I. Background
         Congress enacted the 21st Century Cures Act in 2016 to expand mechanisms for measuring the clinical benefit of therapeutic products in real patients using Real World Evidence (RWE).  Stringent enrollment criteria for clinical trials of New Chemical Entities (NCE’s) in the New Drug Application (NDA) process, unfortunately, routinely screen out patients most likely to need and use the drugs.  Post approval, Real World physicians are forced to extrapolate from the clinical trial data in optimal patients to estimate the doses for their Real World patients, which is a crude calculation at best.  Even payers are now imposing more hurdles to reimbursement.  They want data to show that drugs work in the lives that they insure.  Expanding beyond the laboratory-like conditions in optimal patients with pragmatic research is necessary to bridge the divide between clinical research and medical care that helps drive up health care costs.

         As FDA noted in JAMA this year, pragmatic research will help provide information needed to inform diagnostic and therapeutic strategies that can answer questions about comparative effectiveness, optimal sequences of treatment and more that are becoming more important to payers.  Optimizing therapy for these patients will improve their health, productivity and reduce health care costs.  As the Commissioner Rob Califf of Food and Drugs has repeatedly stated, access to, and participation in, clinical trials increase the health care to patients.  Everyone can benefit.
 
II. The Fertile Regulatory Environment  
         Cures and the @ dozen subsequent FDA/CDER guidelines recognize that the foundation for growth for pragmatic research is trials on drugs with established histories and known safety profiles such as already approved drugs, e.g.  supplements to NCEs, but more realistically §505(b)(2)’s.  Most importantly, CDER is poised to work with industry to accelerate this research. 

         New delivery systems can fine tune the delivery of drugs.  They can also reduce the administrative costs for delivery, e.g.  nursing time.  Of equal importance is the explosion of complementary technologies to target drug therapy.  Technologies to identify and measure the progress of genetic and genomic indications of diseases, to assess patients for identification of disease and to gather medical observations are growing often with the aid of Artificial Intelligence.  All are driving correlative research.  These technologies help measure “clinical benefit.”   Clinical benefit has evolved as the contemporary interpretation of substantial evidence of effectiveness. 

         These technological advances for measuring clinical benefit thus offer opportunities for new indications, patents, market exclusivities, and reimbursement.  In conjunction with the Real-World guidelines, CDER has recognized these developments and created the Center for Clinical Trial Innovation to serve as a center to improve, coordinate, and expand these opportunities.  The stated aim is to replicate the nurturing environment created by the Oncology Center of Excellence during the past several decades.  These efforts focus on already approved drugs, e.g.  505(b)(2)’s.
         Thus, the table is set for increasing the convergence of clinical development and improved medical care in an environment that can generate analogous investment returns and success that has occurred in the field of oncology.  Open, consistent innovative regulatory pathways provide roadmaps for approvals.  Approvals attract capital. 
 
III. The Accessing the Target Population for Practical Trials
a) Recognizing the Potential Target Population
         Over 58 million people are over 65 in the United States and that number is expected to grow to over 82 million in 25 years.  Medicare covers over 50 million people through its Part D outpatient drug benefit.  90 % take at least one Rx drug daily.  80% take two or more.  36% take at least 4 or more.  Medicaid covers over 90 million people.  An ever-increasing percentage of this population is unhealthy.  In addition, the number of unhealthy years in the lives of this population segment is increasing.  Even a worst-case assumption that this population takes the at least 2 Rx drugs daily that the average American takes, shows the large numbers.  These patients disproportionately increase the costs of healthcare for all.  They tend to fall in the lower brackets of the Social Determinants of Health, and they are also disproportionately in rural and inner-city populations.  Providing health care to these people is often challenging due to their infirmities, lack of mobility, lack of support, and lack of transportation.  Sadly, this population segment distrusts most institutions. 

         But these patients have insurance coverage and are easily located.  End points exist for measuring clinical benefits to most therapies for these patients.  Thus, they offer large and potentially remunerative opportunities for all sections of new, improved product development- from drug and technology companies seeking approvals to payers seeking to reduce their pharma spend.

b) Recruitment and Retention
     Most pragmatic trials will be Phase 3 clinical trials.  The purported costs for these trials are $41,000/patient.  Recruiting and retaining patients are 2 major limiting steps in conducting these trials.  Here we know where these patients are, and we know a fair amount about their medical histories- two factors that reduce the costs.  Recent history provides us with examples of how to tap into this group. 

c) Trusted Intermediaries
         Building trust with these patients is STEP ONE.  The Covid vaccination program showed how to approach the most difficult and skeptical of these patients.  Local civic and health care providers are trusted and relied upon.  In inner cities and rural communities collaborating with these leaders led to high vaccinations rates.  Just as all politics are local, trusted health care begins locally.  We now know these local health care leaders and know that they can marshal patients.  University-affiliated health care providers were also perceived as trustworthy, and they also can assemble patients. 

         These channels/sites invariably involve teams of public health professionals to provide health care with a spectrum of backgrounds: nurses, nurse practitioners, pharmacists, social workers, clergy, and administrative staff in addition to primary care physicians.  The patients are already taking approved formulations, and the healthcare team is familiar with the drugs and the difficulties these patients face.  Importantly, they understand the practical clinical benefits that these patients need.  These channels are identifiable and connectable.  This transparent teamwork corresponds to the reality of well-run clinical trial sites.

IV. Identifying and Building the Real-World Sites
a) Patients are the coin of the Realm 
      Training and equipping a site to conduct a clinical trial is a large expense for a one- off study.  In many settings the metrics of medical practice do not reward participation in clinical trials.  But a one -site / one -study view ignores the biggest asset of this population segment: patients on multiple approved therapies that need a lot of health care.  The coin of the realm in clinical trials is patients.  Sponsors realistically go to major cancer and academic medical centers because they have patients which reduces the cost of recruitment and retention.  They also may be parts of existing networks which can reduce costs.

b) Historical perspective
     A look at historical precedent and existing networks offers Real World guidance to gather Real World practical evidence to improve medical care.  One segment of the Contract Research Organization (CRO) industry grew by developing sites for studies in areas that had patient populations with specific diseases, e.g.  asthma, pain.  Another built a cadre of healthy young males for bioavailability studies These were primarily in urban areas.  But others were near college campuses or military bases.  Patients were enticed to participate with financial as well as personal well-being incentives.  Further the ability to participate in the studies attracted patients.  Access to the sites was relatively simple.  The recruiting and retention issues were minimized.  The ability to conduct trials rapidly attracted other sponsors.

         The breadth of health care problems means that most of these areas have large pools of potential clinical trials subjects.  Technological advances and Real-World data development offer mechanisms for conducting and gathering information in even the most remote areas.  E.g.  Cell phone coverage far exceeds high speed internet coverage, and providing these assets to patients can facilitate their participation in clinical trials.  EKG’s, blood pressure, and aerosol monitoring are routinely available on cell phones and remotely.  Wireless monitoring of glucose levels is abundant.  Almost every member of the health care team faces annual Continuing Education requirements.  CE programs focusing on clinical trial participation would be welcomed by most who struggle to get meaningful CE.

c) Tapping into Existing Networks         
      Many networks already exist.  NCI, e.g., has over 60 clinical trials networks.  Project Warp Speed was able to build a clinical trial network using components of these networks.  Congress has asked NCI to consider how to improve this vast network before adding more.  Eyes are watching.  Because of the geographic overlap of cancer incidence to the other predominant diseases of the population, opportunities exist to absorb elements of these networks into new sites or hubs for clinical trials.

d) Potential New Allies
    Current healthcare systems, even those that are University affiliated, are in competition for patients /insureds.  Some are also payers.  Some are expanding their geographic areas.  Providing access to clinical trials can be seen as a promotional asset for these systems, and the clinical trials can answer pragmatic questions that they face as payers.  Working with patient advocates, public health officials, payers, and community leaders can stimulate these systems or open their eyes to the opportunities.

         The electronics health records companies are voracious in their battles for market share.  They too can be an ally.

         Each of the 53 Medicaid state programs (DC, Puerto Rico, and American Samoa too) has a plan for delivery of its services, which HHS reviews.  An association of Medicaid administrators exists which tries to address major issues and creating clinical trial hubs or technological links within are a possibility to assist them in reducing the costs with pragmatic evidence.

         Thus, the sites and patients exist.  New allies exist.

V. Capitalizing on the Virtuality to Connect the Links
        The drug development process is virtual.  A large construct has evolved where no one does every step.  Each step is being further subdivided as technology improves and complexity increases.  Protocol drafting, clinical site identification, personnel training, site management, site auditing, data collection, data management, statistics and now value-added calculations are all pieces of the process.  The fractionalization of the process shows the need for more extensive early-stage planning than ever. 

       Payers are demanding value added from NCE’s.  For (b)(2)’s /value added products, proof of added value is ever more important.  Known and measurable endpoints are the essence of pragmatic trials.  Patients in the Real World are already being monitored for these endpoints.  But Rule One is that you need patients, and the more rapidly you can enroll patients the better.

       The application sponsor is the responsible party.  Everyone looks to the sponsor, regardless of its delegation to subcontractors and regardless of the credibility of the subcontractors.  Accordingly, the sponsor needs to build its credibility and trustworthiness.  Trust is not only essential for healthcare providers and their patients; it is essential for the sponsor to gain FDA’s trust to get your NDA approved.
 
        The fertile regulatory environment and technology offer new practical approaches for sponsors to develop value added products pragmatically and build their reputations.

         Just as 505(b)(2)’s rely on CDER’s findings that the reference drugs are safe and effective, CDER has issued extensive Guidelines on product development that can be mined and relied on.  Each guideline has a contact person and a file that can be analyzed for valuable product development information.  The Summary Bases of Approvals for approved drugs offer nuggets on every step of the process.  Tools such as the §505(b)(2) Platform’s Navacin can mine every approved (b)(2) since the turn of the Century for invaluable data on clinical trials, endpoints, PK, pharmacology, and review issues. 

         The various FDA expedited approval pathways are attractive and offer one consistent benefit- dialogue with the reviewing divisions.  FDA expertise and dialogue can be a treasure trove of insights.  As a sponsor one must take every opportunity to talk to the FDA or more appropriately, listen to FDA.  Therefore, working with segments of FDA that are empathetic is invaluable.

VI. Conclusion
         In sum, FDA/CDER’s message is loud and clear- FDA wants to see more inclusive clinical research and generalizable data.  CDER has restructured.  The Agency’s new diversity action plan guidance, the numerous guidance to implement the Congressional directives for real world data and evidence, and the fiscal pressures to reduce health care costs clearly point the way to the future.  The future is not “woke” or “politically correct”.  It is practical.  FDA does not live in a vacuum, and times change.  Expedited approval programs, expanded access and orphan approvals were the result of public health demands.  The pressure for pragmatic trials is building and can be enhanced.

         Stimulating pragmatic medical care addresses the huge public health issues that our country faces is about saving money.  Many incremental steps are necessary to improve enrollment of real world (diverse) patients in clinical research that will produce better, lower cost medical care.  The public, the regulated industry and payers have led the way to major changes in the past.  The past can be prologue.  Major step changes will only happen if we can bring clinical research into clinical practice.  This change requires trials to be more pragmatic and simpler.  The average clinical practice cannot run a random clinical trial of yesterday.  They can, however, run the pragmatic clinical trials of tomorrow.

​         Join us for discussions of some of these issues during the §505(b)(2) Platform’s Value-Added Medicines Week, Oct.  21-25, virtually.  Future discussions will occur at our annual meeting in NY in March 2025.  And we are always open to more focused discussions of these issue with individuals or groups through our website, www.505b2.org.

By Edward Allera

By using the 505(b)(2) new drug application pathway, sponsors can add value to already approved drugs through calculated steps. New technology, old data, and literature can create sophisticated, novel endpoints. With these pieces, a company can obtain new and improved labeling, market exclusivity, and even patent protection for women’s health products. Recent FDA/CDER actions have created the most conducive environment for approving women’s health products ever.  It is not necessary to start from square one to produce profit in the women’s health space. However, it is important to listen, think, and be interactive. The environment that led to the boom in oncology products is being replicated for women’s health.

1. Background

According to CitiGroup and others, only approximately 4% of health care investment dollars goes to women’s health, yet women account for more than half of the U.S. population. Women are the primary care givers, and according to the Illuminators they make more than 70% of the healthcare spending decisions. Moreover, the pandemic opened the window to active discussion of women’s health issues.  A prime market exists, but how can a company capitalize on this market?

1.  Building Trust

In today’s health care marketplace, “trust” is the rarest commodity. Creating a reputation for trust, integrity, and leadership in specific woman’s health areas can be accomplished in the dynamic regulatory environment that is evolving. With 505(b)(2) applications, a company starts with a drug that has already been shown to be safe and effective, which provides some comfort to potential patients. FDA, NIH (including the National Cancer Institute), and others are publicly committed to expanding clinical trial research and product development in diverse populations, especially women. Why? Because the original approvals were based on data from refined patient groups. Expanding on this effort, FDA has recently issued guidelines that fit perfectly into this environment for women’s health products: conducting decentralized clinical trials, real world evidence considerations for non-invasive clinical trials, and drug delivery output for medical devices. These steps are designed to ensure that approved products are optimally effective in the real world. They can also be relevant to reducing overall health care costs.

1. A New Forum for Dialogue

CDER has over twenty reviewing divisions, and each reviewing division has its own history, precedents, and requirements. Many deal with women’s health issues. Before approaching that reviewing division, it is critical to review that division’s history. The look, listen, and link with new technology approach can work for products in a reviewing division, but the obvious limitations of those divisions led to creation of a new forum. In April 2024, FDA created the CDER Center for Clinical Trial Innovation (C3TI) to attempt to replicate the success of the Office of Oncology Excellence (OOE). Over the past decade, most advances in innovative clinical trials and measurement of clinical benefit have arisen from the OOE. These advances have led to the boom in oncology research and revenue for approved oncology drug products.
C3TI is open for business and will be open minded, as the Federal Register notice announcing its creation states. It is seeking comments from, and dialogue with, industry. Working with this Center to facilitate women’s health product development can help a company establish its bona fides as a thoughtful and creative new player in the women’s health space. You can become a known, reputable commodity in a less crowded field—an invaluable first step.

1. Creating the Dialogue

What do you discuss with C3TI? Because C3TI is in its infancy, it will be looking to learn from industry. A sponsor that listens to women’s needs and concerns for new products provides that company, and C3TI, with invaluable information. That information will help the Center grow and innovate, which is another vital step in building the trust that will pay multiple financial returns.
This approach can also help improve existing treatments and therapies for conditions that only, or disproportionately, affect women or that affect women differently than men. Many of these existing treatments are dated. Many are based on data extrapolations due to the absence, or dearth, of women in the original clinical trials. Literature and medical education may be the only source of information for others.
Further, the signs and symptoms of menopause, perimenopause, and a number of other women’s conditions are not well known and seldom discussed among clinicians let alone patients. Women are often told by clinicians that their symptoms only exist in their heads.

1. Linking the Technology

New technologies, such as artificial intelligence (AI), that can optimize drug delivery, therapy maintenance, and diagnosis of conventional and orphan indications abound. These technologies can mine data for new signs, symptoms, biomarkers, and surrogate endpoints to provide more refined definitions of classical endpoints, diagnosis, and monitoring. Further, AI technology is increasing the rate and ability to identify relevant previously unknown linkages to women’s health conditions.
These technologies can identify new or better endpoints that can refine labeling to permit promotion of safer and better pharmaceuticals that are eligible for market exclusivities. Furthermore, a solid patent strategy can result in listing patents in FDA’s Orange Book. These value-added medicines may also be considered sole source products that can avoid generic reimbursement rates.

1. FDA has Issued Guidelines to Aid and Accelerate the Linkages

Modest technologic changes led to shifts from multiple daily dosing of oral tablets to extended-release daily dosing and topical patches. Improved technology has also led to various new aerosol dosage forms and sophisticated injections. Those technologies created new markets, industries, and innumerable products introduced to the market via the 505(b)(2) and other historical regulatory pathways. All were built on known clinical end points. Those old technologies pale in comparison to the technologic breakthroughs that are being created today that can link endpoints.

1. Next Steps

The 505(b)(2) Platform has a tool, Navicen, to accelerate the identification and development of these value-added products. Of course, thought and planning are required for identifying the right entry point at FDA and creating the dialogue.
On Wednesday, October 23, 2024, Value Added Medicines Week will focus programming exclusively on women’s health issues. This forum will provide additional insight into development of products for women’s health. We hope you will join Platform and Value-Added Medicines Week.