ADEC news

Three new associate members of the Australian Drug Evaluation Committee have recently been appointed:

• Associate Professor Nicholas Glasgow - General Practice
• Dr David Scott - Anaesthesia
• Professor Phillip Mitchell - Psychiatry

Further ADEC information <http://www.tga.gov.au/docs/html/adec/adec.htm>, including meeting dates for 2001, is available.

Clinical and regulatory requirements for the overdosage section

The section of the product information document which advises on the symptoms, signs and recommended treatment of a drug taken in overdose has been a frequent cause for discussion between the TGA, its advisory committees and sponsors. The overdosage section is often poorly drafted in comparison to other parts of the product information, and gives the impression that the contents have not been as rigorously examined. In many cases there has been a need to remove outdated advice from the overdosage section in order to avoid harmful or ineffective management being advocated. There remains a general need to tailor more accurately the overdosage section to the requirements of the treating physicians who are the primary users of the product information document. Given this focus, the information presented should constitute a clinically reasoned set of instructions that are based in evidence of efficacy and a favourable risk/benefit analysis.

The lack of clinical relevance in many overdose sections is demonstrated by a failure to examine the relative merits of the range interventions which might conceivably be useful in managing an overdose. Advocating invasive and dangerous measures before, or instead of, basic supportive care is confusing and counterproductive to good medical practice. A physician reading the overdosage section should not be left in doubt as to what is essential, proven, therapy and what are "wing and a prayer" interventions. It is not sufficient to state that an intervention can be performed, or has been performed at some time, without reference to evidence of its utility in current practice. Gastric lavage, for example, may be useful in a few circumstances but, as the chairman of the Pharmaceutical Subcommittee (PSC) has specifically commented to the Australian Drug Evaluation Committee (ADEC), it is no longer a standard therapy for gut contamination. It should not be mentioned in the overdose section without sufficient evidence that that is an effective means of decontamination for the product in question.

If a therapy is considered useful, clinically relevant information must include the presentation for which benefit has been shown as well as any hazards which might bear on the decision to implement treatment. In the case of activated charcoal, the PSC has advised, for example, that a suitable entry might be "Activated charcoal may reduce absorption of the drug if given within one to two hours of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected". Therefore, even though potentially useful, charcoal might not be indicated in a patient who presents many hours after ingestion. Similarly, various 'antidotes' which are useful in a limited number of overdoses, such as flumazenil in benzodiazepine overdose, should be advocated only if the situation in which their use is of benefit is defined. It should be noted that the main therapy for all overdoses, and the only therapy in many cases, is supportive care and this should be emphasised before any discussion of specific measures.

Because of the importance of supportive treatment and observation in the management of overdose, precise information on the toxicity which may emerge at high drug doses is of considerable value. This includes alterations to pharmacological variables such as half-life, routes of elimination, metabolism or tissue distribution which may occur in overdose. Such information might be informed by data from the toxicological phase of the drug development programme. If it is possible to quantify the incidence of toxic effects for given dosages or plasma levels, this should be done.

Given these clinical considerations, one possible approach for sponsors drafting an overdose section would be to classify the information into subsections according to its clinical significance. One such classification might be:

1. The toxicity associated with overdose, including reference to the size of overdose at which this becomes evident if such data exists. If the toxidrome is erratic in relation to the dose ingested, or delayed, this should be mentioned. Any deaths that have been recorded in single or mixed overdosage with the agent should be mentioned.
2. Relevant pharmacodynamic and pharmacokinetic data on overdose. This includes the sites of metabolism, elimination, half-life and drug interactions.
3. Any measure which is generally considered beneficial in most cases of overdose, i.e including minor or asymptomatic overdose even if treatment only constitutes supportive measures or monitoring.
4. Any measure which is generally considered not beneficial because it is ineffective or harmful in most cases. An example of an ineffective and potentially harmful therapy might be flumazenil in tricyclic antidepressant overdose.
5. Any specific measures which may aid treatment or decontamination. These should provide a brief discussion of the indications or contraindications for implementing each intervention. Immediate, basic and commonly available measures such as activated charcoal should precede discussion of specialist inpatient therapy such as haemodialysis.
6. Any monitoring including specific drug levels which might be clinically useful in the management of the overdosed patient.

The opportunity should be taken by sponsors to review and, if necessary, update the product information at any stage at which other sections of the product information are examined. The registration of new dosage forms, the addition of information regarding drug interactions and metabolism, or pharmacological data should be assessed for possible relevance to the overdose situation. Safety update data and pharmacovigilance reports should be analysed for any information regarding a product's toxidrome or successful approaches to the treatment of overdose.

From a regulatory perspective, it is expected that when the product information document is reviewed there will be evidence to support the inclusion of any statement in the overdose section. This does not imply the need to conduct specific trials, but does require an analysis of existing information on the product. As mentioned previously, this includes animal data that give an indication of useful pharmacological variables or of toxicity in overdose. The toxidrome should be defined in terms of existing studies on the drug, reports received through pharmacovigilence and reference to the literature on the product or similar agents. If there is an absence of any definitive information then advice may be given on theoretical grounds, ie administering a substance which is known to decrease oral bioavailability. Such a justification would, however, be expected to make reference to plausible physiochemical mechanisms, and the lack of direct evidence for efficacy should be included in the product information.

This document has been written primarily to aid sponsors in producing a more current and evidence based product information document. While the clinical relevance of, and supporting data for, statements in overdosage sections may need to be reviewed, many product information documents will also be simplified by the removal of unnecessary information. It is further hoped that a more clinically relevant document will allow clinicians to prevent adverse outcomes from the unintended, but expected, use of registered products in overdose.

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European certificates of suitability

In Issue 31 of TGA News <http://www.tga.gov.au/docs/html/tganews/news31/tganews31.htm> (January 2000), sponsors were advised that the Drug Safety and Evaluation Branch (DSEB) accepts European Certificates of Suitability (CoS) in lieu of Drug Master Files (DMFs) subject to certain conditions. The DSEB now wishes to clarify that the acceptance of a CoS in lieu of a DMF for an active pharmaceutical ingredient (API) does not obviate the requirement for a finished product sponsor to notify the TGA of, or seek prior approval for, any changes made to that API subsequent to the issue of the CoS, in accordance with Appendix 8 of the Australian Guidelines for the Registration of Drugs (AGRD).

Amendments to the CoS that are allowed by the European Directorate for the Quality of Medicines are not automatically accepted in Australia. However, an amended CoS can be submitted in support of an application to make changes to an API.

European Union guidelines

Following consultation between the Drug Safety and Evaluation Branch (DSEB), the TGA Laboratories Branch (TGAL) and the Australian Pharmaceutical Manufacturers Association (APMA), it has been decided that the following European Guidelines should be published as 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 guidelines included in this edition of TGA News will also be included in the next edition of Volume 1 of the AGRD.

Guidelines to be Adopted in Australia

REFERENCE	DOCUMENT NAME	PUBLISHED	EFFECTIVE DATE
CPMP/ICH/283/95	Note for Guidance on Impurities: Residual Solvents	TGA Internet Site	29 November 2000
III/3004/91	Manufacture of Investigational Medicinal Products	ADOPTED as Annex 13 of Volume 4 of the Eudralex Guidelines	15 December 2000
CPMP/QWP/8567/99	Operation of Two-Year Transition Period for Application of Note for Guidance on Residual Solvents to Marketed Products	TGA Internet Site (Included in BP 2000)	1 December 2000
III/3008/93	Note For Guidance: Control Authority Batch Release of Coagulation Factor Concentrates	TGA Internet Site	15 December 2000
III/3009/93	Control Authority Batch Release of Albumin	TGA Internet Site	15 December 2000
III/3010/93	Control Authority Batch Release of: Human Normal Immunoglobulin	TGA Internet Site	15 December 2000
III/5193/94	Note For Guidance on Plasma Pool Testing	TGA Internet Site	15 December 2000
III/5543/94	Validation of Virus Removal/Inactivation Procedure: Choice of Viruses	TGA Internet Site	15 December 2000
III/5830/93	Blood Products and Non-Enveloped Viruses	TGA Internet Site	15 December 2000
CPMP/EWP/021/97	Points To Consider on Hormone Replacement Therapy	TGA Internet Site	15 December 2000
CPMP/EWP/784/97	Points To Consider on Clinical Investigation of Medicinal Products Used in the Treatment of Osteoarthritis	TGA Internet Site	15 December 2000
CPMP/EWP/863/98	Points To Consider on Wording of Helicobacter Pylori Eradication Therapy in Selected SPC Sections	TGA Internet Site	15 December 2000
CPMP/ICH/378/95	Note For Guidance on Dose Response Information to Support Drug Registration	TGA Internet Site	15 December 2000
CPMP/QWP/054/98	Decision Trees for the Selection of Sterilisation Methods (Annex to CPMP/QWP/155/96)	TGA Internet Site	15 December 2000
CPMP/EWP/563/98	Note for Guidance on Clinical Investigation of Medicinal Products for the Treatment of Venous Thromboembolic Disease	TGA Internet Site	25 January 2001
CPMP/EWP/707/98	Points To Consider on Clinical Investigation of Medicinal Products for Prophylaxis of Intra-and Post-Operative Venous Thromboembolic Risk	TGA Internet Site	25 January 2001

The format of these lists is currently under review.

Review of procedures for unregistered drugs and devices

The TGA has completed a review of procedures for unregistered drugs and devices, including use under the Special Access Scheme, by Authorised Prescribers, in Clinical Trials and arrangement for personal importation. The TGA has updated the Guidelines for the Special Access Scheme, Authorised Prescribers, Clinical Trials (both CTN and CTX) and personal importation. These Guidelines and the associated forms for SAS, CTN and CTX, will soon be available on the TGA website.