non-compliance

The TGA conducts post-market compliance reviews of listed medicines and investigates signals of potential non-compliance, including the TGA’s findings from routine monitoring of new or changed listings of medicines on the ARTG. This allows the TGA to determine whether listed medicines comply with relevant regulatory requirements, including conditions of listing and requirements relating to advertising. The infringement notices issued to Global Therapeutics stemmed from the TGA’s monitoring of the ARTG and a subsequent investigation.

About infringement notices

The TGA can issue an infringement notice where it has reasonable grounds to believe a person or business has contravened the Therapeutic Goods Act 1989 (the Act). The payment of an infringement notice is not an admission of guilt or liability.

Provisional determination eligibility criteria

Source: Australian Therapeutic Goods Administration

This guidance helps sponsors to understand the eligibility criteria and supporting documentation required for a medicine to be eligible for provisional determination.

To assist with the process of applying for provisional determination, please see Provisional determination: A step-by-step guide for prescription medicines.

Eligibility for provisional determination

If you have not had a pre-submission meeting with TGA to discuss your prospective application for provisional determination, or if your pre-submission meeting was more than six months ago, you should notify TGA of your intent to lodge a provisional determination application at least one month prior to lodgement. Consider all of the eligibility criteria and supporting documentation before notifying us.

Provisional determination may be granted for the following medicines only:

  • a new prescription medicine which contains:
    1. a chemical, biological or radiopharmaceutical active ingredient that has not previously been included in the Australian Register of Therapeutic Goods (ARTG)

      OR

    2. a fixed combination of chemical, biological or radiopharmaceutical active ingredients at least one of which has not previously been included in the ARTG
  • an already registered prescription medicine with a new indication (a new indications medicine) that:
    1. has the same chemical, biological or radiopharmaceutical active ingredient (or fixed combination of such ingredients) as another prescription medicine included in the ARTG

      AND

    2. does not have the same indications as that other medicine

Provisional determination eligibility criteria

A medicine may be eligible for provisional determination if all eligibility criteria in the table below are satisfied.

Eligibility criteria for provisional determination*
  1. Medicine
a new indications medicine OR a new prescription medicine
  1. Serious condition

an indication of the medicine is the treatment, prevention or diagnosis of a life threatening or seriously debilitating condition

AND

  1. Comparison against existing therapeutic goods

either:

  1. no therapeutic goods that are intended to treat, prevent or diagnose the condition are included in the Register (except in the part of the Register for provisionally registered goods)

    OR

  2. if one or more therapeutic goods that are intended to treat, prevent or diagnose the condition are included in the Register (except in the part of the Register for goods known as provisionally registered goods)—there is preliminary clinical data demonstrating that the medicine is likely to provide a significant improvement in the efficacy or safety of the treatment, prevention or diagnosis of the condition compared to those goods

AND

  1. Major therapeutic advance

there is preliminary clinical data demonstrating that the medicine is likely to provide a major therapeutic advance

AND

  1. Clinical study plan
the person who made the application under subsection 22C(1) of the Act has provided sufficient evidence of the plan to submit comprehensive clinical data on the safety and efficacy of the medicine before the end of the 6 years (starting on the day that provisional registration of the medicine would commence if the Secretary were to provisionally register the medicine).

Provisional determination

The provisional determination for a medicine is specific to the following (section 22D(3) of the Act):

  • the person who is the provisional applicant
  • the medicine
  • each active ingredient of the medicine to which the determination relates
  • the provisional indication

The provisional determination therefore applies to a specific medicine for a specific indication.

The indication proposed at determination may be different to that approved at the time of registration as a result of the assessment of the quality, safety and efficacy data submitted with the registration submission for provisional registration, but must be a related indication.

Provisional determination for one indication and one medicine

You can apply for only one indication and one medicine per determination application. If you are seeking determination for multiple indications or medicines, you must submit one application for each indication and/or medicine. A separate fee applies to each application.

Only one determination can apply to each registration application. A registration application that is a combination of provisional designated and any non-provisional indications will not be eligible for review under the Provisional pathway. You may lodge a separate submission where the scope of the submission is not covered by a provisional determination.

The determination will apply to the corresponding registration application for a new prescription medicine or new indications medicine.

You must apply for more than one determination if your product is for a combination treatment, but not a fixed dose combination

In vitro diagnostic device use

If your provisional determination application is supported by clinical trials where an in vitro diagnostic (IVD) medical device was used to select patients who should or should not be treated, or to monitor patients with the aim of improving the safety or efficacy of the medicine, it is important that you supply the following information:

  • specify the name of the IVD medical device and the name of the manufacturer of the device; and
  • indicate whether the IVD medical device is an in-house IVD medical device (this includes the use of products that are intended by the manufacturer as being for research use only); and
  • if the IVD medical device is included in the ARTG, provide the ARTG entry number and name of the sponsor; or
  • if aware, provide details on any current application for inclusion of the IVD medical device in the ARTG; or
  • if the IVD medical device is not included on the ARTG, we would appreciate an update on what steps the manufacturer of the medical device might be making to include the product in the register in Australia

Supporting documentation requirements

The main body of your application should be no more than 10 pages. Include additional supporting documentation as attachments.

Your application should include a cover letter and be based on preliminary clinical data that is promising evidence of efficacy and safety of the medicine.

  • The main body of the application should address:
    • justifications for addressing all eligibility criteria
    • justification of any early, or surrogate endpoint(s) used to demonstrate clinical benefit specific to the condition that is subject of the application
    • overseas regulatory status
  • Attachments should include:
    • sufficient evidence of a plan to submit comprehensive clinical data on the safety and efficacy of the medicine within the provisional registration timeframes and whether recruitment is completed, commenced, or not started for each study.
    • summaries of pivotal studies or appropriate study summary
    • summaries of any available other important safety data obtained in the preclinical and clinical setting
    • where published papers are highly relevant for the medicine, surrogate or early endpoint, the full text of such literature (including supplementary appendices)
    • other forms of literature references or unpublished reports and expert statements may also be used in addition to the pivotal study summaries but would be considered low-level evidence
    • an abbreviations list

Preliminary clinical data

The determination stage comes before the prescription medicine registration application (for further information refer to Provisional determination: A step-by-step guide for prescription medicines.

The determination application is based on preliminary data and a plan for comprehensive data that confirms predicted benefit and safety as early as possible in the provisional registration period.

Assessment of preliminary data could be based on:

  • a non-validated surrogate endpoint
  • a single arm study
  • a non-randomised comparison
  • an interim analysis/duration of study
  • a small database
  • recruitment from a narrow group of patients

Clinical data supporting provisional determination

For a provisional determination and subsequent provisional registration application, the clinical data available may be limited. For example, data on final outcomes such as morbidity and mortality may not be available yet and results may be based on surrogate endpoints that are reasonably likely to predict clinical benefit. The scientific evidence may therefore be less comprehensive than would typically be required, but needs to be adequate and convincing evidence based on clinical trials (usually randomised controlled trials).

We recommend that you support your application with justifications and as an appendix the pivotal clinical study synopses that would be included as part of the body of the clinical study reports intended to support the registration application. Also include a clinical study plan, including study protocols and top-line recruitment status. Where study synopses are not available, provide a summary of the study with detail comparable to a study synopsis. We do not require a full module 2 summary. Do not submit full study reports.

Where a surrogate endpoint is used it should be recognised to be reasonably likely to predict an effect on clinical outcomes that establish direct clinical benefit (for example morbidity and mortality). A surrogate endpoint does not need to be validated (i.e. be an endpoint that is known to predict clinical benefit and could be used for standard approval), but needs empirical evidence to support that it is reasonably likely to predict direct clinical benefit.

Submit a justification of the suitability of the surrogate endpoint with the application that considers:

  • the ability to predict benefit based on evidence
  • the strength of the evidence
  • the certainty of the prediction
  • why remaining uncertainties are considered acceptable

The appropriateness of a surrogate endpoint for provisional registration will be assessed in the determination application.Consideration will be given to evidence linking the surrogate endpoints to important clinical endpoints, and the clinical study plan that outlines the data that will likely be provided within the period of provisional registration. Whether an endpoint is reasonably likely to predict clinical benefit (i.e. the suitability of the endpoint) will be determined on a case by case basis. Appropriateness of a surrogate endpoint in one condition may not necessarily be appropriate for a different condition.

Choosing the most appropriate registration pathway

The use of a surrogate endpoint as a primary endpoint in a pivotal study of clinical efficacy/safety will not automatically require a registration application to be submitted through the Provisional pathway.

We will determine the appropriateness of a surrogate endpoint or early endpoint for provisional registration versus standard registration on a case-by-case basis. In the case of medicines treating rare diseases where the collection of comprehensive confirmatory data for submission at a later time may not be possible, the standard registration pathway may be more appropriate than the provisional registration pathway. These medicines would not be eligible for the provisional registration pathway if you are unable to demonstrate that you have a plan to collect comprehensive clinical data on the safety and efficacy of the medicine before the end of the provisional registration period.

We strongly encourage you to arrange a pre-submission meeting with TGA prior to lodging your determination application and include this as part of the agenda.

Addressing the criteria

We will determine the validity of your justifications against the eligibility criteria on a case-by-case basis. As part of the routine determination process, the extent to which criteria are met will be assessed at the time a decision is made on the application.

Criterion 1: New indications medicine or new prescription medicine

Only certain types of medicines are eligible for provisional determination. The medicine must either be a new indications medicine or a new prescription medicine, as described in regulation 2 (Therapeutic Goods Regulations 1990).

Criterion 2: Provide a justification of the life-threatening or seriously debilitating nature of the condition

Justify the severity of the disease in Australia (i.e. its seriously debilitating or life-threatening nature), based on objective and quantifiable medical information.

Your determination application must justify the:

  • life-threatening nature of the disease or condition based on figures of mortality and life expectancy in Australia
  • seriously debilitating nature of the condition based on morbidity over the course of the disease and its consequences on patients’ day-to-day functioning

The serious debilitation or fatal outcome should be a prominent feature of both the target disease or condition and therapeutic indication, i.e. affect an important portion of the target population. The therapeutic indication is the proposed indication for ARTG registration, based on the proposed indication at the time of the determination application.

Criterion 3: Comparison against therapeutic goods registered in Australia for diagnosis, prevention or treatment

You must establish that:

  1. there are no registered therapeutic goods for diagnosis, prevention or treatment of the condition in question included on the ARTG

    OR

  2. if such therapeutic goods are on the ARTG that the medicine will provide a significant improvement in efficacy or safety

Any reference to a registered therapeutic good must be limited to the conditions of the relevant ARTG entry. Therefore, a product that is administered or applied outside the approved product information (off-label use) cannot be considered a registered therapeutic good for the purposes of regulation 10L of the Therapeutic Goods Regulations 1990.

Provisionally registered goods on the ARTG are excluded from this comparison.

Registered therapeutic goods

You must review therapeutic goods included in the ARTG for diagnosis, prevention or treatment for the proposed indication in Australia, and provide:

  • details of any registered therapeutic goods for diagnosis, prevention or treatment (overview table of Tradename(s), ARTG number, holder of the ARTG entry, and the registered indication)

    AND

  • either a declaration that there are no existing therapeutic goods in Australia in accordance with ARTG entries at the date of determination lodgement

    OR

    a justification demonstrating a likely significant improvement in safety or efficacy against existing therapeutic goods

If the medicine is already registered for a similar condition, a justification that the new indication should be considered on a provisional basis should be provided.

Justification of significant improvement in safety or efficacy

You must demonstrate, based on preliminary clinical evidence, that the medicine provides a clinical benefit over existing therapeutic goods for the indication that is the subject of the determination application (for either treatment, prevention or diagnosis of the condition) by addressing either of the following:

  • improved efficacy for the entire population relevant to the therapeutic indication

    OR

  • a better safety profile for the entire population relevant to the therapeutic indication

If new goods for the diagnosis, prevention or treatment of your proposed indication are included on the ARTG after you lodge your application, you will have the opportunity to submit a further justification of significant improvement in safety or efficacy in relation to those goods before a decision is made on your application.

Base the supporting evidence on clinical trial data. Surrogate endpoints require a justification, as explained in Clinical data supporting provisional determination.

Comparator studies against registered therapeutic goods are expected to be generated (for pivotal study reports). Scientific argument/justification may be appropriate for demonstrating significant improvement in safety or efficacy of the medicine relative to products not studied in available clinical trials (this may involve cross study comparisons).

For a claim of improved efficacy or safety (eligibility criterion 3(ii)), we will evaluate whether there is a high probability that patients will experience a clinically relevant benefit on the basis of preliminary clinical data. Therefore, this claim must be supported by evidence from summaries of the pivotal study reports that form the basis of the intended provisional registration application, and the justifications you are required to submit. You must consider the evidence/data in light of the particular characteristics of the condition (life expectancy, symptoms, pivotal study surrogate endpoints) and the existing medicines for the treatment, prevention or diagnosis of the proposed therapeutic indication.

TGA will not assess significant improvement in safety or efficacy against comparators that are a subject of concurrent determination or registration applications, those that are the subject of a provisional registration submission that is under review by TGA, or medicines that are currently provisionally registered.

Consider diagnostic performance (sensitivity and specificity), predictive values and likelihood ratios, among other endpoints, for diagnostic agents. Further information is available in the Guideline on Clinical Evaluation of Diagnostic Agents. Justify safety in the same way as for all medicines.

Criterion 4: Justification of major therapeutic advance

You must provide a justification that there is preliminary evidence that the medicine is a major therapeutic advance based on the following aspects:

  • the magnitude of the demonstrated improvement in safety and/or efficacy
  • the likelihood of the early data or surrogate endpoints to predict clinical benefit
  • the impact on patient outcomes taking into account both safety and efficacy
  • the magnitude of the advance in relation to other therapeutic goods registered for the indicated population. Where no product is registered on the ARTG, the comparison should occur against the accepted standard of care
  • the strength of the preliminary evidence, characterising the uncertainty (general TGA adopted guidelines about appropriate trial design apply)

You must include an assessment of the magnitude of the demonstrated improvement in safety or efficacy based on preliminary data (including surrogate endpoints). The demonstration of a medicine’s clinically significant benefit based on improved safety and/or efficacy is not sufficient. Rather, there should be demonstration of a major benefit, i.e. beyond the level that could be described as clinically significant. Due to the uncertainty around the benefits and risks that are demonstrated by the available preliminary data, the observed effects would be expected to translate into a major clinical benefit in order to meet this criterion (for example a major improvement in mortality endpoints). Even if the benefit appears in one aspect only, you must assess the overall impact on patient outcomes taking into account both safety and efficacy.

The medicine should provide a therapeutic advance, in comparison with other registered therapeutic goods, where possible, by addressing a major or urgent unmet need for Australian patients in a substantial way. You must describe how and to what extent the medicine is expected to fulfil a major or urgent unmet medical need with reference to the therapeutic goods registered for the indicated population, the importance of the effects of the proposed medicine, and the added value of the proposed medicine.

The description of the strength of the preliminary evidence should include a brief outline of the main available evidence (for example number and type of clinical interim or final trials with clear delineation of pivotal versus supporting studies, sample size, design and key results) on which the claim is based. In the context of preliminary data, weak data evidence would be weighted less than comprehensive data evidence. See Justification of significant improvement in safety or efficacy for further information on cross study comparisons.

A medicine that demonstrates significant improvement in safety or efficacy may constitute a major therapeutic advance if for example, the medicine that demonstrates cure rates that are considerably higher than those observed in previous treatment options, while also replacing a standard treatment which has poor tolerability and potential for serious side effects.

Criterion 5: Clinical study plan

The purpose of the clinical study plan is to set out how you will achieve submission of confirmatory efficacy and safety data required for full registration. What constitutes sufficient evidence of a plan may vary from condition to condition. In all cases, the plan should address any uncertainties or identified gaps in data that would be required to transition the medicine from provisional to full registration on the ARTG within the registration period.

Ensure that supporting trials are designed and conducted in accordance with established international standards. Plan the pivotal studies to ensure that safety and efficacy, based on comprehensive clinical data, will be established as early as possible in the provisional registration period. In general, confirmatory trials should be fully accrued or near fully accrued following the end of the second round of assessment of the future related registration application. Please supply the recruitment status of the confirmatory clinical studies, whether completed recruitment, in progress or the recruitment is yet to start. Depending on the medicine and indication the extent of the level of accrual will be a consideration for eligibility.

You may provide very early studies as supporting documentation but these cannot be considered pivotal confirmatory studies.

Clinical study plan for provisional determination

You are required to provide sufficient evidence of a clinical trials plan to submit comprehensive clinical data on the safety and efficacy of the medicine within the provisional registration period. This will be required to be updated at various milestones during the registration process and in the provisional registration period.

The clinical study plan for provisional determination application provides an example of the types of information that you could include in your clinical study plan.

Clinical study plan for provisional determination application

Example clinical study plan for provisional determination application (docx,37kb)

Study and Status Summary of objectives Confirmatory nature
(i.e. uncertainty addressed)
Key milestones Recruitment status Proposed submission date

Clinical Trial

Study ID #####

Ongoing

e.g percentage of target number of patients meeting a primary endpoint;

e.g. accrual status as percentage of planned enrolment:

  • not started;
  • started (ongoing or delayed-revised end date ;
  • complete

Patient registry

Study ID ####

Planned


Version history
Version Description of change Author Effective date
V1.0 Original publication Prescription Medicines Authorisation Branch March 2018
V1.1

Minor edit

Update to currency of data required for criteria assessment

Prescription Medicines Authorisation Branch April 2021

Notice of final decisions – ACMS #32, ACCS #29, Joint ACMS-ACCS #26, November 2020 meetings

Source: Australian Therapeutic Goods Administration

Scheduling medicines and poisons

1 Notice of final decisions to amend (or not amend) the current Poisons Standard

This web publication constitutes a notice for the purposes of regulation 42ZCZS and regulation 42ZCZX of the Therapeutic Goods Regulations 1990 (the Regulations). In accordance with regulations 42ZCZS and 42ZCZX, this notice publishes the:

  • decisions made by a delegate of the Secretary pursuant to regulations 42ZCZR and 42ZCZU;
  • reasons for those final decisions; and
  • date of effect of those decisions.

2 Final decision in relation to psilocybin and MDMA [N, α-Dimethyl-3,4-(methylenedioxy)phenylethylamine]

Note that the final decision for psilocybin and MDMA [N, α-Dimethyl-3,4-(methylenedioxy)phenylethylamine] are not published in this notice.

Amended timing on the scheduling process for these substances will be published on the TGA website following the completion of the independent review.

Final decisions and reasons

Contents

  • 1 Notice of final decisions to amend (or not amend) the current Poisons Standard
  • 2 Final decision in relation to psilocybin and MDMA [N, α-Dimethyl-3,4-(methylenedioxy)phenylethylamine]
  • 3 Final decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #32, November 2020)
    • 3.1 Final decision in relation to amygdalin and hydrocyanic acid
    • 3.2 Final decision in relation to bilastine
    • 3.3 Final decision in relation to budesonide and formoterol
  • 4 Final decisions on proposed amendments referred to the Advisory Committee on Chemicals Scheduling (ACCS #29, November 2020)
    • 4.1 Final decision in relation to azoxystrobin
    • 4.2 Final decision in relation to triticonazole
  • 5 Final decisions on proposed amendments referred to the Advisory Committee on Medicines and Chemicals Scheduling in joint session (Joint ACMS-ACCS #26, November 2020)
    • 5.1 Final decision in relation to azelaic acid
    • 5.2 Final decision in relation to 2-hydroxyethyl methacrylate (2-HEMA)
    • 5.3 Final decision in relation to magnesium hydroxide
    • 5.4 Final decision in relation to tetrahydrofurfuryl alcohol
    • 5.5 Final decision in relation to cannabidiol (private application