Creation of Adverse Reactions Unit

A new Adverse Drug Reactions Unit has been created within the TGA. The new Unit is headed by Dr John McEwen, formerly Head of Clinical Evaluation Section 2 in the Drug Safety and Evaluation Branch, and will initially report directly to the National Manager.

The creation of the Unit implements the recommendations of recent reviews which have looked at the effectiveness of adverse drug reaction reporting and monitoring. In particular, it takes up the recommendations of the TGA Review of 1997 regarding the need for monitoring of adverse reactions more broadly across the range of medicines. The Unit will develop a capacity to monitor adverse reactions across the full range of medicines now regulated by the TGA, including prescription drugs, over-the-counter medicines and complementary medicines. Currently the Unit is recruiting appropriately qualified staff.

European Union (EU) 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 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 the TGA News will also be included in the next edition of Volume 1 of the AGRD.

The Guidelines will be adopted with effect from 1 October 1999.

Ref. No. CPMP/ICH/141/95
Note for Guidance on Specific Aspects of Regulatory Genotoxicity Tests

Ref. No. CPMP/ICH/279/95
Note for Guidance on the Photostability Testing of New Active Substances and Medicinal Products

Ref. No. CPMP/ICH/280/95
Note for Guidance on Stability Testing: Requirements for New Dosage Forms

Ref. No. CPMP/ICH/291/95
Note for Guidance on General Considerations for Clinical Trials

Ref. No. CPMP/ICH/294/95
Note for Guidance on Quality of Biotechnological Products: Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products

Ref. No. CPMP/ICH/302/95
Note for Guidance on Preclinical Safety Evaluation of Biotechnology Derived Pharmaceuticals

Ref. No. CPMP/ICH/363/96
Note for Guidance on Statistical Principles for Clinical Trials

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Microbial limits for non-sterile pharmaceuticals

All non-sterile pharmaceuticals should have limits for microbial content in the finished product expiry specifications. This requirement was introduced by the European Pharmacopoeia, 2nd edition, in 1996 and adopted by the British Pharmacopoeia 1993, in the 1996 Addendum. Microbial limits for active raw materials and excipients are generally not assessed by the TGA provided there are adequate microbiological controls on the finished product.

The limits to be applied to finished products are set out in the TGAL Guidelines for Assessing the Results of Microbiological Tests on Non-Sterile Pharmaceuticals for Human Use, dated 7 November 1994. The microbial limits specified in the BP/EP are not acceptable (cf. the article on page 8 of the TGA News, April 1998). Products for rectal use should comply with the limits specified for oral products.

Microbiological testing need not be performed on every batch of a product prior to release, provided a satisfactory product history has been established. In such circumstances, microbiological testing need only be performed intermittently.

Test methods of the BP/EP and USP are acceptable except that, for topical products, a medium should be used that permits the growth of all pseudomonads, at an incubation temperature of 30-32°C.

For registered prescription drug products, incorporation of microbial limits into finished product specifications, or amendment of existing limits to comply with the TGAL guidelines, should be notified to the Drug Safety and Evaluation Branch in accordance with Appendix 8 of the AGRD, volume 1.

New clinical unit for DSEB

As a result of an increasing workload on evaluation of prescription drug applications, a fifth Clinical Evaluation Section has been established within the Drug Safety and Evaluation Branch. The new Section will be headed by Dr Neil Mitchell and will deal with endocrine drugs. These drugs were formerly evaluated within Clinical Evaluation Section 1.

The Heads of the DSEB Clinical Evaluation Sections are:

1. Allan Black
2. Grahame Dickson
3. Phil Chipman
4. Jamie McGinness
5. Neil Mitchell

Section 31 requests on new prescription drug applications

Section 31 of the Therapeutic Goods Act allows the Secretary or his/her delegate to require an applicant to provide information which will allow an application to be evaluated. The period between making the request and receiving the information is not counted as part of any statutory time limits which apply to the application - ie the "clock" stops while the TGA is waiting for the applicant to respond.

In the case of new applications to register prescription drugs, requests for information under section 31 are made in the great majority of cases. Some requests are made prior to acceptance of the application, and the majority during the evaluation phase. Some applications may involve large numbers of section 31 requests. The number of requests made under section 31 depends very much on the quality of the information package provided to the TGA at the outset. The length of the clock stops depends on how long it takes the applicant to provide the requested information.

The pharmaceutical industry has expressed some concern recently about the numbers of section 31 requests being made by the Drug Safety and Evaluation Branch prior to acceptance of applications. The industry has put the view that, if an application is in the required format and is not obviously deficient in information, it should be accepted, and any section 31 requests should be made during the evaluation phase. This would be consistent with the recommendations of the Baume report in 1991.

A recent review of a sample of section 31 requests made by the DSEB prior to acceptance of applications indicates that the great majority arise at that point because the application does not meet the format set out in the Australian Guidelines for the Registration of Drugs.

There are currently several avenues of review available to an applicant who believes that a section 31 request is unjustified. The applicant may contact the delegate who made the request and seek to resolve the matter. The applicant may also seek review by the Standing Arbitration Committee, an informal body consisting of nominees of the TGA and the pharmaceutical industry. Where the request involves bioequivalence data, the applicant may seek review by the Pharmaceutical Subcommittee of the ADEC.

At a more formal level, an applicant may seek review of a section 31 request under section 60 of the Act. This provides for review of the TGA's decision by the Minister or his/her delegate and, if the decision is confirmed, provides for a right of appeal to the Administrative Appeals Tribunal.

At a liaison meeting held between the Australian Pharmaceutical Manufacturers Association (APMA) and staff of the DSEB on 30 March 1999, it was agreed that an additional informal procedure would be put in place by the DSEB to deal with cases where the applicant believes a section 31 request is unjustified. This procedure will apply, for a trial period of three months, in cases where an applicant has contacted the delegate and remains dissatisfied with the outcome. The applicant may refer the matter to the Head of the DSEB Coordination Unit, who will arrange for it to be placed on the agenda for the weekly meeting of DSEB Section Heads. The intention is not for Section Heads to review the decision, but rather to ensure they are aware of the circumstances of the request and the applicant's viewpoint, with a view to achieving consistency by DSEB delegates in making section 31 requests.