Critical Pathways for Patient and Market Access of Orphan Drugs for Rare Diseases in the Emerging and Frontier Markets Sponsored by QCR GLOBAL GROUP - A Niche Life Science Management Consulting Firm

Mapping Out The Rare Disease Landscape

Orphan drugs help to fill an unmet need in the management of patients with rare diseases worldwide. The United States (US), and the European Union (EU) have adopted legislative policies to enable pathways to expedite the review, and regulatory approval of these novel treatments. These policies have enabled an increase in approvals and patient access to new treatments for people with rare disease worldwide. However not all countries have modified their regulations to account for this change. A number of emerging and frontier countries still lack effective regulatory review guidance and legislative policies to expedite the approval of orphan drug therapies and to manage costs for rare diseases.

These markets are of importance due to its growing population and positive future-based economy. At the same time, the recent economic outlook has re-emphasized the relatively inconsistent support of healthcare initiatives to meet the demands of patients with rare diseases. Market access in emerging and frontier markets is also complex due to its diverse stakeholder pathways, and challenges in applying traditional market access strategies.

In this article we will discuss the obstacles in the approval of orphan drugs for rare diseases in the Latin American (LATAM), Asian, and African countries, all are part of the emerging and frontier markets. As well as improvements needed to progress patient access through legislative policies, market access and affordable drug costs in the region.

Sizing Up The Orphan Drug Landscape Worldwide

Rare diseases are manifested in patient populations representing a maximum of 6–8% (or 420 million to 560 million people) of the world’s population. More than 50% of rare diseases appear during adulthood and currently over 7000 rare diseases are listed in the world, with new rare diseases being described every week in medical literature (1). A total of 80% of rare diseases have been identified to be of genetic origins. Other rare diseases are the result of infections (bacterial or viral) and allergies, or they are due to degenerative and proliferative causes. Of this total, <1% is diagnosed and an even smaller number is adequately treated, 75% of the people affected are children and 30% of these children will not survive to see their 5th birthday (2).

Evidence has shown the incentives to successfully develop new pharmaceutical products to treat rare diseases have resulted in an increasing number of licensed orphan drug (ODs).

  1. Prior to 2010, 352 orphan drugs were approved in the US, helping an estimated 12 million Americans, compared to only 10 such drugs in the decade preceding the Orphan Drug Act (1983).
  2. 720 drugs have received orphan drug designation from the European Medicines Agency (EMA) and 63 designated orphan medicinal products have received marketing authorization in the EU.
  3. Data has shown that an average of 15 new orphan drugs are approved annually in the US and 10-12 new orphan drugs are approved annually in the EU (3).

One of the major milestones in orphan drug development is the adoption of legislation to facilitate the development and pathways for approval for novel medicines for the treatment of rare diseases. In the US and EU, a special regulatory authority, such as the Office of Orphan Products Development (OOPD) within the Food and Drug Administration (FDA) in the US and the Committee of Orphan Medicinal Products (COMP) within the European Medicines Agency (EMA) in the EU, were charged with the main task of examining applications for orphan drug designation and planning and regulating the development of ODs for rare diseases.

Although the cost of launching ODs for rare diseases is similar to that of launching drugs for common diseases, the low patient numbers increase the price of ODs. Because of the inverse proportion between patient numbers and prices, no alternative health technology exists for many ODs. This is, of course, one bottleneck in the path of orphan drug development.

Emerging countries, by definition, are those located in “less economically developed countries,” and frontier markets, also referred to as developing countries, are those usually with less robust economies with an underdeveloped industrial base and infrastructure. This includes those countries at greater risk of poor healthcare policy measures, legislative transparency and limited capital investment in its citizens. To manage this situation, many countries and regions around the world will need to offer economic incentives, 1. to make orphan drug development attractive, especially to small- and medium-size pharmaceutical companies; 2. to make it accessible for patients with effective legislative approval policies; 3. to improve healthcare infrastructure; and 4. to make it cost-effective (4).

Advocacy And Gaps For Patient Access In Latin America and Asia

Some Latin American (LATAM) and Asian countries adapted changes to support patient access and research in their regions with the formation of committees on rare diseases and the implementation of legislation, like those used by the OOPD and COMP. For example, in Mexico, Argentina, Chile and Columbia, the EU definition of rare diseases was integrated into the regulatory policy (5).

Brazil’s policy adopted a broader perspective regarding rare diseases, taking into consideration its own established Brazilian National Humanization Policy to include comprehensive and multidisciplinary healthcare for people with rare diseases.

However, not withstanding the progress made by these initiatives in the regions, there continues to be challenges to obtain formulary coverage for rare disease patients. This is of a significant concern not only for LATAM countries but also for those living within heterogeneous populations in countries like the Middle East and Africa (5-7).

In Asia, many countries have implemented rare disease policies to facilitate the review of orphan drugs consistent with the US and EU. Asian countries, including Singapore, Japan, Taiwan and Korea, have adopted standard of care policies to include: (1) defining rare diseases; (2) formulating supportive policy and measures for rare disease patients; (3) establishing rare diseases databases; and (4) requiring insurance framework to cover the expenses of rare disease treatment. Although, not all of Asia has progressed their policies as far as their neighboring jurisdictions.

China, which serves the world’s largest rare disease population, has taken some steps to advance their initiatives in rare disease legislation and just recently drafted a rare disease policy in 2017. Although this is a step in the right direction for patient access to treatment for the acute management of their rare disease. The policy is has not yet been approved and delay has impacted patient access of orphan drugs to patients effectively. Similarly, India had delayed to take action on the critical challenges with its rare disease policies, which do not go far enough with almost 7 million people suffering from rare diseases in the country. India has successfully implemented a rare disease policy enabling effective patient treatment access as of 2017.

China has the largest rare disease population

While China finalizes its rare disease initiative, they have established networks to temporarily support patient access, for example, the Chinese National Birth Defects Monitoring Network has monitored rare diseases, including relevant prevention, diagnosis and research, since 1986 in the country. However, these policies are only partial measures and surely not adequate enough to manage the demands of the country’s rare disease population need for orphan drug access.

Many frontier markets have also moved a little to further their orphan drug approval policies, although economic opportunities exist within Indonesia, and in some African countries, to progress this agenda.

A framework of initiatives is still incomplete with more that needs to be done with frontier country level advocacy partners and industry affiliates, to support clear regulations for the review and approval of ODs in the regions (5,6) The building blocks for collaboration require tenacious stakeholder engagement and policymaker initiatives. These pathways should be prioritized by companies looking to invest in these territories well before product launch and submission of orphan drug dossiers for approval and to ensure investment decisions are made to the benefit of patients in need of OD treatment.

Ratio of projected population in 2030 to estimated population in 2015 by the level of gross national income per capita in 2014, 183 countries or areas.

Graph 1

Insights Into Africa's Market Access Potential

As FDA approval for orphan products has increased, so has the interest in frontier countries’ access to innovative therapies (9). On average, Africa’s regulatory approvals can take up to 2 - 5 years from the time FDA approves an orphan drug. The review includes a WHO pre-qualification done on behalf of a consortium of African nations who are dependent on the WHO due to the lack of OD legislation to facilitate approval by their country’s medicines regulatory authorities (MRAs). The WHO acts as a surrogate on behalf of frontier countries without the infrastructure and resources to effectively review OD dossiers for commercial approval (8).

Graph 2

The process includes a sequential review by the consortium of African nations, which are grouped by region and are dependent on the WHO to negotiate pricing, manufacturing and scientific assessments prior to commercial approval. While bringing decades of regulatory experience to the table, the use of WHO authorities to review ODs also has its drawbacks.

The Framework for Collaboration with These Stakeholders and Policymakers Should Be Prioritized before Launch and Submission of Orphan Drugs for Approval

The WHO pre-qualification review delays access for African patients since African MRAs often wait for Western MRA decisions before commencing action; this puts drug application review decisions in the hands of regulators who have less experience in tropical disease products and patient epidemiology, and are not accountable for the needs and safety of patients in the country (6-9).

Many times, ODs lack the data to support the patient characteristics of those in underdeveloped countries. Western regulations may also omit data requirements vital for safe large-scale use in Africa (e.g., trials assessing the safe interaction of HIV and malaria). For example, when Rifapentine, a widely used and accepted standard of care therapy for tuberculosis (TB), was registered under US OD provisions, its commercial use was not accepted by many African countries, despite having met efficacy and safety standards in the US and EU. Due to the lack of HIV patients in clinical studies used for the approval in Western countries, the efficacy data submitted to the FDA was inadequate for use in African populations and was subsequently rejected since the design excluded HIV-positive patients. While HIV is less commonly associated with TB in the US, it represents up to 70% of TB patients in some sub-Saharan African countries, making the efficacy data submitted to the FDA inadequate for use in African populations (Graph 2). The relative risk-benefit ratio of ODs can be significantly different in Africa than in the West, where analysis against the same criteria can lead to completely different conclusions (6-8).

Many of these problems are heightened in the case of regulatory pathways, such as OD approval and FDA accelerated review, which allow clinical trials to be abridged or downsized in order to expedite registration of treatments for diseases that are rare and life-threatening in US and EU patient populations. However, they exclude important co- morbidities found in frontier country populations (such as malaria), resulting in a suboptimal benefit risk profile for approval in many of the respective frontier countries in Africa.

Even with Article 58, which was indoctrinated by the European Commission, the Committee for Medicinal Products for Human Use (CHMP) to assist underdeveloped countries while they implement improvement to their regulatory processes is underutilized. Efficiencies in approval of ODs for patient access for rare diseases have progressed slightly better than previously noted in 2015. The approval process continues to be inadequate when compared to the OD approval timelines reports in the US, Japan, Hong Kong and EU. Article 58 is not linked to Orphan Drug approval and does not formally expedite approval through WHO drug prequalification, although policies instigated have improved as of 2017 (6).

Despite the regulatory challenges, some policymakers in the region are working to remove these barriers, helping to better streamline regulatory process in the country. Kenya and Nigeria for example recently participated in regional harmonization of regulatory review and manufacturing standards in 2014, thereby revamping an antiquated system. However, no timeline for the implementation of these changes has been reported. In response to the drawbacks of both standard and orphan drug specific regulatory review, product developers have begun exploring alternatives. Some of these offer insights for drug registration in Africa and in the emerging and frontier markets in general.

A Networked Strategy Is Key

To further improve this system, companies should take the lead and collaborate with a multi-stakeholder network and partner to set up government and private stakeholder alliances to support universal regulatory, patient advocacy and policy legislation (Graph 3) to implement the following changes (5-8);

  • Policymakers, key stakeholders and biopharmaceutical companies must look to create alignment on the global definition of rare diseases.
  • Legislative alliances should be created to provide different authorization pathways for orphan drug dossier approvals.
  • Inclusion of endemic country experts in the pre-qualification/standard dossier reviews in the appropriate frontier countries, i.e. Africa. Introduction of WHO, CHMP and country health authorities’ simultaneous review.Integrate Article 58 policy and modify to include ODs with cost incentives for frontier markets.
  • Institute incentives for industry, such as tax credits (US) for R&D, fee waivers (US/EU), and market exclusivity (US/EU).
  • Create global alliances to provide early access/compassionate use programs of ODs. Establishment of country/bio-pharmaceutical-sponsor level funded coordination center to act as a central information resource, a patient/researcher support system, and a promoter of public awareness.
  • Establish timelines for implementation to be done simultaneous to OD commercial approval.
  • Establish a special technical subgroup for rare diseases with health technology assessment (HTA) processes, such as cost-effectiveness analysis/budgetary impact modeling.
  • Global initiative adopting a comprehensive approach, including education, prevention, diagnosis, care and treatment; in addition, support social, basic and clinical research.
  • Involve patient advocacy groups and local clinics in identifying patients, making genetic testing available, and providing resources for screening.

Biopharma companies should take the lead and collaborate with a multi-stakeholder network and partner to setup government and private stakeholder alliances

Specialized Solutions To Create Market Access Capabilities To Patient Care

The biopharmaceutical market access landscape has undergone a significant transition. Healthcare reforms and policy changes have globally redefined the functionalities of the changes in the way companies do business. The need to manage healthcare expenditures while still providing patients continued access to quality healthcare treatments has created a global effort to reset the biopharmaceutical business strategy, particularly in the emerging and frontier markets.

For many years R & D, sales and marketing has been the vehicle to commercial success. Market access, as defined in this article, is the process to ensure patients have expedited and continued access to the appropriate product at the right price.

It includes multi-functional stakeholders within the company, including supply, marketing, and medical and corporate functions. The use of standardized practice tools used across markets, emulating successful strategies, is a good starting point for creating optimized market access pathways. However, it cannot be determined to be the key tool to market success in these regions. Developing country market access tools will help a company determine their priorities for growth in each country within each market.

Clearly defining value propositions for customers, achieving optimal distribution,and continually striving to build sustainable operations and organizations are also important factors. For many companies, understanding market access in these regions is pivotal, due to the non-structured pathway for networking, which creates different challenges compared to the US and EU. The linear and sequential networking footholds are not accessible due to the differences in infrastructure and policy measures in the region; therefore, identifying external stakeholders is important.

  1. They should include the payer, who exercises the greatest degree of control over pricing and reimbursement for any new drug (13).
  2. Patients are also key stakeholders; they are more aware of treatment options and what can be expected to demand justification for the price charged for a drug. They are also concerned with the effectiveness and safety of the drug.
  3. Pharmacies are also key stakeholders who may influence drug access by controlling the availability of the product in the retail or out-of-pocket market. Understanding the dispensary behavior and securing shelf space should be optimized in these regions due to difficulty with some countries’ poor infrastructure in their regions.
  4. Advocacy groups are especially important in the rare disease diaspora.and exert their influence as stakeholders in market access proficiently. Advocacy partnerships are also important early in the concept phase to post-marketing approval of orphan drugs and have considerable influence on policy shaping in healthcare and indirectly in patient treatment guidance. In the emerging markets, these groups especially are growing and becoming more visible, proactively attending conferences and interacting with policymakers on behalf of the patients they represent.
  5. In Africa, the advocacy groups are in their nascent phases, working to gain a consistent foothold when networking with biopharmaceutical companies and policymakers on behalf of the rare disease patient population.
  6. Physicians and key opinion leaders (KOLs) have importance as well in market access, although in the emerging and frontier countries, their role has varied in the value chain. Their influence maybe offset with the importance of local community health clinics that play a vital role in rural areas where poor infrastructure and roadways prevent access to major hospitals and advanced care facilities.
Table 1

Overall, the decision-making landscape is complex in the emerging and frontier markets, with the involvement of different stakeholders adding more variability to the process if not engaged prior to the product launch in the country.

A critical component to ensuring market access in the region is for pharmaceutical companies to identify the right stakeholders who can be engaged as part of the drug approval and market access process, taking note to dedicate and establish market access functions on the local level.

Establishing a dedicated market access team with expertise in the regional payer system and referral process, patient, clinic and advocacy group engagement and pharmacy influence would be optimal. In addition, there is a need to orient and align the corporate functions of the company to the diverse set of stakeholders in the regions that are important in the commercialization process.

“The decision-making landscape is complex in the emerging and frontier markets, with the involvement of different stakeholders adding more variability to the process if not engaged prior to the product launch in the country.”

The cost burden for patients in the lower and lower-to-middle income levels of the emerging and frontier countries is a pivotal point of consideration, especially when implementing a successful strategy to provide patient access in a diverse market forecasted with positive but variable economic trends for the next 10 to 15 years (Graph 4) (13-15).

The population and economies by 2030 in these markets are projected to increase while the developed countries will stabilize (Graph 1). Therefore, the paucity of data critical to market access function (i.e., data on pricing and reimbursement, tenders, formularies) needs to be benchmarked to account for varied results (14, 15)

Implications for Orphan Drug Access In The Emerging & Developing Markets

Patient access to ODs for high risk and rare diseases is beneficial to patient populations only if it is both available in the country where they live and affordable. Comparative analysis of the regulation of rare diseases and ODs worldwide has shown that public authorities in the emerging and frontier countries need to act and make rare disease and OD access a public health priority.

Prioritizing legislation to align on a definition globally and including patient population characteristics and classification of rare diseases inclusive of worldwide populations is pertinent. The complexity of the regulatory pathways for approval in these markets requires improvement to reduce the inefficient timelines (15). It is necessary to institute robust and comprehensive legislation while working simultaneously with western regulatory authorities.

Biopharmaceutical companies play a key role as stakeholders in this process and should form alliances with policymakers to attain uniformed guidance consistent with the scientific integrity of the disease state and patient rights to effectively receive safe and beneficial rare disease OD access.

Assembling an appropriate support system to ensure access to ODs and international cooperation in research and development for all patient types inclusive of those across the world is essential. A pivotal point of networking for companies, advocacy groups, and policymakers is integral to this initiatives success.

Companies should also look to engage with public and private stakeholders to align on market access global initiatives to support pathways for patient access to ODs and universal legislation to sustain mutual benefit in the marketplace.

Moving forward, companies must recognize market access strategies in developed countries have been successful relying on a push strategy to ensure their commercial success. Although successful in wealthier countries, these strategies are unsupportive to today’s, and likely future, emerging and frontier market landscapes.

For market access, companies should also develop an organized group of functional regional experts to invest in building a structurally sound network of stakeholders both internal and external to facilitate successful market access strategies, while working to integrate the ethnic, economic, cultural and demographic characteristics of the country into their commercial strategy.

With the increase of middle-class incomes in these regions, cost of healthcare will change, making access to private health insurance an option to appropriate new drug therapies for some. In many regions, primarily the frontier countries, healthcare reimbursement does not exist for the majority of patients currently. Where it does exist in these regions, there are several restrictions, thus, access in these markets is largely a function of price, channels, marketing to doctors, and government stakeholders.14 Solution-based options will rely on risk/benefit patent negotiations and impactful regulatory reforms that could bring faster availability of ODs with limited impact on prices—a trade-off for better policy legislation for patient access to ODs living with rare diseases.

The therapeutic value assessment, pricing and reimbursement for ODs remains complex in these countries and will need to be managed to account for escalating healthcare costs worldwide, projected economic growth and country level policies, which are sometimes lacking in orphan product pricing and reimbursement strategies 16.

Given this context, key stakeholders, including biopharmaceutical companies and legislative authorities, must collaborate to establish mutually-agreed financial support for patients with rare diseases. The OD pricing environment remains in flux as payers, patients, policymakers and in-country stakeholders will be looking to manage escalating costs for ODs. Although rare disease populations are by definition the smallest, they represent big per-patient outlays, and insurers will be looking carefully at new tools to manage and reduce cost growth as more and more orphan drugs launch, thereby requiring ongoing negotiations with pharmaceutical companies who will look to find mutual benefits to provide global patient and market access for ODs while working to ensure safeguards for product patent protect in the regions.

About the author(s) Dawn Orozco is a Principal Partner & President of Life Science in QCR’s New York office. The authors wish to thank J.Martin for her contributions to this report.


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