Clinical Researcher—September 2020 (Volume 34, Issue 8)

SPECIAL FEATURE

Astha Bhatia, BDS, MPH

 

In 1962, Dr. Frances Kelsey, who joined the staff of the U.S. Food and Drug Administration (FDA) two years prior, was honored by President John F. Kennedy for her refusal to rush approval to officially market a sleep aid called Kevadon^® to U.S. consumers. Dr. Kelsey and her team at the FDA had fought furiously against pressure from the drug’s would-be distributor, the Wm. S. Merrell Company, which assured the FDA that the drug was safe and effective. After all, it had been widely used throughout other parts of the world since the mid-1950s as a sleep aid and as a potent agent against debilitating morning sickness suffered by pregnant women.

The company touted other positives for its product—it had passed animal testing; hundreds of doctors in the U.S. had already been given samples for research; and it was selling elsewhere at a low cost and without a prescription. In Merrell’s view, Dr. Kelsey was simply being stubborn and obstructive.

Today, it is well known that Dr. Kelsey’s steadfast position saved an untold number of women in the U.S.—though not all—from giving birth to severely deformed infants. Kevadon’s ingredient, thalidomide, was identified in 1961 as the culprit of horrible birth defects in possibly tens of thousands of infants born throughout Europe and parts of Africa.

Having earned recognition for her significant contribution to the health and well-being of the public, Dr. Kelsey spent another 43 years at the FDA, primarily in the area of drug testing and establishing policies that strengthened the processes for releasing drugs and medical products to consumers. After 1962, drug makers had to demonstrate the safety and efficacy of their products by way of “substantial evidence” and include “adequate and well-controlled clinical studies.” Manufacturers were also forbidden to market their products until they were given the green light to do so by the FDA.

In fact, restrictions were so strong and statutes so complex that the FDA eventually came under fire for being too slow to approve new medications. In 1997, Congress passed the Food and Drug Administration Modernization Act in an attempt to hasten the agency’s review and approval of new medical treatments.

Then Came COVID-19

Fast-forward to May 2020, when the FDA took more unconventional and situational steps to accelerate the investigation and development of prevention and treatment therapies for COVID-19 in light of the urgency surrounding the pandemic.

Publishing a series of guidance documents, the FDA provided researchers and “innovators” with a roadmap for hastening the development of new drugs and biological products, and for conducting clinical trials to determine their safety and efficacy. This action followed earlier steps the FDA took to work with federal agencies, academic institutions, and drug manufacturers to accelerate medical solutions to the virus, including the launch of the Coronavirus Treatment Acceleration Program (CTAP).

The CTAP is an emergency-access program that administers potential coronavirus treatment options to patients. It provides subject-matter expertise to the COVID-19 treatment-acceleration program launched in April by the Foundation for the National Institutes of Health (FNIH) called Accelerating COVID-19 Therapeutic Interventions and Vaccines, or ACTIV.

The FDA and FNIH are just two of the federal agencies that have joined forces with one another and with private partners from academia, philanthropic organizations, and pharmaceutical companies to collectively prioritize coronavirus tests, treatments, and/or vaccines, applying all available resources to rapidly thwart the pandemic.

Now, questions are beginning to arise. Having heard concerns that the FDA might be moving too quickly on a vaccine, FDA Commissioner Dr. Stephen Hahn in early August assured members of the American Medical Association that the FDA will not compromise safety while rushing approval for a vaccine for the novel coronavirus. “All of our decisions will continue to be based on good science and the same careful deliberative processes we have always used when reviewing medical products,” Hahn said, adding, “We all understand that only by engaging in an open review process and relying on good science and sound data can the public, and you as providers, have confidence in the integrity of our decisions.”

Hahn said he can’t predict when the results will be ready, but large-scale clinical trials have already been initiated on several vaccine candidates, some in less than six months after the virus was detected.

What is the Right Timing?

The speed of drug development is controversial, and no one can prescribe the appropriate timeline for the approval of any drug; what matters most is a drug’s safety and efficacy. Can the public be assured that a cure won’t be worse than its targeted disease? Will the drug accurately and efficiently do its intended job? Can testing move any faster? Should we commit to take the time needed for 100% certainty about the drug’s viability?

To be sure, COVID-19 has proven that there is potential to streamline the clinical research process, but the solution lies in getting health authorities to coordinate and interact with each other to reduce the duplication of efforts—not to eliminate any step in the efforts.

What is needed is a global consensus on study protocol requirements, supporting documentation, and application forms to avoid country-level discrepancies. If researchers were allowed to fill up a centralized application and add some country-specific documentation, the paperwork and time needed to get the research started would be reduced. In other words, it’s the administrative functions, not the research itself, that need to be expedited.

The Devil is in the Documentation

Multiple regulations exist for clinical research across different health authorities, medical associations, and ethics committees throughout the world. Researchers must get all the approvals and complete the required documentations for each prior to initiating any clinical trial. While these regulations were introduced to protect the safety of the study subjects, the number of regulations has increased significantly in recent times and at varying levels.

Further, because health authorities across the globe do not usually interact with each other, getting research started typically takes a long time—often to the detriment of study subjects and the prospective patient population. Yes, it is imperative that clinical research follows proper regulatory guidelines; however, most often these guidelines are complex and disjointed between the various health authorities and countries.

Each country has its own applications to complete, forms to fill out, and guidelines to adhere to. The approval process, thus, is long and, due to the constantly overburdened system, clinical trial applications may take months to be reviewed by each health authority. This is followed by the ethics committees’ reviews, which further take time.

For every new clinical trial, a researcher must follow the nuances of guidelines of each individual country, but those guidelines exist on a splintered continuum, burdening what could be a more streamlined process if there were a central entity accepting and processing the relevant forms and documents.

Often, researchers develop what can be called a culture of fear, worrying about the added cost of filling out these multiple, global applications and going through the added red tape. This is detrimental to bringing new and novel treatments to the patients.

Sometimes, some patients, specifically certain cancer patients, do not have long to live and waiting too long to complete the massive paperwork might deprive these patients of these promising newer treatments. In the most extreme cases, the medical community has witnessed some researchers going out of the U.S. to locations with less-stringent regulations or faster processes to perform their clinical research, hoping for a more rapid outcome that could heal a particularly stubborn illness or even save a life.

Examples of Steps to Streamline

It’s worth noting that the FDA has taken many steps in the past to work with global partners in streamlining drug testing and clinical trial processes, including:

• In 2009, the European Medicines Agency (EMA) and the FDA agreed to collaborate on international Good Clinical Practice inspection activities. In short, the intent was to safeguard clinical trial subjects as clinical research grew more global.
• In 2013, the same two organizations announced an initiative to conduct joint-facility inspections for generic drug applications submitted to both agencies.
• In the fall of 2019, the FDA worked collaboratively with Canada and Australia to develop Project Orbis, a framework allowing concurrent submission and review of oncology products for patients with endometrial carcinoma.

The question then becomes, what is being done globally to streamline clinical research processes? Can there be a globally centralized process for initial protocol approvals? How can we keep countries’ timelines in sync so that there can be more collaboration from one country to another using the same documentation so that the process is simpler and faster?

COVID-19 Again Becomes the Model

In March, the World Health Organization (WHO) created the Solidarity trial, a global effort to rush clinical testing of four potential COVID-19 treatments:

• The anti-malarial drugs chloroquine and hydroxychloroquine (which have since been eliminated from the trial due to ineffectiveness);
• the HIV drugs ritonavir and lopinavir;
• the anti-viral drug remdesivir; and
• a combination of ritonavir and lopinavir with Interferon-β, an immune-system regulating protein.

As of July 2020, some 5,500 patients had been recruited for Solidarity from 21 countries; more than 100 countries expressed interest in joining the trial. WHO Director General Dr. Tedros Adhanom Ghebreyesus said the goal of the Solidarity trial is “to dramatically cut down the time needed to generate robust evidence about what drugs work” against COVID-19.

The advantage here is that these drugs already have a history of effectiveness in treating other maladies; their safety is under less scrutiny than would be if that were not the case. However, it stands to reason that given a similarly centralized and streamlined “clearing house” for initial protocols, documentations, timelines, etc., countries throughout the globe could reduce the time needed for new clinical research trials.

For certain commissions, some bureaucracy could be set aside in the interest of collaboration. Let’s not bury the most promising of drugs deep into the layers of red tape, but rather bring them to the market as soon as possible.

Something Good to Come from COVID-19?

It’s remarkable how effectively government agencies and private organizations have banded together during this COVID-19 pandemic to speed the process for researching, developing, and implementing potential treatments to fight the virus. It begs the question: Why were such dire circumstances required to bring such changes about?

Clearly, the traditional system for bringing therapies to the market is burdened with restrictive rules and regulations and conflicting schedules that actually work to slow the processes. Now that there is proof the system can be streamlined, all parties involved in the efforts against this pandemic need to work together so that this is not the exception, but rather the rule for moving forward on other medical products for the benefit of patients.

Dr. Astha Bhatia, BDS, MPH, (drasthabhatia@gmail.com) is an expert clinical scientist in the field of hematology and oncology, a dental surgeon, and a public health professional. She is passionate about bringing newer and more effective treatments to cancer patients and promoting community public health. For more information, please contact her via e-mail or LinkedIn (www.linkedin.com/in/drasthabhatia). Her article was contributed to ACRP through Trade Press Services.