BioPharma
Strategic
5 January 2015
Regulatory
Review of Medicines and
Medical Devices Regulation Secretariat
Department of Health
MDP 67
GPO Box 9848
CANBERRA ACT 2601
Services
Review of Medicines and Medical Devices Regulation
Stakeholder Submission
Thank you for the opportunity to provide stakeholder input for the above important review being
conducted by the Panel undertaking the Review of Medicines and Medical Devices Regulation on
behalf of the Minister for Health.
BioPharma Strategic Regulatory Services specialises in providing regulatory and strategic drug
development advice and services for prescription medicines, including those developed by the
Australian biotechnology sector. For this reason, the following issues in Chapter 4 of the review:
Regulation of Prescription Medicines are of primary importance:
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Duplication of Regulatory Processes
Lack of flexibility required to facilitate early access to innovative products
Complex Regulatory Framework
In addition to these issues, we would like to add another subject for consideration by the panel – a
review of the orphan drug designation scheme – including release of a new guideline to replace the
previously withdrawn guideline, revised prevalence criteria for orphan drug eligibility (the current
prevalence limit is an absolute figure even though Australia’s population has increased significantly
since orphan drug designation was legislated in 1998) and consideration given to granting market
exclusivity.
DUPLICATION OF REGULATORY PROCESSES
A key issue highlighted by the panel is “The duplication of effort between Australian and
international regulators involved in market authorisation” for new medicines and the view that
assessment by the Therapeutic Goods Administration (TGA) is “unnecessary and … creates a barrier
to timely access by consumers to novel new therapies that have been approved overseas”. Therefore,
the panel is considering the option that the TGA approve a medicine on the basis that it has been
approved for the same indications by a trusted overseas regulator.
As BioPharma Strategic Regulatory Services provides assistance to the pharmaceutical industry, it
would be very tempting to fully support this option. However, we would strongly advise caution in
forgoing the sovereignty of drug regulation in Australia while giving no consideration to the impact of
Australia’s reimbursement process. But, the Pharmaceutical Benefits Scheme (PBS) has been
specifically excluded from the review – and a very large factor in delaying access of Australians to
new medicines is the time, effort and cost involved in gaining reimbursement (more so than TGA
registration, many would argue).
Biotech & Pharma Consultants
Regulatory and Strategic Development
Address: PO Box 2209 Rose Bay North NSW 2030 Australia ● Tel: +61 400 409 206 ● ABN 21 266 041 223
The panel points out: “Australia’s regulation of medicines is highly regarded internationally”. In the
Asia-Pacific region, many countries place great importance on TGA approval when assessing
applications for new medicines – and many send representatives to Australia for training. If the TGA
were to adopt the approach of approving applications on the basis of approval by another agency –
with what appears to be no review – then Australia would be applying a lower level of scrutiny than
many of these same countries – where some level of local assessment is conducted.
As discussed by Prof John Skerritt at the recent 2014 Annual Scientific Conference of ARCS
Australia1, the TGA is making great headway towards cooperation and harmonisation with major
regulators – demonstrated by the number of international initiatives involving the TGA. This was a
key recommendation of the Baume Report following a thorough review of the TGA in 19912 and
should be allowed to continue for TGA to remain a major player in international medicine regulation
rather than risking being left behind. If new medicine assessment became an exception rather than the
norm, the expertise of evaluators and expert committees gained over the past 50-60 years could be
lost.
The panel argues “Advocates for greater use of overseas assessment reports point to the fact that very
few drugs that are approved by one major regulator are subsequently rejected by another”. This is a
broad-sweeping statement with no supporting evidence to justify the claim. In fact, Prof Skerritt
discussed 14 such divergent decisions occurring between Europe and the US in the period 2006 –
20131. Furthermore, even if a medicine is approved by two regulators, this does not necessarily mean
the approved indication is the same.
The European Medicines Agency (EMA) commissioned a study investigating the subjectivity of
evaluators when assessing medicine applications3. The study found: “Regulatory evaluation of
medicinal products involves determining the balance between the benefits promised by the product
and the attending potential harms. This process requires reviewing the clinical data submitted by the
product manufacturer and determining the probability of harm and magnitude, but in doing so
assessors’ belief systems and values are also engaged, giving rise to variability among assessors and
contributing to divergent opinions.”
In 2013, a review of the regulatory decision-making process was published under the umbrella of the
World Health Organisation (WHO)4 . In addition to the observations in the above study, the authors
found that “a regulator’s assessment of the data package is likely to be mediated by informal factors
such as the interaction with external stakeholders (e.g. pharmaceutical companies, patients or other
regulatory agencies) and influenced by socio-cultural and behavioural aspects”. The paper also
discussed the significant cultural and structural differences between the EMA and FDA to help
explain the differences in the regulatory decisions for some medicines.
Divergent regulatory decisions between EMA and the US Food and Drug Administration (FDA) for
oncology medicines were investigated in another study – based on publicly available assessment
reports5. Of the total 100 indications for 42 oncology medicines approved by the two agencies, the
authors found no difference in the indications in only 52 cases. In 47 cases, significant differences
were observed (one case could not be assessed due to the lack of public information). In 19 cases, an
indication was approved by one agency but not the other (3 not approved by EMA and 16 not
approved by FDA). In the remaining 28 cases, one agency approved a more restrictive indication than
the other (FDA more restrictive in 13 cases and EMA more restrictive in 15 cases).
Therefore, any differences between agency decisions need to be investigated thoroughly before
removing such an important safeguard protecting the wellbeing of Australians. For the TGA, each
previous rejection decision for an application approved overseas – or where a more restricted
indication was approved – should be independently audited and the risk-benefit determined for such
medicines if approved in accordance with the rules of a new scheme. This audit would need to
consider, amongst other factors, differences in clinical practice and availability of alternative
treatments between Australia and the other country/countries.
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Instead of TGA “rubber stamping” approval of a medicine based on another regulator’s assessment,
we would think it more prudent to re-visit another recommendation presented in the Baume report2 –
the introduction of the “Category 2” application (only very briefly mentioned in the current review)
whereby an abbreviated evaluation would take place compared to the standard Category 1 application
if the sponsor submitted evaluation reports from two overseas agencies which were on the list of
acceptable agencies – leading to earlier approval. This has been a very under-utilised avenue for
evaluation as most sponsors find the requirements and logistics too onerous, thereby causing delays in
submission. Furthermore, the TGA’s new prescription medicines streamlined evaluation process
makes no distinction between Categories 1 and 2 thereby negating any advantage for sponsors to
submit Category 2 applications.
We therefore recommend:

TGA approval of a medicine on the basis of an assessment by a trusted overseas regulator NOT
to be pursued, and instead;

TGA work with stakeholders to refine the Category 2 evaluation requirements to restore
reduced approval timelines and improve practicality for sponsors

TGA to continue in its endeavours to be a key member of international collaborative initiatives
to strive towards more efficient medicine approval.
Note: Although the PBS has been excluded from the current review, some changes to the current
evaluation process could allow the recently implemented parallel process to work more
efficiently. For example, a major reason for delays in decisions by the Pharmaceutical
Benefits Advisory Committee (PBAC) is the uncertainty around the indication – as only a
clear signal of the clinical delegate’s intent is given in the delegate’s overview which is one of
the last drafted TGA documents. If there was scope to change work processes, it may be
possible for the delegate to recommend an “approvable” indication as part of the first round of
TGA questions (as well as any major objections – which most sponsors have some difficulty
in addressing within the allowed 2-week period prior to the meeting of the Committee on
Prescription Medicines (ACPM)).
LACK OF FLEXIBILITY REQUIRED TO FACILITATE EARLY ACCESS TO INNOVATIVE PRODUCTS
Under the current inflexible requirements and timelines of the new streamlined evaluation process,
there is little scope for accelerated approval for important medicines due to the reliance on the
advance allocation of resources. The Prescription Medicines Registration Process (dated 9 September
2014) makes a brief reference to priority reviews, but noting there is no formal process, and only that
TGA will “wherever possible, work with the relevant applicant with a view to facilitate early access to
the new product”.
Therefore, there is a need for a formal program to ensure Australians have faster access to important
medicines which can be demonstrated to offer significant improvement in survival or quality of life
for life-threatening or chronic debilitating conditions.
If approval would be based on a reduced clinical dataset, then post-approval commitment to further
trials should be discussed with the TGA prior to the submission. The TGA has been including postapproval commitments more and more in the conditions of approval for new medicines (particularly
orphan medicines) and therefore this allowance should not be new to the clinical delegates. This
would be an opportune time for consideration being given to allowing sponsors to submit new data
during the evaluation – which was acceptable prior to the new streamlined evaluation process. Many
overseas regulators allow submission of new data with no impact on timelines to a decision in most
cases.
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To allow the TGA to allocate sufficient resources to accelerate its review, it may be possible for
sponsors to submit a pre-submission earlier than the current 2½ months required for major
applications – if some of the documentation requirements were relaxed.
Another consideration should be assistance provided for Australian biotechnology companies of
which many are in the process of developing products for serious medical conditions. These
companies would greatly benefit from earlier engagement with the TGA in providing feedback on
their pharmaceutical development and non-clinical and clinical programs. There is further discussion
on the provision of scientific advice for such companies under Complex Regulatory Framework;
however, where products are developed for serious medical conditions, it would be very advantageous
for the TGA to adopt a process similar to the FDA Breakthrough program whereby intensive scientific
advice is provided, organisational commitment given from senior TGA managers and a rolling review
of the data as it becomes available. In addition to companies receiving earlier evaluation of their data
and advice on the need to conduct additional studies to address findings, this would facilitate earlier
TGA approval which would assist in obtaining approval internationally.
We therefore recommend:

development of a formal priority review process for important medicines including allowance
for post-approval commitments and submission of new data during the evaluation

development of a process similar to the FDA Breakthrough program for Australian-developed
important medicines
COMPLEX REGULATORY FRAMEWORK
Commercialisation of Australian medical research has been covered in at least three recent
Commonwealth Government reviews and discussion papers, highlighting the importance of the
biotechnology/pharmaceutical sector:
1. Strategic Review of Health and Medical Research, Feb 2013 (Department of Health and Ageing)
2. Boosting the commercial returns from research, Oct 2014 (Departments of Industry & Education)
3. Australian Industry Report, Dec 2014 (Office of the Chief Economist, Department of Industry)
All three reports discuss the high output from Australian research and the potential for strong
prospects for future commercial growth, leading to a significant contribution to the economy. There is
strong backing for additional Government support mechanisms including revision of the R&D Tax
Incentive, plans for a roadmap for long-term research infrastructure investment and creating stronger
incentives for collaboration between researchers and industry. There is an important role TGA can
play in assisting in the success of the local industry.
Considered, objective scientific advice early and throughout the development of a new product is
crucial to maximise approvability6. Even if a company is not necessarily aiming for marketing
approval itself but rather out-licensing or partnering with a larger company, objective regulatory
scientific advice could have a great impact on the value of the intellectual property by helping ensure
drug development proceeds in a meaningful manner rather than the generation of “interesting” results
for the researchers.
Currently, we recommend our clients seek early scientific advice from the FDA which has a culture of
early engagement with industry facilitated by the offer of meetings at important milestones (before
approval of the first clinical trials, before initiation of the phase 3 program and before submission of
the marketing application). Although meetings with the TGA can be valuable, their more informal and
less structured format means the advice provided can vary widely in quality (although personal
experience has been favourable). Furthermore, as the Baume Report (2) stressed the importance of
TGA not requiring additional data to other agencies unless it was seen as critical to the Australian
context, meetings are primarily focused on the acceptability of the completed or near-completed data
package prior to submission of the marketing application rather than TGA assisting sponsors in
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paving the way forward in drug development. Consequently, many TGA evaluators are not
sufficiently experienced in providing such advice to assist Australian companies who are in early
development – although one paper has reported on a “highly informative” series of such meetings
with the TGA (in this case - tripartite meetings also involving the PBAC Secretariat)7.
It would greatly assist the local industry to receive documented scientific advice from the TGA during
drug development. Although many companies will still need to seek advice from the FDA (and
European agencies) to ensure acceptability of the data package internationally, prior structured TGA
advice would be advantageous to better prepare companies and validate their approach to drug
development. It is also much more efficient and beneficial to have early and ongoing dialogue with a
local agency which would potentially be more engaged with the company and its personnel than one
in a foreign country. There may be the possibility be of a pilot program of joint scientific advice
meetings with TGA and FDA (facilitated by teleconference or videoconference) which could be
beneficial to all parties (evaluators from both regulators could appreciate the thinking and concerns of
other regulators as well as the opportunity to educate inexperienced TGA evaluators).
Another form of assistance local small companies which are usually cash-poor would be the
introduction of TGA fee waivers. The FDA currently offers a fee waiver for the first application from
small companies which meet certain criteria. A similar program could be offered by the TGA.
We therefore recommend:

development of a program for scientific advice to assist in drug development for Australian
companies (in addition to the current pre-submission meetings)

introduction of a system of waivers for TGA fees for small Australian companies
I trust the panel will give due consideration to the views and recommendations in this submission. If
there are any questions on any points in this submission, please do not hesitate to contact me by
telephone: 0400 409 206 or by email: r.sinani@biopharmasrs.com.au.
Your sincerely
Ron Sinani
Principal Consultant
BioPharma Strategic Regulatory Services
REFERENCES
1. Skerritt, J. International regulatory cooperation: more important than ever. Presented at Annual
Scientific Conference of ARCS Australia, Canberra 10-11 Sep 2014. Accessed at:
https://www.tga.gov.au/presentation-international-regulatory-cooperation-more-important-ever
2. Baume P, Staples P. (1991). A question of balance : report on the future of drug evaluation in
Australia, commissioned for the Minister for aged, family and health services, the Hon. Peter
Staples. Canberra : Australian Govt. Pub. Service
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3. EMA Benefit-risk methodology project: Report on risk perception study module 24 Jan 2012;
EMA/662299/2011
4. Tafuri G. (2013). Exploring the regulatory decision-making process for medicines. Conducted
under the umbrella of the Utrecht-World Health Organization (WHO) Collaborating Centre for
Pharmaceutical Policy and Regulation,
5. Tafuri G, Leufkens HGM, Laing R, Trotta F (2010). Therapeutic indications in oncology:
Emerging features and regulatory dynamics. Eur J Cancer;46(3):471-5.
6. Regnstrom J, Koenig F (2010). Factors associated with success of market authorisation
applications for pharmaceutical drugs submitted to the European Medicines Agency. Eur J Clin
Pharmacol;66(1):39-48.
7. Wonder M, Backhouse ME, Hornby E (2013). Early Scientific Advice Obtained Simultaneously
from Regulators and Payers: Findings from a Pilot Study in Australia. Value in Health;16:10671073.
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