EVALUATION OF SAFETY REPORTS IN ASIA REGULATORS PERSPECTIVE AND AWARENESS

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EVALUATION OF SAFETY REPORTS IN ASIA REGULATORS
PERSPECTIVE AND AWARENESS

• TAN, LIE SIE
• NATIONAL PHARMACEUTICAL CONTROL BUREAU
• MINISTRY OF HEALTH MALAYSIA

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OVERVIEW

• Drug regulation and pharmacovigilance practices
  in the 1990s
• Current scenario
• ADR Monitoring in Malaysia
• Case study to reflect changing paradigms
• Impact of ASEAN harmonisation
• Future directions

MALAYSIA
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PAST

• Registration of New Chemical Entities was very
  much dependant on the status of products in the
  reference countries
• Changes to product information was mainly
  industry driven
• Few pre-clinical studies conducted in the region
  and hardly any Phase IV studies
• Adverse drug reaction reporting was very minimal
  and mainly involved reports submitted by health
  care professionals

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PAST

• Signal detection not possible as there were too
  few reports
• Only able to detect some quality defects of
  generics which manifested as ADRs
• Pharmacovigilance was mainly about getting ADR
  reports and submitting them to WHO
• No significant regulatory changes made based on
  these reports
• Most reports were for known reactions involving
  older drugs which were used in government-run
  hospitals

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CURRENT SCENARIO

• Increased awareness and interest amongst doctors
  and pharmacists to report ADRS as they have seen
  some benefit in reporting
• Increasing number of clinical trials being
  conducted especially in Singapore, Thailand and
  Malaysia
• GCP training for investigators serve to increase
  awareness of SAE and ADR reporting amongst health
  care professionals and the industry

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CURRENT SCENARIO

• On-line reporting system available less hassle
  than submitting hard copy reports
• Increasing involvement by hospital pharmacists in
  pharmacovigilance during clinical ward rounds
  and when counseling patients
• PSUR mandated for new products

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Feedback given to registration holders
receive ADR report
report ADR
Pharmaceutical company
ADR form
National ADR centre
Health professionals
WHO
recommendations
Malaysian ADR Advisory Committee (MADRAC)
Drug Control Authority (DCA)
ADR MONITORING SYSTEM IN MALAYSIA
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FROM ADR REPORT/ALERT TO DRUG POLICY
Receive ADR report/information
Verify information
Assessment
Discuss at MADRAC meeting
WHO
Requires regulatory action?
Prepare policy paper for DCA
IMPLEMENT POLICY
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SAFETY MONITORING-SCOPE OF ACTIVITIES

• Detection of unknown ADR
• Detection of increased frequency of ADR
• Identification of risk factors
• Communicating information for safe, rational and
  effective use of medicines
• Monitoring for appropriate product information
  and updating

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REGULATORY CHANGES

• Increasing number of NCEs and biotech products
  being registered almost concurrently with
  reference countries
• Implementation of provision for Compulsory
  Licensing for anti-retroviral drugs
• Market penetration of bio-tech products from
  countries such as Cuba, China

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PARADIGM SHIFT

• Reducing reliance on reference countries
• CASE STUDY Gefitinib
• New Chemical Entity
• Approved relatively quickly in view of its use
• Indicated in the treatment of patients with
  locally advanced or metastatic non-small cell
  lung cancer after failure of other chemotherapies
  
• At time of registration, product was approved in
  USA and Australia
• Conditions for registration in the USA were not
  known at that time i.e. that company had to
  undertake to do a post market study to further
  look at efficacy data

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CASE STUDY Gefitinib (cont)

• In a pivotal study, gefitinib did not
  significantly prolong survival in the overall
  population
• Regulatory actions taken
• In USA, Canada, Australia product only
  available to patients who have benefited from the
  drug.
• In the EU, company withdrew its application
• Japan, Singapore, Malaysia product remains on the
  market because a sub-group analysis of the
  clinical study showed evidence of prolongation of
  life in non-smokers and patients of Oriental
  origin
• Further analysis of Malaysian patients who
  comprise of Malays, Chinese and Indians showed
  some benefit in terms of prolongation of life
  compared to placebo

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CASE STUDY Gefitinib (cont)

• Since product not marketed in USA, EU and there
  are safety concerns with this product, company
  was asked to develop a Pharmacovigilance Plan
• Regulatory body also had to liaise directly with
  prescribers to
• Highlight current scenario
• Bring to their attention the safety issues
• Remind them to report any ADRs to this product
• MAH HQ will have to continue to produce and
  submit PSURs although the product is not actively
  marketed in any of the ICH countries with the
  exception of JAPAN

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• More of such cases probably to come in the future
• Pharmacogenetics
• Ethnicity
• Regulators and industry need to be self reliant
  and better prepared to monitor adverse reactions
  and develop systems for signal detection
• In such instances, hopefully WHO/UMC can be aware
  of such issues and focus attention on monitoring
  these drugs as well

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CONSUMER REPORTING

• Not well established in any of the ASEAN
  countries yet
• WHO WPRO conducted a study on consumer reporting
  in Malaysia and Philippines in 2007.
• Integrating consumer in medicine surveillance
  will be an extension and expansion of the
  existing surveillance activities safety,
  quality, efficacy, counterfeits, unregistered
  products

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TO BE FAIR IS TO BE BEAUTIFUL

• 1997 A young Malay lady called in to complain
  that she had used a whitening cream which
  initially was very effective
• On continuous usage, her skin started to get
  hyperpigmented instead
• Her face looked so terrible she did not even want
  to venture out of her house

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• Information on product used and where it was
  purchased was provided
• Sample taken for testing found to contain 25
  hydroquinone
• Actions taken
• GMP audit done of manufacturing premise
• Found gross violation of GMP principles
• Manufacturer instructed to shut down
• Total product recall
• Decision made to regulate hydroquinone as a
  scheduled poison

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G-G AGREEMENTS

• ASEAN HARMONISATION
• Memorandum of Understanding
• Singapore Malaysia (initiated)
• Singapore Australia
• Free Trade Agreements
• USA Singapore
• USA Thailand (on-hold)
• USA Malaysia (ongoing)
• Pharmacovigilance Discussion groups
• Singapore-Australia-New Zealand
• All have a bearing on how drugs will be
  regulated and thus on pharmacovigilance as well

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FUTURE

• Changing treatment modalities
• Emerging new diseases such as SARS, Avian Flu,
  dengue fever which are more prevalent in the
  Asian region
• Transfer of technology from the developed
  countries to developing nations
• Countries will need to monitor these products to
  ensure quality, efficacy are the same
• Increasing emphasis on the use of biotechnology
  products
• Increasing demand for fast track approval of new
  drugs REQUIRED
• BETTER IMPROVED
  PHARMACOVIGILANCE BY
• ALL PARTIES CONCERNED

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PUBLIC AWARENESS

• Currently, database of ADR reports not available
  for public viewing
• Increasing pressure by media and consumer
  associations for transparency when products with
  safety concerns are marketed
• Easy access to information through the internet
  by consumers has led to more queries being
  received on safety issues

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WISH LIST

• v Increased information sharing
• v More emphasis on post market monitoring rather
  than pre market assessment
• Greater emphasis on patient safety
• Improved reporting
• Bigger pool of trained regulatory staff to be
  involved in pharmacovigilance
• Improved cooperation from Industry

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THANK YOU