As we enter the latest wave of the novel coronavirus attack, we are only nine months into a public health war that is proving difficult and lengthy. In the first few months, the fog of war required split-second decisions about novel and critical issues with limited data available. The Department of Health and Human Services' (DHHS) Operation Warp Speed quickly mobilized to bring together the resources of several government agencies. In those early moments, individuals from every phase of the healthcare industry engaged in the fight. Developing theories and in vitro data, recounting and compiling anecdotal data, and repurposing potential therapeutic agents were the opening salvos of the battle. Concurrently, academic institutions, medical centers, healthcare systems, federal and state agencies, and pharmaceutical and biotechnology companies—both large and small—mobilized their own efforts as well.
Since March, remarkable progress has been made with the help of the creativity and open-mindedness of the public and private sectors. This includes the U.S. Food and Drug Administration (FDA), which has so far reviewed over 560 requests, often within a week of submission, for the use of therapeutic agents against the novel coronavirus. Now that time has passed, we know more about the vector, mechanism of action, transmission, and course of disease. FDA, the National Institutes of Health (NIH), and other public and private entities have worked diligently to coordinate the molecular, biological, and medical aspects of COVID-19 with the science of clinical trial development. Participants in the dialogue have emerged from a broad swath of groups with varying expertise, and various forums have evolved to host this dialogue. These forums include FDA's Coronavirus Treatment Acceleration Program (CTAP), NIH's Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership, and the Reagan-Udall FDA Foundation's and Friends of Cancer Research's COVID-19 Evidence Accelerator.
FDA's CTAP illustrates the enormous volume of information about COVID-19 being generated. Even more complexity and difficulty will arise as the data are accumulated for submission and vaccines become available. According to the CTAP website, in addition to the more than 560 active pre-investigational new drug application (IND) discussions between FDA and sponsors, the Agency has permitted over 370 clinical trials to proceed. Five COVID-19 treatments have received Emergency Use Authorization (EUA), and one treatment has been approved.
Likewise, NIH's ACTIV public-private partnership has evaluated hundreds of available therapeutic agents for the novel coronavirus and has prioritized the most promising candidates. It has designed and harmonized five adaptive master protocols for ACTIV clinical trials, and has selected numerous NIH-supported networks to launch these clinical trials to test the prioritized therapeutic candidates. These master protocols are centralized around immune modulators (ACTIV-1), outpatient monoclonal antibodies and other therapies (ACTIV-2), inpatient monoclonal antibodies and other therapies (ACTIV-3), antithrombotics (ACTIV-4), and big effect trial (ACTIV-5).
Finally, the COVID-19 Evidence Accelerator is providing a platform for FDA, academia, health systems, and data organizations to share information about trials, data results, and possible treatments. The Accelerator is divided into two pathways—one for diagnostics and one for therapeutics. Each pathway offers meetings and working groups to listen, share ideas, and learn about cutting-edge developments.
These are enormous achievements by any stretch of the imagination. However, as the initial fog of war clears, it reveals that we are still in for a lengthy fight—regardless of access to a vaccine. We have miles to go before we can rest. Accordingly, it is useful to assess what we have learned so far and how we can leverage that information to adjust the battle plan as we enter a new phase of the war against COVID-19.
- Arguably, more has been learned about the novel coronavirus and COVID-19 in this brief period than was learned in the decade of research on other communicable diseases, such as acquired immunodeficiency syndrome (AIDS). Indeed, as PhRMA has observed, it took only two weeks to fully sequence the genome of the novel coronavirus. We have accomplished in months what took years, if not decades, to learn about AIDS. Such cooperative efforts have built new pathways for research and therapeutic product development that have rapidly gained speed and traction. These new pathways are carving channels into the existing and prospective patient populations for therapeutic development that are becoming ever more focused. Accordingly, it is critical to monitor changes that are emerging weekly, if not daily.
- Many early-stage studies may prove dramatically underpowered to show any reliable and replicable evidence of effectiveness. Some people have mistakenly equated FDA's initial speed of response with a change in the bedrock principles of demonstrating safety and effectiveness. Early on, many sponsors opened COVID-19-related INDs for repurposed drugs or drugs that were then under development for other uses. FDA has been willing to consider everything and to move quickly—though its safety and effectiveness standards have not changed. So beware of reading too much into the speed of FDA's initial response.
- Likewise, many early protocols may not be directed to the right stage of the disease. We have learned logarithmically more about the course of the disease and how to treat it than we knew six months ago. Moreover, vaccines are on the horizon. It is important to define the study endpoints based on the stage of the disease being targeted. You must assess if you are targeted at the right stage of the disease as treatments have morphed rapidly. And how to optimize the data that are being collected.
- New types of clinical trials are evolving and highlighting the value of data. Study methods that historically took decades to develop have been instituted within months. These methods and pathways are becoming the standards of development and the standards for assessing products more quickly. Data from studies that were initiated early on, less than six months ago, may prove to be less than robust or useful. As treatment approaches have morphed rapidly, it is critical to ensure that clinical trial design will provide meaningful data based on both the endpoints chosen and the stage of the disease. Interacting with as many players as possible in both the private and public sectors is central for awareness of the scientific trends that are evolving and collection of use of data in the most practical way.
- The cost of entry for developing a COVID-19 therapeutic has increased. The reality is that the best-funded and best-organized clinical development efforts have an enormous advantage over smaller or one-off development efforts. The value of planning, persistence, and patience cannot be overstated. The tortoises are prevailing over the hares in the race to develop COVID-19 therapeutics.
- The centralized protocols of FDA and NIH have become the preferred modules for collecting data. “Big pharma” and some specialty pharma companies are accustomed to working methodically within a larger clinical trial framework. They are also known to clinical investigators and FDA, thus averting the inevitable period of time that smaller companies must spend to introduce themselves and their technology to these agencies. Some may believe that they are smarter, quicker, and have more insight than the regulators. While it may be true that some developers may be the smartest people in the room it is irrelevant. The smaller and less well-known the company (i.e unknown entities) need to establish their bona fides in the eyes of the clinical investigators and regulators.
- Participate in one of the many forums that exist to discuss COVID-19 therapeutic product development. Numerous forums have been created where FDA, academia, and members of industry are discussing real world evidence, data reporting, and other difficulties that may be arising. The ability to connect with others is helping to address these problems. A participating company will gain insight, and regulators, investigators, and researchers will see the company in a new or different light. Each of these interactions provide additional value to a development program, and participation can help avoid the mistakes of others.
- Companies interested in joining the battle need to find the best mechanism to fit into the existing framework. FDA is performing near heroically in reviewing the vast volume of data being submitted for COVID-19 therapeutics. However, when the next wave of inadequate data inevitably hits, companies with limited experience will grow angry, more concerned, and disillusioned. It is therefore critical that inexperienced entities determine how they can fit into the larger battle plan.
- Development of COVID-19 therapeutics and diagnostics is not a zero sum game. Although we are nearer to a vaccine than we were months ago, there are still numerous opportunities for companies to engage in the COVID-19 fight. Patients remain in need of cutting-edge diagnostics, medical devices, drugs, and biologics to deal with the novel coronavirus. For example, much remains to be learned about the so-called “long haulers”—the recovering patients who continue to experience residual effects for months. Companies should think about how their proposed product fits into the bigger and longer-term picture.
We have seen these lessons played out during our own client counseling experiences. COVID-19 therapeutic development and clinical trials are rapidly-evolving areas. The decisions are made in Washington. Therefore, companies need to be tuned in and listen to the Washington dialogue. Patience and persistence are also key. Most importantly, companies need a well-planned strategy—or they will find themselves triaged to the side and waging a lonely battle.
Our experience shows that engaging the right people and groups is critical to the success of a COVID-19 therapeutic development plan. Consulting with Washington regulatory and legal counsel can be very important to navigating this evolving situation, as is working with people who understand the on-the-ground politics. The more that companies apply these lessons, the better prepared everyone will be to collectively win the COVID-19 war.
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