Complementary Healthcare Consultative Forum

A full report of the fifth meeting of the Complementary Healthcare Consultative Forum (CHCF) is now available.

Included in the items on the Forum's agenda were:

• discussions on the regulation of complementary medicine practitioners, including the funding program for the Establishment of Uniform National Registration Systems for Suitably Qualified Practitioners;
• progress on Trans-Tasman Regulatory Reform; and
• discussions on the complementary medicines industry in Australia and international competitiveness.

The CHCF, which is chaired by Senator Tambling, was established as part of the reforms in complementary medicines introduced in 1999 to facilitate consultation between government and the complementary healthcare sector. The Forum includes members from all mainland states and territories of Australia and draws on a wide input from practitioner, research, consumer, educator, manufacturer, marketing and policy-making interests.

Data requirements for new sunscreen active ingredients

The Medicines Evaluation Committee (MEC) advises the TGA on the regulation of OTC medicines (including sunscreens) in Australia. The committee recently considered data requirements to support the approval of new sunscreening agents for use in listed sunscreen products.

For the benefit of sponsors who may be considering a new sunscreening agent, the committee's initial advice is presented below. This advice is of a general nature and is intended to assist sponsors in submitting appropriate data. A different approach may be warranted for particular substances.

The following studies should form the basis of the application:

• acute oral toxicity
• acute eye irritation
• skin sensitisation
• acute dermal irritation
• toxicokinetics¹
• genotoxicity testing²
• reproductive toxicity testing³
• photostability
• sub-chronic oral toxicity
• carcinogenicity⁴
  1. Toxicokinetic studies. An in vivo determination of dermal and oral absorption is needed to establish systemic exposure via both routes and to enable the interpretation of the toxicity studies.
  2. Genotoxicity testing in bacterial and mammalian cell lines, photomutagenicity test in bacteria, photomutagenicity in a chromosomal aberration test and an in vivo chromosome aberration assay.
  3. For assessment of developmental and fertility effects.
  4. In vivo carcinogenicity and photocarcinogenicity bioassays or justification for not providing these studies. A justification could be based around issues such as:
     • the expected pattern of use (identify possible low exposure)
     • results of mutagenicity studies
     • lack of similarity to existing molecules with known carcinogenic activity
     • low persistence in the skin
     • low in vivo absorption
     • lack of photosensitisation or phototoxic potential
     • proven photostability
     • lack of possible adverse effects on the skin (change to epidermis/dermis)

Another issue that should be addressed is the potential for interaction with other commonly used sunscreening agents, since sunscreen products generally contain more than one active ingredient.

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European Union (EU) guidelines

Following consultation between the TGA Drug Safety and Evaluation Branch, the TGA Laboratories Branch and the Australian Pharmaceutical Manufacturers Association, it has been agreed that the following European Guidelines should be adopted in Australia. The EU Guidelines are generated by the Committee for Proprietary Medicinal Products/International Conference on Harmonisation (CPMP/ICH) and are to be regarded as part of Volume 1 of the Australian Guidelines for the Registration of Drugs (AGRD).

The format of these lists is currently under review.

EU Guidelines adopted in Australia since February 2001

These guidelines have been published on the TGA website

CPMP/BWP/477/97
Note for Guidance on Pharmaceutical & Biological Aspects of Combined Vaccines
Published: TGA Internet Site
Effective: 13 February 2001

CPMP/ICH/282/95
Note for Guidance on Impurities in New Medicinal Products
Published: TGA Internet Site
Effective: 13 February 2001

CPMP/EWP/602/95 Rev 1
Points to Consider in the Assessment of Anti-HIV Medicinal Products
Published: TGA Internet Site
Effective: 13 February 2001
Amendment: "This amendment principally concerns surrogate markers used for approval under Exceptional circumstances (Article 13(2) of Council Regulation No 2309/93). There are no legislated "exceptional circumstances" provisions in Australia. Therefore, only the scientific principles for assessment in the revised guideline are adopted."

CPMP/EWP/565/98
Points to Consider on Clinical Investigation of Medicinal Products for the Treatment of Amyotrophic Lateral Sclerosis (ALS)
Published: TGA Internet Site
Effective: 23 February 2001

CPMP/EWP/556/95
Points to Consider on Clinical Investigation of Slow-acting Anti-Rheumatic Medicinal Products in Rheumatoid Arthritis
Published: TGA Internet Site
Effective: 23 February 2001

CPMP/EWP/235/95 Rev 1
Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Cardiac Failure
Published: TGA Internet Site
Effective: 23 February 2001

CPMP/SWP/1042/99
Note for Guidance on Repeated Dose Toxicity
Published: TGA Internet Site
Effective: 23 February 2001

CPMP/BWP/390/97
The Introduction of Nucleic Acid Amplification Technology (NAT) for the Detection of Hepatitis C Virus RNA in Plasma Pools Addendum to Note for Guidance on Plasma derived Medicinal Products (CPMP/BWP/269/95)
Published: TGA Internet Site
Effective: 23 February 2001

CPMP/ICH/281/95
Note for Guidance on Validation of Analytical Procedures: Methodology
Published: TGA Internet Site
Effective: 23 February 2001
NB. As guideline CPMP/ICH/281/95 specifically identifies, with respect to the approach to methodology, that biologicals and biotechnological products may be treated differently than chemical entities, the TGA recognises that the detection and quantitation limits expected of standard chemical assays (including HPLC/GC) may not be applicable to biological assays.

CPMP/QWP/159/96 Corr
Note for Guidance on Maximum Shelf Life for Sterile Products After First Opening or Following Reconstruction (Annex to the Note for Guidance on Stability testing of New active substances & Medicinal products (CPMP/ICH/380/95))
Published: TGA Internet Site
Effective: 23 February 2001
NB. The allowance "...unless reconstitution/dilution (etc) has taken place in controlled and validated aseptic conditions" detailed in the section: 'Unpreserved Sterile Products - Specific Text for Preparations for Infusion or Injection.' will only be permitted for products prepared in TGA licensed compounding facilities and in those hospital pharmacies that have been formally audited to the NCCTG standard and SHPA guidelines and have demonstrated that they can provide the appropriate level of sterility assurance.

CPMP/BWP/269/95 Rev 2
Note for Guidance on Plasma-Derived Medicinal Products
Published: TGA Internet site
Effective: 19 April 2001

CPMP/BWP/328/99
Development Pharmaceutics for Biotechnological and Biological Products (Annex to Note for Guidance on Development Pharmaceutics)
Published: TGA Internet site
Effective: 19 April 2001

CPMP/BPWG/198/95 Rev 1
Note for Guidance to Assess Efficacy and Safety of Human Plasma Derived Factor VIII:C and Factor IX:C Products in Clinical Trials in Haemophiliacs Before and After Authorisation
Published: TGA Internet site
Effective: 19 April 2001

CPMP/BPWG/388/95 Rev 1
Note for Guidance on the Clinical Investigation of Human Normal Immunoglobulin for Intravenous Administration (IVIg)
Published: TGA Internet site
Effective: 19 April 2001

CPMP/BPWG/575/99
Note for Guidance on the Clinical Investigation of Human Anti-D Immunoglobulin for Intravenous and / or Intramuscular Use
Published: TGA Internet site
Effective: 19 April 2001

CPMP/EWP/197/99
Points to Consider Concerning Endpoints in Clinical Studies with Haematopoeitic Growth Factors for Mobilisation of Autologous Stem Cells
Published: TGA Internet site
Effective: 19 April 2001

CPMP/EWP/504/97
Points to Consider On Clinical Investigations of Medicinal Products in the Treatment of Patients with Acute Respiratory Distress Syndrome
Published: TGA Internet site
Effective: 19 April 2001

CPMP/EWP/519/98
Note for Guidance on Clinical Investigation of Steroid Contraceptives in Women
Published: TGA Internet site
Effective: 19 April 2001

CPMP/EWP/562/98
Points to Consider on Clinical Investigation of Medicinal Products in the Treatment of Patients with Chronic Obstructive Pulmonary Disease (COPD)
Published: TGA Internet site
Effective: 19 April 2001

CPMP/EWP/570/98
Points to Consider on the Clinical Investigation of New Medicinal Products in the Treatment of Acute Coronary Syndrome (ACS) Without Persistent ST-Segment Elevation
Published: TGA Internet site
Effective: 19 April 2001

CPMP/EWP/2655/99
Points to Consider on Pharmacokinetics and Pharmacodynamics in the Development of Antibacterial Medicinal Products
Published: TGA Internet site
Effective: 19 April 2001

CPMP/ICH/364/96
Note for Guidance on Choice of Control Groups in Clinical Trials
Published: TGA Internet site
Effective: 19 April 2001

CPMP/ICH/2711/99
Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric Population
Published: TGA Internet site
Effective: 19 April 2001

CPMP/QWP/158/96
Note for Guidance on Dry Powder Inhalers
Published: TGA Internet site
Effective: 19 April 2001

CPMP/QWP/604/96
Note for Guidance on Quality of Modified Release Products - Section (Quality)
A: Oral Dosage Forms
B: Transdermal Dosage Forms
Published: TGA Internet site
Effective: 19 April 2001

CPMP/BPWG/1561/99
Note for Guidance on the Clinical Investigation of Recombinant Factor VIII and IX Products
Published: TGA Internet site
Effective: 19 April 2001

CPMP/ICH/136/95
Mod Note for Guidance on Reproductive Toxicology: Toxicity on Male Fertility (Addendum to CPMP/ICH/386/95 Note for Guidance on Reproductive Technology: Detection of Toxicity to reproduction for Medicinal Products)
Published: TGA Internet site
Effective: 19 April 2001

CPMP/ICH/2736/99
Note for Guidance on Stability Testing of New Drug Substances and Products (Revision of CPMP/380/95)
Published: TGA Internet site
Effective: 19 April 2001

CPMP/ICH/286/95 Mod
Note for Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
Published: TGA Internet site
Effective: 19 April 2001

CPMP/EWP/566/98 Rev 1
Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Epileptic Disorders
Published: TGA Internet site
Effective: 19 April 2001

CPMP/EWP/560/95
Note for Guidance on the Investigation of Drug Interactions
Published: TGA Internet site
Effective: 19 April 2001

CPMP/CVMP/QWP/115/95
Note for Guidance on the Inclusion of Antioxidants and Antimicrobial Preservatives in Medicinal products
Published: TGA Internet site
Effective: 19 April 2001

Volume 2B - Presentation and Content of the Dossier Notice to Applicants of the Rules Governing Medicinal Products in the European Community
Published: TGA Internet site
Effective: 19 April 2001
Amendment: "Note that the administrative details in these rules do not apply in Australia"

CPMP/986/96 (SWP)
Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-cardiovascular Medicinal Products
Published: TGA Internet site
Effective: 4 April 2001

CPMP/EWP/482/99
Points to Consider on Switching between Superiority and Non-inferiority
Published: TGA Internet site
Effective: 29 June 2001
Amendment: "Please note that there is no requirement in Australia to demonstrate superiority."

CPMP/ICH/367/96 Corr
Note for Guidance on Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
Published: TGA Internet site
Effective: 29 June 2001

CPMP/EWP/552/95, Rev 1
Note for Guidance on Postmenopausal Osteoporosis in Women
Published: TGA Internet site
Effective: 30 August 2001

CPMP/BWP/269/95 Rev 3
Note for Guidance on Plasma-Derived Medicinal Products
Published: TGA Internet site
Effective: 30 August 2001

CPMP/EWP/567/98
Note for Guidance on Clinical Investigation of Medicinal Products for the Treatment of Bipolar Disorder
Published: TGA Internet site
Effective: 30 August 2001

CPMP/ICH/300/95
Note for Guidance on Duration of Chronic Toxicity Testing in Animals (Rodent and Non-rodent Toxicity Testing) with TGA Amendment
Published: TGA Internet site with amendment
Effective: 30 August 2001
TGA amendment:
It should be noted that while the ICH guidance recommends nine-month chronic toxicity studies in non-rodents, the TGA considers nine-month studies in non-rodents acceptable for most drug development programs, shorter studies may be equally acceptable in some circumstances and longer studies may be more appropriate in others, as follows:

• Six-month studies may be acceptable for indications of chronic conditions associated with short-term, intermittent drug exposure, such as bacterial infections, migraine, erectile dysfunction, and herpes.
• Six-month studies may be acceptable for drugs intended for indications for life-threatening diseases for which substantial long-term human clinical data are available, such as cancer chemotherapy in advanced disease or in adjuvant use.
• Twelve-month studies may be more appropriate for chronically used drugs to be approved on the basis of short-term clinical trials employing efficacy surrogate markers where safety data from humans are limited to short-term exposure, such as some acquired immunodeficiency syndrome (AIDS) therapies.

Twelve-month studies may be more appropriate for new molecular entities acting at new molecular targets where post-marketing experience is not available for the pharmacological class. Thus, the therapeutic is the first in a pharmacological class for which there is limited human or animal experience on its long-term toxic potential.

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Listing process redevelopment

Readers may be aware that a model for a new listing system was developed by the Listed Medicinal Products Project Advisory Committee (PAC) in the period from late-1998 to mid-2000. The model includes new legislative, administrative and IT arrangements and is aimed at streamlining market access whilst enhancing post-market monitoring and review of medicines. Under the new listing system, sponsors will assume greater responsibility in relation to self-assessment and the certifications they make under the legislative controls of the Therapeutic Goods Act.

The new legislation came into effect on 22 September 2001, delivering changes to the regulation of listed medicines. New administrative arrangements were introduced at the same time so that the TGA delivers as many aspects of the listing model as possible. Unfortunately the forecast release date of the new electronic lodgment system for listed medicines (ELF3) has been extended. As an interim measure, an update of ELF Version 2 (ELF 2.5) was released in September and will remain in operation until ELF3 is implemented. Work is continuing on the development of ELF3 and the TGA will keep sponsors informed of progress through their industry associations.

New conditions of listing to guard against aristolochic acid

Aristolochic acids are primarily present in Aristolochia species of plants and are known to be potent nephrotoxins and carcinogens which have caused severe kidney damage in a significant number of cases overseas. To the best of the TGA's knowledge there is no safe level of exposure to aristolochic acids and Aristolochia species are restricted from inclusion in human medicines. However, aristolochic acids have also been detected in a number of medicines not labelled to contain Aristolochia species. This is thought to arise from misidentification of raw plant materials or confusion with traditional Chinese names and is most commonly associated with material from the genera Akebia, Asarum, Bragantia, Clematis, Cocculus, Diploclisia, Menispernum, Saussurea, Sinomenium, Stephania and Vladimiria.

Regardless of the reason for the presence of aristolochic acids in different medicines, it is important that such products are not supplied in the Australian marketplace. The TGA is imposing additional conditions of listing to products containing herbal material from any of the eleven genera listed above to ensure that complementary medicines supplied in Australia do not pose a public health risk due to aristolochic acids. The additional conditions of listing require the submission of evidence that Aristolochia species or aristolochic acids are not present in the product. Acceptable forms of evidence are either a certificate of chemical analysis confirming the absence of aristolochic acids or a certificate of botanical identification confirming the identification of the raw herbs used in manufacture. The certificates must be supplied on a batch by batch basis and be submitted to the Office of Complementary Medicines prior to supply of each batch on the Australian market.

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New substances approved for listed medicines

Since the last update, provided in the June edition of TGA News, new substances have been approved for use as active ingredients in listable medicines following an evaluation of their safety by the Complementary Medicines Evaluation Committee and publication of a notice in the Commonwealth of Australia Gazette.

The approved substances are: (S)-S-Adenosylmethionine and ademetionine in the form of sulphate, tosylate or mixed sulphate/tosylate salts and must be supplied with a label that includes a statement to the following effect:

"Individuals who are using prescription anti-depressants, or suffer from bipolar depression should not use this product unless under the supervision of a health practitioner".

Amendments to Item 10, Part 1 of Schedule 4 of the Regulations have also been made to allow the use of additional amino acids in listable medicines. These changes result in the following substances being made listable: calcium diglutamate, glutamic acid, glutamic acid hydrochloride, magnesium diglutamate, methionine, monoammonium glutamate, monopotassium glutamate, monosodium glutamate. Please note that these amino acids and salts are listable in the L form only. DL and D forms are not listable. Other salts of L glutamic acid are not listable.

New Therapeutic Goods Order for the labelling for medicines - TGO 69

Therapeutic Goods Order No. 69 General requirements for labels for medicines <http://www.tga.gov.au/docs/html/tgo/tgo69.htm> (TGO 69) took effect on 12 September 2001.

This new labelling Order replaces Therapeutic Goods Order No. 48 General requirements for labels for drug products (TGO 48) and its subsequent amendments. Transition arrangements provide for existing medicines to be labelled in accordance with either TGO 69 or TGO 48 until 30 June 2004, thereby allowing sponsors to make any necessary changes to labels at convenient times within production programs. However, medicines that are the subject of an application made on or after 1 January 2002 will need to be labelled in accordance with TGO 69.

TGO 69 is the end-result of a comprehensive review of labelling requirements undertaken by the Therapeutic Goods Committee and involving industry, consumers and the TGA. Closely involved in the review were the Australian Pharmaceutical Manufacturers Association, the Australian Self-Medication Industry Inc., and the Complementary Healthcare Council of Australia.

Some of the key differences between TGO 69 and its predecessor TGO 48 include:

• updated terminology and definitions;
• provision for product types not previously included;
• provision for new packaging types and manufacturing technologies;
• extension of reduced labelling requirements for small containers to containers with a capacity up to 20 millilitres; and
• revision of the list of excipients to be declared on labels in order to address safety concerns such as allergy or the needs of patients with specific medical conditions, and introduction of group names for this declaration where two or more excipients within a group are present.

Copies of the Order may be obtained from the TGA website or purchased from the TGA Publications Office (tel 1800 020 653).

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Safety related notifications (SRN) to product information

As foreshadowed in TGA News, Issue 31, January 2000, this article follows "Editorial Changes to Product Information" providing a history of Safety Related Notifications and comments about successful Safety Related Notifications.

In July 1991, the Baume Report¹ recommended (R49) that:

"Sponsors should be permitted to make safety-related changes to product information without approval if the changes place further restrictions on the use of the product. The TGA should be notified of the changes within 5 working days".

Accordingly, Section 32(4) of the Therapeutic Goods Act 1989 (the Act) makes provision for this change to the Product Information via a Notification facility, provided that the provisions of the Act are satisfied, that is,

TGA News, Number 6, August 1991, identified, along with reminding sponsors to alert the medical profession to the new safety concerns, that the requirements for these Notifications were:

• the changes must serve to restrict further the use of the product, ie to delete an indication, reduce the patient population or to add a warning, precaution, adverse reaction or contraindication;
• the TGA must be notified of such changes within five working days;
• the notification must take the form of submitting a copy of the approved Product Information on which the changes have been made and are clearly identified; and
• an accompanying letter should state that
  • no other changes have been made, and
  • the changes are supported by data in the sponsor's possession. Supporting data should not be submitted at the time of Notification, but may be requested later.

TGA News, Number 8, December 1991, stated that not all Notifications that had been received by then were within the intention of the Baume Recommendation and, as they were outside the provisions of the Act, left the sponsor unprotected from unapproved or incorrectly notified changes to Product Information. That is, the supply of Product Information documents with unauthorised, non-safety-related changes is a technical breach of the conditions of supply for the registered good(s).

Successful Safety Related Notifications

The basic principle to remember about the acceptability of a safety related Notification is that the net effect of the Notification would be to:

• reduce the patient population for the use of the product, or
• provide a cautionary statement which, if observed, would also serve to reduce further the use of the product by reducing non-considered use in particular "at-risk" patient groups.

The following checklist may provide a useful working tool for making Safety Related Notifications:

• Are the statements editorial, eg changing or adding headings, substituting one name for another, replacing text? If so, the changes are not acceptable under Section 32(4) of the Act.
• Does the Notification reduce the patient population? If so, the Notification is acceptable.
• Does the Notification actually add a warning or precaution? If so, the Notification is acceptable.
• If in doubt, ring the Application Entry Team (AET) to discuss your concerns on 02 6232 8113.
• As a courtesy, if the safety related notification concerns a significant adverse reaction that could affect the use of the medicinal product, please telephone the relevant Head of the Clinical Evaluation Section concerned.
• Remember to notify changes to both versions of a product information document (ie for both the "all registered" and "marketed only" documents) where this applies.

You are reminded that changes to the Categorisation of Risk of Drug Use in Pregnancy² which involve a change to a more restrictive Categorisation of Risk, are acceptable as a Safety Related Notification.

New application entry cell processes

Sponsors already receive acknowledgment letters upon receipt of their Notifications. Since problems continue to occur, the TGA will now formally advise of the acceptability of the Notification, that is, whether it complies with the Act or not. All attempts will be made to provide this response promptly, however care should be taken by the sponsor prior to the lodgement of the Notification, to ensure that the Notification is acceptable (see Section 5.2.3.1 "The Guidelines", Australian Guidelines for the Registration of Drugs Vol.1, July 1994).

It would assist the TGA and the sponsor to maintain accurate records if:

• The sponsor includes all product information documents that are the subject of the notification (ie the document that applies to all registered products and the document that applies to the marketed products). The inclusion in the covering letter of all relevant AUST R numbers is a good practice that will avoid the need to re-notify products that might be otherwise unnoticed.
• The TGA's approval date is included in the approved product information text, as is required. The safety related notification dates should be listed separately on the document.
• The date on the covering letter matches the date shown on the product information document and the covering letter identifies the new text that has been added.

The relevant processing fee/s should accompany each notification. If there is doubt about this, please contact the Application Support Team on 02 6232 8121.

Examples of incorrect notifications

Some examples of common misinterpretations of the provisions of Section 32(4) of the Act, are as follows:

• The addition of headings (as per CIOMS III) to augment additional Adverse Reactions.
• Correction to the name of the sponsor or the sponsor's address.
• Statements employing phrases such as "unknown clinical significance".
• Inclusion of the list of excipients in the Description section of the product information document, even in combination with the general Contraindication, "Hypersensitivity to any component of the product". (The mention of specific substances in a new contraindication would be acceptable).
• Changing Brand Names to generic name.
• Editorial changes (irrespective of whether notified with one acceptable safety-related warning).
• Changes to Dosage and Administration section of the Product Information.
• Adding a Warning against use outside of the approved indications (this could potentially broaden the use of the product).
• Adding a Warning or Precaution based on a comparative claim with a member of the same drug class, eg using data on systemic absorption to warn against topical absorption of a drug in the same class.
• Adding a Warning or Precaution, being a comparative warning or precaution, of a drug with a drug of the same class, eg clinical studies show that drug A appeared to be much less toxic in acute overdose than drug B.
• Adding a reference to a Clinical Trial as a Warning.
• Adding a Warning or Precaution that does not actually provide a cautionary statement about the use of the product, eg a non-committal epidemiological statement.
• Adding elaborate and detailed drug interactions involving CYP450 systems may require evaluation.
• Adding information on treatment of overdose.
• Removing the frequency of occurrence of an ADR without replacing it with a more frequent occurrence, or adding a causality where none existed previously.

The Safety Related Notification facility provides a unique opportunity to sponsors to make important safety-related changes to their Product Information. Under the provisions of the Act, if the Notification is appropriately selected, then the sponsor has a statutory right to approval. This opportunity allows for timely changes to be made to the Product Information to ensure the continued safe use of the product.

References

1. Peter Baume, A Question of Balance. Report on the future of Drug Evaluation in Australia. July 1991, AGPS 1991.
2. Prescribing medicines in pregnancy <http://www.tga.gov.au/docs/html/medpreg.htm>, 4th edition, 1999