Oncology Drugs: The journey From Manufacturer To The End User
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Transcript of Oncology Drugs: The journey From Manufacturer To The End User
ONCOLOGY DRUGS:THE JOURNEY FROM
MANUFACTURER
TO END USER
Dr. SALMAH BAHRI
Director of Pharmacy Enforcement
Pharmaceutical Services Division
Ministry of Health Malaysia
INTRODUCTION
• Health is a fundamental human right. Access tomedicines is a fundamental element of the right tohealth.
• Key issues related to access to medicines include :availability and affordability; sustainable financing; priceand quality control; efficacy and effectiveness ofmedicines; procurement practices and procedures,supply chains.
• By law, before a medicine can be placed on the market,it must be given a marketing authorisation (productlicence) by a medicines regulator
• FIRST STEP in ensuring AVAILABILITY of the medicine:Marketing authorisation (via product registration) in thecountry
FROM DRUG DEVELOPMENT TO
MARKETING
During the lifecycle of a new medicine, there are considerable
hurdles to overcome before the medicine successfully reaches
the market.
REGULATORY SYSTEM IN MALAYSIA
• Control of Drugs and Cosmetics Regulations (CDCR)
1984 - Legal framework and empowers the Drug
Control Authority (DCA) to implement drug registration.
• Under the CDCR 1984, Regulation 7(1): Except as
otherwise provided in these Regulations, no person shall
manufacture, sell, supply, import, possess or administer
any product unless:
(a) the product is a registered product; and
(b) the person holds the appropriate licence required and
issued under these Regulations.
• National Pharmaceutical Control Bureau (NPCB) set
up in 1978, currently serves as the Secretariat to DCA
OBJECTIVE OF REGISTRATION
Protect the health of our public by
ensuring safety, efficacy and
quality of pharmaceutical
products marketed in Malaysia
WHY REGISTRATION IS IMPORTANT?
The registration system is designed to:
• guarantee that all those involved are answerable for their actions;
• ensure that processes, supplies, and quality can bethoroughly monitored;
• enable swift corrective action to be taken when needed.
• It is not influenced by the cost effectiveness or value formoney of a medicine;
• License will be granted a medicine meets high standardsof safety and quality, and that it works for the purposeintended. This is denoted by a product licence ormarketing authorisation number (MAL.....)
REQUIREMENTS FOR REGISTRATION
7
National Pharmaceutical Control Bureau
Part I
Common Administrative
Data
& Product Information
(for all category of products)
Part II
Quality
(for all category of
products)
Part III
Non-clinical
(for innovator, new
chemical entity &
biotechnology products
Part IV
Clinical
(for innovator, new
chemical entity &
biotechnology products
ACTD
Country specific,
administrative data, not
part of
ACTD
Registration requirements based on ASEAN Common Technical Dossiers ACTD,
adopted from ICH CTD, has been implemented in Malaysia since July 2003.
PRODUCT REGISTRATION CRITERIA
Products Particulars Product Formula
Labeling Requirement
Interchangeability
Manufacturer-GMP
-CPP
-CFS
Compulsory
labeling
requirement
Additional
Warning/
Precaution
Product Name
Product Description
Pack size
Type of container
Bioequivalence
/Bioavailability
Studies
Banned ingredient
Limits,
Product testing,
FPQC, Stability
(QUALITY, SAFETY, EFFICACY)
Product Evaluation Committee
(within NPCB) /Mesyuarat JKPP
Verification of GMP status (approval from recognised authority
of the country of origin), CPP
Protocol Evaluation (NCE & Generic Rx & OTC) and Sample
Testing (Traditional)
Drug Control Authority
(DCA)/ Mesyuarat PBKD(decision making body
-meets monthly)
NCE & Biotech products – sent to panel of experts for comments.
RegisteredIssue MAL no.
Application rejected
Applicant can appeal through
Minister of Health for review of
DCA’s decision
Evaluation of application dossier
REGISTRATION PROCESS
POST REGISTRATION
• The NPCB continues to monitor safety, efficacy & quality
of products through pharmacovigilance
• Malaysian Adverse Drug Reactions Advisory Committee
(MADRAC) was established under Drug Control
Authority (DCA) to perform the function of
pharmacovigilance for drugs registered for use in
Malaysia.
• Health professionals & pharmaceutical companies carry
the responsibility to report ADR to MADRAC.
• ADR reporting form is accessible at
http://portal.bpfk.gov.my
POST REGISTRATION
• Post-registration, a medicine must be listed in MOH Drug
Formulary before it can be used in MOH facilities;
• MOH Drug Formulary objective -
To ensure only efficacious, safe and cost-effective drugs
are used in MOH institutions;
• In line with Malaysia National Medicines Policy’s
(MNMP) main aim: Towards achieving rational use of
safe, effective & affordable essential medicines
12
MINISTRY OF HEALTH FORMULARY
Registered Products by
DCA
MOH Formulary
MOH Hospital
Formulary
MOH Primary
Care Formulary
July 2014
1642 items
• 828 chemical
entities
• Including 320
items in NEML
September 2014
Poison 7143
OTC 4185• Drugs approved
to be used in
MOH facilities
by Drug List
Review Panel
• Reviewed 3
times a year
13
Governance in Medicines
Quality Use of Medicines
Partnership and Collaboration for the Healthcare Industry
Quality, Safety and Efficacy of
Medicines
Access to Medicines
MNMP II COMPONENTS
MOH DRUG FORMULARY
LISTING PROCESS
MNMP Strategy for Access to Medicines:
Selection of Medicines
A fair and transparent medicines selection mechanism
in accordance with the country’s health needs by
emphasising clinical effectiveness and cost-
effectiveness of treatments
Pharmaceutical Expenditure
Global medicines spending has surpassed US
$1 trillion per year
Medicines spending accounts for up to 67% of
total health expenditures in some countries ,
mostly paid out of pocket by consumers.
Asian countries, pharmaceutical share of total
health spending range between 8% -50%
Malaysia, pharmaceutical expenditure is 8.8% of
total health expenditure
Source :Wagner et al. BMC Health Services Research 2014 ; OECD/ WHO (2012), “Pharmaceutical
expenditure” in Health at a Glance Asia Pacific 2012
16
17
ACCESS & BUDGET CONSTRAINTS
1.76
Billion
1.98
Billion
2.2
Billion
2011 2012 2013
Medicine Expenditure as % of Total MOH Operating Budget (2012) = 11.4%
Source: Malaysia Health System Review 2013
There is a need to have balance between access and
affordability considering the budget constraints and
increasing trends in medicine in expenditure.
MOH medicines expenditure:
# Top 5 Principal Causes of Death
in the MOH, 2013
%
1 Diseases of the circulatory system 24.38
2 Diseases of the respiratory system 22.73
3 Certain infectious and parasitic
diseases
13.96
4 Neoplasms 12.12
5 Injury, poisoning and certain other
consequences of external causes
5.05
Burden of Disease
MOH EXPENDITURE ON ONCOLOGY
MEDICINES
YEAR
TOTAL
EXPENDITURE ON
ONCOLOGY
MEDICINES
PERCENTAGE
SPENT ON
ONCOLOGY
(FROM TOTAL
MEDICINES
EXPENDITURE)
2012 RM 167,224,314.66 8.4%
2013 RM 187,573,860.88 8.6%
FORMULARY
LISTING PROCESS Specialist/ FMS/
Medical Officer/
Pharmacists fill
proforma
Hospital/
Health Drug
Committees
State Drug
Committees
National Drug Formulary
Secretariat (PSD)
Technical Drug
Working CommitteeDrug Evaluation
(Pharmacoeconomic Unit,
PSD)
MOH Drug
List Review
Panel
Inform all States/ MOH
Institutions via circular
Request closed/ filed
List into local formulary
Proposer informed/
Request filed
Proposer informed/
Request filed
Approved
2 sets of proforma with
clinical references/ papers
Hospital/
State Drug
Committees
Appeal
Results
Feedbacks
FORMULARY LISTING PROCESS
Evaluation by Pharmacoeconomics Unit
Presentation to Drug List Review Panel
Dissemination of Results
Application received & screened by MOH Drug Formulary Secretariat
Receive application for formulary listing from Oncologist/Clinican\
FORMULARY LISTING PROCESS
• Decision making for formulary listing :
– Evidence-based Approach
• Economic evidence is one of the key elements
considered
• Thus requirement for submission of supporting
documents by proposer to include:
– Evidence on clinical efficacy/effectiveness
– Evidence on safety
– Economic evidence
1. In the absence of economic evidence:
– Cost analysis in comparison to alternatives
currently available is done.
– Calculation of budget implication using estimated
patient population and drug acquisition cost.
2. Critical appraisal of all evidence is conducted. After
appraisal, evidence is selected, synthesised and
presented to the MOH Drug List Review Panel.
3. Feedbacks obtained from relevant Technical Working
Drug Committees also presented
FORMULARY LISTING PROCESS
SUMMARY FOR SELECTION OF MEDICINES
INTO MOH FORMULARY
Decision making for selection of
medicines:
• Based on therapeutic value of
medicine using Evidence-based
Medicine (EBM) Approach
• Tools / Techniques used: Systematic Drug Review
Multi Criteria Decision Analysis
(MCDA): new tool to assist in
formulary decision making,
transparent, explicit decision-making
process. First attempt: HMG-CoA
reductase inhibitors (statins)
• Medicines with added therapeutic
value will be listed in Medicines
Formulary (encompasses the
National Essential Medicines List-
NEML)
WAY FORWARD:
• Review current formulary listing process.
– Proposers of submission will be the
registration holder.
– Submission of local economic studies by
the proposer is encouraged
– Mandatory submission of economic studies
may be a requirement in near future.
• ‘Pharmacoeconomic Guideline for Malaysia’
launched on 31 March 2012 will serve as a
standard for preparation of pharmacoeconomic
studies in Malaysia.
• Plan to develop Centre for Pharmacoeconomics
to facilitate PE research in Malaysia.
24
ACCESS TO MEDICINES
NOT LISTED IN MOH FORMULARY
• Access to new innovative medicine is feasible via special mechanism
• Application is approved by Director General of Health
• Approval is given for two categories of oncology medicines:
– registered
– unregistered
• Applications need strong justification :-
-individual patient basis; existing alternatives have been tried; budget availability; cost implication & evidence on efficacy and safety
• Critical Appraisal is done before recommending for approval by Director General of Health
STATISTICS ON SPECIAL APPROVAL (SA)
FOR ONCOLOGY MEDICINES
2012 2013
Registered medicine (%)RM 9,016,094.48
(15.2%)
RM 9,873,077.03
(18.6%)
Unregistered (%)RM 2,852,375.73
(4.8%)
RM 800,348.30
(1.51%)
Total SA expenditure RM 59,202,688.39 RM 52,965,116.08
A) Percentage expenditure on non-formulary oncology medicines
applied via SA over total expenditure for SA medicines
B) Percentage of oncology SA expenditure over total oncology
medicines expenditure:
2012 2013
Total oncology expenditureRM 167,224,314.66
(8.4%)
RM 187,573,860.88
(8.6%)
Total oncology SA
expenditure
RM 11,868,470.21
(7.1%)
RM 10,673,425.33
(5.7%)
POST SPECIAL APPROVAL MONITORING
• Objective:
Obtain more information on effectiveness and
safety of the medicine
• Clinicians to submit patient progress report
every 6 months
• Immediate reporting of ADR if any
Variability in Drug Response
• Each patient is different from every other patient due to
uncertainty in response.
• Medicines are approved based on empirical evidence of
efficacy from RCT. Efficacy expressed as average drug
response. Average effects within an RCT population
may be quite different from effects expressed by a
given individual.
Limitations of RCTs in Populations:
Not Always the Gold Standard of Evidence
• Comparability (Internal Validation)
– Assumes a superior treatment (vs placebo) is the best
choice for any given individual in the population
– It could be the wrong drug for many people because of
adverse events
– It could be the best drug for many people who are not at
risk for the adverse event
– Relatively low average responses to many drugs means
non responders receive treatment with no value.
• Generalizability (External Validation)
– Most RCT populations are not representative of patients
who will consume the drug (inclusion/exclusion criteria)
Variability and Uncertainty
• Medicines acting on a cellular target that participates in
the pathogenesis of a disease - Targeted Therapy
• Personalized Medicine – when a biomarker for target
status is used to define a subgroup of patients who have
a different benefit/risk ratio than an unselected
population.
Managed Entry Agreements (MEA)
• From a literature perspective there seems to be a
general agreement that MEAs can, under certain
conditions, help address post licensing uncertainty and
enable early access to innovative treatments
• In general, MEAs offer flexibility in dealing with new and
often expensive technologies, which are characterized
by significant levels of uncertainty
Managed Entry Agreements (MEA)
• Different types of schemes exist in order to address
different needs (budget impact, weaknesses in clinical
evidence, etc.).
• Difficulties to sustain agreements-
Volume based without risk sharing schemes
• Their potential is further amplified by the possibility to
combine financial and non-financial elements in the
same agreement and address different issues at the
same time. e.g. budget impact and use, access and
cost-effectiveness, etc.
Managed Entry Agreements (MEA)
• Agreement including a health-outcome component [e.g.
coverage with evidence (CED) development, payment
for performance]
Collection of information on medicine use and
effectiveness in different sub-groups of patients under
real-life clinical conditions, i.e. outside a clinical trial,
to update treatment guidance, reduce uncertainty and
reach the final reimbursement decision (CED
development).
Need to address quality and safety of unregistered
medicines.
Terminated Patient Assisted Program (PAP) terminated
due to Non Fulfilment of Quantity Requirements
Name of Drug/ Indication Mechanism
Bevacizumab 400mg Injection
[Targeted cancer therapy – breast cancer & colorectal cancer]
3 cycles free for every patient
Everolimus 5mg &
Everolimus 10mg Tablet
[Advanced renal cell carcinoma]
Cost sharing:
- 4 months (MOH), 8 months
(company)
- MOH buys 1 month, bonus 1 month.
- For 4 times purchases (the first 8
months) - given 4 months bonus for
the rest of the year treatment).
Terminated Patient Assisted Program (PAP) terminated
due to Non Fulfilment of Quantity Requirements
Name of Drug/
Indication
Mechanism
Sunitinib12.5mg Capsule[Treatment of GIST after disease progression on or intolerance to ABC & advanced renal
cell carcinoma]
Program started in 2009 as a 3 year pilot for patients in private and public hospitals. Recruitment was by participating physicians and run by an independent third party to maintain patient data privacy . Patients are categorized into different groups. Group 1 - MOH purchase 4 boxes; Group 2 - MOH purchase 8 boxes;Group 3 - MOH purchase 12 boxes;Group 4 - MOH purchase 16 boxes; For all groups, bonuses for the rest of the treatment needed.Program was terminated in 2011 where enrolment was ceased. However, existing patients would still receive the drugs until disease progression ceased.
WHAT IS NEXT FOR NEW INNOVATIVE
ONCOLOGY MEDICINES?
• Value Based Assessment
• Methods review for Highly Specialised
Technologies methods review
• New developments
– Early Access to Medicines
– Adaptive Licensing
• Working with other regulatory & HTA
agencies
CONCLUSION
• As healthcare providers we carry the
responsibility to provide best care within
limited resource setting.
• The current procedures from registration
to post-registration have significant
implications on ensuring the provision of
safe, efficacious/efffective, cost-effective
and quality treatment.