The novel coronavirus (COVID-19) pandemic has created an unprecedented global health crisis and all industry sectors are working to assess both the impact and the optimal path forward. While some biotechnology and pharmaceutical companies are rising to the challenge and working to develop potentially effective therapies and vaccines for COVID-19, many who are focused on other therapeutic areas are working to identify the best strategies to keep their clinical development programmes on track or to rapidly restructure them.
Impaired access to the healthcare system, travel restrictions, guidance from regulatory agencies and a shift in healthcare resources to address the COVID-19 pandemic are having a wide-ranging and immediate impact on the initiation and completion of hundreds of clinical trials involving investigational therapies for many serious diseases. As these plans are being developed, there are many uncertainties about what the future holds, as well as the longerterm implications on clinical research in terms of timing, patient identification and access, design and protocols. Experts from the Life Sciences Practice at the global consulting firm CRA conducted a recent analysis involving interviews with a range of industry stakeholders including regulatory and policy experts, venture capitalists and contract research organisations (CROs) to try to better understand both the short- and long-term impacts of COVID-19 on clinical development programmes.
Managing the impact of COVID-19 in the near term
The FDA, EMA and several national-level European governments have all issued guidance on conducting clinical trials during the pandemic, recognising the goal to keep programmes moving forward while stressing the importance of protecting patient safety and maintaining trial integrity. These guidelines outlined the essential need to adapt trials to accommodate the impact of the pandemic and indicated that regulatory agencies are committed to being flexible in evaluating changes to protocol, deviations and clinical data during these unprecedented times.
Many industry insiders agree that this evolving guidance provides a framework for drug developers to move forward and adapt to trial changes dynamically with the essential level of freedom to address many unique challenges. But even with this guidance, many trials at both smaller life sciences companies and in big pharma are paused or delayed. In one example, Provention Bio was forced to temporarily pause a phase 3 study evaluating its investigational therapy for type 1 diabetes. Eli Lilly, Bristol-Myers Squibb and Pfizer also have multiple development programmes that are paused or delayed. While the impact of COVID-19 on trials is broad, the magnitude and nature of its impact will vary from trial to trial and company to company. Clinical trials with the following characteristics are especially likely to be delayed due to COVID-19:
- Patient populations – trials with vulnerable populations (eg, the elderly, the immunocompromised, patients with pulmonary conditions such as COPD)
- Endpoint type – any endpoint that can only be assessed in person or using hospital infrastructure or equipment (eg, imaging-based endpoints like CT and PET scans)
- Indications – trials in indications with minor safety or quality of life implications for patients or where a patient’s environment strongly affects therapeutic success (eg, psychiatric and neurological indications)
- Trial stages and phases – trials that are currently in recruitment and phase 1 trials with healthy volunteers
- Trial site locations – trial sites that are located within hospitals or tertiary academic centres and in areas with high COVID-19 case density, which can limit staff available to perform required activities and potentially increase the risk of adverse events or patient drop-off
- Therapy mechanism of action – immunosuppressive therapies and therapies that require complex and prolonged hospital visits (eg, CAR-T and gene therapies)
- Trial size – trials with minimal margins for determining statistical significance and trials evaluating rare disease drugs (eg, where patient accrual is already difficult and the pandemic increases the risk of patient loss).
Biopharma companies seem to be primarily focused on pausing or delaying trials that are in patient recruitment or planning stages. Clinical trials in progress or those with patients fully enrolled are less likely to experience delays, although that may change as the crisis evolves. In addition to recruitment challenges, trials may also face protocol violations and patient loss that could affect the rigor of efficacy and safety data and consequently their chances for regulatory approval.
Long-term aftershocks
As companies face the near-term challenges of COVID-19, most stakeholders are concurrently turning their attention to the potential long-term implications for clinical research and product development. Our findings indicate that drug developers must consider how any changes in conducting clinical trials will impact their business from financial, regulatory and policy perspectives and assess what strategies they may need to put in place to advance their development programmes under these conditions as rapidly and costeffectively as possible.
Based on our discussions with venture capitalists, many anticipate potentially severe cash flow issues for drug developers. Small to mid-sized biotechs may be especially vulnerable, particularly companies with a single asset. Delays in clinical trials may lead them to need additional funding at a time when their stock values have likely dropped significantly. As a result, many companies may be forced to make difficult cuts or prioritise development opportunities. Many with promising and potentially high-value platforms may be at risk of acquisition from larger companies based on unfavourable terms. Acquisitions might present the opportunity for larger companies to expand their pipelines with additional assets during a time when they might be losing revenue from marketed products. Delays in clinical trials will also likely translate into delays in launch timelines, which may result in shorter periods of patent exclusivity post-launch and lower revenue forecasts.
COVID-19 will have regulatory implications in terms of required documentation, protocol changes and deviations, data collection and the interpretation of trial results. Regulatory experts, trial site investigators and CROs expect that establishing new procedures for additional documentation and collection could be a significant burden for trial sites and their staff, with the bulk of the burden being front-loaded due to the establishment of new protocols, procedures and forms. Once collected, experts expect that the processing of additional documentation and clinical data will result in delays in regulatory review and prevent companies from quickly responding to follow-up inquiries from regulatory agencies. Travel restrictions and social distancing measures are likely to make protocol updates and deviations inevitable.
Consistent with guidance from the FDA and EMA, trial sponsors will not be required to report protocol deviations prior to annual reports if the changes do not substantially impact the validity, safety or efficacy of the trial. Instead, sponsors and trial sites should meet with the relevant institutional review boards (IRBs) to seek approval for protocol updates. While this introduces the risk that sponsors will make changes to trial protocols that ultimately may be rejected by the FDA or EMA, our analysis indicates that this is unlikely because such changes likely would have been flagged during IRB consultation.
There is also the risk that if patients contract COVID-19 while participating in a clinical trial, it may impact the validity of the data. Affected patients could introduce COVID-19-related symptoms to the study with a resultant impact on efficacy and safety data. They could succumb to the disease, in which case they will need to be removed from trial data sets, potentially impacting the ability of trials to reach statistical significance. These impacts could be particularly devastating for companies that are conducting smaller trials, including studies of rare disease drugs where the pool of eligible patients is already limited.
The impact of the pandemic on clinical trials is likely to be felt on a policy level, including in drug pricing negotiations. In one example, the Pan-Canadian Pharmaceutical Alliance has already announced its intention to delay price negotiations for non-COVID-19 therapies. Similar delays can be expected in Europe where many regulators have indicated that non-COVID-19 therapies must be a lower priority during the health crisis.
Looking ahead
As the COVID-19 pandemic continues and leaders in research around the world are working to develop an effective vaccine and new treatment options, most anticipate the impact on the life sciences industry will be immense and far-reaching. Clinical trial sponsors will need to balance factors including patient safety and trial integrity against funding and revenue considerations on a trial-by-trial basis in order to be successful.
Companies also will need to re-evaluate the competitive landscape for both their marketed products and pipelines of investigational therapies. Trial delays may upend years of planning and forecasts related to competitors. Companies that are able to rapidly identify changes in the competitive landscape and shift their strategies accordingly will have an advantage. In addition, shifting priorities in health spending may decrease payers’ willingness to reimburse for some products and put new levels of pricing (and thus further revenue) pressure on companies.
Stakeholders in all categories generally agree that there will not be a one-size-fits-all solution for the many challenges ahead related to COVID-19. To be successful, companies will be required to be flexible, assess their risk and develop many new and potentially previously untried strategies to weather this crisis.
The views expressed herein are the authors and not those of Charles River Associates (CRA) or any of the organisations with which the authors are affiliated.