Literature based submissions - success or failure?

Introduction

In the early 1990's, the Australian Drug Evaluation Committee became concerned that many companies had not upgraded the Product Information documents of older products to reflect contemporary and scientifically justifiable medical practice that had evolved since the time of registration of the product. Ajoint working party comprising representatives from the APMA, TGA and the ADEC met in a co-operative spirit to find a solution to this problem. It recommended that TGA should accept submissions from sponsors for extensions of indications and other changes to the PI which included published papers of high standard in peer review journals and/or literature reviews, consensus guidelines and/or supporting documentation from professional societies and colleges.

A Policy Guideline was released in August 1993 to assist sponsors in reducing problems associated with the use of published data. This introduced the concept of performing a literature search and providing the search strategy together with a justification for the selection of the studies submitted in support of the application, including comments on the quality of the studies. DSEB's approach was further codified with the release of the 'Literature Based Submissions - Points to Consider' document in October 1995. The Points to Consider (PTC) document embodies the approach that should be taken when undertaking a systematic review of the literature and is very much in keeping with the world wide trend toward evidence based medicine, such as that practised by the Cochrane Collaboration. It was intended that this type of approach be used for updating PIs with respect to extensions of indication, change of dose or dose frequency and changes in route of administration.

The purpose of this review is to examine the period after the release of the PTC document in order to assess the success or otherwise of DSEB's current approach to literature based submissions (LBS). In the period from 1993 to the release of the PTC document, LBS were not flagged on the DART system and it is almost impossible to identify how many LBS were received. The situation after release of the PTC document is much clearer, as all LBS received since then have been flagged on the DART system.

The first 18 months after the release of the Points to Consider document

1. Number of submissions received by DSEB

In the period 16.10.95 to 16.4.97, 30 LBS were submitted by 13 sponsors. In the same period, 430 category 1 applications were received. Thus, LBS represented approximately 7% of major (category 1) applications.

2. The type of application received

PURPOSE*	No. LBS
Extension of indication (4A)	9	30%
NCE (1A)	3	10%
New combination (3)	1	3.3%
Change in dose/dosage regimen (7)	1	3.3%
Change in patient group (7A)	1	3.3%
Change to PI - clinical aspects (8F)	14	46.7%
New strength (9)	1	3.3%
TOTAL	30	100%

* where a submission was associated with more than one application type, the major application type has been used

It can be seen that the types of application are consistent with those expected to be associated with LBS. Furthermore, applications for three New Chemical Entities (NCE) and one new combination were accepted in that time. Ordinarily, conventional data would be required for such applications. The drugs in question were NCEs in Australia by virtue of the fact that they were not on the ARTG. However, two of these drugs had been marketed for more than 10 years in overseas countries and for the other there were extenuating circumstances such that there was little possibility of the sponsor being able to conduct studies in order to meet conventional data requirements. This underlines DSEB's flexible and case by case approach to LBS.

3. Marketing history of the drug

As shown below, approximately 77% of LBS have involved older drugs with a marketing history of greater than 10 years. The fact that 20% of the LBS were for drugs marketed less than five years indicates that DSEB and sponsors have taken a wider view than originally intended by the Joint Working Party on Product Information (see comments relating to NCEs above).

Duration of marketing in Australia	No. LBS
NCE	3	10%
New combination	1	3.3%
<5 years	2	6.7%
5-10 years	1	3.3%
>10 years	23	76.7%
TOTAL	30	100%

4. Current status of applications

The current status (as at 1.6.97) of the 30 LBS included in the above tables is shown below:

STATUS	Number of applications
Accepted for evaluation	26
Evaluation completed	11
Pre ADEC phase	2
Post ADEC phase, but not finalised	1
Approved	7
Rejected	1
Evaluation ongoing	15
Application entry phase	2
Application withdrawn	2

The two applications withdrawn during the application entry phase were submitted in the period immediately after the release of the PTC document. It is fair to say that this was a period during which sponsors were still coming to terms with what is required of a literature based submission. One of the applications was withdrawn, not because the sponsor could not comply with the recommended data 'requirements', but as an acknowledgement by the sponsor that they had failed to address any of the issues raised by ADEC when an earlier application for the same indication had been rejected. It is also important to note that the 11 applications for which evaluations have been completed were submitted prior to July 1996. Despite difficulties encountered in these earlier times, all but one of the applications submitted during this time that have been to ADEC have been successful. The one rejection so far was made on the basis that there were inadequate and insufficient data to support the proposed change to the recommended dose and method of administration of the drug concerned. It is also noted that in this case the sponsor had chosen not to follow DSEB's PTC document. It is important to highlight here, firstly, that adherence to the PTC document is not a prerequisite for a submission to be accepted or approved and secondly, that the PTC document is intended to provide sponsors with assistance in preparing the best possible data package through a systematic review of the literature.

Recent events

It is clear, from the Review of TGA undertaken by KPMG Management Consulting and, more recently, DSEB's Independent Review of the Product Information, that there is a perception among sponsors that there have been few LBS and that these have not been successful. This is not supported by the figures above, but highlights the limited opportunities for feedback from DSEB to sponsors. The only feedback to sponsors as a group since the release of the PTC document was at the ARCSTGA conference in August last year.

Another concern is the view that DSEB has implemented 'overly bureaucratic and rigorous' data requirements. DSEB acknowledges it has set a high standard and in so doing, has made the task of updating PIs more difficult than industry had expected when the recommendations of the joint working party were first released.

In response, DSEB has set up a LBS working group to address these concerns about updating PI documents for older drugs. This group has already identified a number of areas where difficulties have been experienced. One of these has been the planning and conduct of literature searches by sponsors. Also, a particular concern is that LBS have not assisted sponsors to make changes of a more minor but equally as important nature, such as pharmacology/pharmacokinetic information.

The future

DSEB is taking a two pronged approach to the updating of PI of older drugs. Firstly, with respect to extensions of indication and changes in dose and route of administration, it is expected that the current recommendation that a thorough literature search be performed and justification for selection of papers be provided as part of the submission will remain. As a result of the planned implementation of the KPMG recommendation that DSEB participate in presubmission consultations, sponsors intending to submit LBS will be asked to meet with DSEB with a view to reaching an agreed strategy for the performance of literature searches at the earliest stages of planning for the LBS. In the past there have been considerable delays for sponsors in having LBS accepted for evaluation because DSEB has not agreed with the strategy of the literature search. In some cases this has resulted in sponsors having to perform a new search, reassemble data packages and have the Expert Report rewritten. These problems should be overcome if DSEB and the sponsor can reach an agreed position on the search strategy to be used.

Secondly, DSEB is actively pursuing avenues by which sponsors can make other updates through the use of published literature, but without the requirement for an extensive search and through the use of standard reference texts. It is envisaged that the current PTC document will eventually become one of a series of documents at the disposal of sponsors to assist them in updating the product information of older products.

Finally, DSEB will be providing regular feedback on these developments and our ongoing experience with LBS through the TGA News.

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European Union guidelines

Detailed below is a list of European Union (EU) Guidelines - Committee for Proprietary Medicinal Products/International Conference on Harmonisation (CPMP/ICH) documents that have been considered by the Drug Safety and Evaluation Branch (DSEB), the TGA Laboratory Branch (TGAL) and the Australian Pharmaceutical Manufacturers Association (APMA) and agreed for adoption in Australia since the last update for Volume 1 of the Australian Guidelines for the Registration of Drugs (AGRD) in July 1994.

Ref. No. III/3477/92
Production and Quality Control of Medicinal Products Derived by Recombinant DNA Technology. (Revision 1994)

Ref. No. III/3630/92
Biostatistical Methodology in Clinical Trials in Applications for Marketing Authorisations for Medicinal Products.

Ref. No. III/3673/92
Clinical Investigation of Medicinal Products in the Treatment of Anxiety Disorders.

This Guideline is to be adopted. However, intending Sponsors for drugs for this purpose in Australia are asked to take into account Australian clinical practice in this area, particularly with regard to the:

• duration of studies, given that panic disorder and obsessive-compulsive disorder are long-term illnesses;
• sample size of clinical trials; and
• measurement scales used to assess efficacy; objective outcome measures should be considered wherever available.

Ref. No. III/3612/93
Use of Transgenic Animals in the Manufacture of Biological Medicinal Products for Human Use.

Ref. No. III/5863/93
Gene Therapy Products - Quality Aspects in the Production of Vectors and Genetically Modified Somatic Cells.

Ref. No. III/5081/94
Toxicokinetics: A Guidance for Assessing Systemic Exposure in Toxicology Studies.

Ref. No. III/5082/94
Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution.

Ref. No. III/5083/94
Carcinogenicity: Guidance for Dose Selection for Carcinogenicity Studies.

Ref. No. III/5084/94
The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions.

While the DSEB has supported the adoption of this Guideline, attention is drawn to:

1. Applicability, Section 7, which states that circumstances exist in which the Guidelines may not be applicable. It should be noted that the listing of exceptional circumstances is not exhaustive. Sponsors should give careful attention to whether, in any particular instance, the clinical safety of the product would be adequately supported by the numbers of subjects proposed, and;
2. Supplementary data, Section 8 is not adopted. To permit decisions within legislated timeframes, the sponsor should include in the initial submission all clinical safety data necessary to support registration.

Ref. No. III/5272/94
Contribution to Part II of the Structure of the Dossier for Applications for Marketing Authorisation - Control of Starting Materials for the Production of Blood Derivatives.

Ref. No. III/5626/94
Validation of Analytical Methods: Definitions and Terminology.

Ref. No. III/5271/94
Production and Quality Control of Monoclonal Antibodies.

CPMP/142/95
Note for Guidance on Impurities in New Drug Substances.

CPMP/ICH/233/95
Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Chronic Peripheral Arterial Occlusive Disease.

CPMP/EWP/234/95
Note for Guidance on the Clinical Investigation of Anti-Anginal Medicinal Products in Stable Angina Pectoris.

CPMP/EWP/235/95
Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Cardiac Failure.

CPMP/ICH/237/95
Note for Guidance on Antiarrhythmics.

CPMP/EWP/239/95
Guidance on Clinical Requirement for Locally Applied, Locally Acting Products of Known Constituents.

CPMP/BWP/268/95
Note for Guidance on Virus Validation Studies: The Design, Contribution and Interpretation of Studies Validating the Inactivation and Removal of Viruses.

CPMP/ICH/269/95
Note for Guidance on Plasma Derived Medicinal Products.

CPMP/602/95
Points to Consider in the Assessment of Anti-HIV Medicinal Products.

CPMP/243/96
Revised Note for Guidance on Allergen Products.

It has been decided that the following documents will not be adopted in Australia:

CPMP/175/95
Note for Guidance on the Procedure for Competent Authorities on the Undertaking of Pharmacovigilance studies.

This document relates to administrative matters within the EU.

CPMP/180/95
Guideline for PMS Studies for Metered Dose Inhalers with New Propellants.

This document was noted with interest, but there is no need to adopt it in Australia at this time.

CPMP/PhVWP/005/96
Rapid Alert System (RAS) in Pharmacovigilance.

This document relates to administrative matters within the EU.

Prescription drug evaluations

Over the past five years or so, industry and the TGA have made a concerted effort to improve the way in which prescription drugs are evaluated. To this end, there is now agreement on improved liaison and information exchange processes. While this might sound simple it means that, for the first time:

• There is now an agreed way of actually addressing issues of concern to the APMA, and for resolving these, bringing a new level of accountability to TGA decisions about procedures, new guidelines and so on; and
• Sponsors can now meet with TGA's evaluators to discuss product applications before submitting them and can have further discussions with TGA between evaluation and consideration by the ADEC. Both of these should reduce problems sponsors have encountered in the past, ultimately reducing wasted time, effort and resources.

On another front, the TGA has agreed processes with the APMAfor providing greater flexibility in the use of USP and BP standards. A similar flexibility has been offered to the PMAA, NFAP and the CFTAA as follows:

• The TGA will consider the use of a USP monograph where a company demonstrates that safety, quality or efficiency would not be compromised. In the case of a biological, a company will also need to demonstrate that concurrent availability of products conforming to BP and USP would not cause ambiguity. The TGA could then allow use of a USP monograph in place of an existing BP monograph by issuing an exemption for compliance with the BP under Section 14 of the TG Act.
• The TGA Laboratories Branch will continue to test therapeutic goods using any of the tests defined in Regulation 28 including a BP monograph, an applicable Therapeutic Goods Order, a test accepted for the purpose of registration or any suitable test that the Secretary requires to be performed. Where a product fails testing according to the BP it may be re-tested against the agreed standard.

Many of the changes to DSEB processes will be implemented by the end of July with the Parliamentary Secretary issuing a further statement later this year.