The Stakeholders Involved in the Neurodegenerative Disease Drug Development Process

Introduction

Neurodegenerative diseases (NDDs) are a class of disorders that cause the progressive loss of structure or function of neurons, leading to declines in cognitive and physical abilities. Drug discovery and development for these diseases is a complex, multi-stakeholder process involving a variety of entities across the United States, including government agencies, businesses, research institutions, academic institutions, and non-profit organizations. These stakeholders interact with each other at various stages of the non-linear cycle of drug development, which typically involves a range of activities including pre-clinical research, clinical trials, regulatory approval, and commercialization.

Given the complexity of this process and the challenges involved in developing effective treatments for NDDs, it is important to better understand the role of different stakeholders and the potential barriers they face. This blog aims to provide a deeper examination of the various stakeholders involved in NDD drug discovery and development, and to offer an initial hypothesis on key challenges that may be contributing to the lack of disease-altering therapies for these conditions.

Drug development and discovery process

The drug development and discovery process is a complex and multi-step process that involves many different stages and activities.

Figure 1 depicts the various stages of the drug discovery process schematically, showing the progression from basic research to pre-clinical studies, clinical trials, and review and approval.

Basic Research:

The drug development and discovery process begins with basic research, which involves activities such as molecular biology, pathophysiology identification, and genetics mapping. These studies aim to gain a better understanding of the underlying biology of a particular disease or condition, which can provide important insights into potential therapeutic targets and strategies.

Research and Development (R&D):

Once this basic research is completed, the next phase of the process is research and development (R&D), which involves activities such as target identification, compound screening, and lead identification and optimization. These activities aim to identify potential therapeutic compounds and evaluate their potential effectiveness in treating a particular disease or condition.

Pre-Clinical Studies:

The third phase of the drug development process is pre-clinical studies, which involve in-vitro and in-vivo efficacy studies, proof of concept and mechanism of action studies, and IND-enabling studies. These studies aim to further evaluate the safety and effectiveness of potential therapeutic compounds in animal models, and to gather the necessary data and information to support the subsequent clinical trials in humans.

Clinical Trials:

The fourth phase of the process is clinical trials, which involve testing potential therapeutic compounds in humans to assess their safety and efficacy. Clinical trials typically progress through three phases: Phase I, which involves a small number of healthy volunteers or patients; Phase II, which involves a larger number of patients with the target condition; and Phase III, which involves a large number of patients and is designed to confirm the efficacy and safety of the therapeutic compound.

Review and Approval:

Once a potential therapeutic compound has successfully completed clinical trials, the final phase of the drug development process is review and approval. This phase involves the submission of a New Drug Application (NDA) to the Food and Drug Administration (FDA), which evaluates the safety and efficacy of the compound based on the data and information gathered during the clinical trials. If the FDA approves the NDA, the compound can be manufactured and made available to patients. However, the process does not end here, as post-release monitoring is also an important part of the process, to ensure that the therapeutic compound continues to be safe and effective in the long term.

Cross-Cutting Activities:

In addition to these main phases of the drug development process, there are also other cross-cutting activities that are important for the success of the process. These include activities such as funding, portfolio and risk management, and patient advocacy and awareness. These activities aim to support the development and discovery of new therapeutic compounds and ensure that they are made available to patients in a timely and effective manner.

Key Stakeholders

The drug discovery and development process for neurodegenerative diseases (NDDs) involves a wide range of stakeholders from government, business, research, and non-profit sectors. These stakeholders play a critical role in advancing the development of new treatments for NDDs and ensuring that they are made available to patients in a timely and effective manner.

Figure 2 provides a table highlighting the various stakeholders involved in the drug discovery process for neurodegenerative diseases.

Government

One key stakeholder on the government side is the National Institute of Health (NIH), which is one of the largest funders of NDD research in the United States. The NIH houses three important institutes that conduct and support NDD research, including the National Institute of Aging (NIA), National Institute of Neuro Disorders and Stroke (NINDS), and National Institute of Mental Health (NIMH). The Department of Defense (DoD) is another leading funder of research programs in this area. Additionally, some states support NDD-related research. For e.g. California funds the California Alzheimer's Disease Centers.

Regulatory authorities, such as the Food and Drug Administration (FDA), are also key stakeholders in the drug discovery process. The FDA is responsible for reviewing drug applications and assessing risks and benefits before approving new treatments for use.

Business

On the business side, pharmaceutical and biotech companies are the most important stakeholders in the NDD drug discovery process. These companies fund research and development efforts and clinical trials, often in collaboration with other stakeholders such as the NIH. Biotech start-ups, which are typically funded by venture capital, are also leading research on niche therapeutic areas and treatment development for NDDs.

Research

Research organizations, such as research centers focused on NDDs, are also key stakeholders in the drug discovery process. These centers provide resources and opportunities to participate in research and develop new ways to improve care for patients. This category also includes research centers housed in hospitals and medical institutes, such as the Mass General Institute for Neurodegenerative Disease (MIND) at Massachusetts General Hospital. Leading academic institutes also have centers focused on NDD research, such as the Institute of Neurodegenerative Diseases at UC San Francisco, the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania, and the Alzheimer's Disease Research Center at the Mayo Clinic.

Investors

Investors, such as venture capital firms, private equity firms, and private debt providers, also play a critical role in the drug discovery process for NDDs. These investors provide critical funding to support the research and development of new treatments for NDDs, particularly at the early stages of the process when the risks are higher and the potential returns are uncertain. In addition to providing funding, investors also often bring expertise and experience in the pharmaceutical and biotech industries, which can help to support the development and commercialization of new treatments.

In addition to private investors, public markets also play a role in the drug discovery process for NDDs. Publicly traded pharmaceutical and biotech companies may raise funds through the sale of stocks or bonds, which can be used to support the research and development of new treatments. Additionally, the stock market can provide a useful measure of the potential value of new treatments, which can help to guide the direction of research and development efforts.

Overall, investors play a critical role in the drug discovery process for NDDs, providing the necessary funding and expertise to support the development of new treatments and bringing them to market. However, returns on these investments may change from different stages of drug discovery. We will discuss this in a later section.

Patient advocacy groups

Patient advocacy groups are another important stakeholder in the drug discovery process for NDDs. These groups represent the interests of patients and their families, and work to ensure that their needs and concerns are heard and addressed. Patient advocacy groups can play a fundamental role in advancing the development of new treatments for NDDs, as they can help to raise awareness about the importance of research and development efforts, and provide a powerful voice in pushing for progress. The Alzheimer Association remains one of the largest non-corporate funders of AD focussed research.

In addition to raising awareness and advocating for patients, patient advocacy groups can also provide important support and resources to patients and their families. This can include providing information about available treatments and clinical trials, as well as support for accessing care and managing the challenges of living with an NDD.

Philanthropic organizations

Philanthropic organizations play a critical role in the drug discovery process for NDDs. These organizations mobilize financial commitments and fill gaps in NDD drug development by providing support for early-phase clinical studies and research. For example, the Alzheimer's Drug Discovery Foundation (ADDF) has mobilized commitments worth $50 million from partners including Bill Gates, Leonard A. Lauder, the Dolby family, the Charles and Helen Schwab Foundation, and additional partners including Jeff Bezos and MacKenzie Scott.

Stakeholder mapping

The above stakeholders participate in the NDD drug development process across various stages.

Figure 3 provides a table highlighting the role that various stakeholders play in the drug discovery process for neurodegenerative diseases.

Federal agencies play a crucial role in the development of treatments for neurodegenerative diseases (NDDs) by supporting and funding basic research and clinical trials. While the private sector often focuses on later stage clinical trials with a higher likelihood of success, early stage research is often considered too risky and therefore attracts little private investment. Public-private partnerships (PPPs) have emerged as a new financial model to spread the costs and risks of trials across all stages of drug development. One example of a PPP is the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), which focuses on a rare form of Alzheimer's disease that affects younger people. DIAN-TU is led by the Washington University School of Medicine in St. Louis and funded by a consortium of organizations including the University of Washington, the Alzheimer's Association, and the National Institute on Aging, as well as pharmaceutical companies such as Biogen, Eisai, Janssen, Eli Lilly, and Roche/Genentech.

While the development of NDD treatments can be financially rewarding if successful, the high risk involved means that venture capital is often limited to supporting the development of new drug and treatment ideas by biotech companies. Research organizations and academic medical centers (AMCs) are at the forefront of innovation in the NDD field, providing support for research that can lead to the development of new drugs and treatments. AMCs are typically funded by federal agencies such as the National Institutes of Health (NIH), or occasionally by industry players.

Advocacy organizations also play a crucial role in supporting patients and their families, advocating for greater investment in NDD research, and collaborating with federal and private stakeholders to provide funding for research. Philanthropists often contribute to advocacy organizations or research centers to support high-risk projects and fill funding gaps.

It is important to note that stakeholders may be involved in different stages of the drug development process and often interact with each other. For example, the Food and Drug Administration (FDA) review committee may include experts and representatives from pharmaceutical companies and government agencies such as the NIH.

Early analysis: Gaps in stakeholder participation and accountability

Early analysis raises questions on some of the several challenges in the neurodegenerative disease (NDD) drug development process that have hindered progress in the field and the development of effective treatments and cures for NDDs. These challenges may include a deficiency of basic research, a lack of market accountability for drug approval and value, and a lack of innovative financial vehicles.

Not Enough or Inefficient Basic Research?

One major challenge in NDD drug development is the deficiency of basic research. Despite millions of dollars being spent on clinical trials each year, a lack of investment in understanding the underlying causes of NDDs has limited the progress made in this field. It is evident that a greater understanding of the underlying mechanisms and complexities of diseases would enhance the effectiveness of drug discovery and development. Such knowledge would enable researchers to identify specific targets for drug intervention and design treatments that are more targeted and effective. A deeper understanding of disease pathways would also facilitate the development of personalized medicine, allowing for the creation of treatments tailored to individual patients' needs. Overall, investing in basic research to increase our understanding of diseases would be a valuable step towards improving the success rate and efficiency of drug discovery and development.

One reason for this deficiency may be that return on investment is higher at later stages of drug development, when the chances of capitalizing on research with drug sales is higher. This incentivizes stakeholders, particularly private players, to focus their resources on these stages. We must, therefore, find ways to expand and incentivize basic research in NDDs. Lack of investment and diversity in basic research has led to a shortage of resources for valuable research that could support the development of more effective drugs and treatments.

Seeking the lowest approval bar for the highest price?

The market rewards companies for high revenues rather than the creation of effective drugs. This has two major impacts on the NDD drug development process. First, drug developers often tailor their drug discovery endpoints to meet the minimum requirements for approval, allowing them to sell their drugs. Second, companies seek to price their drugs as high as possible to recoup the significant investment required for drug development, which is inherently risky. Patients, who have few alternative treatments available, are forced to pay these high prices for suboptimal drugs. This may create a cycle in which not entirely effective drugs are approved and sold at exorbitant prices.

Need for new economics?

Finally, the lack of innovative financial vehicles to support NDD drug development has hindered progress in this field. The high costs associated with the high-risk NDD drug discovery compared to the potential return have discouraged an elevated number of private players from investing in this area. Why should one focus their resources for a low chance of economic success? Many sophisticated biotech investors state that “you should never invest above the neck”, and thus spread their bets on cardiovascular, viral or metabolic diseases that have better known pathophysiologies and lower failure risks.

This has slowed down the process of drug development and discovery. While public-private partnerships (PPPs) have emerged as an alternative way to spread risk across multiple entities, more innovation is needed to develop financial models that can help de-risk the NDD drug development process and accommodate the high failure rate. This may include creating classes of tax-free investments, government matched investment programs, or policies to pool resources in more efficient fiscal ways.

Looking Ahead

In future research, we will aim to diagnose the interactions between various stakeholders in the NDD drug development process and explore how these stakeholders are currently incentivized to participate at different stages of drug development. This analysis will aim to identify gaps and challenges in the existing process and highlight areas where technology and policy interventions could create a more holistic and collaborative approach that incentivizes stakeholders to participate and invest in impactful research.

Our research will focus on understanding how stakeholders such as federal agencies, pharmaceutical companies, research organizations, and advocacy groups interact with each other during the NDD drug development process. By examining the incentives that drive stakeholder participation and the challenges they face, we can identify opportunities for improvement and suggest potential solutions.

In the next few months, we will conduct interviews and surveys to identify opportunities for technology and policy intervention that can create a more collaborative and efficient NDD drug development process that incentivizes stakeholders to invest in research and development. By addressing the gaps and challenges in the existing system, suggesting use cases for existing technology, and creating the right policies, we may be able to accelerate progress towards effective treatments and cures for NDDs.