Lead Author: Zakir Thomas
Organization: The author is an independent researcher
Country: India


Goal 3 of SDG will be met only if new drugs can be made available for neglected diseases. The absence of market forces, lack of clinical trial infrastructure and unclear regulatory pathways dissuade the for-profit pharmaceutical enterprises from investing in expensive clinical trials. The global attention to this problem since the year 2000 has resulted in a robust pipeline. But this pipeline is not getting translated into promising therapies as the industry is not investing in the development phase.

The current policy environment is IP driven and market oriented. They do not drive innovation in neglected diseases. The solution proposed is a public policy approach which de-risk the development phase and facilitate regulatory clearances. The proposal is based on the evidence of the current approach of the industry on TB drugs. The industry can be incentivised to take up drug development by:
i. Creation of a global fund to de-risk of clinical trials
ii. An Intellectual Property (IP) policy that facilitates access and affordability
iii. Build up clinical trial infrastructure and regulatory capacity in developed countries through a globally coordinated action.

The solution proposes creation of a global fund to support clinical trials in developing countries. The originator company will retain its IP rights in the developed world. They will grant a non-exclusive license to a common IP pool for the rest of the world in lieu of accessing the fund to conduct clinical trials. This licensing model is voluntary and functions like a patent pool, but the incentive is access to the fund. The generic industry business may then access this pool and manufacture drugs after paying a royalty.

The solution also proposes a global monitoring mechanism to ensure new drugs for neglected diseases and an active role for PDPs to ensure development of trial infrastructure.


The Problem
There is a gap in translating the existing advances in the early stage drug discovery in neglected diseases to drugs accessible to patients who need it most. There are no appropriate policy measures at the development phase to facilitate such translation.

Background of the Problem
Neglected diseases disproportionately affect developing countries, causing significant morbidity and mortality in already disadvantaged populations – more than six million people die each year due to neglected diseases such as tuberculosis (TB), malaria and others, classified as Type II and Type III diseases in WHO Classification.

The neglected diseases problem arises due to the absence of market forces. These diseases are mostly restricted to countries in the tropical regions and that too predominantly among the poor patients. The market is not big enough to be commercially attractive, though the number of patients are large. Therefore, there is insufficient market pull to attract investment by private industry to invest in the risky and expensive development phase. In this background the advances made in the recent years may not translate from bench to bed.

Experts point to the urgent need for new drugs for TB, Malaria and other neglected diseases. If new drugs are not available to the disease burden countries, Goal 3 of SDG will not be met.

The Silver Line – A Robust Early Stage Pipeline
There has been increased attention on the neglected diseases problem since 2000 due to the efforts put in by WHO and others. This led increased industry attention and to the setting up of product development partnerships (PDP) like Global Alliance on Tuberculosis (TB Alliance), Medicines for Malaria Venture (MMV), Drugs for Neglected Diseases Initiative (DnDI) and others. This increased global attention led to increased public and philanthropic funding as evidenced by the G Finder Surveys that are conducted every year .

The increased global engagement on neglected diseases has translated into a robust early stage pipeline of potential drug candidates. The G Finder Survey of Product Pipelines has reported that there are 485 new products in the pipeline for 34 neglected diseases as of October 2015 . The survey reported 117 new products in the pipeline for TB, 124 for Malaria, 84 for HIV and so on. This is hailed as an unrecognised revolution in global health .

The constraint that limits the optimism on a robust early stage pipeline is the limited number of actual candidates that moves through the clinical trials.
There are no mechanisms or policies that incentivise the conduct of clinical trials and to get regulatory approvals for the neglected diseases in the developing countries. The industry is the major player at the translational phase of drug discovery. Ironically, there are policy mechanisms in the developed world where the impact of the disease is relatively less, like Orphan Drug Legislation and issue of Priority Review Voucher (PRV) of United States Food and Drug Administration (FDA), which incentivises the industry. No such mechanism exists in the developing world.

The regulators in the developed world seem to be more abreast of the need of new drugs for neglected diseases than their counterparts in developing world. For example, US FDA and EMA has approved conditional marketing of two TB drugs to the needy TB patients while Phase III trials are ongoing. The industry sponsoring these drugs has not approached the developing world regulators for permission to conduct clinical trials. Therefore, while the drugs are available to the developed world markets for the diseases that predominantly affect the developing world, the drugs are not available in those markets. No clear policies are available to get new drugs to the market which need them most.

TB is an illustrative example. It is estimated to be having the largest market among the neglected diseases and thus provides the best case scenario in terms of market. The following examples show how the existing policy incoherence limits the access to drugs for the patients in the developing countries.

There are a few new drugs that are undergoing clinical trials. The two most advanced are Janssen Pharmaceutical’s Bedaquiline (tradename Sirturo) and Otsuka Pharmaceutical’s Delamanid (tradename Deltyba). FDA has approved conditional marketing of Bedaquiline based on Phase IIb results, while Phase III trials are ongoing. EMA has approved the conditional marketing of Otsuka’s Delamanid based on Phase IIb results; its Phase III trials are still ongoing. WHO has issued guidelines for their use. These drugs are thus available for patients in US and EU and not elsewhere.

Sutezolid, developed by Pfizer remained dormant in the hands of Pfizer for a long time and in 2013, it granted Sequalla the license to this drug. Sequalla has not yet announced any plans for trials in the developing world, while there are reports of it raising funds for further clinical trials in US.

Another example is Astra Zeneca’s AZD 5847. Astra Zeneca closed down its R&D facility dedicated to neglected diseases which was at Bangalore in India, in 2014. It pursued the Phase IIa clinical trials of AZD 5847 with funds from US National Institute of Allergy and Infectious Diseases (NIAID).

TB Alliance has ventured into the developing world and is testing new TB drug combinations in South Africa, Brazil and India. Being a non-profit and a PDP, TB Alliance is not purely driven by market forces and has therefore taken risks. But they are also dependent on philanthropic and public funds for trials.

This show that on their own the for-profit pharmaceutical companies are not venturing into the developing world. The obvious conclusion is that unless supportive measures at the translational phase are introduced, the pipeline developed for neglected diseases will not translate to drugs for the patients in the developing countries.

The Policy Vacuum
Goal 3 of SDG will not be met unless drugs are pushed into the developing world market. This requires policy tools that support access to new drugs in market failure situations. The policy tool has to address the following issues:
i. Clinical trials are risky and expensive. Lack of market forces dissuade industry from taking the risk at its own time and effort.
ii. Capacity to conduct clinical trials for neglected diseases (which are mostly infectious in nature) are not available in most of the developing world. Capacity will have to be created both in terms of physical infrastructure and manpower competence to conduct complex clinical trials.
This will require globally coordinated action. Some effort has been made by TB Alliance to identify the gaps in clinical trial capability across the globe for TB . Such activity will have to be undertaken for all diseases and corrective measures will have to be undertaken at a global level. The industry will not wade into this space and create such competence.
iii. Regulatory Capacity Building: The regulators in many developing world and most least developing countries are inexperienced to handle complex clinical trial permission requests. Such regulatory capacity will have to be built and in regions with similar genetic composition, regional trials could be contemplated with strong post market surveillance mechanism.
iv. Availability of Drugs: The experience of TB drugs Bedaquiline and Delamanid are indicative that the pharmaceutical industry will not, on its own, take proactive steps to take the drug to the developing world.
The currently available public policy tool for pharmaceutical drug development are
i. Patent based exclusivity which has demonstrated its effectiveness in market, but not in market failure cases
ii. Public and philanthropic fund support for early stage drug discovery
iii. Limited financial support for translational activities as provided by NIH
iv. Market driven incentives like PRV of FDA

These do not address the problem of supporting the development phase in market failure cases.
The provision public funds for early stage research to promote innovation helps both market driven and market failure cases. There is evidence to show that pharmaceutical companies are moving to a business model where early stage discovery is mostly done in universities and research institutions. The industry in-licenses promising candidates and focus on development phase, translating the promising innovations to drugs by taking it through the pre-clinical and clinical trials. There is market pull in the development phase and the industry takes the risk in diseases with market.

There are public policy tools which functions as a push mechanism at the development phase put in place by US and EU in market failure cases such as the Orphan Drug legislation and PRV to which industry has positively responded to. The experience of TB drugs discussed above show that these might enable provision of drugs in the markets where these are operating but not in developing world.

Policies are required to overcome three major hurdles.
i. Conduct of the expensive and risky clinical trials
ii. Underprepared Regulatory Agencies
iii. Ensuring Access and Affordability

Framework of the Solution
The best mechanism to ensure access and affordability is a competitive market. The market driven generic drug industry business model meets this challenge. Therefore, if policies can be framed to bring the generic drug industry on board after the first two hurdles are crossed, market forces can arrive at the right price. The competition in the market could push access as competing firms look for newer markets. This measure could also help generic manufacturing divisions of the research based pharmaceutical companies.

What is required is a public policy tool that combines the de-risking of clinical trials and facilitate regulatory clearances.

Solution Proposed: De-Risk + Push (Regulatory Facilitation) + Market Pull
The solution proposed is a public policy approach which de-risk the development phase and a globally coordinated approach to facilitate regulatory decision making. It has to have the following components
i. Public Fund to de-risk of clinical trials
ii. An Intellectual Property (IP) policy that ensures access and affordability
iii. Build up clinical trial infrastructure and regulatory capacity in developed countries through a globally coordinated action.
iv. Generic industry business model to facilitate market competition based delivery.
This solution presupposes that the current policy approaches and commitments that has enriched the neglected diseases pipeline will continue to provide enough candidates for development.

De-Risk Development through a Fund
De-risking of clinical trials can be implemented by creating a global fund - Fund for Neglected Diseases Drug Development (the Fund) - to conduct clinical trials for neglected diseases in the developing countries.

There are working models of such fund promoting innovation in agricultural sector like Consultative Group on International Agricultural Research (CGIAR). The CGIAR Fund is administered by the World Bank. The Global Fund to Fight TB, AIDS and Malaria is an existing mechanism which support DOTS treatment of neglected diseases. Their mandate may be expanded to manage the Fund.

Such fund should be available for any industry or academic or other institutions to tap into if they propose to conduct clinical trials on a neglected diseases candidate which has been approved after review by the fund’s scientific reviewers.
Conditional Access to the Fund

The fund should be available for conducting the development process in the developed and developing markets. The condition for accessing the fund should be adherence to the IP policy detailed below to ensure access and affordability in developing world markets.

IP Policy
The IP Policy of this solution is derived from the existing patenting approach of the pharmaceutical industry with regard to neglected diseases.

TB is taken as the illustrative example to study the patent protection approach of the industry, as it has the largest market among the neglected disease. The industry approach of two new drugs, Bedaquiline of Janssen Pharma and Delamanid of Otsuka Pharmaceuticals is below:
i. In the case of Bedaquilin, the patent for the compound has been filed in all developed countries and in 32 high burden TB countries, including African countries like Central African Republic, Chad and 16 others . But the firm is currently marketing only in US and EU.
ii. In the case of Delamanid, the information available is limited on whether the patent covers all high burden TB countries . However, patent has been granted in India, China and Russia and the international patent application has entered national phase in Egypt, Indonesia, Pakistan, South Africa, Ukraine and Viet Nam. But, Otsuka has registered Delamanid in only four countries (Germany, Japan, South Korea, and the United Kingdom) .

Both the companies have been criticised by activists for their not registering the compounds in high burden countries and also on the high price of the drug.
The above pattern show that the industry’s main focus is developed market and they are reluctant to enter other markets.

Based on the industry practise, a tiered IP approach is proposed:
Tier I. Developed Markets: No change from the current IP based approach. The industry will have exclusive rights and will enjoy the incentives of Orphan Drug legislations, PRV and other incentives of the market.

Tier II: Countries where Patent has been filed: Industry will be required to make the patent as non-exclusive and non-discriminatory in exchange of the access to the Fund to conduct clinical trials. The data of the clinical trial will be made open for use of regulators anywhere. Generic industry which meets the quality standards may be allowed to manufacture the drug. They will be required give a pre-fixed royalty on sales as decided to the originator industry.
The implementation of this requires industry to submit their patents to a common pool for access by generic industry for sale in developing world. This can be done through the Medicines Patent Pool, already established by the United Nations.

Tier III: Rest of the world where patent has not been filed, the originator industry will not receive any royalty. The countries will have access to the drugs as they benefit from the generic competition arising out of the voluntary license granted in Tier II.

Licensing Model:
The above IP approach is voluntary subject to the access to funds for conduct of clinical trials based on the following licensing model:
i. They retain exclusive rights in the developed world markets.
ii. For the developing world, the drug after approval by regulatory authorities, will be licensed to a pool for use in developing world markets. For manufacturing, the generic drug generic industry may access the pool in a non-exclusive and non-discriminatory manner, subject to them meeting quality restrictions. Thus a voluntary non-exclusive license is provided by the originator to the developing world markets through the pool.
iii. The data from the clinical trials would be kept in the public domain as open data.

Push Mechanisms:
Regulatory Push
The facilitation of appropriate regulatory environment in the developing world for neglected diseases has two components:
i. Create clinical trial infrastructure and develop clinical research competence among physicians and support staff
ii. Regulatory Capacity building for conduct of complex clinical trials.
This will require access to funds and willing partners. The Fund should have a component to develop clinical trial and regulatory capacity. PDPs may be entrusted the responsibility of creating the above capacities by accessing the Fund.

Reorient PDPs
PDPs have done a commendable job in the discovery and development phases. Currently PDPs are focussing on their own internal drug candidates, working more or less like a pharmaceutical company. They could be reoriented to a more outward looking facilitator and set up capacities discussed above. They may be allowed to tap into the Fund to support their activities.
They PDPs should look at the progress of various candidates and should be charged with the responsibility of ensuring that the drugs are available in all countries. In case the industry is not pursuing any candidates in the developing world markets, the PDPs should step in to get the trials and regulatory clearances carried out by accessing the patent pool.

Market Pull
The last mile of ensuring access is through the market based competition by the generic industry. The industry gets license from the Pool in a non-exclusive and non-discriminatory manner creating multiple players for the market. Generic competition will create a market pull that will facilitate access and affordability.

Set up an International Monitoring Authority
For each neglected disease an international mechanism should be established and charged with responsibility to take the pipeline forward. This is necessary if SDG Goal 3 has to be met in just 14 years. This body has to play a coordinating role among various agencies to identify bottlenecks and bridge the gaps.

The market failure creates a big impediment in neglected diseases drug development. The available evidence in TB points to this complexity. New policies and strategies suggested above are required to bridge the loss in translation. Clearing the regulatory hindrances and setting up clinical trial capabilities across the world will help the pharmaceutical industry in general and in facilitating future drug innovations.

Bibliography and References

Assessment of global capacity to conduct tuberculosis drug development trials: do we have what it takes?
C. van Niekerk, A.Ginsberg; INT J TUBERC LUNG DIS 13(11):1367–1372 http://www.tballiance.org/newscenter/research_papers/IJTLD_Nov2009_Assessemet_of_global_capacity_to_conduct_TB_drug_development_trials.pdf