medicine and vaccine shortages: what is the role of...

A report by The Economist Intelligence Unit Supported by the Parenteral Drug Association

Medicine and vaccine shortages: What is the role of global regulatory complexity for post approval changes?

Supported by

MEDICINE AND VACCINE SHORTAGESWHAT IS THE ROLE OF GLOBAL REGULATORY COMPLEXITY FOR POST APPROVAL CHANGES?

© The Economist Intelligence Unit Limited 20181

Medicine and vaccine shortages: what is the role of global regulatory complexity for post approval changes? is an Economist Intelligence Unit (EIU) Healthcare study which was sponsored by the

Parenteral Drug Association (PDA). Aditi Karnad, Senior Healthcare Analyst and Anelia Boshnakova, Senior Information Specialist were

the main project researchers. Annie Pannelay served as senior advisor.We wish to thank the experts listed in the Expert interviews section for their time and insights. The

Economist Intelligence Unit bears sole responsibility for the content of this report. The findings of the report and the views expressed in it do not necessarily reflect the views of the experts involved.

About this report



Executive summary 3

Burden, impact and causes of shortages 5

The regulatory process in the context of shortages 10

The case for regulatory harmonisation 14

Milestones towards regulatory harmonisation 17

Discussion and findings 20

Concluding remarks 25

Expert interviews 26

References 27

Contents



This study aims to explore whether the varying regulatory requirements for pharmaceutical products across the world are associated with medicine and vaccine shortages. This research

project included a rapid literature review involving database and grey literature searches and a series of interviews with representatives of academia, industry, regulatory authorities, international organisations and global non-governmental organisations.

Key messages from the findings of the literature review and insights from the expert interviews are presented below.

Medicine and vaccine shortages are a global problem affecting rich and poor countries alikeMedicines and vaccines shortages are a global problem with significant impact on populations and health care systems. Shortages continue to persist, despite increased efforts from a range of stakeholders including international organisations, governments, regulators, healthcare providers, pharmacists and industry over the past decade. Vaccines shortages in particular are a serious public health issue, as they can lead to reduced population coverage and delays in prevention and control programmes for infectious diseases.

Causes for shortages are complex, multifaceted and not well understoodCauses for shortages are complex and interrelated, and vary for different products and countries. To channel the activities for prevention and mitigation of shortages, we need more research into the interplay of related causes, with a particular emphasis on economic and market-related causes. There is a need to identify critical products such as vaccines and risk factors that could affect the uninterrupted supply of these products to the people who need them.

This study found little evidence for the existence of a direct correlation between the global complexity of regulatory requirements for post approval changes and shortages This study explored the question of whether the global complexity of regulatory requirements for post approval changes (PACs) to the terms of marketing authorisation could be a contributing factor for medicine and vaccine shortages; however we found little evidence in support of this hypothesis. In situations of shortages however, the regulatory complexity for PACs on a global scale could be an aggravating factor that delays or hinders mitigation actions.

There is a universal agreement that regulatory convergence and harmonisation are beneficial to all stakeholdersRegulatory harmonisation has been supported by the World Health Organization (WHO) since the 1980s. Numerous global and regional initiatives have been set up, including the European Regulatory System for medicines and the International Council on Harmonisation (ICH). There is a trend towards greater co-operation and regulatory convergence in the Americas, Asia-Pacific and South-East Asia, which could only be positive in terms of strengthening the regulatory systems in these regions and building trust between national regulatory authorities (RAs). The developments in Africa leading towards the establishment of an African Medicines Agency that follows the European model will also have a positive effect on the processes and timelines for PACs.

Executive summary



Trust and strong political will are required for harmonisation and convergence initiatives to succeedIt is important to develop an understanding of the expectations and priorities of all stakeholders, and to pursue the harmonisation goal, even though progress may seem slow at times. A look at the history of the European Medicines Agency (EMA) since its establishment in 1995 shows that it has taken decades of work and strong political will to achieve the current level of harmonisation. The recent increase in mutual recognition agreements between the EMA and other RAs shows that regulators can work together to avoid duplication in effort and rely on each other’s expertise in challenging areas for regulatory science. The adoption of WHO guidelines for procedures and data requirements for changes to approved vaccines by national RAs, and further developments related to ICH quality guideline proposals for product lifecycle management, would help to reduce the complexity of requirements for the same changes across different jurisdictions.

Finding a permanent solution for shortages is critical for achieving global health goalsWe hope that this report will help to raise awareness about the global impact of medicine and vaccine shortages, and the need for coordinated action from multiple stakeholders at international and national level. Finding a permanent solution for shortages is crucial for achieving the UN Sustainable Development Goal for health, including access to “safe, effective, quality and affordable essential medicines and vaccines for all” by 2030.1, 2



Medicine shortages are a global problem Medicine shortages are a global issue, impacting the health of populations all over the world. Shortages of essential medicines have been reported in countries from varying income levels, some widespread and others localised to one country or region. The WHO recently reported on a Belgian pharmacy journal listing 21 countries that have experienced supply disruptions, citing that they were occurring “from Afghanistan to Zimbabwe.”3 One such example took place in the region of Kerala, India, which faced a shortage of 130 medicines from the regional Essential Medicines List.4

One of the challenges facing organisations trying to resolve this complex issue is the lack of common understanding and a universally accepted definition of shortages. A workshop convened in 2016 in response to World Health Assembly Resolution (WHA69.25) for addressing the global shortage of medicines and vaccines proposed new definitions for shortages and stockouts.5, 6 According to these definitions, shortages occur when the supply of medicines and vaccines identified as essential by the health system is insufficient to meet public health and patient needs; stockouts refer to the complete absence of a particular product at the point of service delivery to the patient.2, 6

In 2009 tuberculosis (TB) was responsible for 1.7 million deaths and 9.4 million new cases globally.7 Yet in 2010, a shortage of an injectable formula of streptomycin, an antibiotic used to treat TB, was reported in 15 countries, with eleven more predicting stockouts of the product before their stocks could be replenished.3 Further to this, the Bacillus Calmette-Guérin (BCG) vaccine used to preventively immunise children from TB has also experienced shortages in in different parts of the world since 2012.4

Shortages are not only happening across the globe, they are also occurring more frequently and for longer durations.2, 8 The International Pharmaceutical Federation reports that in some countries the frequency of medicine shortages has tripled between 2005 and 2010.9 In the US alone, statistics from the University of Utah Drug Information Service and the American Society of Health System Pharmacists (ASHP) show that from 2005 to 2010, the annual number of drug shortages increased from 74 to 211, peaking at 267 shortages in 2011. Promisingly, concerted efforts in the US to address the issue since 2012 have led to a drop in the number of shortages, with 154 recorded in 2016 and 105 in 2017.10 In Europe, 86% of hospital pharmacist respondents from 36 countries reported in 2014 that medicine shortages were a current problem in their countries, stating that they occurred on a weekly and sometimes even daily basis.11

The number of drug shortages is rising at an alarming rate, with most involving injectable formulations such as vaccines, cancer medications, antibiotics, anaesthetics required for surgery and emergency medicines.2, 11 Based on data from the ASHP Resolved Drug Shortages website, a 2016 study found that in a sample of 29 generic injectable drugs, the greatest proportion of shortages (28%) were for oncology medicines and 21% were for drugs specific for the central nervous system.12

Vaccines are essential Immunisation has been hailed as “public health’s best buy” by GAVI, the Vaccine Alliance. Vaccines are essential to health systems and are an important resource populations must have access to. Through

Burden, impact and causes of shortages



both direct medical savings and indirect economic benefits, vaccines and immunisation are known to be a cost-effective way to prevent the spread of harmful diseases, save lives and provide lifelong protection.13 A recent study estimated that for every US dollar invested in childhood immunisation there is return on investment of US$16 in terms of healthcare cost, wages and productivity.14 For example, polio is a crippling infectious disease. Yet, since the launch of global polio eradication efforts using the polio vaccine in 1988, the incidence of this potentially deadly disease has been reduced by more than 99% globally, from an estimated 350,000 cases at the time to 37 reported in 2016.15, 16 Similar results have been seen for other vaccines, including rubella, mumps, tetanus and measles.17 The benefits of vaccines are undisputable, and access to vaccines and immunisation programmes are prioritised in most countries. Organisations such as GAVI, the Pan American Health Organization (PAHO) and United Nations International Children’s Fund (UNICEF) coordinate joint procurement efforts for affordable vaccines in low- and middle-income countries.18

Yet with policies in place and with vaccines developed for a large number of infectious diseases, why is it that vaccines still do not make it to the shelf? In 2012 WHO member states adopted the Global Vaccine Action Plan (GVAP) framework to achieve the goal of universal access to immunisation across the globe with the aim to have a world “free of vaccine-preventable diseases”.19 The monitoring and evaluation framework is organised around six strategic objectives, one of which focuses on vaccine stockouts and sustainable supply of quality assured products.19, 20 Data are collected from the WHO-UNICEF Joint Reporting Form and UNICEF’s Vaccine Forecasting Tool.20 A study by Lydon et al analysing these data for the period 2011-15 reported that one in three WHO Member States experienced at least one stockout of at least one vaccine for at least one month every year. It also highlighted that a worrying 38% of Sub-Saharan African countries reported stockouts of vaccines annually; 43% of the stockouts were for the diphtheria, pertussis and tetanus (DPT) vaccine, while stockouts of the BCG vaccine accounted for 31%.21 In 2015 65 countries reported vaccine stockouts (34% of countries). The average duration was 44 days.21

In 2015 55% of vaccine stockouts occurred in middle-income countries; nevertheless, they are also an issue in the more advanced economies—25% of stockouts took place in high income countries.21 The current and ongoing global shortage of the hepatitis B vaccine has led to rationing in the UK, with measures expected to continue into 2018.22 Similarly, in the past the US has experienced shortages of many of the vaccines recommended in the childhood immunisation schedules.23 Figure 1 shows the percentage of vaccine stockout events by income group from 2010 to 2015, as reported in the GVAP study.21

In 2016 the European Centre for Disease Prevention and Control (ECDC) reported on the ongoing shortage of vaccines containing acellular pertussis (aP), which has led to adjustments of the immunisation policies in nine EU/EEA countries.24 The ECDC assessment established that the shortage arose as a result of reduced production capacities for the aP antigen. As this vaccine is not a standalone, the ongoing shortage posed a risk for the availability of any combination vaccine containing this component, including vaccines protecting against tetanus, diphtheria, polio and Haemophilus influenzae type b (Hib). The ECDC report declared that the ongoing shortage of aP-containing vaccines presents a public threat to the EU.24



The Sixty-ninth World Health Assembly (WHA69.25) resolution for addressing the global shortage of medicines and vaccines highlighted the importance of continuous supply of medicinal products in the context of achieving the global access to medicines goals as part of Goal 3 of the Agenda 2030 for Sustainable Development.2 Vaccine shortages present a major challenge to achieving this goal, as they result in disruptions and delays to vaccination programmes, compromising immunity and putting a large number of individuals at risk. During epidemics, shortages can disrupt mass reactive vaccination campaigns. For example, in Niger during an outbreak of meningitis there was a shortage of the meningitis vaccine. The International Coordinating Group on Vaccine Provision for Epidemic Meningitis had ordered vaccines for their emergency stocks from three manufacturers. However, one of the manufacturers faced production problems and the other two companies were unable to increase their production in time to curb the meningitis outbreak. That particular outbreak caused almost 7000 cases of meningitis and over 400 deaths, as at May 2015.23

Causes and drivers of medicine and vaccine shortagesThere are a number of causes for shortages. These include manufacturing issues, unpredictability of demand and economic reasons leading to a limited supplier base, to name just a few. Furthermore, it is the combination of multifaceted causes that makes shortages such a complex issue to address.9, 21, 25, 26

A presentation at the meeting of the WHO Strategic Advisory Group of Experts (SAGE) on Immunisation in April 2016 categorised the causes of vaccine shortages in three main groups: supply factors limiting availability, demand factors affecting access, and information/communication causes hampering the mitigation of shortages.26, 27 In an analysis of the causes for shortages of the BCG vaccine, the main areas of concern were supply factors related to the limited number of manufacturers with prequalified products (only four in 2015, and five in 2016), technical issues at the production sites and low market attractiveness. In the case of shortages of aP-containing vaccines, which include both traditional and newer vaccines, there were multiple causes related to all three categories.27 The GVAP study showed that the majority of the stockouts were the result of government funding delays, delays

Source: Lydon et al.21

Figure 1. The % of stockout events by income group, from 2010 to 2015, GVAP

0

5

10

15

20

25

30

35

40

Low income Lower-middle income Upper-middle income High income

% o

f sto

ckou

t eve

nts

Countries - by income group

2010 2015



in the procurement processes, poor planning and stock management at country level. However in 9% of the cases the stockouts were due to global supply shortages.21 The GVAP reports that in low-income countries the primary reasons for stockouts are inaccurate forecasting and issues around stock

Table 1. Causes and drivers of shortages 21, 26-28

Fluctuations in global demand

The spread of infectious disease is unpredictable. Therefore, when a sudden outbreak occurs it is challenging for market authorisation holders (MAHs) to ensure a continuous supply of vaccines. This can result in them having to prioritise vaccine production for the outbreak, potentially leading to shortages of other products that they are currently responsible for supplying.

Market conditions—low market prices

Entering the market is a business decision, and low market prices make production of some vaccines unattractive to manufacturers, which results in either manufacturers not entering the market in the first place (non-availability) or withdrawing from the market, which can lead to shortages.

Funding and procurement delays

Lengthy national procurement processes as well as delays in the release of funds for the financing of vaccines can in some cases interfere with the provision of a continuous supply of medicines

Limited number of manufacturers

Vaccines are biological products requiring technical knowledge for a complex manufacturing process. This, combined with uncertain demand, has resulted in a limited supplier base.

Technical issues

Sudden shocks such as technical issues and manufacturing problems can increase the risk of shortages. This is particularly an issue when the manufacturer has a small number of manufacturing sites and production lines.

Long lead times

The long lead times associated with vaccine manufacture make it difficult to respond to unexpected short-term vaccine shortages. In addition, building a new facility to produce the vaccines required would take significant time.

Quality-related delays

Vaccines have to go through a long process of rigorous quality control. When the product does not comply with Good Manufacturing Practice (GMP) or when safety concerns arise, it affects the supply and can lead to shortages.

Diversity of regulatory requirements

Regulatory requirements vary across the globe and can impact planning and production for MAHs, acting as an aggravating factor during a shortage. As vaccines are biological products, both the production process and the actual product have to be licensed by regulatory authorities. This can increase manufacturing lead times and hinder how quickly shortages can be mitigated.

Lack of timely communication about supply and demand information

The lack of timely communication and accurate information about demand forecasting or the risk of an upcoming shortage can result in situations where countries and MAHs are unable to prepare for the event and seek alternative solutions. This can cause misalignment and mistrust between stakeholders.

Lack of knowledge on alternative solutions

During a vaccine shortage, national authorities are sometimes not aware of alternative solutions. This means that they are fully reliant on MAHs to supply and are unable to mitigate a shortage.



management; in middle-income countries, stockouts are the result of procurement and funding delays; and in high-income countries, stockouts are often caused by the lack of vaccine products available on the market.19, 21

As shown in Table 1, there are several factors affecting both generic and innovative products. This is in no means an exhaustive list, but a summary of interrelated causes recently identified in several research reports.

However, of most interest to us in this paper is to explore whether there is a connection between medicine shortages and the varying regulatory requirements across the world. In the rest of this report we investigate that hypothesis.



Pharmaceutical manufacturing is one of the most heavily regulated industries. Regulatory authorities across the world are in a unique position that entails taking on a legal role of enforcing

national laws and regulations while promoting and protecting public health.29 Ensuring “uninterrupted supply of high-quality, safe and effective” medicines and vaccines has become part and parcel of the public health mission of the regulators in many countries.30 For example, in the US the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA), directed the FDA to establish a task force to develop a strategic plan for prevention and mitigation of drug shortages.31 The role of regulators also involves providing support for the pharmaceutical industry and encouraging innovation, which could sometimes be seen as competing with RAs’ public health role.29

The regulatory process spans the three key lifecycle stages of medicinal products: research and development (R&D), marketing authorisation and post-authorisation.32 At the R&D phase, the regulatory system can impact the developments of effective, safe and quality products, for example, by “improving the clinical trials enterprise”.29 By design, the regulatory system controls the availability of medicines and vaccines on the market through the marketing authorisation (MA) process. Products not licensed or approved by the relevant regulatory authorities are not available for use in a given country. After approval, regulators need to monitor the ongoing safety and quality of licensed medicines and vaccines throughout their lifecycle. The regulatory requirements and processes for the MA and post approval stages can differ significantly across different countries and regions.

Regulatory requirements for vaccines Vaccines are biological products that are difficult to formulate and have a lengthy manufacturing process—one batch can take up to two years on average from start to finish. Quality control is performed regularly during the manufacturing phase; due to the nature of vaccines, in-vivo methods may be used to ensure their high quality before they are ready for batch release. In addition, there is no way to test the quality until each step is finished. The regulation of quality systems is essential to make certain that all pharmaceutical products, not just vaccines, meet the standards set by both national and international regulators, and that they are safe for use by individuals across the globe. Figure 2 shows the different points at which regulatory approval needs to be granted during the development and manufacturing stages for vaccines.33, 34

Vaccines are not only highly technical biological products, but they also have to be produced in different formulations for different countries, populations and age groups. Moreover, some products exist in standalone and combination formulations, which increases the number of products that need to be manufactured.25 The complexity of vaccine production can be particularly challenging when market authorisation holders (MAHs) need to keep several production lines running with different product versions.

The regulatory process in the context of shortages



Regulatory requirements for post approval changes Batch production methods required for vaccines are a process of ongoing innovation – for maintaining production facilities, for efficiency purposes, and to ensure compliance with rigorous and evolving quality standards and regulatory requirements. Ongoing changes can include changes to vaccine composition or manufacturing process, new test methods, the use of new manufacturing equipment or a new supplier, or setting up a new production site.25, 35 These changes are referred to as post approval changes (PACs), as they take place after a medicine or vaccine has already been licensed and received market authorisation. PACs, or variations, as they are called in the EU36 and some other jurisdictions (for example, Singapore37), refer to changes “to the terms of the marketing authorisation”.38 PACs are a natural phenomenon in the product lifecycle and are necessary to ensure continual improvement and innovation as new knowledge is acquired.

Different countries and regions have their own requirements and processes for dealing with PACs. Most RAs use a classification system for PACs, depending on the level of risk to public health, and the impact on the quality, safety and efficacy of the medicines. Some changes require notification by the MAH either before or after implementation. The changes with the highest potential impact may require a complete scientific assessment, as is the case with new medicines.38

A 2016 report by the French Society of Pharmaceutical Sciences and Techniques (SFSTP), focusing on managing changes on industrial sites that export internationally, described the complexity of the regulatory requirements for post approval variations in the manufacturing of medicines and biologicals.39 Different countries or regions use different classification systems for PACs. There is also

Research &Development

Manufacturing processAssembling rawmaterials

Combining all ingredientsFilling

Packaging

Batch release

Distribution

Bulk antigenmanufacturing

Quality control

Several controls take place as all the processes described below have to comply with Good Manufacturing Practice (GMP)

standards

Source: IFMPA, 201433 and Vaccines Europe, 2016.34

Figure 2. Regulatory requirements within the vaccine manufacturing chain



diversity in the reporting categories as specified in Table 2. Different RAs may also require different formats for application such as electronic or paper submission. This system of reporting PACs highlights inefficiencies in the regulatory processes when viewed from a global perspective as MAHs are required to submit notifications on different timescales for each country in which their medicine is already approved for use.

The different requirements and varying timelines to regulatory approval can make PACs difficult to manage, and create a complex and time consuming process for MAHs.39 This may particularly be the case for global companies that manufacture the same or similar products for a large number of countries. As part of the PACs regulatory process, MAHs report that they are required to submit different applications for the approval of a product, with differing data and scientific requirements in each market sometimes resulting in additional clinical trials and animal studies.28 This becomes challenging when trying to mitigate a shortage, as regulatory timescales and complexities can increase lead times and impact how quickly a population receives a vaccine.28, 40

A number of factors are involved in creating a complex, multilayer system for introducing changes that could take months and years from start to finish. The SFSTP paper reported that average approval times in over 70 countries for 10 concrete changes ranged from under 50 days in some countries to over 1,100 days in others. Many of the factors listed below are interrelated: 39

the number of countries where medicines are marketed;

inconsistent classification of changes leading to a mismatch of categories in different jurisdictions;

multiple stakeholders are involved;

variability in national regulations for submission and approval;

variability in timescales; and, consequently,

lengthy transitional periods until change is approved by last country; thus requiring

parallel production of numerous product versions.

The evaluation time can vary from 2 to 30 months for certain products in EU countries when national submission is required. Waiting for approval from all jurisdictions is also not an option as some countries, such as Belgium, Portugal, Romania and Japan, impose a maximum timeframe for implementation. Certain mechanisms such as staggered submission based on projections for approval timescales have been used; however, they are not an option when shortages occur or when

Table 2. Differences in regulatory requirements for approval and implementation of variations39

EU US Canada Japan

Do & record* × × √ ×

Do & tell* √ √ √ √

Tell & do** √ √ √ ×

Tell, wait, & do*** √ √ √ √*Mostly minor changes; **Mostly moderate changes; ***Mostly major changes.

Key: × – category not used; √- category used



changes are necessary owing to quality or safety issues. 39 The different timelines are associated with unpredictability for manufacturers, which makes planning difficult, especially when shortages arise.

Similar issues are reported in other regions. For example, the assessment of post-approval amendment applications by the Medicines Control Council (MCC) in South Africa entails a lengthy approval timeline of approximately two years for a major change.41 Furthermore, before the application for an amendment is approved, the manufacturer is “blocked” from submitting any further applications, which could be a significant problem for products undergoing rapid chemistry, manufacturing and control (CMC) evolution.41 Table 3 shows the significant variations in the timelines for PACs in different jurisdictions.

Table 3. Timelines to approval for variations in different countries/regionsApproximate timelines

Country/Region Regulatory agency Minor Major

Argentina42 ANMAT 180 days 180-240 days

European Union37 EMA Type IAIN: 30 daysType IB: 30 days

Type II: 30-90 daysType II extension: 210 days

Japan43 MHLW, PMDA 30 days 365 days

India37 CDSCO 90 days 180 days

Saudi Arabia37 SFDA Type IA: 60 daysType IB: 120 days

Type II: 145 days

Singapore37 HSA MIV-1: 120 days MAV-2: 180 daysMAV-1: 180-270 days

South Africa41 MCC Type A: 0 daysType B: 30 days

Type C: ~ 730 days

USA44 FDA Moderate: 0 - 30 days Prior approval supplement (PAS): 180-300 days

WHO prequalification programme45

WHO/national RAs Minor (N): 30 daysModerate (R): 365 days

Major (A): 90-150 days

Key: ANMAT - National Administration of Drugs, Foods and Medical Devices, CDSCO - Central Drug Standard Control Organisation, EMA

- European Medicines Agency, FDA - Food and Drug Administration, HSA. - Health Sciences Authority, MCC - Medicines Control Council,

MHLW - Ministry of Health, Labour and Welfare, PMDA - Pharmaceuticals and Medical Devices Agency, SFDA - Saudi Food and Drug

Authority



The International Pharmaceutical Federation (FIP) is not the only organisation emphasising the issues arising from using national regulatory frameworks for increasingly global products—with

global R&D, manufacturing, and supply and distribution, there is almost unanimous agreement that the regulatory requirements for all stages of the lifecycle of medicinal products need to be standardised and aligned. 9, 29, 40, 46

The WHO has played a key role in a number of global and regional harmonisation initiatives as they impact some of its most important objectives – providing access to medicines and strengthening health systems, including strengthening national regulatory authorities. In a 2016 statement the WHO

The case for regulatory harmonisation

1980 90 2000 10 20

EMA-EC31 countries

1980ICDRA194 countries

1995ICH

39 countriesPIC/S

49 countries

1999ASEAN10 countries

GCC-DR7 countries 2009

APEC10 countries

AMRH55 countries

2012ICMRA

Global initiatives Regional initiatives

2000PANDRH36 countries

EAC

2015ZAZIBONA4 countries

21 countries

6 countries

Figure 3. Timeline of harmonisation initiatives

Source: The Economist Intelligence Unit. Number of member countries (excluding observers).Key: ICDRA - International Conference of Drug Regulatory Authorities; ICH - International Council for Harmonisation of Technical Requirements

for Pharmaceuticals for Human Use; PIC/S - Pharmaceutical Inspection Co-operation Scheme; EMA-EC - European Medicines Regulatory

Network/European Commission/European Medicines Agency; ASEAN - Association of Southeast Asian Nations Pharmaceutical Product Working

Group; GCC-DR - Gulf Central Committee for Drug Registration/Harmonisation Initiative; PANDRH - Pan-American Network for Drug Regulatory

Harmonization; APEC - Asia-Pacific Economic Cooperation/Life Sciences Innovation Forum/Regulatory Harmonization Steering Committee;

AMRH - African Medicines Regulatory Harmonization; ICMRA - International Coalition of Medicines Regulatory Authorities; EAC – East African

Community; ZAZIBONA – ZAZIBONA Collaborative Medicines Registration



estimated that three out of ten regulatory authorities in the world are not fit for purpose owing to underfunding, workforce issues, and lack of understanding of the regulatory role within the broader healthcare system.47 The weak performance of a national regulatory system can impact access to medicines through long timelines to authorisation and medicine shortages.47 Vaccines are particularly challenging, as they are complex biological products and require both regulatory knowledge and experience, which many RAs may to some degree be lacking. The WHO advocates for harmonisation “to the greatest extent possible” to ensure the supply of high-quality, efficacious biological products. Through its “consultative approach” in consolidating opinions and providing guidance documents on a range of issues, as well as specific products, the WHO has played a critical role in improving the regulatory environment for critical biological products such as vaccines.48

Harmonisation initiatives have gained momentum since the 1980s, when one of the earliest initiatives was founded, the International Conference of Drug Regulatory Authorities (ICDRA).49 As Figure 3 shows, several harmonisation initiatives have continued to emerge in the past decade. Box 1 provides a brief description of the main objectives of some of the major international harmonisation initiatives.

Some of the regional initiatives are coordinated by the WHO’s regional offices, such as the Pan American Health Organization (PAHO) leading the Pan American Network for Drug Regulatory Harmonization (PANDRH) initiative, or in co-operation with regional organisations, such as the ASEAN-WHO Joint Assessment project to Strengthen the Implementation of ASEAN Harmonized Requirements (SIAHR).53, 54

In addition to international collaborations, the World Bank has been involved in a number of regional regulatory harmonisation initiatives alongside the WHO and other partner organisations. The African Medicines Regulatory Harmonization (AMHR) programme was set up in 2009, and the East African Community (EAC) initiative was the first regional economic community (REC) to receive support from the Global Medicines Regulatory Harmonization Multi-Donor Trust Fund (GMRH MDTF), after its inception in 2011.The EAC includes the following countries: Burundi, Kenya, Rwanda, Tanzania, and Uganda.55

A number of initiatives are coordinated by the WHO; however, others operate in silos, focusing on different issues and stakeholders. Not only could this lead to duplication of efforts and exhaustion of limited resources, but it could also yield divergent solutions, for example in the area of standards development.29 This issue was highlighted at a 2013 workshop convened by the US Institute of Medicine (IOM), where participants discussed meta-harmonisation, or the need for “harmonising the harmonisation efforts”.29



Box 1 Harmonisation initiatives

International Conference of Drug Regulatory Authorities (ICDRA), 1980

Forum for regulatory authorities from WHO member states established to facilitate collaboration and develop international consensus on priority issues.49

Pharmaceutical Inspection Co-operation Scheme (PIC/S), 1995

Established as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970, PIC/S comprises 49 members from across the world (Europe, Africa, America, and Asia Pacific).

Example of a co-operative, non-binding arrangement between regulatory authorities to harmonise inspection procedures worldwide by developing common standards in the field of Good Manufacturing Practice (GMP).50

The International Conference on Harmonisation (ICH), 1995

Joint initiative of pharmaceutical industry associations and regulatory authorities in the European Economic Area member states (EU member states plus Iceland, Liechtenstein, and Norway), Japan and the US.

In 2015 it was renamed the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

Now includes regulatory authorities from other countries ( including Brazil, Canada and China), and many other countries have joined as observers (such as Australia, India, Mexico and Russia). A number of global organisations such as the WHO, international industry associations such as the International Federation of Pharmaceutical Manufacturers & Associations , and regional organisations are also involved as observers.51

International Coalition of Medicines Regulatory Authorities (ICMRA), 2012

Established to enhance international co-operation to address challenges in global regulation, including the “growing complexity in globalised supply chains” and the increasing complexity of medicinal products.52

It emphasises that the main question is not whether regulators need to co-operate, but how they can best co-operate to achieve the desired results.52

The coalition has identified a range of strategic areas such as generic medicines, GMP inspections, information sharing and integrity of the supply chain.46

One of the first activities was to map the harmonisation activities across the globe, with the aim to raise awareness about the numerous international initiatives and inform the direction of future activities of the ICMRA 46



I t is evident that there is significant interest and willingness to achieve harmonisation, as highlighted by the number of initiatives taking place on an international and regional level. The initiatives have

different objectives, scope and geographic coverage. Some aim to achieve regulatory harmonisation, defined by the FDA as “the process by which technical guidelines are developed to be uniform across participating authorities”.56 Others are more focused on achieving gradual convergence of regulatory requirements across countries or regions, via a process of adoption of international standards, principles, and procedures.56 However, it has been noted that while “simple in concept, harmonisation is difficult in execution”.29 Although there are significant challenges to achieving harmonisation, the initiatives described below are among the best practice examples of regulatory harmonisation in action. They demonstrate both the scope for harmonisation and some of the most important achievements in this area.

The European medicines regulatory system: an example of internal harmonisation and external collaboration with other agenciesThe best example of regulatory harmonisation in action is the European medicines regulatory network for the European Economic Area (EEA), which includes the EU member states plus Iceland, Lichtenstein, and Norway. The consistent approach to medicines regulation by the European Commission and the EMA allows for different routes for marketing authorisation via a centralised procedure, decentralised procedure or a mutual recognition procedure.40, 57 The centralised procedure that is used for medicines for specific conditions requires one application, one assessment, one market authorisation for the whole of the EU.57

A number of interviewees agreed that the European regulatory system provides a model that other areas can learn from or look to emulate. However, many agreed that harmonisation does not mean unification, and the idea of having a global regulatory agency that follows the European centralised procedure is not realistic for various reasons. Even in Europe not all medicinal products follow the centralised procedure.

On the other hand, more and more national regulators acknowledge the benefits of work-sharing and resource-sharing and reliance on scientific assessments carried out by other RAs through mutual recognition agreements, such as the EU-US Mutual Recognition Agreement to recognise inspections of manufacturing sites, which entered into force in November 2017.58 At the post approval stage, regulatory harmonisation is achieved through the use of mutual recognition agreements between the EMA and third-country authorities (for example, those of Australia, Canada, Israel, Japan, New Zealand, Switzerland, and United States) for conformity assessment of regulated products.58, 59 The reliance on other countries’ assessments can be complete or partial—in the latter, a national RA could still review an application, but the review will not be very stringent. An example is the abbreviated assessment procedure for new medicines used by Medsafe, the New Zealand Medicines and Medical Devices Safety Authority. When a medicinal product has been approved in other markets and an evaluation report is issued by a trusted RA in Australia, Canada, an EU country or the US, the approval follows an

Milestones towards regulatory harmonisation



Abbreviated Evaluation Process. This reliance, however, does not extend to PACs, although the agency considers evaluation reports by other RAs.60 Another model of reliance on the work of other agencies is unilateral recognition, through which a country decides to rely on the work of a specific trusted RA.

Well-developed regulatory agencies are also interested in co-operation when they face common challenges—for example, in areas such as biologics or complex generic drugs ( including generic products with complex active ingredients, or complex drug-device combinations such as metred dose inhalers for asthma treatment), as well as some expensive injectable drugs.61

Building the foundations for the establishment of an African Medicines AgencyDevelopments in Africa over the last couple of decades show steady progress towards the establishment of a regulatory framework inspired by the European regulatory systems. Many of the harmonisation and convergence activities in the 55 countries in the continent are channelled through the five regional economic areas, including the East African Community (EAC), West Africa and the South African Development Community (SADC).47, 62 The main goal of the EAC initiative was to increase access to essential medicines by harmonising their evaluation and registration in the EAC’s six member countries.63 The ZAZIBONA initiative in Zambia, Zimbabwe, Botswana and Namibia is another example where countries have pooled limited resources to improve access to medicines for priority diseases by an expedited process for medicine registration.64 This project aimed to achieve registration within 11 months, including the time for applicant responses—a timeline comparable to that of more established RAs.64 South Africa joined in 2016, and the initiative can be expanded to include any of the 15 SADC countries. The different harmonisation initiatives in Africa have laid the foundations for the establishment of a single African Medicines Agency in the near future.65, 66

Asia-Pacific, Southeast Asia and the Americas are working towards regulatory convergence Initiatives in other world regions are also working towards convergence of regulatory requirements for medicinal products. The two key initiatives in the ASEAN (Association of Southeast Asian Nations) and APEC (Asia Pacific Economic Co-operation) regions are the ASEAN-WHO Joint Assessment project to Strengthen the Implementation of ASEAN Harmonized Requirements (SIAHR) the 2009 APEC initiative led by a Regulatory Harmonization Steering Committee and the APEC Harmonization Center. 29 The Pan American Network for Drug Regulatory Harmonization (PANDRH) initiative, founded in 2000, focuses on promoting technical co-operation between the countries in the region—some of which do not have strong RAs and, therefore, are less interested in harmonisation activities.29

Global success stories of harmonisationThe International Generic Drug Regulators Pilot (IGDRP) project (2012-15), involving the WHO alongside the 28 EU countries and 11 other countries across the globe, was launched to address issues with increasing workload for RAs associated with the growing number of generics, some of which involve complex production and distribution processes. This pilot aimed to achieve regulatory convergence, which in turn could lead to greater co-operation between RAs, with the ultimate goal of facilitating timely approval and availability of generic medicines.40

One of the most impactful global initiatives is the International Council on Harmonisation. It aims to achieve “greater harmonisation worldwide to ensure that safe, effective, and high quality medicines are



developed and registered in the most resource-efficient manner.” 51 To develop harmonised guidelines, the ICH follows a five-step process:67

1. Consensus building – Technical document 2. A. ICH Parties consensus on Technical Document; B. Draft guideline adoption by regulators3. Regulatory consultation and discussion4. Adoption of final ICH harmonised guideline 5. Implementation

Unlike many harmonisation initiatives in which the key stakeholders are RAs and intergovernmental organisations, ICH members include representatives from industry as well as regulatory agencies from 39 countries ( including the 31 EU/EEA countries). The ICH has focused in four main areas: quality (12 guidelines), efficacy (19 guidelines), safety (11 guidelines), and multidisciplinary guidelines, such as the Common Technical Document (CTD) and the Electronic Common Technical Document (eCTD), as well the development of Electronic Standards for the Transfer of Regulatory Information (ESTRI).51



Is there a connection between regulatory requirements for PACs and shortages?A few studies have suggested a connection between medicine shortages and varying requirements from multiple regulators. A 2014 report by the International Pharmaceutical Federation stated that the “tension between global manufacturing and national regulatory frameworks” can lead to disruption in the supply of medicines. 9 A 2016 study funded by the International Federation of Pharmaceutical Manufacturers & Associations investigated the socioeconomic impact of the “multiplicity of PACs evaluation processes” for vaccine PACs in Brazil and Mexico in comparison with the processes in EU and US. This study showed “a number of direct and indirect health effects and a model estimated the socioeconomic impact of hypothetical PACs scenarios (shortage of vaccine, indication extension, delayed approval), revealing that a significant societal burden might be posed by delays due to regulatory redundancies in the evaluation of vaccines’ PACs”. Further details were not provided, as the study was published as a conference abstract only.68

The current global regulatory environment for PACs may contribute, albeit unintentionally, to increased risk for errors, non-compliance with regulatory requirements, and reluctance to introduce innovation and process improvements. However, in our research we found little direct evidence in support of the hypothesis that the complex regulatory requirements for variations on a global scale are a major factor for shortages.

This overall consensus from the interviews with stakeholders representing various perspectives, including academia, industry, regulators, global policymakers and non-governmental organisations confirmed the findings from the literature review. Most of the people that we interviewed agreed that the varying regulatory requirements for PACs across different markets may impose a significant burden on MAHs in terms of cost, time and resources, as MAHs need to submit applications and get approval for certain types of changes from multiple regulators. One of the biggest challenges for MAHs is managing several licensed versions of the product at the same time, which could involve the use of different analytical methods or manufacturing processes. The long times for approval from the first to the last regulator could delay the introduction of particular products in some markets or give rise to shortages, but most interviewees considered the likelihood of this scenario to be quite low.

Some interviewees mentioned that although sometimes delays in approval of changes could pose a theoretical risk for shortage, MAHs have the primary responsibility to plan and work to get medicines to the markets. It should also be noted, that the timeframes provided in Table 3 refer to the maximum times. In some cases, the reasons for long timelines to approvals do not reside only with the regulators. The time to approval depends on the communication process between MAHs and regulators, and delays can be caused by incomplete applications or lack of timely responses from the MAHs as well as by lack of capacity or expertise within the regulatory authorities.

Stakeholders were in general agreement that the causes for shortages are mainly economic or market-related, with factors such as pricing, procurement and low profitability for generic products

Discussion and findings



playing a significant role. When a product is no longer economically viable many MAHs withdraw from the market, thus reducing the number of manufacturers, which in turn can lead to increased risk of shortages. Industry representatives mentioned that regulatory frameworks for PACs can be a barrier to making changes; as a result, products can become less economically viable and production facilities may become obsolete.

Nevertheless, the main objective of the regulatory system is to protect patients from unsafe, falsified, low quality or inefficient medicines by ensuring the supply of safe, effective, high quality products. Regulatory frameworks are not designed to be unnecessarily complex. The priority for regulators is to protect the patient, especially in the case of vaccines where safety is the main consideration as vaccines are administered to healthy people.

It is only in recent years that the regulatory authorities in many countries have been assigned the responsibility to prevent or manage shortages when they occur. For example, the FDA, the EMA and the Heads of Medicines Authorities forum in the EEA have a responsibility to work within a clearly defined legal framework for prevention and mitigation of medicines and vaccines shortages. Interviewees and researchers recognise that shortages are a complex, multifaceted issue that needs a multi-stakeholder approach to resolve and mitigate it. Even the very definition of what constitutes a shortage needs to be harmonised.6

As medicines are no longer national products but global commodities, the overlay of different regulatory requirements may pose some issues in terms of availability or disrupted supply of medicines. Although regulatory requirements are not a cause for shortages, harmonisation of regulatory frameworks and other proposed mechanisms, such as using the manufacturers’ pharmaceutical quality system (PQS) for change management, may help to ensure more efficient supply of medicines and vaccines, and prevent and mitigate shortages resulting from the interplay of many factors.69

Harmonisation is beneficial for regulatory authorities, industry and patientsPublished reports and expert opinions are in agreement that regulatory harmonisation is beneficial for RAs, MAHs and patients. 62 In the early days of harmonisation initiatives there were concerns about the potential implications of harmonisation for drug safety and public health.70, 71 Experts interviewed for this project state that there has been no negative impact whatsoever on public health, and with increased international co-operation and strengthening of regulatory systems across the world, harmonisation will lead to higher safety standards, especially in the developing world.

Future directions proposed by ICH quality guideline for product lifecycle management (Q12)The Institute Of Medicine Workshop on International Regulatory Harmonisation highlights that the ICH focus on technical requirements was “an excellent place” to start harmonisation.29 Earlier guidelines developed by the ICH focus on the first two stages of the lifecycle of medicinal products—R&D and market authorisation. Many of these (such as the Common Technical Document—CTD—and the Electronic Common Technical Document—eCTD) have been implemented by regulators and industry for years. A new draft guideline, ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, focuses on the post approval stage and proposes a new framework for



the management of chemistry, manufacturing and control (CMC) changes to approved medicines.72 This guidance was adopted by the ICH assembly in November 2017 and released for 12-month public consultation. It is hoped that the implementation of ICH Q12 will provide more predictability for CMC changes and lead to continual improvement, more innovation and strengthening of the quality-assurance processes, and as a result ensure better reliability of product supply and reduction of shortages.73

ICH Q12 builds on previous guidelines e.g. Q8, Q9 and Q10 which have been in place for almost ten years. The Q12 guidance differs from these by proposing a paradigm shift for the regulation of CMC changes at post approval. This lessens the need for regulatory oversight and promotes more reliance on the risk management systems and pharmaceutical quality systems (PQS) of the MAH.74 Risk-based approaches to changes now exist in some regions, although risk categories may vary (as seen in Table 3), while in other regions there is no risk assessment and all changes must be pre-approved by the regulator (this is the case in Taiwan, for example). ICH Q12 makes practical recommendations for the management of most PACs by MAHs themselves within the PQS thus reducing the number of regulatory submissions. The guideline describes some tools and enablers that can help MAHs to manage changes these include post approval change management protocol (PACMP) and an effective pharmaceutical quality system.74

In 2018 the FDA published draft guidance on CMC changes to approved applications for biological products to assist MAHs in determining the appropriate reporting category for a PAC.75 This guidance proposes reclassifying the risk associated with specific changes. The revised recommendations “will result in a less burdensome approach for reporting changes” and facilitate quicker distribution of affected products as well as “promoting continual improvement and innovation over the product lifecycle”, thus minimising the risk of shortages.75

Trust and strong political will are required for harmonisation and convergence initiatives to succeedMost interviewees were positive about future developments moving in line with the Q12 recommendations, but also emphasised the need for building a relationship of trust between MAHs and RAs. The need for a risk-based assessment of changes and a harmonised classification of changes was highlighted by all experts. In 2014 the WHO developed guidelines for procedures and data requirements for changes to approved vaccines that were adopted by the Experts Committee on Biological Standardization.35 These guidelines categorise the quality changes based on their potential impact on the safety and efficacy of vaccines into major, moderate and minor quality changes, and provides a comprehensive list of changes and the information required to support each change.76 The adoption of these guidelines by national RAs would help to reduce the complexity of requirements for the same changes across different jurisdictions.

It is important to develop an understanding of the expectations and priorities of all stakeholders, and to pursue the harmonisation goal, even though progress may seem slow at times. Interviewees mentioned that it took about 40 years to shape the European regulatory system. A look at the history of the EMA since its establishment in 1995 shows that it has taken decades of work and strong political will to achieve the goal of protecting public health in the EEA and globally “by assessing medicines to



rigorous scientific standards and by providing partners and stakeholders with independent, science-based information on medicines”.77 The recent increase in mutual recognition agreements between the EMA and external regulatory authorities in a number of areas shows that different RAs can work together to avoid duplication in effort and rely on each other’s expertise in challenging areas for regulatory science.58

Finding a permanent solution for shortages requires concerted actions from multiple stakeholdersResearchers and experts agree that the causes for shortages are complex and multifaceted. A meeting of the WHO Strategic Advisory Group of Experts (SAGE) on Immunisation in April 2016 discussed a range of causes related to supply factors and the impact of the regulatory system. The meeting reported that in 2014 the vast majority of vaccine-producing countries (36 out of 44 countries) did not have a functional national RA.26 In some countries, such as India, national RAs have limited capacity to deal with the high workload, a situation leading to national supply shortages.26 The SAGE meeting discussed the actions taken at national, regional or global level to prevent or mitigate vaccine shortages. These actions range from adjustments in the immunisation schedules (such as in the EU) to fast-tracking of approvals of new products (the WHO Prequalification Programme, Box 2).26 The 2016 International Conference of Drug Regulatory Authorities recommendations for WHO member states highlighted the importance of using collaborative approaches for prevention and management of medicines shortages, and the need to identify products vulnerable to supply interruption.”49

Box 2 WHO Prequalification Programme

Although the WHO Prequalification Programme (PQP), which is used by international procurement agencies and individual countries to guide bulk purchasing of medicines, was not established for the purpose of regulatory harmonisation, it is a good example of what a successful regional collaborative model could look like.78 The centralised process for the scientific assessment of products under this programme is a prerequisite for the approval of specific products by national RAs. The programme provides an example of an efficient regulatory process using dossier submissions based on a CTD and a joint assessment by a team of experts from different RAs led by the WHO, followed by inspections of manufacturing sites for compliance with GMP standards. When the data provided are sufficient, the process can take “as little as three months”. 78 In a recent case, this collaborative work-sharing scheme with the involvement of 22 national RAs in Africa resulted in the registration of 152 pre-qualified essential medicines and succeeded in reducing the time to approval from several years to an average of 78 days.47

In the case of variations for prequalified vaccines, the PQP requires immediate notification (minor or type N changes), annual reporting (moderate or type R changes) or submission of application for approval for major changes before they are implemented (type A changes).79 To ensure timely supply of vaccines, a streamlined procedure can be used through which type A variations can be approved based on previous approval by a responsible national RA.79



Experts also emphasise the need for a multi-stakeholder approach for resolving this complex issue. The commitment of industry to continuous improvement and innovation is essential, however addressing the economic causes for shortages is crucial for the prevention of shortages, and this will require concerted efforts from all stakeholders. Regulatory harmonisation and strengthening regulatory systems across the world will definitely play a role in finding a permanent solution for medicines and vaccines shortages.



This study found that medicine and vaccine shortages continue to persist, regardless of the fact that governments and regulatory authorities across the world have implemented a number of

measures to prevent and mitigate shortages. The causes for shortages are complex and interrelated, thus making it difficult to isolate particular causes and estimate their impact. In this study we were not able to find a direct correlation between the complexity of the global regulatory environment for post approval changes and medicine and vaccine shortages. There is a consensus that the major causes of shortages are economic or market related. Future research on shortages should focus on the mechanisms of these causes and potential counter-measures that address the drivers of shortages and create an environment for reliable supply of medicines and vaccines. The complex issue of shortages could only be resolved with the concerted efforts of all stakeholders, including international organisations, national governments and regulatory agencies, industry, pharmacists, and healthcare providers.

Harmonisation initiatives are considered beneficial for all stakeholders, including regulators, industry and patients. There is a trend towards greater co-operation and regulatory convergence in the Americas, Asia-Pacific and South-East Asia, which could only be positive in terms of strengthening the regulatory systems in these regions and building trust between national regulatory authorities. Greater regulatory convergence will lead to the wider implementation of science- and risk-based assessment of PACs and more consistent timeframes for approval. The developments in Africa leading towards the establishment of an African Medicines Agency following the European model will also have a positive effect on the processes and timelines for PACs.

Numerous organisations such as the WHO, the International Council of Harmonisation and the recently established International Coalition of Medicines Regulatory Authorities are pursuing the goal of regulatory harmonisation, and although everyone agrees that a unified global regulatory system is not a realistic solution, the existence of regional regulatory systems and networks will make a huge difference towards achieving the UN Sustainable Development Goal for health, including access to “safe, effective, quality and affordable essential medicines and vaccines for all” by 2030.1, 2

Concluding remarks



To support the research that was conducted and analysed for this report, the EIU interviewed experts in regulatory affairs and policy working in academia, industry, regulatory authorities,

international organisations, and global non-governmental organisations. We wish to thank these experts for their time and insights. Participants are listed below:

Deborah M Autor JD, Head of Strategic Global Quality and Regulatory Policy, Mylan

David Doleski, Compliance Head for Biologics Quality Operations, Sanofi

Caitríona Fisher, Director of Quality, Scientific Affairs and Communications, Health Products Regulatory Authority, Ireland

Hans V Hogerziel, Professor of Global Health, University of Groningen

Robert Iser, Vice President, PAREXEL Consulting

Murray Lumpkin, Deputy Director – Integrated Development (Regulatory Affairs), Lead for Global Regulatory Systems Initiatives, Bill & Melinda Gates Foundation

Laurence O’Dwyer, Scientific Affairs Manager, Health Products Regulatory Authority, Ireland

Andreas Seiter, Global Lead – Private Sector, Health, Nutrition and Population, World Bank Group

Rebecca Snow, Senior Policy Research Specialist, Mylan

Expert interviews



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