Author byline as per print journal: Peter J Pitts, BA; Michael S Reilly, Esq
Submitted: 1 June 2018; Revised: 29 October 2018; Accepted: 30 October 2018; Published online first: 2 November 2018
When it comes to monitoring the quality, safety and efficacy of biological medicines, distinguishable naming is imperative because biosimilar therapies are similar to, but not exactly the same as, existing biological medicines. Since no biosimilar is perfectly identical to its innovator parent, every biological – whether reference product or biosimilar – must be fully distinguishable from other biologicals to permit quick and accurate tracing of its manufacturer, should an adverse event be observed. Precise naming of all biologicals will improve patient safety by reducing confusion and mishaps in prescribing and holding manufacturers accountable. Also, differential nomenclature helps enable national health authorities to collect and compare real-world data that measure the clinical effects of biologicals including biosimilars. Insights from such data, over time, will enable us to better measure a drug’s effectiveness in delivering successful health outcomes for patients.
The World Health Organization (WHO) must finalize their Biologic Qualifier guidance. It is this organization that has the responsibility to ensure that developing nations of the world have access to affordable, quality medicines. Safety is mission critical and the Biological Qualifier is a potent tool on behalf of global public health.
Over the last few years we have travelled to many countries around the world, visiting with medicines regulators from Australia, Europe, Latin America and the Middle East. Although a wide range of topics were discussed with these regulators, one of the most pressing issues for all was the urgency of access to quality medicine.
This paper will focus on medicines regulation in the Middle East and North Africa, specifically Algeria, Egypt, Iraq, Jordan, Kuwait, Lebanon, Morocco, Oman, Qatar, Saudi Arabia, Turkey and the United Arab Emirates (UAE). We will also discuss the importance of the World Health Organization’s leadership around establishing a global nomenclature policy that will help maintain the quality, safety and efficacy of biological and biosimilar medicines for that region.
Without quality, safety and effectiveness are non-starters and access is without meaning. Without quality, healthcare spending is not just wasteful – but harmful. Without quality it is all about ‘lowest price tenders’ without any consideration for value. Without quality, regulation is a sham.
Medicine quality is on the minds of leaders in the Middle East. At the Second Annual Arab Conference on Food and Drugs (Sharm El Sheikh, Egypt, 11-13 April 2015), a conference of regional regulatory agencies, Dr Rasha Ziada (Egyptian Ministry of Health) made the important point that if a pricing authority does not take outcomes into consideration; it will lead to overall price distortions. Amen! Dr Ola Ghaleb (Ministry of Health UAE), spoke about the UAE’s strategy of performance-based risk-sharing arrangements. Outcomes are now capitalized and bolded in the international lexicon of healthcare policy. The necessary precursor to positive outcomes is quality.
A significant number of the conference presenters discussed the value of sharing pharmaceutical economic data across borders, but there was not an equal counterbalancing discussion of the value of sharing clinical data for approvals and outcomes-based decision-making processes. The opportunity to enhance regulatory capacity and product quality through collaboration and information sharing is significant. Unfortunately, cost is too often the primary focus while other priorities such as quality are left to languish.
There was certainly an effort (both on many of the panels as well as during the breaks and after hours) to stress the urgency of the quality agenda. The good news is that speaker after speaker (sometimes in passing and other times passionately) made the point that it must not just be about ‘getting the lowest price’, but also appropriately pricing the most clinically effective treatments. Cost savings without quality are no bargain.
The crisis in drug quality is very real. In Saudi Arabia, according to Alhawassi et al. :
The list of essential medicines from WHO is also considered essential in primary health care in Saudi Arabia. Yet, unfortunately, many medications from this list are among the most widely substandard and counterfeited . For example, one study conducted in Saudi Arabia showed that amoxicillin has already been identified as substandard . Consequently, one of the central aims of advancing pharmaceuticals and patient care in Saudi Arabia is the ‘safe use’ of quality medications .
Access to medicine alone is not enough; medicine quality is an essential element of patient care. Quality – even for relatively common and easily evaluated medicines like amoxicillin – is a challenge and must be a policy priority. As put forth by Alhawassi et al. :
One initiative of the Saudi 2030 vision plan should be to advance patient care through a more robust, safety/quality-centred culture together with a more collegial relationship between local and international drug manufacturers and Saudi regulatory authorities. Such an enhanced working relationship would result in a higher quality care to the public (Saudi, 2030 ). This concept of aggressive attention to better patient care through greater attention to quality and safety is only now emerging in developed and less developed countries.
The observation of scientist W Edwards Deming applies today as it did decades ago. ‘Change is not required. Survival is not mandatory’.
As in the West, generic drugs provide greater access to medicine for millions of patients in the Middle East. As in other parts of the developing world, assuring quality through robust regulatory oversight is often at counter-point with available human and financial resources. As in every part of the world, Middle Eastern health officials (from national ministries of health to local inspectorates) recognize the imperative that ‘the most expensive drug is the one that does not work’. No nation can afford to buy low quality products.
Countries around the world are struggling to adequately monitor the quality of medicines available to their citizenry. From more regular manufacturing inspections, to risk-based investigations into the sourcing of ingredients, to a rethinking of post-marketing surveillance (pharmacovigilance), there is not one single solution.
Attention to quality cannot end at product approval. This dimension is clearly elucidated from the Jordan Food and Drug Administration (JFDA). In a recent journal article Dr Hayel Mohammad Obeidat, JFDA’s Director General writes, ‘We believe that 21st century pharmacovigilance must also include tighter and more regularly monitored post-approval bioequivalence measures. It is a new and difficult task and calls for better validated methodologies for both data collection and signal prioritization. It is the responsibility of JFDA to take the leadership role and help educate our various constituencies to the importance of 21st century Phase IV monitoring and interventions ’.
What we need are standards and systems that recognize the situation as it exists and provide both a path for convergence with global best practices and immediate tactical programmes that can address the true situation on the ground. In brief, regions such as the Middle East require tactical, pragmatic regulation that recognizes the asymmetries inherent in an evolving regulatory ecosystem. Global institutions can play an important role in facilitating this.
A key issue driving the development of 21st century regulatory pharmacovigilance strategies is the need for updated post-marketing surveillance of biosimilars. Biological medicines have revolutionized the treatment of many serious and life-threatening diseases; as patents for these products expire around the world, biosimilars are becoming available. Biologicals are very complex medicines made using living cells and cannot be copied exactly, thus copies are called biosimilar, not generic drugs. Appropriate approval standards, specific to biological medicines, are a threshold requirement for all medicines that are deemed ‘biosimilar’. The problem of alleged copies approved outside of a scientifically sound biosimilar framework is a serious safety problem and a topic for another paper. However, even in the context of sound scientific standards, vigilance cannot stop at approval for any biological.
Issues related to the particularities of biologicals (sources, process, quality requirement and new safety profile) require sophisticated new thinking.
Fundamentally, all of the players in the pharmacovigilance ecosystem will have problems characterizing biosimilar issues since we do not have an existing, validated predictive models of potential ‘hot spot’ products, base ingredients and/or suppliers. Consequently, pharmacovigilance for biologicals will have to evolve at the same time as new medicines are launched into this space. Small numbers and the novelty of biological products and their safety profiles – alone and in combination with other medicines – for manufacturers, medical providers and patients will likely render monitoring challenging. This is where global institutions can step in.
We are in a situation of post-marketing ‘indetermination’ and the first step should be to develop new epidemiological approaches that based on a better understanding of the differences between the concepts of ‘generic’ and ‘biosimilar’. We understand there can be different safety profiles for generics (based on differing bioequivalence ranges, excipient and active pharmaceutical ingredient sourcing). When it comes to biosimilar pharmacovigilance, however, variability-induced iatrogenesis concerns, differences between batches by multiple manufacturers, and the elastic definition of ‘similarity’ is not a question of ‘safety profile’, but rather of ‘concept’ .
It is into this maelstrom that the steady hand of WHO is needed. And nowhere is this more true or urgent than in the current debate over biosimilar medicines generally and product nomenclature specifically.
WHO has published a draft proposal for a global system to assign ‘biological qualifiers’ (BQs) to biologicals and biosimilars . A BQ is a random four-letter code assigned to a biological manufactured at a specified site. WHO said the scheme would be voluntary for each regulatory authority and applicable retroactively. The qualifier would not be part of a biological’s International Nonproprietary Name (INN), although WHO’s INN expert group would oversee the scheme. WHO said the proposed scheme is intended to avoid separate national qualifier systems. It will also permit less developed national regulatory systems to institute a globally consistent protocol that will help to guarantee the quality, safety and efficacy of biological and biosimilar medicines.
Consider Lebanon, ‘the hospital of the Middle East’. Minister Ghassan Hasbani, Lebanon’s Deputy Prime Minister and Minister of Health, is revamping the medicines tendering programme for Lebanon and one of the key tenets being weighed in the new national decision-making process is value. As His Excellency said from the podium, ‘It is not only a cost, it is an investment’. And, as with any investment, it is impossible to understand the cost without proper consideration of the return.
Minister Hasbani recognizes that biosimilars represent an important tool in expanding access to patients in Lebanon. But, as in the West, it must be access combined with quality and safety.
When it comes to health care, clarity is better than confusion, especially when it comes to drug safety — the sine qua non of medicines regulation. And that means clarity in biosimilar nomenclature.
What is so important about a biosimilar’s name? Patient safety. According to the US Food and Drug Authority, distinct and precise nomenclature for all biologicals, innovator and biosimilar, will promote accurate prescribing and facilitate accurate attribution of adverse events .
Distinguishable naming is imperative because biosimilar therapies are similar to, but not exactly the same as, existing biological medicines. Since no biosimilar is perfectly identical to its innovator parent, every biological – whether reference product or biosimilar – must be fully distinguishable from other biologicals to permit quick and accurate tracing of its manufacturer, should an adverse event be observed. This facilitates manufacturer accountability.
On a global level, an INN  is used to identify the active ingredient in a drug, which in the case of a chemical/generic drug is equivalent. Biosimilars are not identical to their innovator parents; they are ‘highly similar’.
The differences, however, are crucially important since there is the potential for all biologicals to elicit dangerous immune responses. For this reason, if biosimilars use identical INNs and prescribing, dispensing or adverse event records identify products only by INNs, global regulators cannot recognize precisely which product is causing a problem. Testimony to WHO showed that there is a high level of ambiguity in attributing adverse events to a specific manufacturer when products share the same non-proprietary name . Efforts to include other identifiers, such as batch number, that would distinguish between products and manufacturers routinely fail . The addition of a unique suffix to the non-proprietary name provides a distinguishing feature that can be used to enhance traceability in a marketplace with multiple similar options.
Precise naming will improve patient safety by reducing confusion and mishaps in prescribing and dispensing; biosimilars are not identical to the reference product or one another, thus switching from one product to another may not be appropriate. Also, differential nomenclature helps enable national health authorities to collect and compare real-world data that measure the clinical effects of biologicals including biosimilars. Insights from such data, over time, will enable us to better measure a drug’s effectiveness in delivering successful health outcomes for patients.
WHO must finalize their BQ guidance. It is this organization, after all, that has the responsibility to ensure that developing nations of the world have access to affordable, quality medicines. Safety is mission critical and the BQ is a potent tool on behalf of global public health.
Our experience with healthcare regulators worldwide has reinforced our belief that health care and health policy professionals devoted to ensuring timely access to innovative medicines, quality generic drugs and biosimilars. It is not easy, and it is not only a job – it is a personal public health mission.
There are many issues surrounding the introduction of biosimilars into the global healthcare ecosystem: safety, effectiveness, interchangeability, potential adverse medical events, appropriate regulatory labelling and physician prescribing guidelines. But, even so, biosimilars are here. They are safe and effective. They are less costly. And they deserve a seat at the therapeutic table.
When it comes to biosimilar nomenclature, it is important for WHO to look … backwards. According to the 10th century Arab physician, Ibn Sina, ‘The time of action must be observed, so that essence and accident are not confused’.
This paper is funded by Alliance for Safe Biologic Medicines.
Competing interests: Mr Peter J Pitts declares no conflict of interest. Mr Michael S Reilly, Esq, is the Executive Director of and employed by Alliance for Safe Biologic Medicines. Mr Reilly served in the US Department of Health and Human Services from 2002–2008.
Provenance and peer review: Not commissioned; externally peer reviewed.
Peter J Pitts, BA
Former Associate Commissioner, United States Food and Drug Administration
Visiting Professor, Université Paris Descartes Medical School
President, Center for Medicine in the Public Interest
757 Third Avenue, 20/F
New York, NY 10017, USA
Michael S Reilly, Esq
Alliance for Safe Biologic Medicines
PO Box 3691, Arlington
VA 22203, USA
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Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
Disclosure of Conflict of Interest Statement is available upon request.
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