Like companies in all industry sectors, many biotechnology and pharmaceutical companies are struggling to understand and find strategies to address the challenges presented by the COVID-19 outbreak. For many, the impact of the pandemic on the conduct of clinical trials has forced both smaller biotechs and Big Pharma to make tough decisions to pause ongoing trials and reconsider timelines for data readouts, regulatory reviews, and product launches. Factors including impaired access to the healthcare system, travel restrictions, patient willingness to participate in trials, new guidance from regulatory agencies, and a shift in resources to fighting the pandemic are influencing the ability to advance many clinical research programs around the world. As companies focus on the immediate impact of COVID-19 on their development efforts, industry insiders are now starting to consider what the longer-term implications will be and how to address them.
The Life Sciences Practice at CRA recently reached out to a number of industry stakeholders, including regulatory and policy experts, venture capitalists, and contract research organizations (CROs), to better understand concerns about the impact of COVID-19 on clinical trials and how new challenges are likely to reverberate through the industry. Findings indicate that the impact on clinical development programs is already severe and will be broad and long-lasting, while the magnitude and nature of the impact will vary from trial to trial and company to company.
Addressing Short-Term Implications
In response to the pandemic, the FDA, EMA, and several national-level European governments have acted quickly to assess the impact and issued new recommendations related to clinical trials, including strategies for how companies can adapt to the current situation while reinforcing the essential need for any change to meet acceptable standards in patient safety and trial integrity. The agencies have also communicated their intention to remain flexible in evaluating protocol changes, deviations, and clinical efficacy and safety data. Industry insiders generally agree that the new guidelines provide a sufficient framework for trial sponsors to adapt their trial designs and protocols as needed at this stage.
As companies learn to adapt and consider implementing new strategies to keep clinical trials on track, in many cases the only option is to temporarily pause or delay development programs. For example, Provention Bio recently paused a Phase 3 trial in type 1 diabetes and Iveric Bio temporarily stopped a pivotal trial in geographic atrophy. But these decisions are not limited to smaller companies. Eli Lilly, Bristol-Myers Squibb, and Pfizer have announced pauses or delays in multiple development programs.
While consensus is that the impact of COVID-19 on clinical trials will be far-reaching, our analysis suggests that the level and duration of this impact will be especially severe in studies that have the following characteristics:
- Enrolled vulnerable populations, including the elderly, the immunocompromised, and patients with pulmonary conditions (e.g., COPD)
- Have primary or secondary endpoints that require in-person visits or hospital infrastructure and equipment (e.g., CT and PET scans) for assessment
- Involve indications with minor safety or quality of life implications for patients (e.g., “lifestyle drugs”) and indications where a patient’s environment has a significant impact on therapeutic success (e.g., psychiatric and neurological indications)
- Are currently in the patient recruitment stage or are in Phase 1 with healthy volunteers
- Have trial sites located within hospitals or tertiary academic centers and in areas with high COVID-19 case density, potentially reducing the availability of staff to perform required activities and increasing the risk of adverse events and patient loss
- Are evaluating immunosuppressive therapies or therapies that require complex and prolonged hospital visits (e.g., CAR-T cell and gene therapies)
- Involve smaller patient populations where there are minimal margins of statistical power or people living with rare diseases (because patient accrual is already difficult, and the pandemic increases the risk for patient loss)
In the earliest stages of the pandemic, trial sponsors were primarily focused on essential decisions to pause or delay trials that were in the recruitment or pre-recruitment stages. Attention then shifted to trials in progress, where decisions related to protocols or timetables could have an impact on data integrity and statistical power.
The Longer-Term Impact
Looking ahead, organizations involved in clinical research are working to identify and assess financial, regulatory, and policy considerations that will affect their clinical programs in the longer term. Many are recognizing the need to plan for implementation of new and previously untried strategies to advance drug development programs.
In working to address the challenges of COVID-19, small biotechs could face potentially severe cash flow and financing issues as a result of trial delays. Companies with a single asset could be especially vulnerable. Delays in clinical trials may lead smaller companies to need additional funding at a time when their stock values have likely dropped and market conditions are not optimal. Many companies may be forced to make difficult cuts or prioritize development opportunities. Companies with potentially high-value products and platforms may be at risk of acquisition based on unfavorable terms.
Delays in clinical trials are likely to cause delays in projected launch timelines. This may in turn lead to shorter periods of patent exclusivity (barring patent term restoration) and lower near-term revenue forecasts. Changes in launch timelines also may shift the competitive landscape in many therapeutic areas, possibly presenting new opportunities for competitors that are able to adapt and act quickly in response.
From a regulatory standpoint, many stakeholders, including regulatory experts, trial site investigators, and CROs, anticipate that global agencies will require additional documentation and new protocols and procedures when considering new drug applications. The need for additional documentation can present significant challenges to trial sites and staffs. Processing this information also could cause delays in regulatory reviews and the ability of trial sponsors to quickly reply to follow-up inquiries from agencies.
Travel restrictions and social distancing measures will make protocol updates and deviations inevitable. Fortunately, per recent guidance from the FDA and EMA, trial sponsors will not be required to report protocol deviations prior to annual reports as long as the changes do not significantly impact the validity or safety of the trial. But sponsors and trial sites should meet with the appropriate institutional review boards (IRBs) to seek approval for protocol updates to reduce the risk that any changes could ultimately be rejected by the FDA or EMA.
The fact that trial participants cannot or will not attend in-person visits with investigators is a critical issue affecting many trials, but companies also should recognize the potential consequences if patients introduce COVID-19 to the trial itself. If patients contract the disease, it may impact clinical data by introducing elevated rates of related symptoms with a corresponding impact on endpoints. Any COVID-19-related fatalities would require these patients to be removed from data sets, potentially impacting the ability of trials to reach statistical significance. These consequences could be especially devastating for trials in rare diseases, where available patient populations are very small.
Based on our analysis, the impact of the pandemic on clinical trials will be felt on a policy level, including in drug pricing negotiations. The Pan-Canadian Pharmaceutical Alliance has already announced their intention to delay price negotiations for non-COVID-19 therapies. Pricing negotiations in Europe also could be impacted by the pandemic, especially for some non-COVID-19 therapies (e.g., the third or later drug to market in a class) where historically there has been a perception of low unmet need.
While most regulatory agencies have stated an intention to be flexible during these unprecedented times, it is critical that drug developers continue to monitor their risk diligently and develop contingency plans to adapt and respond to factors that affect their clinical development programs. Sponsors will need to balance patient safety, trial integrity, and statistical power considerations against funding and revenue issues on a trial-by-trial basis. In addition to reevaluating clinical development plans, companies may need to reassess their assumptions around pricing and revenue as well as the competitive landscape for both their pipeline and in-line products. There will not be a one-size-fits-all solution for the many short- and long-term challenges caused by COVID-19, but companies that are willing and able to rapidly adapt are likely to have the strongest chances for success.
Source: Clinical Leader