Lessons Learned from COVID-19 is an Opportunity to Reduce Drug Shortages

Lessons learned from COVID-19 is an opportunity to reduce drug shortages

Vision and practical solutions 

By Anders Vinther, Ph.D., former Chief Quality Officer

Summary:

The COVID-19 crisis has demonstrated that the global regulatory framework for managing Post Approval Changes (PACs) is not capable of handling a pandemic. Emergency procedures have been implemented across the globe to avoid drug shortages. By working drastically different together the unimaginable happened: in less than a year a vaccine was developed, approved, produced, and provided to people. In light of these actions, we have a unique opportunity to retire the old system for managing PACs and replace it with a new agile and patient centric approach built on lessons learned from the global pandemic response. Our new approach must be science and risk based, rendering it capable of not only managing our response to a future pandemic but also facilitating the implementation of new knowledge in close to real-time.  We will then be able to take major steps to secure the supply chain, incentivize continual improvement and innovation, and ultimately avoid drug shortages. Our solutions must reflect the following: that diseases and science are global in nature, that we strive for more harmonization in how we work collectively while taking strength in our unique competencies and experience, and that we acknowledge national sovereignty of decision-making. We need to develop a common language and understanding of regulatory reliance and regulatory flexibility and use that to make our work products transparent to each other. We cannot miss this opportunity. We, industry and regulators, cannot fail those depending on the supply of drug products or vaccines wherever they may live. This article describes both a vision and a practical approach to reduce drug shortages worldwide.

Introduction & Context

As of early March 2021, more than 115 million people in 192 countries have tested positive for COVID-19. The pandemic is truly a global public health crisis at a dimension not seen for many years. It has forced massive changes in our lives, from how we interact socially to how and where we work. In addition to its impact on global health, the pandemic has also caused severe financial challenges for many individuals, families, businesses and states. Conversely, our collective response to these challenges has generated some significant positives in terms of how people and organizations have found new ways to interact and work safely, ways that would have been unimaginable if it wasn’t for the pandemic. Milton Friedman once said that “only a crisis, actual or perceived, produces real change.” It is time for us to learn from this crisis and produce real sustainable change where it will benefit public health including patient safety and availability of drug products and vaccines.

In this article I outline lessons learned in terms of working together differently in health care during the COVID-19 pandemic, the opportunities we have specifically to reduce drug shortages and enhance innovation globally while solving some of the structural issues associated with Post Approval Changes (PACs) in drug product manufacturing. Before getting too far along with this story, let’s first take a step back.

I have worked in health care for more than 30 years, with most of that time in senior Quality roles for the pharmaceutical industry. During that time, I have met and worked with many people who are incredibly dedicated to improving public health:  nurses, doctors, pharmacists, manufacturing operators, frontline managers, or support staff. Whether filling those roles working for a Health Authority (Regulatory Agency) or a pharmaceutical company we have done the best we can within our roles and the environment, we operate in. We know that our actions and decisions have a direct impact on patients’ health and well-being.

Diseases are Global. How we Manage them is Local

Diseases do not know borders between countries. COVID-19 is an example of this. It passes from person to person and by that mechanism has traveled to infect people all over the world. Similarly, each specific COVID-19 vaccine that has been produced works to prevent the disease the same way no matter whether you live in Japan, Australia, Tanzania or anywhere else. However, each country or region approves the new vaccine based on local regulatory requirements and their own assessment of the available scientific evidence for safety and efficacy. The COVID-19 virus is at least a step ahead of us by being global in nature and conquering the virus will be best accomplished when we work in a more globally harmonized way. 

Prior to approval of a new drug product or vaccine in a given country (or region in a few cases) the pharmaceutical company submits a dossier (file) to the respective national Regulatory Agency where they seek authorization to provide the drug product or vaccine to people in that specific country. The dossier includes a wealth of information about how the drug product or vaccine is produced. This includes raw material specifications and suppliers, details of the manufacturing process, production equipment used and associated operating ranges, test methods and analytical equipment used, in-process and final drug specifications, stability of the product, and much more. After approval, this dossier becomes the “contract” between the national regulatory agency and the company. For a drug product or vaccine to become available globally then, many, many individual “contracts” are required, one for each country or region. 

Post Approval Changes (PAC) & The Complex Global Regulatory Framework

After a company has received initial approval, things do not remain static but change over time. There might be a need to upgrade an existing manufacturing or testing facility or build a new one, new regulatory requirements might come into effect, suppliers might change, or the producer would like to implement operational improvements based on new knowledge gained. We call these changes Post-Approval Changes (PACs).  Critically, many PACs require approval by the national Regulatory Authority of each individual country (or region) prior to implementation.

In keeping with the current fragmented state of affairs, the approval process for PACs is not standardized across the world. Each country (or region) has its own reporting requirements (or levels) for prior approval of a PAC, distinct documentation requirements for the change, and different review/approval timelines. Each country does their own individual scientific and technical assessment of the PAC. It typically takes 3-5 years (or more) from the first to the last regulatory agency approval of the same PAC even when circumstances would warrant a more rapid response, such as when the change improves patient safety or reduces risk of drug product or vaccine shortage. However, it is important to note that during the COVID-19 pandemic national regulatory agencies have found ways to drastically reduce the review/approval timelines specifically to ensure drug product supply to COVID-19 patients. We can learn from what has been done at national and international level but let me first illustrate the global PAC complexity.   

Figure 1 shows a real example of a single change involving a vaccine approved in 138 countries. The change was a simple scale up of an early process step. It was concluded by the company that there were no safety, efficacy or quality impact to people receiving the vaccine. 62 countries classified the PAC as a major change requiring prior approval, while 37 countries classified it as a minor change not requiring prior approval, and 39 countries did not require reporting. 

Figure 1. An example of the global regulatory framework complexity for one PAC

In response to the proposed change the company received 177 questions from 22 countries following the individual assessments, but in reality, there were only 19 different questions as many were asked by multiple countries.   

The complexity of the global regulatory framework (from here onwards let’s call it the ‘System’) wouldn’t be a big problem if the number of PACs per year were few, there was no urgency in implementing the change or the drug product or vaccine was manufactured for a few countries only. However, this is often not the case. Companies normally submit many such changes each year, and each change results in many prior approval submissions. (In the case shown in Figure 1 the number was 62). For companies supplying multiple drug products or vaccines globally the total prior approvals for PACs number in the thousands every year. As it takes at least 3-5 years for a ‘worldwide’ approval of each PAC this results in the company potentially managing many versions of the same product at any given time. As a result of this, some countries would have the most up-to-date version of the manufacturing process.  Most wouldn’t, however, because they have unapproved PACs in their regulatory authority PAC inbox. 

Managing this many versions at the same time is a big logistical challenge for the manufacturer; it leads to inefficiencies, increases risk of regulatory non-compliances if batches were released to a country that is out of line with the approved variant for that country, and ultimately it can cause drug shortages. Remember too that the supply chain for a drug product or vaccine is in many cases global, from the raw materials and active substances used, through manufacturing and testing stages, to the supply of the final drug product or vaccine.

The lack of efficiency is not limited to the manufacturer only. At a global scale the many parallel national scientific assessments of the same PAC are also inefficient with colossal duplication of effort. 

Our Opportunity to Achieve Regulatory Agility & Reduce Drug Shortages 

When COVID-19 first attacked our world, the global regulatory framework as currently constructed was not capable of managing the pandemic with agility. The ‘System’ with its years long approval timelines could not with sufficient speed react when there might be a drug shortage tomorrow and when the number of changes drastically increases. However, something happened at a larger scale. Regulatory Agencies and pharmaceutical companies started working together with the common objective of avoiding drug shortages for COVID-19 patients. Regulatory Agencies moved to rely more on each other’s PAC assessments and facility inspections before they made decisions. Regulatory Agencies also began to rely more on the company’s Quality Assurance Department’s own quality, safety and efficacy assessment of individual PACs. Everybody work more together, trust each other more, more information is shared electronically using digital tools, and as a result PACs can be implemented in a matter of days. What if this new way of working wasn’t just temporary during the pandemic but became our new way of managing PAC? In my view we have the following opportunity right now:

Our Opportunity:

Imagine if we applied the same behaviors and new ways of working together that made it possible to achieve the unthinkable to develop, approve, produce, and provide COVID-19 vaccines to people in less than a year to how we manage Post Approval Changes (PACs). Right now, we have an opportunity to retire the old system for managing PACs and replace it with a new agile and patient centric approach built on lessons learned from the pandemic response. Our new approach must be science and risk-based, rendering it capable of not only managing our response to a future pandemic but also facilitating the implementation of new knowledge in close to real-time. We will then be able to take major steps to secure the supply chain, incentivize continual improvement and innovation, and ultimately avoid drug shortages. Our solutions must reflect the following: that diseases and science are global in nature, that we strive for more harmonization in how we work collectively while taking strength in our unique competencies and experience, and that we acknowledge national sovereignty of decision-making. We need to develop a common language and understanding of regulatory reliance and regulatory flexibility and use that to make our work products transparent to each other. We cannot miss this opportunity. We, industry and regulators, cannot fail those depending on the supply of drug products or vaccines wherever they may live.

Below I am suggesting how can we make this opportunity not only a vision or aspiration but reality. However, let’s first look at solutions developed during the COVID-19 pandemic as well as the history of global PAC challenges and potential solutions.

Working Differently Together to Achieve Our Opportunity

The complexity (different reporting levels, documentation requirements and timelines for review of PACs at a global level) of the “System’ has been known for years. Solutions to simplify it have been developed and available for years as well. So why hasn’t the ‘System’ changed? How can we change it now? These are questions I will address below, but let’s first look at what is being done during COVID-19.

To avoid drug shortages Regulatory Agencies have had to circumvent the traditional lengthy PAC approval process and several countries have developed their own guidance related to COVID-19. A common theme to these emergency procedures is to manage PACs from a science and risk-based approach. Companies have been asked to: 

1. Apply formal quality risk management (QRM) tools and processes per ICH Q9 guideline (QRM, Reference 1)
2. Document the change and the risk assessment in a transparent manner in their Pharmaceutical Quality System (PQS) per ICH Q10 guideline (PQS, Reference 2) 
3. Ensure that the company Quality Assurance department is the decision maker/approver of the suggested PACs prior to implementation. This would be per existing Good Manufacturing Practice (GMP) legal expectations. 

These three principles, first implemented in response to the pandemic, can now be key elements in building a new ‘System’ for managing non-crisis PACs in a company’s PQS only, as opposed to requiring a full prior approval process going forward.  

In fact, a practical and standardized solution as to how this can be done has been developed by the One-Voice-Of-Quality on Post-Approval Changes (1VQ on PAC) Initiative sponsored by the Chief Quality Officers (CQOs) of the world’s 25 largest pharmaceutical companies. The solution is built on the principles of ICH Q9, Q10 and Q12 (Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Reference 3) and described in detail later in this article.

In addition to allowing more PACs to be managed in a company’s PQS only, many Regulatory Agencies have during the COVID-19 crisis begun to rely more on each other’s assessments. This is in line with World Health Organization (WHO) recommendations. The WHO document “Good reliance practices in regulatory decision-making: high level principles and recommendations” (QAS/20.851, Reference 4) states “The WHO supports the implementation of reliance on other regulators’ work as a general principle in order to make the best use of available resources and expertise.” The guidance describes increasing levels of reliance from accepting standard processes and the practice of work-sharing between Regulatory Agencies to full reliance and recognition of other Regulatory Agencies work. WHO also has detailed guidance documents for managing specific types of PACs including recommending a maximum 6 month prior approval timeline. These documents have been developed through collaboration with the 194 WHO member states. Some countries have chosen to follow the WHO guidance documents for PACs, but many have resisted these practices and developed their own national or regional guidance.  However, it seems obvious that relying more on other Regulatory Agencies and the WHO guidance documents (or some other harmonized approach) would help reduce the overall PAC complexity.

I wrote earlier that problems with the ‘System’ have been known for years. Almost 20 years ago, in 2002, FDA kicked-off what they called “Pharmaceutical Quality for the 21st Century Initiative.”  The idea was to encourage the adoption of new technologies and risk-based management approaches as well as to facilitate the application of modern quality management practices (Reference 5). FDA’s stated vision desired, “A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight.” Three years later, in 2005, the ICH Q10 Concept Paper (Reference 6) stated that “Delays in the implementation of innovation and continual improvement for existing products may occur due to different expectations in the three regions (Japan, EU, USA).” In support, many governmental and non-governmental organizations have written Position Papers on the PAC complexity topic as well and the attendant need to simplify the ‘System.’ 

In 2008 ICH Q10 was finalized and Annex 1 (Reference 2) includes a potential solution to reduce the complexity of the ‘System.’ It states that when a company can “demonstrate effective PQS and product and process understanding” there exists an opportunity to “optimize science and risk-based PAC processes to maximize benefits from innovation and continual improvement.” The intent here is that if a company meets the above-mentioned criteria more PACs can be managed in a company’s PQS rather than being submitted to a Regulatory Agency for prior approval. As you will see later the implementation of this regulatory flexibility is at the core of the 1VQ on PAC Initiative solution.

So where do we stand today, more than a decade after ICH Q10 was finalized and almost two decades after FDA communicated the vision of an agile and flexible manufacturing sector without extensive regulatory oversight? The answer is that the situation has gotten worse. In my own experience and from that relayed to me in conversations with other Quality and Regulatory Affairs leaders, it is clear that over the intervening period, global regulatory complexity has only increased. More countries are requiring independent prior approval of PACs with ever increasing documentation requirements and a commensurate increase in the volume of data for submission of an average PAC.  The intent of ICH Q10, Annex 1 has not turned into reality. 

So why is it that this decades long problem is still a problem and hasn’t been solved yet? What will it take to change the ‘System’ to get closer to real time implementation of new knowledge and reduce drug shortages? One answer to the latter question is a crisis such as a the current COVID-19 pandemic. It has forced everyone to find new and agile ways of working together as I have discussed above. For the first question, in my view the answer is as complex as the problem itself. The reasons, I feel, include a lack of trust between stakeholders, a ‘System’ that is self-preserving, and the problem looking different from different points of view. Unfortunately, I am sure there are more reasons, but these seem the strongest factors.

If you look at the problem from two angles, the regulator assessing the PAC and the company’s Quality Head, it does look different.  This difference in perspective is demonstrated in Figure 2. In the top half of the figure, you see the view of one PAC from the regulator’s and the Quality Head’s side, respectively.

Figure 2. The PAC complexity looks different from different angles.

While the Regulator is assessing one PAC, the company has submitted that same PAC to many countries in accordance with each country’s guidelines and as a result is managing supply of batches based on which countries have approved the change. If you recall, in the example in Figure 1, the number of countries was 62. (for simplicities sake, the right side of Figure 1 above only includes 18 countries) In actuality, the PAC reality is much worse than what is described above because a given company doesn’t manage just one PAC at a time only but several, which I have illustrated in the lower part of Figure 2. Assuming, for this example, that a company is managing 13 PACs at the same time, each with 18 submissions.  This results in an incredible 234 PACs in total. Global pharma companies with several approved drug products or vaccines manage thousands of prior approval PACs every year. 

Given the above, the complexity of the ‘System’ has the unintended consequence of disincentivizing companies to continually improve simply because of the burden of the many PACs and the need to manage several versions of the manufacturing process at the same time. Costly and ineffective, it increases the risk of making mistakes, and it delays the implementation of new knowledge. More concerning than the tamping down of future improvements, the complexity of the ‘System’ can result in drug shortages in various ways. Imagine that a company runs out of stock of product for one version of the production process while waiting for regulatory approval of another version. Alternatively, what if a company found it too complex and not financially viable to run many versions of the same process and instead waited for complete worldwide approval of the PAC before switching from one version to the new, or worse, decided to maintain the status quo only. Some reports state that one of the reasons for drug shortages is manufacturing quality issues. However, in my experience, upon digging deeper and asking a couple of ‘whys’ it often leads to an underlying root cause being the complexity of the ‘System’. The recent advances in response to COVID-19 notwithstanding, my prediction is that this will not permanently change until companies are incentivized to continually improve. Unfortunately, I also predict that the new way of working during the pandemic will evaporate when the crisis is over unless we do something now to fundamentally change the broken ‘System.’

Drug Shortage is a Wicked Problem

The problem of drug shortage has previously been termed ‘wicked’ (Reference 7). In this context, a ‘wicked’ problem is defined as one that is highly resistant to solutions. Additional characteristics include no definitive formulation of the problem, no rule for when the problem stops, solutions are not true-or-false but rather good-or-bad (Reference 8). A ‘wicked’ problem is often explained in ways which best fit the intentions of the person explaining the problem and which conform to the action prospects available to the same. (Note: The ‘wicked’ problem of drug shortages is in reality bigger than the global regulatory framework. It also includes political, economic, and other factors, but for this article we will limit it to just the global regulatory framework).

Unfortunately, ‘wicked’ problems offer up no simple or definitive solutions. As noted, for this type of problem it is easier for the single stakeholder to see the ‘System’ from their angle only and try to find a solution that would work best for them, without taking into account other, related stakeholders. Accordingly, the one-stakeholder-at-a-time ‘optimization’ will never stabilize the ‘System,’ only make it more complex. However, in my view, when we all acknowledge that the problem is ‘wicked’ we can start having a dialog about good-or-bad solutions. Through that dialog the perspective of the problem can shift so that no one person, organization, or stakeholder fully owns the problem or the solution. We all do. Together. It will take leadership from many to reduce the problem.

‘Systems’ React to Change

Experts in organizational systems thinking tell me that systems tend to push back against attempted changes, and those changes usually end up adding ‘band aids’ that add complexity rather than appreciably changing behavior.  Change is seen as a threat. As described earlier, the global PAC ‘System’ has become more complex over the past decades. As a reaction to drug shortages some national or regional Regulatory Agencies have suggested increasing the oversight of manufacturers as well as increasing reporting requirements at a national level on the part of the pharma company.  Both actions, rather than helping to reduce the complexity of the ‘System’ at a global level, have only added to requirements, work and ultimately complexity. 

The ‘System’ has many stakeholders and people involved, and each has an important role to play: their ‘identity’ in the ‘System’. Performance, personal and organizational, is evaluated based on how well one performs within the system. Assessors at national Regulatory Agencies complete a scientific evaluation of every PAC that the company submits to the agency. They have a role to play to ensure that drug products and vaccines in their country are safe and efficacious with the right level of quality when they do their scientific assessment. Assessors in other agencies have the same role but for a different country. The company pays the agencies for their work. Company regulatory experts ensure that every PAC submitted meets the reporting requirements for the particular country where it is submitted. Last time I asked around the vast majority of the company CMC Regulatory Affairs employees work with prior approval PACs. The Quality Assurance department works closely with the logistics department in the company to ensure that only batches of product versions approved in the destination country are released for that country. These are not simple tasks, but currently necessary to meet the needs of patients. 

The PAC ‘System’ was broken a long time before COVID-19. The pandemic just surfaced the inability of the ‘System’ to act with agility because it came under extra pressure. For years the ‘System’ has been far away from real-time implementation of new knowledge. One can see the ‘System’ as a collection of many subsystems for PAC management, one for each country or region. Global companies providing drug products or vaccines to people worldwide must work with each of these countries, each of which decides independently on how they manage PACs in general and for each PAC specifically. As long as companies can manage this massive complexity caused by national Regulatory Agencies collectively the ‘System’ works, and the national Regulatory Agencies have limited incentive to harmonize work processes. As a result, the responsibility for managing the systemwide complexity with many manufacturing process versions in parallel lies mainly with the manufacturing companies.

I think it is important to maintain the national sovereignty in Regulatory Agency decision making but because the core of a PAC assessment is scientific it should be possible for Regulatory Agencies to start the work towards common standards and harmonized procedures as well as relying more on each other. 

Another characteristic of the PAC ‘System’ is that there is inadequate trust between individual agencies, resulting in the limited use of regulatory reliance, and between agencies and companies in their area of responsibility, resulting in the large number of PACs requiring approval before implementation.  Neither condition allows either party to depend on the other’s work. We need to address this trust issue before we will see real improvements. Although this certainly not is a ‘flip of a switch’ activity, there are ways that can lead to more trust between the stakeholders. 

With all of this said, where do we go from here? Is it all just going back to the ‘same old, same old’ complex ‘System’ after the pandemic is under control? There certainly is a risk of that happening based on the self-preservation of systems and how they react to change. That would not only be a shame, but it would also be a failure for patients around the world. 

What Change to the ‘System’ Would Have the Biggest Impact?

Figure 3 shows an example of how various changes to the ‘System’ would impact the number of open PACs (awaiting Regulatory Agency approval) that a company manages at any given time. This example assumes a company submits 100 prior approval PACs globally every month and that worldwide approval takes on average 3 years for each PAC. This means that the company at any given time would be managing 3600 open PACs. The first example reflects a reduction of the average time from first to last approval from 3 years to 6 months. As can be seen this would reduce the number of open PACs to 600 (83% reduction). If regulatory agencies relied more on each other’s assessments this would also reduce number of open PACs. If 10 Regulatory Agencies (Health Authorities, HA) agree to rely on each other, it would have the effect of bringing the number of open items down to 360 (90% reduction). The next two columns show the impact of managing 50% and 80% of the current prior approval PACs in the PQS only, thus not having to go through the prior approval process before implementation, as described in ICH Q10, Annex 1. This would reduce the number of open PACs to 1,800 and 720 respectively from the original 3600. Finally, the last two columns show examples of a combination of regulatory reliance and application of ICH Q10, Annex 1, which would reduce the number of open PACs to 30 and 12, respectively, achieving reductions for both of more than 99%. As you can see all three ‘dimensions’ mentioned 1) reduction of approval timelines, 2) regulatory reliance and 3) managing more PACs in the PQS only, would help to reduce the overall number of open PACs at any given time and thus the complexity. 

Figure 3. Impact of regulatory reliance and/or more PACs managed in the PQS only.

Solution: Reduction of ‘Global’ Approval Timeline

What should be a generally expected target timeframe for approving a PAC?  As stated earlier, WHO has published a recommended 6-month maximum period for the approval of a major (prior approval) PAC. However, as written in this document the actual time for ‘worldwide’ approval of a PAC is more like 3-5 years at a minimum. Although each country assesses the PAC on its own timeline, the approval timelines of other agencies have an impact for all countries because of the complexity it causes for the manufacturer to manage several versions of the same product, which can lead to drug shortages. Many Regulatory Agencies now appreciate this complexity. The regulatory approval timeline obviously depends on the resources available by the national agency to assess the influx of PACs. I do appreciate that agencies are resource constrained, but because every country should strive for the latest version of the drug product or vaccine with the newest knowledge and technology and because late approvals impact every country, I think a mechanism should ‘kick in’ if the 6-month mark is passed. This could be reliance on the assessment from another Regulatory Agency that has already approved the PAC. Regular publication of a “Regulatory Agility Performance Index” for PAC approvals by country can visualize where improvements would be beneficial and how countries change over time.

Solution: Regulatory Reliance

As stated earlier the WHO has been promoting regulatory system strengthening and regulatory reliance for a number of years. WHO’s definition of reliance is “the act whereby the National Regulatory Authority (NRA, Regulatory Agency) in one jurisdiction may take into account and give significant weight to assessments performed by another NRA or trusted institution, or to any other authoritative information in reaching its own decision. The relying remains independent, responsible and accountable regarding the decisions taken, even when it relies on the decisions and information of others” (Reference 4). Regulatory Agencies relying on each other for individual PACs makes a lot of sense because the assessment is science based. Not only does regulatory reliance reduce the redundancy of work and allows for a better use of resources but it also allows for the allocation of specialized expertise across the Regulatory Agencies. This is important because technologies develop so fast that it is difficult for all the worlds Regulatory Agencies to be up-to-date with all development at all times. 

One topic that often surfaces when talking regulatory reliance is what would national Regulatory Agency employees do if they didn’t have as many PACs to assess? This is a good question that is important to consider. One consequence of pooling the resources for PAC assessments globally and do much more work-sharing would be the opportunity to reduce the overall PAC approval timelines to no more than 6 months. Additionally, the national resources could be redistributed to put greater focus at a national level on activities that cannot be done by other national agencies such as in-country vigilance activities, oversight of local manufacturing and distribution, identification and avoidance of falsified medicines. 

An absolute pre-requisite for reliance would be that national regulatory agencies trust each other. WHO has defined what they call “WHO-listed Authorities” (Reference 9) which are NRAs that comply with specified indicators and requirements and has been performance evaluated to satisfaction. Both WHO and PAHO have published documents on the topic of regulatory reliance. PAHO states the following five principles and critical elements (Reference 10): 

• Sovereignty – the NRA decides which other NRAs they will rely on, final decision on a PAC remains with each national NRA
• Transparency – ability to see the work process and documentation for individual PAC assessments
• Consistency – predictability in how the work is being done and convergence to harmonized or same standards
• Legal basis – meets existing or changed legal framework in each country
• Competency – experts performing the PAC assessment are technically competent and experienced in the specific type of change

This is a very good approach in my view and could be the basis for a global approach amongst Regulatory Agencies. Work sharing and reliance is already in place in certain regions, such as the European Union (EU) and amongst some countries, such as the ACSS Consortium (Australia, Canada, Singapore and Switzerland). Reliance has increased during the COVID-19 pandemic out of a necessity as stated in the beginning of this article. There is also a general increased awareness amongst leaders of NRAs that the current very complex global PAC ‘System’ is not sustainable, is not capable of handling another pandemic, and has built in a lot of non-value-added redundancy that delays implementation of new knowledge and increases risk of drug shortages. Senior leaders of NRAs are now talking more about how rather than if reliance will be used more in the future to simplify the ‘System’ for the benefit of patients. We should all encourage more reliance amongst NRAs worldwide. 

We shouldn’t expect a drastic change in global regulatory reliance overnight, but if Regulatory Authorities can reach a consensus on the vision for global or regional reliance for PACs this will facilitate work towards more transparency and harmonization of reporting levels, reporting requirements and how individual PAC assessments are performed. In my view the WHO guidance documents developed by 194 countries is a good starting point for harmonized approaches and if WHO gets funded adequately the organization could take on a larger role in this regard.

Solution: Regulatory Flexibility

As written earlier the need for greater regulatory flexibility was identified almost twenty years ago (Reference 5). ICH Q10, Annex 1 (Reference 2) outlines a path for this as it states that when a company can “demonstrate effective PQS and product and process understanding” it is an opportunity to “optimize science and risk-based PAC processes to maximize benefits from innovation and continual improvement”; thus, managing more PACs in the PQS only rather than being submitted for prior approval. But how does a company demonstrate an effective PQS specifically for managing PACs? 

The Chief Quality Officers (CQOs) from the 25 largest pharmaceutical companies have come together to define exactly that through an Initiative called One-Voice-of-Quality on Post-Approval Changes (1VQ on PACs, Reference 11). The group published a Concept Paper (Reference 12) in 2019 in which they state that the global PAC ‘System’ “severely hinders and disincentivizes continual improvement, innovation, and timely implementation of knowledge gained during commercial operations, even when the PAC can result in patient risk reduction, process and technical improvements, or closure of compliance gaps”. The CQOs are decision makers and accountable for their company’s PQS. They are working on the manufacturing frontline balancing a secure supply chain, cGMP compliance and the implementation of new knowledge while the global PAC complexity and reporting requirements continue to increase. The CQOs published a solutions paper (Reference 13) in 2020 that “lays the foundation for an aligned and standardized industry position on the topic of effective management of PACs in the PQS”. The solutions are following a practical, standardized, science and risk-based approach to establish and demonstrate an effective quality system for managing PACs. The solutions are in line with the principles of ICH Q9, Q10, and Q12 and “intended to drive a paradigm shift from a country-specific approach to an enhanced science and risk-based approach for approval expectations focused on patient safety and product availability”. The CQOs are inviting other companies to join the initiative and are seeking an active convergence and harmonization dialog between the CQOs and regulatory agencies on this topic.

As is the case for increased reliance between Regulatory Agencies, the topic of trust is also important between Regulatory Agencies and pharmaceutical companies if Regulatory Agencies are to accept more PACs being managed by the company in the PQS only or via notification pathways. A question I hear sometimes is this “What if there is a ‘rotten apple’ amongst these companies that does not do a proper job of assessing the PAC?”. I think we need to move away from a situation where all companies are treated as potentially being a ‘rotten apple’, and replace it with transparency, flexible regulatory oversight that allows for agile PAC implementation, and robust self-controls in the industry to quickly identify and weed out any ‘rotten apples’. 

The 1VQ on PAC solutions include a description of each of the two enablers and four PQS elements of ICH Q10 specifically related to PACs. The CQOs have also developed practical examples and documents related to the PAC topic. Regulatory Agency experts have developed a draft guidance to assess a company’s Change Management system (one of the four PQS elements) through the organization PIC/S (Reference 14). This is a good example of how companies and regulatory agencies can work together.

Conclusion

The topic of drug shortages truly is a ‘wicked’ problem, that doesn’t have an easy solution as I have outlined in this paper. Optimizing the solution for one stakeholder only doesn’t work and usually makes the problem more complex. Identifying good solutions require that all stakeholders listen to each other and agree on what would be an overall best approach. Drug shortages is a global problem, and it requires a global solution. 

The complexity of the global regulatory framework for managing PACs, the ‘System’, has kept increasing over the past decades and the current ‘System’ is broken to an extent that the lack of regulatory agility hinders timely implementation of new knowledge into the manufacturing of drug products and vaccines even when it reduced risk to patients, it is an aggravating factor in drug shortages, and COVID-19 has demonstrated that the ‘System’ is not capable of handling a global pandemic. 

We have seen that during the COVID-19 crisis Regulatory Agencies have increased relying on each other and that they also have been relying more on pharmaceutical companies in terms of PAC management. This is encouraging and we now have an opportunity to learn our lessons on how we can take the best temporary solutions and make them more permanent.

Our approach must be patient centric, science and risk-based and achieve close to real-time implementation of PACs.  It must be capable of not only managing a future pandemic but also facilitating the implementation of new knowledge close to real-time to secure the supply chain, incentivize continual improvement and innovation, and avoid drug shortages. Our solutions must reflect that diseases and science are global in nature and our response should strive for also being more global while acknowledging national sovereignty of decision-making. 

I have outlined practical solutions and steps towards how I think we can work towards developing a common language and understanding of regulatory reliance and regulatory flexibility for managing PACs. We cannot miss this opportunity to learn from the pandemic. We cannot fail people depending on the supply of drug products or vaccines irrespective of where they live. We can only solve this ‘wicked’ problem and reinvent the ‘System’ if we do this together. It requires many, many more people to step up and lead regardless of which country you work in, whether you work for a Regulatory Agency, or a pharmaceutical company or elsewhere, and no matter where you sit in the organization. 

Are you in? 

References

1. ICH Q9, Quality Risk Management, 2005
2. ICH Q10, Pharmaceutical Quality System, 2008
3. ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, 2019
4. QAS/20.851, WHO draft, Good reliance practices in regulatory 5 decision-making for medical products: 6 high-level principles and considerations, 2020
5. Pharmaceutical CGMP Initiative for the 21st Century – a Risk Based Approach, FDA, 2002
6. ICH Q10, Concept Paper, 2005
7. Vinther, Drug Shortage is a ‘Wicked Problem”, PDA Letter, 2016
8. Rittel & Webber, Dilemmas in a General Theory of Planning, Policy Sciences 4 (1973), 155-169
9. QAS/19.828, WHO, Policy: Evaluating and publicly designating regulatory authorities as WHO listed authorities, working document 2020
10. PAHO, Regulatory Reliance Principles: Concept Note and Recommendations, 2018
11. 1VQ on PAC website. https://prst.ie/1vq/
12. Vinther, Ramnarine, Solving the Global Continual Improvement and Innovation Challenge: How an Effective Pharmaceutical Quality System Can Transform Post-Approval Change Management, PDA J Pharm Sci and Tech 2019, 73 517-521
13. Ramnarine, Vinther, Bruhin, Tovar, and Colao, Industry One-Voice-of-Quality (1VQ) Solutions: Effective Management of Post-Approval Changes in the Pharmaceutical Quality System (PQS)—through Enhanced Science and Risk-Based Approaches, PDA J Pharm Sci and Tech 2020, 74 456-467
14. PIC/S, PI 054-1 (Draft 1), How to Evaluate / Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management, 2019

Acknowledgement

Thank you to the many people who have provided feedback during the development of this document.