drug regulation in several countries

I N T R O D U C T I O NWhen the regulatory review and approval of new

medicines is studied at a global level, it is appar-

ent that the division between the International

Conference on Harmonization (ICH) regions

and the rest of the world is changing and is no

longer so well defined. The CMR International

Institute for Regulatory Science (hereafter the

Institute) has been studying the regulation of

medicines in some of the so-called emerging

markets in order to benchmark and analyze

these changes, particularly in relation to the

availability of new medicines to patients in the

countries studied.

For the purposes of this study, the term

emerging markets was used to encompass not

only those countries with an expanding phar-

maceutical market, of increasing interest and

importance to the pharma industry, but also

those countries where it is the regulatory

agency that is emerging. These countries are es-

tablishing regulatory procedures and practices

that are likely to influence the development of

agencies in neighboring countries within their

regions and therefore to have an impact on

product approval that extends beyond national

boundaries.

B A C K G R O U N DSince 2004, the Institute has been working in

association with the industry and agencies on

an Emerging Markets Programme designed to

develop a greater understanding of the regula-

tory aspirations, barriers, and priorities that im-

pact the review and availability of new medi-

Drug Information Journal, Vol. 43, pp. 349–359, 2009 • 0092-8615/2009Printed in the USA. All rights reserved. Copyright © 2009 Drug Information Association, Inc.

Emerging Markets and Emerging Agencies: A

Comparative Study of How Key Regulatory

Agencies in Asia, Latin America, the Middle East,

and Africa Are Developing Regulatory Processes

and Review Models for New Medicinal ProductsNeil McAuslane, BSc,

MSc, PhDDirector, CMR International

Institute for RegulatoryScience, United Kingdom

Margaret Cone, BPharm,MRPharmS

Director, RegulatoryPublications, CMR

International Institute forRegulatory Science,

United Kingdom

Jennifer Collins,* MA, BSc, MSc

CMR Institute forRegulatory Science,

United Kingdom

Stuart Walker, BSc, PhD,MFPM, FRSC, FIBiol,

FinstD, FRCPathVice President and Founder,

CMR International Institutefor Regulatory Science,

United Kingdom

An ongoing study has been set up by the CMRInternational Institute for Regulatory Science torecord and analyze the regulatory proceduresfor the authorization of new medicines in 13 keycountries, outside the ICH regions, where thepharmaceutical market is expanding or the reg-ulatory agency plays an important role in re-gional development. These countries are Ar-gentina, Brazil, Mexico, Egypt, Saudi Arabia,South Africa, China, India, Indonesia,Malaysia, Singapore, South Korea, and ChineseTaipei. In the study, data were collected fromsenior personnel in the national agencies andfrom multinational pharmaceutical companieson the review and assessment processes for newactive substances (NASs) and major line exten-sions (MLEs). The quality measures being ap-plied by the agencies to monitor those proce-

dures were also recorded. The design of the studycollected information for a status report at onetime point, as summarized here, but also pro-vides the basis for recording and benchmarkingthe progress and changes made by the agenciesover time. A cross-comparison of informationfrom the authorities indicated that regulatoryaspirations, barriers, and priorities are essen-tially similar across agencies. The review stepsare also similar although there are major differ-ences in the assessment process. Most agenciesare using risk stratification methods for their re-view of new medicines, based on the level of reg-ulatory scrutiny the product has already under-gone by agencies elsewhere. There is anawareness of the importance of building qualityinto agencies’ regulatory processes and prac-tices and this is a changing and evolving area.

Key Words Regulatory review; Emerging

markets; New medicines;Quality measures; Asia,

Latin America, Middle East,and Africa

Correspondence AddressDr. Neil McAuslane, CMRInternational Institute for

Regulatory Science, TheJohnson Building, 77 Hatton

Gardens, London EC1N8JS, United Kingdom (email:

[email protected]).

*Ms. Collins was formerlywith CMR InternationalInstitute for RegulatoryScience and is now with

GlaxoSmithKline,Weybridge, Surrey, UK.

GOOD REGULATORY SC I ENCE IN AS IA/PAC I F I C : PART 2 349

Submitted for Publication: January 20, 2009Accepted: February 15, 2009

GOOD REGULATORY SC I ENCE IN AS IA/PAC I F I C : PART 2350 McAuslane, Cone, Collins, Walker

cines in countries outside the ICH-affiliated re-

gions (1).1 The study started with a broad-based

fact-finding investigation of regulatory proce-

dures in over 30 countries, but later it focused

on issues in a smaller group of key countries

where it was felt that changes could make a pos-

itive difference at national, and possibly region-

al, levels (see Figure 1).

The third phase of the study, which is the sub-

ject of this article, covered 13 countries, includ-

ing Argentina, Brazil, Mexico, Egypt, Saudi Ara-

bia, South Africa, China, India, Indonesia,

Malaysia, Singapore, South Korea, and Chinese

Taipei, in greater depth in terms of the type of

assessment they undertake, the review models

employed for the approval of new medicines,

and how quality is built into the regulatory

processes. Data were collected from regulatory

agencies primarily through face-to-face meet-

ings and from companies via a questionnaire.

The quantitative data from the study enabled

comparisons of the regulatory performance of

agencies in terms of timelines and identified ap-

parent divergences between agency targets and

industry experience.

The more qualitative information on proce-

dures, objectives, and quality management

helped identify issues and activities that could

impede or enhance the efficient and effective

registration of medicines.

A primary objective was to support arguments

for regulatory reform and feed these back, as ap-

propriate, to the agencies in order to help ongo-

ing strategies to bring about change.

M E T H O D O L O G Y DATA COLLECTION

A questionnaire was used to collate comparative

information (Figure 2) from the 13 authorities

included in phase III of the study and, with the

exception of China and India, the data were cap-

1. The primary regions of the ICH are the EU, US, and Japan. Affiliated countries are Canada and Switzerland

(official observers to the ICH process), and other countries that have adopted the ICH guidelines are Australia

and the European Economic Area countries Iceland, Lichtenstein, and Norway.

F I G U R E 1

Phased approach to the study of regulatory procedures.

Phase I: Understandingthe current environment

2004

Phase II: Effectingchange

2005-2006

Phase III: Maximizingefficiency and effectiveness

2006-2007

Authority survey24 countries3 regions SE AsiaMiddle East & AfricaLatin America

Data onregulatorypolicies and

practices

Industry Survey10 companies30 countries

Industrydiscussionmeeting

3 regionalauthorityreports

3 regionalindustryreports

Authority survey13 countries

Countrysituationanalyses

highlightingpriority issues


Countryspecificreports

4 R&DBriefings

Authority survey13 countries

Data on processplans

target timesquality

proceduresapproval times

Industry Survey13 countries


Country-specificreports

Report onindustrydata

Regulatory Processes and Review in Emerging Markets GOOD REGULATORY SC I ENCE IN AS IA/PAC I F I C : PART 2 351

Drug Information Journal

tured primarily through face-to-face meetings

and interviews with senior agency staff. The

questionnaires for China and India were com-

pleted using information from the public do-

main and with the assistance of experts with ap-

propriate, first-hand knowledge of the national

regulatory systems.

Data were collected on the review procedures

and approval of new active substances (NASs)

and major line extensions (MLEs) submitted or

approved from 2004 to 2006. After the data had

been analyzed in the Institute, a second round

of visits and meetings was organized in order to

obtain further clarification and information, as

necessary. The return visits also provided an op-

portunity to present and discuss cross-compar-

isons of review practices among the regulatory

authorities included in the study.

Data collection from industry sources was car-

ried out using written questionnaires. Thirteen

multinational research-based companies, which

are actively registering and marketing products

in all or most of the selected countries, partici-

pated in the study and they were asked to com-

plete separate questionnaires for each market.

As for the data collection from the authorities,

the study was restricted to NASs and MLEs sub-

mitted and/or approved from 2004 to 2006.

SCOPE OF THE STUDY

Key milestones in the review process were

mapped (for both marketing and clinical trial

applications) and information on these and re-

lated activities was collected from the authori-

ties, including the quality measures that are be-

ing applied within their regulatory procedures.

Metrics on numbers and timing for NAS and

MLE applications for 2004–2006 were among

the data that were sought for the study.

The data collected from participating compa-

nies fell into two categories: Product-related

metrics from their own marketing and clinical

trial applications; and industry perceptions of

the activities carried out at authority level (eg,

target review times and procedures for handling

clinical trial applications).

ANALYSIS

All data relating to individual products have

been aggregated and anonymized for confiden-

tiality reasons. Metrics on the time taken to re-

view and approve applications were converted to

calendar days for uniformity and calculated as

medians. Since the variation of results about the

median, within the same authority, was an im-

portant element for comparative purposes, a

“box and whisker” layout was used to present the

F I G U R E 2

2007 Emerging MarketsProgramme datacollection.

Drug registrationInformation on regulatory agency(eg, scope and remit)Type and size, fee structure andbudgetType of data assessmentData requirementsExtent of scientific reviewReview stages and milestones

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

•

Type of authorization procedureGeneral model for review ofCTAsMilestones and timelinesScientific assessment

Clinical trial applications* Quality in the reviewQuality measures in placePeer reviews, SOPs, GRPQuality managementInternal trackingTrainingTransparency

*Subject of a subsequent, more detailed study in 2008

Authority-level data


results (see Figure 3) in which the box represents

the 25th–75th percentile and the whiskers the

5th–95th percentile.

R E S U LT S A N D D I S C U S S I O NAPPROVAL TIMES AND TIME TO MARKET

When the median approval times for NASs, cal-

culated from data supplied by the 13 participat-

ing companies, are compared for 2004–2006,

they vary widely around an overall median of 290

calendar days, from 127 days (Argentina) to

1,388 days (Egypt). (Figure 3). The approval time

is not, however, the only factor to have an impact

on the rollout time that it takes for new medi-

cines to reach the different markets compared

with first approval anywhere, usually in an ICH

country (Figure 4). There is a critical time inter-

val between approval by the first authority and

subsequent submission for approval in another

market. For the countries studied, this ranged

from minimal or no time elapsing in some Latin

American countries to delays of over a year.

The main components affecting the delay in

submitting an application are national applica-

tion requirements (eg, the need for a CPP [Cer-

tificate of a Pharmaceutical Product],2 require-

ments for local clinical trials) and company

strategy in selecting priority markets. The differ-

ing national approval times are then related to

the type of review carried out by the agency.

One of the objectives of the institute study was

to provide a better insight into these factors.

TYPES OF ASSESSMENT

One of the recommendations to emerge from

the early phases of the emerging markets study

and related workshops (2,3) was that “All parties

would benefit from a much greater openness in

accepting that most agencies do not have the

resources and skills to carry out a full review of

new active substance (NAS) applications and

that there should be greater clarity in defining

the review process that is actually followed.” To

this end, assessment types were classified as

Type 1, verification; Type 2, abridged; and Type

3, full (see Table 1).

F I G U R E 3

Regulatory approval times from date of submission to date of approval for NASs approved between 2004 and 2006 (company data).

2500

2000

1500

1000

500

0

Time

(day

s)

Regional MediansLatin America = 179

Middle East and Africa = 671Asia Pacific = 292

Overall median for allauthorities = 290

Argent

ina (2

0,9)

Brazil

(23,8)

Mexico

(19,8)

Egypt

(8,3)

Saudi A

rabia (

15,7)

South

Africa

(9,4)

China

(12,6)

India (

7,3)

Indone

sia (2

3,9)

Malaysi

a (10

,6)

Singap

ore (1

1,5)

South

Korea (

13,8)

Chines

e Taip

ei (13

,8)

Authority

Data are shown for NASs that were approved between January 1, 2004, and December 31, 2006. (n1) = number of drugapplications, (n2) = number of companies providing data. Box: 25th and 75th percentiles. Whiskers 5th and 95th percentiles.Diamond = median.

2. CPP issued under the WHO Certification Scheme for the Quality of Products Moving in International Com-

merce, http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/en/index.html.



This classification was used to compare the as-

sessment models used by the different agencies.

The results showed that more than one type of

assessment is used by the agencies in some

countries when all types of application are con-

sidered. When the assessment predominantly of

NAS and MLE applications is considered, how-

ever, this picture emerged:

• Argentina was the only country routinely using a

Type 1 assessment for major applications.

• Mexico, Egypt, Saudi Arabia, Malaysia, and Singa-

pore generally used assessment Type 2 for most

products.

• Brazil, South Africa, China, India, Indonesia, South

Korea, and Chinese Taipei routinely apply a full as-

sessment (Type 3) process to NAS applications but

this is only completely self-standing in South Africa

as the other countries still require evidence of ap-

proval in a reference country before a final author-

ization for local marketing can be issued.

EVIDENCE OF AUTHORIZATION

ELSEWHERE

A cornerstone of assessment Types 1 and 2 is

that there should be evidence that the prod-

uct is registered elsewhere. The CPP remains

the most common means of verifying this but

timing and requirements vary. The CPP is re-

quired at the time of submission by Argentina,

Egypt, and Saudi Arabia, but in Brazil and

most of the Asia-Pacific countries studied it

can be submitted after the application but be-

fore authorization. The need for legalization

of the CPP through an embassy or consulate

in the exporting country remains a require-

ment in Brazil, Egypt, Saudi Arabia, and Chi-

nese Taipei and has been identified, by indus-

try, as one of the factors that impede rapid

and efficient rollout of new medicines to new

markets.

As noted, most countries that follow Type 3

procedures still prefer the safety net of not be-

ing the first agency to register an NAS. The CPP

is not required in South Africa and both Singa-

pore and Indonesia can carry out a full review

without prior authorization elsewhere but,

when such evidence is required, there is some

flexibility and evidence other than the CPP can

be accepted.

F I G U R E 4

Comparative median roll-out times for NASs in dif-ferent markets. EM, emerg-ing markets.

Argentina

Brazil

Mexico

Egypt

Saudia Arabia

South Africa

China

India

Indonesia

Malaysia

Singapore

South Korea

Chinese Taipei

Regu

lator

y Au

thor

ity

Median time intervals: First market submission to EM market approval (days)

0 250 500 750 1000 1250 1500 1750 2000 2250 2500

Median approval timein first market

Median gap: Firstmarket approval – EMsubmisssion

Median EM countryapproval time


REVIEW PROCESS MODELS

The basic process map that is common to almost

all agencies in both ICH-affiliated regions and

the emerging markets consists of the following

elements:

Validation → Scientific Assessment →Questions to Sponsor → Final Report →Approval Procedure

This sequence was used to construct a generic

model to map the stages in the review process

(see Figure 5). The model also indicates the dif-

ferent stages at which timing might be recorded

to allow targets and timelines to be set.

Agencies were asked questions about their

procedures, based on this model, and individual

processes were mapped accordingly. Some of

the most noticeable differences that were found

among agencies were in the procedures and the

sequence for referring the application to out-

side experts or committees. Other differences

were found in the timing of questions to the

sponsor and in whether the different sections of

the application (safety, quality, and efficacy)

were assessed in parallel or in sequence.

Although an overall similarity between coun-

tries and regions was found, there are, as noted

in Figure 5, key areas where notable differences

were found between processes. Mexico, for ex-

ample, has introduced a voluntary preapplica-

tion procedure that allows companies the op-

portunity to discuss NAS applications with a

committee of experts prior to submission. In

China, a full IND and clinical development pro-

gram must be undertaken in the country before

an application for marketing can be made.

Queue times can vary widely with applications

being picked up for review almost immediately

in some countries (eg, Chinese Taipei and South

Korea) or waiting six months to a year in others.

The classic review sequence is to carry out a

parallel review with the quality, safety, and effi-

cacy sections of the application being assessed

at the same time. Examples of a sequential re-

view were, however, reported from Indonesia,

where safety and efficacy must be approved by

the expert committee before resources are as-

signed to the quality section and in Mexico

where quality is assessed before the review of

safety and efficacy commences.

T A B L E 1Type 1: Verification Assessment

This model avoids duplicating the assessment of a new product that is identical to one which has been approved elsewhere. The elements are: • Recognition of an authorization by one or more reference or benchmark agencies.• A verification process to validate the status of the product and ensure that the product for local marketing conforms to the author-

ized product.

Type 2: Abridged Assessment

This model also conserves resources by not reassessing the full scientific supporting data but focuses on aspects that must be evaluatedspecifically for the local environment. • It is a prerequisite that the product has been registered by a reference or benchmark agency.• An abridged assessment is carried out in relation to the use of the product under local conditions (eg, focusing on aspects of quality

such as stability and on a benefit-risk assessment for the local medical practice/culture and patterns of disease).

Type 3: Full Assessment

In this model the agency has suitable resources, including access to appropriate internal and external experts, to carry out a full reviewand evaluation of the supporting scientific data. • A full, independent review of quality, preclinical (safety), and clinical (efficacy) data is carried out.• Information on registrations elsewhere (if any) is taken into consideration but is not a prerequisite to filing or for authorization.*

* In practice, prior authorization was a legal requirement in some countries, before local authorization could be finalized, but filing the application and the review wasnot delayed.

Types of Data Assessment



Procedures for the final authorization process

differ and can cause delays if matters other than

the scientific review need to be finalized before

the authorization is issued. Three authorities—

Brazil, Egypt, and Saudi Arabia—require pricing

agreements before authorization and sample

analysis is required in Egypt and Saudi Arabia

and for certain biologicals in Brazil and Mexico.

TARGETS

Agencies were asked, with reference to the

process map, about the stages for which targets

and deadlines are set. Although these are im-

portant in making the review more predictable

and project management more efficient, not all

agencies had documented targets. For valida-

tion, the targets ranged from none to less than

five weeks, for scientific assessment from none

to 160 calendar days, and for the authorization

procedure from none to one month. Targets for

overall approval times ranged from none to a

year and different targets applied in countries

(eg, Singapore) where different assessment

routes could be followed.

A comparative summary of the target times for

the different stages of the review for countries in

Asia is given in Table 2.

P E R C E P T I O N S O F R E V I E WP R O C E D U R E SBoth agencies and industry were asked for their

viewpoint on factors that contribute to and

those that impede the effectiveness and effi-

ciency of the review. The positive factors were:

political will; adequate resources; training (and

retaining) qualified and experienced staff; elec-

tronic tracking systems; and standardization of

the review process through good regulatory re-

view practices (GRP) and standard operating

procedures (SOPs). Complete submissions from

industry are also a major contribution to the

process.

F I G U R E 5

Review process: generic model.

Key areas where the review process can differ:• Preapplication requirements and validation process• Queue time and whether there is a backlong.• Scientific assessment and how the scientific reviewis conducted: Parallel vs. sequential assessment of safety, quality, and efficacy Use of advisory committees Available resources and use of external experts• Questions to sponsors: timing, time limit to respond,batching of questions, and interaction with the sponsor• Authorization Additional criteria for the decisions on applications (eg, Pricing, Sample Analysis) Responsibility for the final decision

xx days

Xx days

Xx days

xx days

Validationtime

Admin

time1

Assess

ment

time1

Admin

time2

Milestone recorded

Milestone recorded

xx days

xx days

Milestone recorded

Reviewed in parallel

Preapplication procedure

Date application receivedReceipt and validation procedures

Accepted for review Milestone recorded

Queuing for review

Scientific review starts

Quality Safety Efficacy

Scientific Assessment

Questions to sponsor Timing recorded

Questions processed by sponsor

Reply from sponsor Timing recorded

Scientific Assessment continues

Start of Committee procedure

Committee ProcedureOpinion received

Final report

Scientific assessment ends

Approval procedureApproval granted Milestone recorded

A

B

C

D

E1

F

G

H

I


In practice, of course, for every positive factor

that helps the review there is an opposite nega-

tive factor that might impede the process.

Pharmaceutical companies’ observations on

review processes fell into four areas:

• Evidence of registration elsewhere needs to be ra-

tionalized and the timing and requirements for the

CPP continue to cause concern.

• Transparency and communication during the review

process are perceived as important benefits, as are

targets and optional procedures (as in Singapore).

• Data requirements should be within international

norms (ie, ICH guidelines for new medicines) and

other issues such as pricing and site inspections

should be separated from the scientific review

process.

• The organization of the agency should be ade-

quately resourced and operate with as much flexi-

bility and as little bureaucracy as possible.

Q U A L I T Y O F T H E R E V I E WThe study looked at how the authorities are pe-

riodically evaluating quality in the review

process and the activities being undertaken to

improve communication and transparency of

decision making, as well as the main factors that

are driving authorities to improve quality.

Quality is a notoriously difficult concept to de-

fine, but an earlier and ongoing study among es-

tablished regulatory agencies (4) has identified

eight key measures that are essential for GRP.3 In

the Institute study on emerging markets, these

T A B L E 2Target in Working (wkd) or Calendar (cd) Days Primary Scientific Assessment

Inter- Review ReviewAuthor- Overall nal or Parallel by by Use of

Scientific ization Approval Exter- or Agency External ExternalCountry Validation Assessment Procedure Time nal Sequential Staff Staff Experts

China* √ 90 wkd 1–3 months 175–195 Int Parallel QSE Ad hoc Expert(standard) wkd opinion

80 wkd (special approval)

India √ X X 6 months Int Parallel QSE Ad hoc Not given

Indonesia 2 wkd X <1 month P1 = 100 wkd Int Sequential QSE Ad hoc ClinicalP2 = 150 wkd and opinionP3 = 300 wkd Ext

Malaysia <5 weeks 14 cd <1 month NAS <7 Int Parallel QSE S&E Clinicalmonths and opinion

Ext

Singapore 21 wkd X X T1 = 90 or 60 wkd Int Parallel QSE S&E ClinicalT2 = 180 wkd opinionT3 = 270 wkd

South Korea N/A 60 wkd 25 wkd 85 wkd Int Parallel QSE Ad hoc Advice on technical

issues

Chinese N/A 160 cd 1–3 months 380 cd Int Parallel QSE Ad hoc Clinical Taipei (no CPP) with CPP opinion

100 cd 440 without (with CPP) CPP

P1, P2, P3 = different assessment routes for Indonesia; T1, T2, T3 = different assessment routes for Singapore; QSE = quality, safety, and efficacy data.

Target Times and Features of the Review Process for Countries in Asia for 2007 (Authority Data)

3. The CMR International Institute Benchmarking Study, initiated in 1998, collects data on the regulatory re-

view processes in the US, EU, Canada, Australia, and Switzerland.



eight components of a quality review were de-

fined, as set out in Table 3, and were used as the

baseline for obtaining comparative data from the

agencies in the study.

MOTIVATION

When 11 agencies were given a list of seven pos-

sible reasons for introducing quality measures

and asked to select the three most important, the

first selection was “to ensure consistency” (10/

11), the second “to ensure efficiency” (8/11), and

the third “to minimize errors” (6/11).

QUALITY MEASURES IN PLACE

Agencies were given a list of quality measures

and asked whether they were currently imple-

mented or planned for the near future. It was

noted that the agencies are at different stages of

development and also that they were undergo-

ing rapid change, even in the two years since the

study was initiated.

Looking at the overall approach to quality

management, eight authorities (Argentina,

Brazil, Mexico, India, Indonesia, Malaysia, South

Korea, and Chinese Taipei) had, at the time of

the study, an internal quality policy. Indonesia,

South Korea, and Chinese Taipei had a member

of staff responsible for the development of qual-

ity and good review practices and four (Argenti-

na, Brazil, India, and Malaysia) stated that they

had a department for assessing and ensuring

quality, but there are differences in the struc-

ture and resources allocated to these internal

units.

With respect to quality documentation, 10 au-

thorities use SOPs for the guidance of scientific

assessors: Argentina, Brazil, Mexico, India, In-

donesia, Malaysia, Singapore, South Africa,

South Korea, and Chinese Taipei. Eight authori-

ties use assessment templates for reports on the

scientific review of a new active substance: Ar-

gentina, Brazil, Indonesia, Malaysia, Singapore,

South Africa, South Korea, and Chinese Taipei.

These templates set out the content and format

of written reports on scientific reviews. Egypt

and Saudi Arabia indicated that they intended

to introduce both SOP and assessment tem-

plates within the next two years.

Four authorities (Indonesia, Mexico, South

Korea, and Chinese Taipei) indicated that they

T A B L E 3dddd

1. Key quality documentation: regularly updated and com-prehensive quality policies, standard operating procedures, andassessment templates.

2. Professional development of assessors and retaining ofstaff: adequate incentives to competent staff and regular train-ing of assessors that focuses on improved practices; scientific andtechnological advancements; knowledge and skills transfer.

3. Built-in quality controls such as systematic managementchecks, structured approach to decision making, and robust in-ternal tracking systems.

4. Internal reviews: a structured and integrated peer reviewsystem, as well as expert reviews by independent advisory com-mittees.

5. Benchmarking and key performance indicators such asregular use of quantitative indicators on processing times; re-sponse times; frequency and number of withdrawals; as well asthe carrying out of benchmarking exercises that compareprocesses or outcomes.

6. Continual improvement activities: conducting internalquality audits, self-assessments, analyses of feedback fromstakeholders, postapproval analysis with other authorities andindustry, management reviews, and using the results to take cor-rective action or introduce improvements to the review processand decision making.

7. An established setup and process that allows regularcontact with industry: for example, to discuss development andreview plans, clarify statutory requirements, provide scientificand regulatory advice, inform the applicant on how the review isprogressing, and develop partnerships and synergies betweenthe two parties.

8. A transparent system that provides important review in-formation to the public: for example, open public hearings ofadvisory committee meetings, or the publication of the summarybasis of approval and assessments following approval.

Components of a Quality Review


have implemented a GRP system and Malaysia

has all the components of such a system. There

can, however, be considerable differences in the

extent of development of these systems. Argenti-

na, Egypt, Singapore, and South Africa reported

that they planned to introduce a GRP system in

the near future.

Continuous improvement measures included

collecting feedback from stakeholders following

a review, which is carried out by all 11 agencies

studied, and reviewing feedback from the asses-

sors themselves (10 agencies). Ten agencies had

internal tracking systems to monitor applications

and review progress and eight reported that they

had formal training programs. External quality

audits were relatively infrequent (3/10), and in-

ternal audits were even more infrequent (3/11).

COMMUNICATION, TRANSPARENCY,

OPENNESS

Companies place great emphasis on the advan-

tages of working with an agency that operates in

an open and transparent manner, but there is a

perception among authorities that transparen-

cy does not always work both ways and that com-

panies can be criticized for poor communica-

tion and lack of transparency.

When asked about their general perceptions

of the need for transparency, 8 out of 10 agen-

cies that responded assigned a high priority to

being open and transparent. (Information was

not available from Brazil, China, and India.)

In relation to the specific benefits to be at-

tained, 9 out of 10 agreed that it increased con-

fidence in the system, 8 felt that it helped pro-

vide assurances on safety safeguards, and 6

believed it led to better staff morale and perform-

ance. Some of the specific attributes used as a

measure of transparency are shown in Figure 6.

There was general agreement that authorities

can enhance their standing with the public,

health professionals, and industry by allocating

time and resources to provide information on

their activities and decisions in an open and

transparent manner.

S U M M A R Y QUALITY MEASURES

Most authorities in the countries studied have a

range of quality systems and measures but they

are at different stages in their development and

maturity. The smallest number of implemented

measures was found in the Middle East coun-

tries in the study (Saudi Arabia and Egypt).

F I G U R E 6

Communication and trans-parency in the regulatory review process.

Industry can trackprogress of applications

Official guidelines to assist industry

Presubmission scientific advice to industry

Details of technicalstaff to contact

Feedback to industryon submitted dossiers

Attribute

1086420

Number of authorities

3

6

9

11

11



CONTINUOUS IMPROVEMENT INITIATIVES

Many agencies have focused on improving their

assessment of feedback from stakeholders and

reviewers as well as establishing tracking sys-

tems, although few have either internal or exter-

nal quality audits.

GOOD REGULATORY REVIEW PRACTICE

The importance of establishing and implement-

ing a GRP system is well understood although

few agencies have achieved this to date. Several,

however, are planning this within the next two

years, although the level of detail and value has

yet to be assessed.

O V E R A L L C O N C L U S I O N S F R O M T H E S T U D YThe regulatory aspirations, barriers, and priori-

ties are essentially similar across agencies. The

review steps are also similar although there are

major differences in the assessment process.

Regulatory review procedures and require-

ments are undergoing rapid change in the 13

countries studied and both authorities and

companies are seeking to understand better the

factors that impact on performance.

Most agencies are using risk stratification

methods for their review of new medicines,

based on the level of regulatory scrutiny the

product has already undergone elsewhere. The

challenge is how best to evolve these methods to

ensure timely access of patients to new medi-

cines within an appropriate benefit/risk deci-

sion-making process.

Regulatory authorities are aware of the impor-

tance of building quality into their regulatory

processes and practices, although there are cur-

rently differences in the way in which quality

measures are being applied.

Acknowledgments—The authors would like to thank

both the companies and agencies that gave their time

and provided information that made this study possi-

ble.

R E F E R E N C E S1. McAuslane N, Cone M, Collins J. A cross regional

comparison of the regulatory environment in

emerging markets. CMR International Institute

for Regulatory Science R&D Briefing No. 50,

February 2006. Available at: http://www.cmr.org/

institute/PDF/RD50.PDF.

2. Walker S, Cone M, Collins J. The emerging mar-

kets: regulatory issues and the impact on pa-

tients’ access to medicines. CMR International

Institute for Regulatory Science Workshop Re-

port, April 2006. Available from Institute@

cmr.org.

3. Walker S, McAuslane N, Cone M, Collins J.

Emerging markets: models of best practice for

the regulatory review of new medicines. CMR In-

ternational Institute for Regulatory Science

Workshop Report, March 2008. Available from

[email protected].

4. Cone M, McAuslane N. Building quality into reg-

ulatory activities: what does it mean? CMR Inter-

national Institute for Regulatory Science R&D

Briefing No. 46, June 2006. Available at: http://

www.cmr.org/institute/PDF/RD46.PDF.

All authors at the time of this study were employees of CMR International Institute for Regulatory Science,

which is funded by unrestricted membership dues from biopharmaceutical companies. The authors declare no

competing interests.

drug regulation in several countries

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