>> The European Union has a clear goal. As part of their “Pharmaceutical Strategy for Europe”, politicians plan to promote competition, innovation and sustainability in the pharmaceutical sector1. Another focus is to improve access. The World Health Organization (WHO) reports similar challenges2. Comprehensive health care depends on the availability of quality-assured, affordable health care.
health technologies in sufficient quantities, and “good health is not possible without access to pharmaceutical products,” she writes in a report. According to the WHO, lack of access to medicines is “one of the most complex and vexing problems”. What barriers are there – and what are possible solutions?
1. Four dimensions of a problem
Scientists have published a number of studies on this question in recent years. However, in their work they use different definitions - from the date of the first inclusion of a new preparation in reimbursement lists to company activities or sales dates. The focus is also on certain segments, such as innovative medicines, vaccines or essential medicines. The results can hardly be compared. It therefore makes sense to break down access to pharmaceuticals into individual steps and consider each area separately (Fig. 1).

1.1 Approval of new medicinal products
In the EU, the European Medicines Agency (EMA) evaluates data from manufacturers and issues approvals. During the pandemic, conditional marketing authorizations or accelerated procedures such as rolling reviews were more common than before.
In these cases, there may be problems with the evidence, for example due to a short study duration, the exclusion of certain groups such as children or pregnant women, and small cohorts.
Of the 52 new drugs approved in 2020 (excluding emergency approvals), only 20 percent had more than 1,000 patients in their studies3. For 31 orphan drugs with new active ingredients introduced in 2020, the median number of participants was 221, while for the 21 non-orphan drugs there were 785 participants.
Although progress in accelerated approval procedures is positive, the gap between assessment criteria used by authorities such as the EMA and payers in individual countries is immense. If there is too little data, companies may face certain challenges later despite successful approval.
In Germany, for example, two highly publicized drugs were withdrawn from the market for price reasons: the gene therapy Betibeglogene Autotemcel (“Zynteglo”) from Bluebird Bio4 for the treatment of thalassemia and “Piqray” (alpelisib) from Novartis5 for the treatment of postmenopausal women with a certain form of Breast cancer. Medical societies criticized “Piqray” in particular for a gap in the pricing process that was to the detriment of the affected patients. This is mainly due to methodological problems. The Federal Joint Committee (G-BA) refused to use the extension of progression-free survival, they write in statements.

1.2 Market access and reimbursement
The EFPIA patient WAIT indicator is
a method for measuring reimbursement for innovative medicines. WAIT stands for “Waiting to Access Innovative Therapies”. In the latest edition, published in May 20215, it continues to show dramatic differences in the availability of innovative medicines (Fig. 2).
In many countries, doctors are prescribing outdated therapies that have already been optimized several times, and new active ingredients face strong headwinds.
There are 27 individual markets with the associated sales and access channels. But seven markets accounted for 88 percent of global sales of new drugs launched between 2015 and 2020. The United States alone accounted for 64 percent of total new drug sales, even though U.S. residents make up only four percent of the world's population. All figures are based on list prices without discounts or discounts.
The five major European markets (EU4+UK) – with a total population very similar to that of the United States – are far behind, accounting for 17.4 percent of global sales.

1.3 Financing
Innovative medicines are used to treat conditions more frequently for which there were no suitable therapies before. These can be rare diseases with small numbers of patients - or major widespread diseases. By improving quality of life, alleviating symptoms and, ideally, healing, healthcare systems save money in the long term; however, in the short term, their expenses increase. Countries with low purchasing power find it difficult because they can hardly finance therapies with additional benefits until the benefit becomes noticeable.

1.4 On-site availability
In addition, new drugs are sometimes only available in insufficient quantities in the first few months after their market launch. At first a few packs roll off the assembly line; Only later do manufacturers ramp up their production6. Regional differences also play a role; not every country is supplied to the same extent. Redistributions between individual nations can remedy this to some extent. This is also where parallel trading comes into play. Regardless of the manufacturer, companies purchase pharmaceuticals in one country and sell them in other markets.
Special storage conditions further complicate the spread. Examples include some vaccines, CAR T-cell therapies and gene therapies, as well as other products with strict cold chain requirements.
SARS-CoV-2 and the associated trade restrictions imposed by many countries during the pandemic further exacerbated shortages. However, previous research shows that 77 percent of all active ingredients needed to produce innovative medicines in the EU come from Member States, providing some protection7.
2. What factors limit access to innovative
medicines?
Understanding why certain pharmaceuticals are available – or not – requires a systematic review of all key stakeholders and issues in the pharmaceutical market. It is important to include all stakeholders in analyses. Each instance can help or hinder the process.

2.1 More innovations – but also more challenges in application
First, a look at new active ingredients. The pharmaceutical industry, together with academic research institutions, has developed more innovative medicines than ever before. All approvals reached a peak in 2020 despite Covid-19 (Fig. 3).
The complexity of innovative medicines is constantly increasing because they are used for small patient groups. This is particularly clear in oncology. For some therapies, doctors carry out tests for biomarkers in advance. CAR T-cell therapies, on the other hand, require extensive laboratory work and special skills on the part of doctors.
That was not always so. In 2008 and 2009, the EMA did not approve any orphan drugs; In 2010 there were only four preparations. And today? In 2021, the number of orphan drugs approved by the EMA will reach a historically high level. Monoclonal antibodies continue to dominate events. However, cell and gene therapies are becoming increasingly important. The associated complexity and cost of these innovative medicines may partly explain the problem of low access to medicines in certain markets.

2.2 Data Transparency
To verify whether a drug is available in a particular market, researchers need information. Previous studies have relied on publicly available data to ensure that commercially sensitive information is not disclosed. Long-term information on a drug's submission status is rarely available for all markets from national authorities or regulators, limiting conclusions about whether companies have submitted their drugs for approval. Even at the National Institute for Health and Care Excellence (NICE) in Great Britain, an authority with a high level of transparency, not all data is available8,9.

2.3 Regional factors
The availability of innovative therapies may vary from country to country. 53 percent of all new active ingredients approved worldwide since 2010 are not approved for use in Europe. This often happens with a delay because manufacturers focus on the USA. The EMA works with strict approval criteria, but other variables such as the origin of the company and standards of evidence can also play a role in the lower availability.
Within Europe, Bosnia and Herzegovina (ALMBIH), Macedonia (MALMED), Russia (MHRF), Serbia (ALIMS), Switzerland (SwissMedic) and Turkey (TTICK) have their own local approval processes. These regulators often work slower than the EMA. Access to affordable medicines is poorer in these countries and innovations are introduced later.

2.4 Economic effects
Given the growing number of innovative drugs, drug spending is expected to increase. Covid-19 vaccines, cell or gene therapies or treatments for hepatitis C involve considerable costs, but help save money in the medium term. Because they make it possible to cure or prevent serious, chronic illnesses.
Exact figures on expenses are unknown. Manufacturers often grant payers significant discounts on list prices, but only under the seal of secrecy. It remains unclear how much of a role this factor plays in the availability of innovative pharmaceuticals.
To pay for innovation, alternative models such as performance pricing could be used. Novartis has signed agreements on an innovative model for “Zolgensma” for the treatment of spinal muscular atrophy. The manufacturer bears the full economic risk if his treatment does not work.
In healthcare systems or markets where early treatment decisions are made and a high level of clinical expertise exists, there is more willingness to treat patients with innovative therapies. Gathering experience with a drug is often overlooked in analyses. Markets that are less experienced in dealing with innovative medicines due to long-standing spending constraints risk access without clinical support having a negative impact on patients.

2.5 Effects of international price referencing
International Reference Pricing (IRP) is also likely to have significant consequences for the availability of medicines across Europe10. Countries select other countries in their shopping cart where the product has already been introduced - at a reasonable price. This leads to a trickle-down effect (to trickle down): some regions are
forced to wait for other countries to agree on a reimbursement price before taking action themselves.
Manufacturers, in turn, strategically decide on the sequence and timing of market launch, which can lead to further delays. Smaller markets are unique in that prices are as low as possible, which ultimately leads to poorer – and later – access to medicines. The importance of favorable conditions for countries with limited budgets is important, but access to innovative therapies has greater long-term benefits.
Here are some examples. In Bulgaria, Estonia, Latvia and Romania, more than a third of all products examined were available six years after market approval. This phenomenon cannot be explained by delays in approval. The responsible Lithuanian authority, for example, stipulates that a price must be available in eight reference countries and throughout the EU before it begins negotiations itself. For companies wanting to enter the market in Lithuania, this means waiting a long time or doing without.

2.6 Different priorities in evaluations by authorities
Committees for assessing the benefits of a therapy (Health Technology Assessment, HTA) set different priorities. Criteria can be clinical effectiveness, the possibility of saving money in the medium term or the consequences on overall budgets.
In the past, all former EU5 countries had decided to recommend a product for inclusion in reimbursement lists, 70 percent of Central and Eastern European countries followed this recommendation - much faster than without a decision from the (former) EU5 nations (today : EU4+UK).

2.7 Niche products are available in fewer markets
Smaller biopharmaceutical companies with niche products may find it more difficult to navigate the more than 25 systems and stakeholders associated with accessing markets in Europe. The EU4 markets + UK account for 70 percent of the total European market by revenue and 43 percent of the population, highlighting the inequality and difficult situation for most companies11.
On average, a product launched by a large pharmaceutical company is available in 17 markets, compared to only nine for small and medium-sized companies (SMEs). This is because smaller companies (defined by market share) often develop drugs for rare diseases.
Only a few companies are generally successful in bringing medicines to market in European markets. The need to understand different systems leads to an increasing need for full-time staff and consulting services.
3. How can access to innovative medicines be improved?
Factors that play a role in access to medicines in Europe are a network of policies and effects within individual countries. To address the problem, one must be clear about which of the four components (regulation, reimbursement, affordability, physical availability) should be addressed. And in many cases a country-specific approach is required. What might strategies look like?

3.1 More transparency in approvals
Regulatory authorities have significant
Progress has been made in improving the transparency of approval pathways, allowing medicines to be approved through accelerated and conditional approval pathways, although the EMA takes longer in Europe than other regulators. By supporting new designs in clinical trials, making greater use of real-world data, and improving dialogue between developers and regulators, all steps are becoming more transparent.

3.2 New ways to evaluate innovations
In the reimbursement process, committees for assessing the benefits of a therapy are extremely restrictive. There are currently only a few mechanisms tailored to accelerated approvals. A re-evaluation is considered the optimal approach, in contrast to conditional approval, in order to gain further insights from practice. Leading reimbursement authorities in Europe are beginning to adapt procedures to improve the availability of innovative therapies.

3.3 Rethink cost structures
The affordability of medicines also plays a key role. The current system is based on prices in other countries and on fluctuating currencies. This creates price corridors and requires price adjustments for countries with a wide range of purchasing power. Transparent pricing without reference prices and without parallel trading would also optimize the availability of new pharmaceuticals.

3.4 New ways of inventory management
In addition to political and strategic
The physical availability of pharmaceuticals must also be taken into account. New models such as regional hubs or agile supply chains only work with transparency, for example using cross-border product codes. <<

from:
Max Newton1, Eva Kersey2 and
Rebecca Coady3
*

1: Senior Consultant, Global Supplier & Association Relations, IQVIA
2: Senior Principal, EMEA Consulting Services, IQVIA
3: Principal, EMEA Consulting Services, IQVIA

German editing:
Dr. Gisela Maag, press spokesperson/IQVIA Germany

Source: IQVIA White Paper, 2021: “Perspectives on the availability of Innovative Medicines”. Link: https://bit.ly/3aoPih8

1: https://ec.europa.eu/health/sites/default/files/human-use/docs/pharma-strategy_report_en.pdf
2: https://www.who.int/publications/10-year-review/chapter-medicines.pdf
3: https://www.iqvia.com/insights/the-iqvia-institute/reports/global-trends-in-r-and-d
4: https://www.dgho.de/aktuelles/news/news/2021/bluebird-bio-nahme-das-gentherapeutikum-zynteglo-r-aus-wirtschaften-gruenden-vom-deutschen-markt
5: https://www.dgho.de/aktuelles/presse/pressemeldeen/marktruecknahme-von-alpelisib-zulasten-von-brustkrebspatient-innen
6. https://www.iqvia.com/library/white-papers/reporting-of-medicine-shortages-in-europe
7: https://www.efpia.eu/news-events/the-efpia-view/blog-articles/eu-strategic-resilience-in-pharmaceuticals-global-value-chains-and-innovation/
8. https://accesstomedicinefoundation.org/publications/2021-access-to-medicine-index
9: https://www.efpia.eu/publications/downloads/efpia/efpia-patients-wait-indicator-2019-survey/
10: IQVIA Global Market Insights International Reference Price rules database Q1 2021
11: IQVIA MIDAS dataset Q2 2021 analysis (Rx only) excludes rebates and discounts