The coronavirus disease 2019 (COVID-19), a novel respiratory disease, has spread globally within a short span of time. Given its novel status, health care professionals have had limited options for treating this often-deadly respiratory disease. The pandemic has garnered widespread media coverage and prompted public discussion about clinical trials conducted by the government, academic centers, and pharmaceutical companies searching for COVID-19 treatment options.
Affidavit of William Thomas Beaver, M.D. in the case of Pharmaceutical Manufacturers Association v. Robert H. Finch and Herbert Ley, Civil Action No. 3797, United States District Court for the District of Delaware. Dr. Beaver was the clinical pharmacologist at Georgetown University who is credited with drafting the initial regulations defining ‘adequate and controlled’ clinical studies.
Clinical trials provide foundational evidence for selecting a therapy for a particular patient with a specific disease state and additional differentiating factors, such as age and concurrent health conditions. While some may view clinical trials as unnecessary, profit-driven “experiments,” and would prefer that their own doctors select the therapy that’s best for them, it’s worth noting that clinical trials provide an objective comparison of patients in controlled conditions to determine the benefits and risks of a drug. The US Food and Drug Administration (FDA) plays a critical role in this discussion by ensuring the availability of safe and effective treatments.
IMPAQ Researchers Develop Tool to Analyze COVID-19 Clinical Trial Data
To provide information on the current landscape of clinical trials for COVID-19 treatment, a team of IMPAQ researchers, led by Dr. Sanchari Ghosh and Zippora Kiptanui, developed a Tableau dashboard to summarize clinical trial data by intervention type, category, status, clinical phase, location and population studied. This tool is intended to help both the general public and health care professionals to find the latest clinical trial advancements through various filters, as well as to see the general scope and demographics of current clinical trials. The data for this dashboard is sourced from ClinicalTrials.gov, a publicly available website that is maintained by the US National Library of Medicine. The IMPAQ research team will update this dashboard bi-weekly with recent data from COVID-19 trials.
In this post, we provide an overview of:
- Why clinical trials are important: a historical perspective on the need for safe and effective treatments.
- How clinical trials work: learn about procedures established by the FDA to facilitate the development of safe and effective therapies.
- COVID-19 clinical trial landscape: what is the current status of COVID-19 clinical trials and how can we track them?
Source: The White House
Learning from the Case of Thalidomide
In December of 1956, a mother in Germany gave birth to a baby born with no ears. Over time, thousands of other children around the world whose mothers took the drug thalidomide while pregnant were born with birth defects including severe physical disabilities, spinal cord defects, shortened arms and legs and in some cases, no limbs.
In the 1950s, thalidomide was developed in Germany and widely used in Europe as a safe sleeping pill. Some doctors began recommending thalidomide to pregnant women to relieve morning sickness, and soon this practice was generalized to 48 countries, including the United States. At the time, thalidomide was not an approved treatment for morning sickness in the US.
In September 1960, Dr. Frances Oldham Kelsey, a medical reviewer at the FDA charged with the review of thalidomide for approval, raised concerns about the lack of rigorous scientific evidence supporting the drug’s safety, especially in pregnant women. Additionally, many pregnant patients participating in clinical trials of thalidomide in the US later reported having infants with physical deformities. Dr. Kelsey’s persistent requests for more safety data from the manufacturer are thought to have delayed thalidomide’s approval in the US.
In November 1961, evidence linking birth defects to the drug became public, resulting in the withdrawal of thalidomide from the global market. President John F. Kennedy awarded a Distinguished Civilian Service Medal to Dr. Kelsey in 1962 for her role in exposing the dangers of thalidomide.
This experience with thalidomide led the US Congress to pass legislation giving the FDA greater authority than it previously had to regulate drug approval. Specifically, the 1962 Kefauver-Harris Amendments to the 1938 Food, Drug, and Cosmetic Act established the requirement that drug manufacturers must prove through clinical trials both the safety and effectiveness of a medication before it is brought to market.
FDA Clinical Trial Procedures Facilitate the Development of Safe and Effective Therapies
Before the thalidomide experience and the 1962 Amendments, there were limited federal regulatory requirements for approval or oversight of clinical trials. After 1962, drug developers, or sponsors, were required to not only show that a product was safe, but also effective for the specific condition. The amendments also mandated FDA approval of a new drug application before the sponsor could market the product. Prior to this, if the FDA did not disapprove a drug application within six months of submission, then the drug would automatically be considered approved within the subsequent 60 days.
Drug Discovery, Development and FDA Approval Process
Drug manufacturers are continuously analyzing multiple compounds to seek out those that may have a therapeutic effect. During preclinical testing, the manufacturer completes synthesis and purification of the drug in a laboratory and conducts limited animal testing.
In the US, if a sponsor identifies a drug that shows promise during the preclinical (i.e. lab and animal trials) testing phase, then the sponsor submits an Investigational New Drug (IND) Application, or a Biologics License Application (BLA) for biological products (such as a vaccine or blood serum) to the FDA.
If the FDA determines that development of the drug can continue, an Institutional Review Board that will oversee this research must approve the clinical trial protocol, which includes the following:
- the population eligible to participate in the clinical trial
- the timeline for the procedures and tests
- the dosages of the drug that will be studied
- the duration of the study, ongoing monitoring of participant status and ultimate outcomes
The clinical trials for drug approval submission are divided into three phases. Phase 3 depends on the successful completion of Phase 2, which in turn depends on the success of Phase 1.
Following successful completion of Phase 3, the sponsor submits evidence from these trials to the FDA as part of a New Drug Application (NDA). This is the final formal step a sponsor must take in order to get the FDA to approve the new drug for marketing and distribution in the US. The average review process lasts 10 months. The approval process for a BLA is similar to that of an NDA, with some differences in the specific requirements on the application as pertaining to a biologic versus a drug.
After a drug is approved, it may undergo Phase 4 post-marketing trials to gather more information about the drug’s optimal use, such as measuring safety and effectiveness in the general population (as opposed to the more controlled settings of a clinical trial).
In order to add a new indication to an FDA-approved drug or biologic, a supplemental NDA or BLA must be submitted. The safety profile of the drug in a supplemental NDA must mirror that of the clinical trials from the original NDA to be considered for approval.
FDA Support to Accelerate COVID-19 Treatments
In certain cases, the FDA allows specialized approval processes for drugs that are for rare diseases, or that may need to be utilized in an emergency situation, as we are facing today. These include fast tracking an approval, assigning a breakthrough therapy status designation to the drug in the NDA, performing an accelerated approval process, and assigning a priority review designation to the NDA.
On January 31, 2020, the Secretary of Health and Human Services (HHS) declared a national emergency to combat the COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2. As a result, the FDA created the Coronavirus Treatment Acceleration Program (CTAP) in order to ensure that the multitude of possible treatment options for COVID-19 are accelerated through the review process in any means possible while closely evaluating safety.
In May 2020, the FDA issued two pieces of guidance to further CTAP’s goal of accelerating treatment approval for COVID-19. These guidance documents offer recommendations to support scientists and manufacturers to reach the investigational new drug application (IND) stage as well as support clinical trial design considerations for later phases of these studies.
- Pre-investigational new drug application guidance: This guidance recommend that sponsors schedule a pre-IND meeting with the FDA, which allows early and thorough review and discussion between the sponsor and FDA. The goal of this guidance is to provide sponsors/manufacturers with early feedback and help them get their products into clinical trials in a quick and efficient manner.
- Guidance on development of clinical trials: To accelerate access to potential treatments, the FDA provided guidance with recommendations for the design of Phase 2 and 3 clinical trials under development to treat or manage COVID-19. Specifically, for drugs that have successfully completed Phase 1, the FDA is providing guidance on clinical trial design including the population, trial design, efficacy endpoints, safety considerations, and statistical considerations for such clinical trials. While this guidance prioritizes clinical trials for drugs with direct antiviral activity or immunomodulatory activity, the FDA notes that they may be applied to the development plans for other drugs.
Under the Federal Food, Drug, and Cosmetic Act, the FDA Commissioner has the authority to grant an Emergency Use Authorization (EUA) to allow the use of unapproved medical products or unapproved uses of approved medical products to diagnose, treat, or prevent serious life-threatening conditions when there are no other approved and viable alternatives. Authorization of drugs through the EUA mechanism includes an acknowledgment that “the known and potential benefits outweigh the known and potential risks of the drug for the diagnosis, treatment, or prevention of an appropriate disease or condition.”
As a result of HHS’s declaration of COVID-19 as a national emergency, the FDA can grant EUAs for any medical countermeasure that facilitates the diagnosis, prevention, or treatment of COVID-19. On March 28, 2020, the FDA approved an EUA for the emergency use of chloroquine phosphate and hydroxychloroquine sulfate for the treatment of COVID-19. Although the EUA was later revoked, it set a precedent for future specialized approval processes for drugs designed to prevent or treat COVID-19. For example, an EUA was approved for remdesivir in early May. EUAs were issued for many other drugs and devices that could help with COVID-19 treatment.
In addition to those with EUAs, multiple treatment options are being tested through clinical trials for COVID-19 diagnosis, treatment, and prevention. Treatment modalities in clinical trials include antivirals, immune system enhancers, immune response suppressors, symptom-based treatment, and vaccines, among others.
Why We Developed the IMPAQ COVID-19 Clinical Trials Tracker
Given the current COVID-19 pandemic and the novel nature of the virus, finding appropriate treatment options to ensure the health and wellbeing of the public is essential. While there is an inherent urgency to identify treatment for this serious illness, it is equally critical that approved treatments for COVID-19 are both safe and effective. Clinical trials are the safeguards designed to protect patients from risks of an ineffective treatment which may lack adequate directions for use, or from irreversible harm such as what occurred with the unapproved use of thalidomide.
We leave you with quotes from two of the health authorities in the frontline of leading COVID-19 treatment and prevention efforts in the United States: