Elizabeth Rountree

	The novel coronavirus (SARS-Cov-2 or COVID-19) pandemic has created an unprecedented global health crisis. As of April 8, the virus has spread to 184 countries, infected over 1.4M people, and resulted in over 80,000 deaths.

Experts forecast that the death toll in the United States alone will exceed 100,000, and a global recession is widely expected.

In response to the pandemic, dozens of countries and regions have instituted shelter-in-place orders and some institutions have issued guidelines urging people to minimize non-essential healthcare and/or clinical research. 

	Impaired access to the healthcare system, travel restrictions, guidance from regulatory agencies, and a shift in resources to fighting the pandemic are beginning to impact the conduct of clinical trials. We held discussions with a selection of CRO, policy, regulatory, and venture capital experts to understand the implications of the pandemic on trials. We found that the pandemic will have an immediate (or short-term) impact on the conduct of trials, as well as a long-term impact that may reverberate through the industry in the coming years. 

	On March 18, the U.S. FDA issued guidance on conducting clinical trials during the pandemic and the EMA (as well as several national-level European governments) have done so as well in recent days. The guidance documents stress the paramount importance of protecting patient safety, followed by maintaining trial integrity. They also included guidance on adapting trials to meet the current situation; stated their intention to be flexible in evaluating protocol changes, deviations, and data; and emphasized the importance of thorough documentation.

	Reactions to the guidance documents have been positive. Experts believe that the FDA and EMA have provided a sufficient framework for sponsors to move forward, and adapt to trial changes dynamically, without being overly prescriptive. Nonetheless, more explicit guidance on the use of remote monitoring is expected. Consistent with this feedback, a survey conducted by BioCentury among 99 pharma and biotech companies found that explicit guidance on telemedicine and remote visits was one of the top areas where companies would like additional guidance.

	The pandemic has led to a substantial number of trials being paused or delayed. Examples range from biotechs like Provention Bio (who paused their Phase III Type 1 diabetes trial for PRV-03

) and Iveric Bio (who paused their pivotal trial for Zimura in geographic atrophy

) to large pharma companies including Eli Lilly, BMS, and Pfizer (multiple programs paused or delayed

). While the impact on trials is expected to be broad, the magnitude and nature of impact varies from trial to trial. Trials with the following characteristics are especially likely to be delayed:

-trials with vulnerable populations (e.g. the elderly, the immunocompromised, patients with pulmonary conditions [e.g. COPD])

-any endpoint which warrants hospital infrastructure for determination (e.g. imaging based endpoints like CT and PET scans)

-trials in indications with minor safety or QoL implications for patients (e.g. “lifestyle drugs”); trials in indications where patient environment strongly affects therapeutic success (e.g. psychiatric and neurological indications) 

-trials that are currently in recruitment,Phase I trials with healthy volunteers

-trial sites that are located within hospitals or tertiary academic centers, trial sites in areas with high Covid-19 case density (e.g. potentially reducing availability of staff to perform required activities and increasing likelihood of AEs and patient loss)

-immunosuppressive therapies, therapies that require complex and prolonged hospital visits (e.g. CAR-T therapies, gene therapies)

-trials with minimal margins of statistical power, rare disease trials (patient accrual is already difficult with the pandemic increasing the risk for patient loss)

	Thus far, sponsors appear to be focused on pausing or delaying trials that are in the recruitment or pre-recruitment stages, though trials in-progress may also experience delays as the crisis develops. For the latter, protocol violations and patient loss to follow up with subsequent data integrity and statistical power issues are among the most likely potential consequences of the pandemic.

	In the medium-to-long term, there are implications arising from COVID-19-related clinical trial delays from financial, regulatory, and policy perspectives.

	The financial implications of trial delays could be significant with different consequences for small biotech companies versus larger pharmaceutical companies. Venture capitalists anticipate cash flow issues for small biotechs, particularly single-asset companies.

Many biotechs have finite financial runways tied to tight development timelines. Delays in clinical trials may lead them to seek additional funding at a time in which their stock values are likely to have dropped substantially (in line with the rest of the stock market).This could result in some small companies being forced to make difficult cuts or prioritization decisions in their clinical development plans and/or face acquisitions on unfavorable terms. The latter may present an opportunity for pharma companies who may be looking to backfill their pipelines and lost revenue. 

	Delays in clinical trials will likely translate into delays in launch timelines. This may result in shorter periods of patent exclusivity post launch (barring patent term restoration

) and lower forecast revenues for products than originally anticipated. Delayed launches will neither impact periods of orphan exclusivity (which are determined relative to launch date) nor periods of market exclusivity due to new indications. Launch delays also will have implications for competitive dynamics as landscapes shift. This opens opportunities for companies who act with agility and adapt to rapid changes in their competitive environment.

	From a regulatory perspective, COVID-19 will have implications in terms of required documentation, protocol changes and deviations, data collection, and the interpretation of trial results. 

	Regulatory experts, trial site PIs, and CROs expect establishing procedures for additional documentation and collecting it will be a significant burden for trial sites and their staff, with the bulk of the burden being front-loaded with the establishment of new protocols, procedures, and forms. Once collected, experts expect that processing the additional documentation will result in delays in regulatory review and in a sponsor’s ability to reply to follow-up inquiries from regulatory agencies.

	Travel restrictions and social distancing measures will make protocol updates and deviations inevitable. Consistent with the FDA and EMA’s guidance, sponsors will not be required to report protocol changes to them prior to annual reports as long as the changes do not substantially impact the safety and efficacy implications of the trial. Instead, sponsors and trial sites should confer with the relevant IRBs to seek approval for protocol updates. While this formally introduces the risk that sponsors will make changes to trial protocols that will be rejected by the FDA or EMA 

, our interviews indicate that this is unlikely because such changes would likely have been flagged during IRB consultation.

	Consistent with the FDA/EMA’s guidance, trial sponsors, site managers, and regulatory experts anticipate that the agencies will be as flexible as possible when evaluating protocol deviations and data generated during the pandemic. Experts anticipate that regulators will be more flexible when evaluating data relating to secondary and exploratory endpoints than for primary endpoints (where they anticipate little flexibility). They also anticipate that the risk to trials will vary based on the type of primary endpoint. Trials with primary endpoints that are assessed in-person in a way that cannot be easily shifted to a remote setting are at particularly high risk. An example of this would be an oncology trial that is using regular imaging to assess Progression Free Survival (PFS): if participants miss imaging visits, they may experience progression and it would be difficult or impossible to assess the impact of the investigational product afterwards. One expert speculated that the FDA may make an exception in cases where the secondary endpoint is “hard” (e.g. survival), and where the unmet need is substantial. In this case, they speculate that the FDA may weigh the secondary survival endpoint sufficiently heavily to approve the product, though they admit that there is little to no precedent for such a move. 

	In addition to the risk of patients missing visits because they are unwilling or unable to attend, there is also the risk introduced by COVID-19 infection itself. If patients contract the disease, it may impact the data by introducing elevated rates of related symptoms and/or impacting the metrics being measured in the study. Additionally, if patients succumb to COVID-19 and die, they will need to be removed from trial data sets, which could impact the ability of trials to reach statistical significance given their original power assumptions. These impacts are likely to be particularly acute for smaller trials with smaller thresholds for patient dropouts (e.g. rare disease trials). 

	Regulatory experts anticipate that the challenges outlined above, in combination with challenges in terms of agency staff availability, will result in delays in the evaluation of non-COVID-19 therapies. Indeed, the FDA has already pushed back the PDUFA dates for several drugs that were otherwise expected to launch in March or April this year.

Further, there is likely to be a deluge of NDAs filed in the months following the pandemic as sponsors play catch-up. 

	The impact of the pandemic on clinical trials will also be felt on a policy level. Outside the US, the pandemic is likely to impact price negotiations. The Pan-Canadian Pharmaceutical Alliance (pCPA) has already announced their intention to delay price negotiations for non-COVID-19 therapies. In Europe, we believe that price negotiations also will be impacted, particularly for non-COVID-19 therapies where there is a perception of low unmet need (e.g. the 3rd or later drug to market in a class). 

	While the impact of the COVID-19 pandemic on the pharmaceutical industry is likely to be immense and far-reaching, the magnitude and nature of the risks introduced by trial delays will differ substantially across trials and companies. Trial sponsors will need to balance patient safety, trial integrity, and statistical power considerations against funding and revenue considerations on a company-by-company and trial-by trial basis. 

	Smaller companies with limited financial resources will likely have fewer options available to them. They may be forced to make difficult cuts or prioritization decisions, struggle to raise funds on capital markets, and/or face acquisitions on unfavorable terms. This could present an opportunity for large pharmaceutical companies to mitigate losses in revenue arising from product launch delays by back filling their pipeline with assets purchased at what would have been substantially discounted rates pre-crisis. 

	In addition to reevaluating clinical development plans, biotech and pharma companies will need to reevaluate their assumptions around the competitive landscape for both their pipeline and in-line products. Trial delays may upend years of planning and competitive intelligence assumptions and companies that rapidly identify these shifts and respond will have an advantage over those that do not.

	Finally, biotech and pharma companies should reevaluate pricing and revenue assumptions for their pipeline assets. Clinical trial delays paired with delays in pricing negotiations in some markets likely will result in shorter periods of post-launch patent exclusivity and a corresponding decrease in revenue. Further, the pending global recession and shifting health spending priorities may decrease payers’ willingness-to-pay and put pricing, and thus further revenue, pressure on companies. 

	The implications of clinical trial delays arising from the COVID-19 pandemic will be heterogeneous and there will not be a one-size-fits-all solution to the resulting challenges. In order for companies to adapt, they will need to individually assess risk and develop context-specific remediation strategies to weather this crisis. 

is a Senior Associate in the Life Sciences Practice at CRA, based in Switzerland. 

is a Principal in the Life Sciences Practice at CRA, based in San Francisco. 

The views expressed herein are the authors’ and not those of Charles River Associates (CRA) or any of the organizations with which the authors are affiliated.

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Articles

A discussion of how the coronavirus pandemic will have a multitude of impacts on the conduct of trials, as well as on the industry itself.

Elizabeth Rountree

Articles

COVID-19 Will Have a Heterogeneous Impact on Clinical Trials, Biopharmas