In recent years there has been a proliferation of pharmacovigilance guidelines and regulations. Regulatory authorities have implemented different requirements, templates and regulations, and some of them have asked pharmaceutical companies to produce many documents with overlapping content. These requirements risk draining resources from the scientific assessment of safety information to bureaucratic tasks. It is proposed that pharmacovigilance regulations are harmonised and simplified. The implementation of the drug safety master file could be a step towards this goal.
In recent years pharmacovigilance has been recognised as being one of the most important sciences in the health sector and this has led to develop new regulations and guidelines not only in Europe, but also in the developing countries around the world. The only goal of pharmacovigilance is protecting safety and this, of course, is also the aim of new regulations. However, following the proliferation of drug safety regulations and guidelines, it is now time to question if they have really reached the aim of protecting patient safety or if they have become too cumbersome and complex, thus representing an excessive burden for the healthcare sector, thereby, failing to achieve their objectives.
For a drug safety professional working at global level, one of the most striking weaknesses of the drug safety regulations is the lack of harmonisation.
An example is Periodic Safety Update Reports (PSURs). In 2012 the International Conference on Harmonisation (ICH) released a guideline describing a new format for PSURs. But this guideline has not been implemented by all countries. For example, in China and Brazil PSURs are required in the old format. In the US, both PSURs (in the new format) and Periodic Adverse Drug Event Experiences (PADERs) are accepted. However, the periodicity with which PADERs need to be prepared (quarterly for the first two years since product launch and then annually) is different from that of PSURs. In Europe they need to be prepared every six months after the drug is placed on the market, then once a year for two years and finally every three years, unless the list of European Union reference dates and frequency of submission of periodic safety update reports, known as the ‘EURD list’, has different requirements. This implies that a company marketing a drug in Europe, the US and China, will need to prepare country-specific documents for the same drug. In addition to this, Brazil requires the PSURs to be submitted with an ad hoc cover letter that summarises the information contained in the PSURs itself and in the Risk Management Plan. Therefore, the same safety information is presented in different formats, thereby increasing the bureaucratic burden.
Unluckily, the inconsistencies of document format and submission timelines is far from being limited to PSURs, Individual Case Safety Reports (ICSRs) are another example of these different requirements. The international standard for submitting ICSRs to the authorities is the form developed by Council for International Organizations of Medical Sciences, known as CIOMS I form, if the report is submitted on paper and the ICH E2B format, if the report is submitted electronically to the authority. However, in China, there are three templates for submitting ICSRs: the first one, for cases originated from China, is similar (but not identical) to the CIOMS form, then there is a separate form for cases originating outside of China and finally another form for submitting cases associated with a product complaint. The differences regard not only the ICSRs submitted on paper, but also those submitted electronically. In fact, it is sufficient to compare the number of pages of the document on the regional and technical implementation of electronic reporting requirements in the EU to those in the US (more than 100 pages and 15, respectively), to understand how the same requirements have been differently implemented in these two regions.
The list of divergent requirements is too long (and boring) to be detailed within this article, so only another example will be made: the timelines for submitting ICSRs. For non-serious cases, these go from 90 days (in some European Countries) to 10 working days in some Latin American Countries.
The role of ICH is that of harmonising the pharmaceutical sector guidelines at an international level. The above described lack of harmonisation in pharmacovigilance guidelines shows that there is a need for widening the role and scope of ICH. However, in recent times, some countries seem to look elsewhere rather than to the ICH guidelines. The Arab League, for example, has implemented Good Vigilance Practices and the Pharmacovigilance System Master File, a document that is not mentioned in ICH guidelines. It is not surprising that some countries are looking to the European guideline as a model since they are by far the most detailed and comprehensive.
European guidelines also tend to be redundant and complicated. Volume 9a (the pensioned European pharmacovigilance guideline) was a single 229 page document. It has been replaced by Good Vigilance Practices; at the time of writing this article there were 12 finalised Good Vigilance Practices and three which were still not finalised, an addendum, a sixty page template for Risk Management Plans (RMPs), one for PSURs and nine ‘other pharmacovigilance guidance’. Additionally, there are guidance documents on a number of ‘“other pharmacovigilance related’ topics. Only for data submission on medicines to the European Authority there are nine guidelines; of these ‘chapter 3.1:specifications‘ is 224 pages.
This large number of voluminous guidelines not only implies that it is increasingly difficult and complex to be aware of the regulations and comply with them, but, more importantly, they require the pharmaceutical industry to prepare many redundant documents. Signals, risks or the benefit-risk balance of an authorised medicinal product are described by PSURs, RMPs, Signal Detection Reports, Addendum to Clinical Overview (a document, similar to the PSUR, that needs to be submitted upon product renewal) and, if the drug undergoes a referral, by the documents that need to be submitted during this procedure. In addition, if the product is still in clinical development, signals, risks or the benefit-risk balance of the drug need to be described in the Development Safety Update Report and in the Investigator’s Brochure. According to the new EU Clinical Trial Regulation, they also need to be reported in the protocol and in the Investigational Medicinal Product Dossier. When we add the different documents requested by the non-harmonised regulations of other countries (such as the PADER or the PSUR old format as previously mentioned) to the documents containing redundant information due to the EU requirements, we understand the extent of the burden on drug safety departments. The risks of having similar documents with contradictory information or of drug safety departments being absorbed by copy and paste exercises instead of focusing on understanding the risks of a drug and how to minimise them are far from theoretical.
Interestingly, the European Authority has recognised that some pharmacovigilance documents are redundant: the EU document implementing the Periodic Benefit-Risk Evaluation Reports (PBRERs, the new version of PSURs), states that, out of the 40 sections of a PBRER, 16 share commonalties with PSURs and 4 with RMPs. The guidance, therefore, encourages interchangeable use of the sections of these documents. In practice, however, this is seldom possible because the periodicity with which PBRERs, DSURs and RMPs need to be prepared is different, and the safety profile of a drug evolves over time.
To be fair, it has to be noted that the tendency of having ever more demanding requirements is not limited to the EU. For example, the ICH guideline on Periodic Safety Update Reports which now requires this document (PBRER) is made of 19 chapters, while in the old version it consisted of ten. Similarly, the ‘old’ E2B guideline on electronic reporting of individual case safety reports (E2B) was 29 pages. The new guideline has a 166-page implementation guide and 8 appendices.
With such a tendency to develop more and more demanding and redundant regulations, it is not surprising that not all countries have implemented the new ICH guidelines or the European regulations. Probably in a developing country they would not be sustainable from an economic point of view due to the resources needed to implement them.
However, even in developed countries, the economic aspects cannot be ignored. In a sector such as pharmaceutical, where costs increase but margins don’t, the industry does not tend to develop drugs with low margins such as antibiotics, but focuses on sectors where the margins are higher— such as orphan drugs (where it is easier to get a drug on the market), monoclonal antibodies (biogenerics are more difficult and expensive to register), or on widespread and severe disease, such as cancer and hepatitis, where a novel and more effective drug can be sold at a high price. Pharmaceutical industries stop selling old drugs with very low margins and when there is only one pharmaceutical company left to sell a drug, then it is likely that, all of a sudden, the price of that drug will skyrocket as the company has gained a market monopoly.
In pharmacovigilance, in order to contain the increasing costs, companies tend to outsource or insource work to low-cost countries (where quality is not always the highest), work is sometimes done by under qualified personnel (because it costs less and the increased requirements demand more skilled, experienced and qualified pharmacovigilance professionals than there are on the market) or it exceeds staff capacity. Finally, due to the need to repeat the same information in different documents and formats, there is the risk of doing copy-and-paste exercises rather than focusing on understanding what are the risks of a drug, their characteristics and how to minimise a risk.
Pharmacovigilance regulations and guidelines have an essential role in requiring collection of high quality and complete safety information, driving a sound scientific assessment of the received information and facilitating the production of high quality documents that drive appropriate risk minimisation actions so as to protect patients’ safety. However, when regulations and guidelines increase the administrative burden and bureaucratic requirements are complex, posing different requirements in different countries, the results will be the opposite of the above-mentioned desired situation. The reason is that, in a resource-constrained world, economic pressure limits the quality and quantity of the human resources available for doing the job. Even if complex and redundant regulations and guidelines require more and more quality personnel to prepare the required documents, due to economic pressure, the necessary increase in human resources will not be available. Therefore, the risk is that regulations and guidelines transform pharmacovigilance in a tick-box exercise, draining resources from detecting the risks of a drug and minimising them to a bureaucratic exercise, which is not in the interest of patient safety. In order to avoid this risk, it is necessary that pharmacovigilance adopts a systematic approach: the pharmacovigilance system should not be the sum of single rules, regulations and guidelines that have each been developed in isolation, without considering the relationships among all the socio-technical components. This means that in order to have an efficient and effective pharmacovigilance system, the interactions between all stakeholders, components and factors need to be taken into account. The aim of protecting patient safety is not achieved by adding one requirement to the other, but by designing a pharmacovigilance system through a wholesome and holistic approach.
As previously mentioned, one of the factors that cause pharmacovigilance to be ineffective is the lack of harmonisation in the requirements of different countries. Thus, there is a need to have a global organisation (be it ICH or a new organisation), where the regulators of every country discuss and agree a minimum set of pharmacovigilance guidelines that should be adopted in as many countries as possible. Of course, complete harmonisation would be very hard to achieve, if not unrealistic. However, in the interest of patient safety, a minimum set of regulations should be agreed upon. Countries should be free to add additional (but not different) requirements, taking, however, into account that having too many requirements are not in the interest of the patients.
Another factor that causes pharmacovigilance to be less efficient and effective is the requirement for many aggregate reports containing at least partially overlapping information. To avoid this redundancy, it is necessary to disassemble these documents and identify their single components. In essence, drug safety aggregate reports describe:
• What is known about a medicinal product (e.g. its mechanism of action and metabolism, the extent of patient exposure, the actions taken by regulatory authorities or by the marketing authorisation holder for safety reasons, the most important outcomes of the studies that have been conducted, the effect of products of the same class etc.)
• What is not known about a product (e.g. safety or efficacy in specific population subgroups)
• The main risks of the drug (including the risk characteristics as well as the paucity of information relevant to them)
• The drug’s efficacy
• New safety information received during the reference period (e.g. new risks, new information on risk characteristics, signals, new information on the drug benefits)
• How drug risks are minimised
• What has to be done to collect information on what is unknown regarding the product
• Benefit-risk evaluation
The above list might not include all the topics that characterise aggregate reports, but it helps to set the basis for defining a single modular document that could describe all that is known on the safety profile of a drug. In analogy with the pharmacovigilance system master file (the document describing a company’s pharmacovigilance system), this document, that could be named drug safety master file, could be updated every time there is new information impacting on the drug’s benefit-risk balance and could serve to be the solitary document which needs to be submitted to regulatory authorities. Having only one document for describing the safety profile of a drug would avoid all the inconveniences and costs of having multiple overlapping documents and would finally permit pharmacovigilance departments to focus on understanding risks of drugs and how to minimise them rather than being absorbed by bureaucratic exercises.
The pharmaceutical sector should learn from what happened in 1994 when a US army Blackhawk helicopter was shot down by friendly fire in north Iraq. The analysis of the accident showed that there were multiple layers of control to identify which aircraft was a friend and which was foe. Many departments were involved and there were many overlapping responsibilities. The operations had become so complicated that different departments in charge of controlling aircraft traffic were using different communication codes and different wavelengths. Not surprisingly, problems in communications contributed to the accident.
This should teach us that complication, redundancy and overlap do not prevent failure: more is not always better, it can be worse. In pharmacovigilance, it is time to stop thinking that we are protecting patient safety by continuously adding regulations and guidelines. We should, instead, change our mind-set and think about how we can do things in a smarter way.
The Author would like to thank Mr David Power, HelsinnBirex Pharmaceuticals, for reviewing this chapter
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