Why Do Clinical Trials?
Clinical trials are an important — and government-required — step on the way from an idea to a commercial medicinal product. All new pharmaceutical and biological products and most generic “follow-on” products are required to conduct clinical trials to demonstrate the proposed product’s safety and efficacy. By their very nature, clinical studies involve human subjects. The COVID-19 pandemic introduced new challenges for sponsors — those ultimately responsible for the management and oversight of clinical trials — from subject recruitment, to travel restrictions, to gaps in data analysis. This brief overview takes a look at the key challenges and ways they are being addressed.
What and Who Are Involved in Clinical Trials?
In general, clinical trials go through several phases, which ensure a gradual progression from smaller to larger scope as more and more information about safety and appropriate dosing is learned through the trials.1
- Phase 1 is done with healthy volunteers, with the main goal to examine safety.
- Enrollment: typically tens to hundreds of volunteers
- Typical time: several months
- Phase 2 may recruit healthy volunteers as well as patients, and is focused on safety as well as dose-finding for efficacy.
- Enrollment: typically hundreds to a few thousands
- Typical time: 1–2 years
- Phase 3 may involve healthy volunteers and definitely includes patients, to examine safety and efficacy in a large population.
- Enrollment: typically in the several thousands
- Typical time: 1–5 years
- Clinical studies may extend into so-called Phase 4, when the product enters the market. The goal here is to monitor longer-term safety and efficacy, and sometimes to fulfill specific post-market commitments required by FDA or other agencies.
- “Enrollment” could be all who are prescribed the product.
- Typical time: up to 10–20 years
A clinical study protocol — the document that includes the goals, methods, types of subjects to be enrolled, approaches to data analysis and safety to trial subjects — needs to be developed by the sponsors in advance and agreed to by appropriate regulators (in the U.S., the Food and Drug Administration (FDA)). In addition, independent ethics review committees (in the U.S., institutional review boards (IRBs)) oversee the trial design, conduct, data review and appropriate patient-consent forms, which provide transparency for the participants regarding the purpose of the study, risks, benefits, rights and privacy.
Clinical trials are often conducted at hospitals or clinics, and are implemented by the local medical personnel under the supervision of the lead/principal investigator.
What Has Changed During COVID-19?
- Significantly increased awareness of the need and impetus to increase subject diversity in clinical trials 2
- Emerging models for broader subject enrollment, where individuals could be assigned to different trials for different types of treatments — e.g., vaccines, therapies — and the importance of public-private partnerships to increase and enhance this enrollment and communication
- Lack of participant pools in certain areas due to unwillingness to “break quarantine” for what may be perceived as a non-essential function for the individual
- Instead of on-site visits, increased use of:
- Drive-through sites for collecting subjects’ samples
- Home visits by nurses to collect samples in subjects’ homes
- Subjects’ self-collection of samples (and mailing or digitally submitting them)
- Telemedicine — virtual visits using telephone or videoconferencing
- Partnership to collect samples with entities not otherwise part of a study — e.g., a local clinic versus requiring the subject to drive to the study site
Study Design and Data Analysis
- A trend for increased application of adaptive trial designs, which enable one to make prospectively planned changes to trial designs based on results of interim analysis
- Increased recognition of the need for decentralized trials
- Increased flexibility from regulators regarding missing data or ongoing reporting due to inability to collect samples, inability of patients to visit clinics or patients dropping out of trials. Regulators are nevertheless putting emphasis on careful and comprehensive documentation of:
- What information is missing and the reasons?
- If alternate methods of collecting information are used or changes made to protocols, those changes must be documented and rationales/justifications made.
- During the pandemic, regulatory agencies have made significant efforts to adjust to new restrictions. Rules were published to increase flexibility — e.g., for conducting audits of manufacturing sites via virtual tours. On the other hand, the divergence of requirements by the region — which has always existed to some extent — may have increased because individual states are introducing some rules unilaterally. Even in situations where rules are issued at the federal level (e.g., in the U.S.) or union level (e.g., in the EU), they are often interpreted differently in different states. Harmonization has always required a deliberate effort, collaboration and negotiations; while the circumstances of the current public-health crisis have not yet afforded the time and opportunity to identify and then to reduce these new emerging divergences.
- For many regulatory agencies there is a common focus on: maintaining the safety of trial participants and personnel; comprehensive documentation of any deviations in the trial plan; and management and assessment of risks associated with trial changes. Most guidelines provide for alternative means to collect information from patients — e.g., home visits by nurses, telephone or web-based meetings, use of digital tools to collect some clinical information. These types of provisions are also seen in guidelines beyond those in the U.S. and EU, including China 3 and Japan.4
- The lockdowns and border closures made the flow of raw materials, supplies and off-site services more uncertain. This may also be affecting analytical testing schedules, since the testing samples — e.g., from the clinical trials themselves or from chemistry manufacturing and controls tests — often are shipped to remote laboratories for analysis.
- If a company’s established suppliers cannot deliver on time, or if there is a need to find new or additional vendors for any reason, these new suppliers need to be validated, and quality and technical agreements established, requiring further time and investment. Agreement on timeframes for security of supply may also need to be established.
Other Ongoing Challenges
- Technologies for testing off-site (by medical personnel at home or self-testing) are relatively new although rapidly evolving.
- In part due to relative immaturity of these methods, certain aspects have not been worked out to the same extent as in traditional clinical trials. For example:
- Measurements of heart rate and blood pressure using consumer apps could add variability into data due to lack of standardization/calibration of those tools.
- Incorrect or inconsistent recording of the time a sample is taken can throw off the results overall.
- The accuracy of self-measured values could be dependent on a subject’s skill.
- Video or phone interviews with subjects could miss clinically important signals if the subject does not volunteer them and if those signals cannot be ascertained just by looking at the screen image of a person’s face (e.g., atypically pale skin, limping, unnatural fatigue, etc.)
Where Are the Trends Pointing?
- Analytical and statistical methods for generating and interpreting data from off-site testing will be further developed, validated more broadly, adopted more widely, and their performance (strengths and weaknesses) better understood with time.
- Novel devices and mobile apps will continue to proliferate.
- Increased use of real-world data and real-world evidence to help design clinical trials (as well as capture clinical information about products post-market), and increased need for digital systems to connect the data and information from patients to hospitals to developers to regulators, etc.
Regulations and Standards
- Regulatory agencies — after the initial shock and resulting increased flexibility early in the pandemic — have started to re-introduce pre-pandemic requirements (e.g., re-starting in-person audits in addition to virtual audits).
- Privacy protection requirements will continue to be strengthened.
- There likely will be an increase in standards for validation of digital tools.
- Some industry leaders are suggesting that some changes seen during COVID-19 are here to stay, catalyzing a transformation of the overall regulatory landscape long-term.5 Regulators have also hinted at using learnings to consider where flexibilities could be integrated into future regulatory practice.6
The COVID-19 pandemic has created a series of unique challenges for clinical trial sponsors. Although regulators have responded by permitting flexibility, sponsors should keep pre-existing regulatory frameworks and tools in mind even during this unprecedented time. It is likely that the changes made during COVID-19 will lead to some permanent changes in regulatory frameworks, but regulators will continue to emphasize the same objectives and considerations they focused on prior to the pandemic.