FDA Guidance "Development and Licensure of Vaccines to Prevent COVID-19" - sample size situation for phase 3 studies

Last week, FDA issued its guidance for industry "Development and Licensure of Vaccines to Prevent COVID-19". Unlike the usual FDA guidance where FDA issues the draft guidance with a comment period, this guidance is immediately effective as the final version upon its issuance.

The guidance sets its expectations for the development and licensure of vaccines to prevent coronavirus disease (COVID-19), including considerations for manufacturing, nonclinical and clinical studies, and post-licensure requirements.

The guidance provided details about the pivotal (phase 3) efficacy and safety study. For phase 3 study, the primary efficacy endpoint should be "the incidence of laboratory-confirmed symptomatic COVID-19" specified in the guidance as the following: 

Section E of the guidance 'Statistical Considerations' provided the specific requirements for the statistical success criteria (i.e., point estimate of vaccine efficacy at least 50% and the lower bound of the alpha-adjusted confidence interval at least 30%).  

What does the vaccine efficacy of 50% mean?

Vaccine Efficacy (VE) = [(COVID-19 attack rate in the unvaccinated group - COVID-19 attack rate in the vaccinated group) / COVID-19 attack rate in the unvaccinated group] * 100%

where the attack rate is equivalent to the incidence rate. 

Using the relative risk (RR) or risk ratio [= (incidence of COVID-19 cases in the vaccinated group) / (incidence of COVID-19 cases in the unvaccinated group)], VE = 1 - RR.

Suppose after 3-6 months observation period post-vaccination, there are 100 cases of laboratory-confirmed symptomatic COVID-19 patients in the unvaccinated group and 50 cases in the vaccinated group, assuming the total follow-up time (person-time) are similar between the unvaccinated and vaccinated groups, the VE will be calculated as (100-50)/100 *100%= 50%.

In practice, the person time (PT) in the vaccinated group and unvaccinated group will be included in the calculation of attack rate or incidence rate where the attack rate = the number of cases observed in the vaccination group or unvaccinated group / Person Time (PT) in the vaccination or vaccination group. If the Poisson regression method is used, the person time will be used in the model as an offset variable. Person time (PT) is the same concept as person-year or patient-year and can be calculated in the same way as the person year with a perhaps different unit. 

VE at least 50% is a point estimate - not dependent on the sample size. For a much smaller trial, if we have 5 cases in the vaccination group and 10 cases in the vaccination group, the VE will still be 50%.

For sample size calculation, we will also need to know the confidence interval. As indicated in the FDA's guidance,  the lower bound of the appropriately alpha-adjusted confidence interval around the primary efficacy endpoint point estimate needs to be greater than 30%.

How to calculate the sample size? Which parameters do we need to calculate the sample size? 

The commercial software (such as EAST, SAS Proc Power, PASS, NQuery Advisor) can all be used to calculate the sample size. In a hypothetic example in the previous post, the sample size was calculated using EAST module for Ratio of Poisson Rates. 

Matthew M. Loiacono had a thesis on "Sample Size Estimation and Power Calculations for Vaccine Efficacy Trials for Exceedingly Rare Diseases" where two SAS macros were developed to estimate the sample sizes: one based on the Exact Conditional Test and one based on the Z Test Normal Approximation.

The sample size calculation will need the following five parameters:

• Incidence of laboratory-confirmed symptomatic COVID-19 cases in the unvaccinated group 
• True efficacy of test vaccine under the alternative hypothesis (according to FDA guidance, this is 50%) 
• Minimum efficacy of test vaccine, under the null hypothesis (according to FDA guidance, this is 30%)
• Power: pre-specified statistical power desired to achieve (usually 80% or 90%) 
• Alpha: pre-specified maximum one-sided level of the test (usually 0.05 for experimental level)

The most critical parameter is the incidence of laboratory-confirmed symptomatic COVID-19 cases - it is difficult to predict; it shifts with geographic location and time; it is impacted by the COVID-19 prevention strategies and policies. In general, the lower the incidence of COVID-19 cases, the larger the sample size is needed for phase 3 study to demonstrate the vaccine efficacy. 

Assuming the incidence of COVID-19 is 0.01 in unvaccinated (placebo) group, with 80% statistical power and alpha = 0.05, using the SAS macro based on Exact Conditional Test method, 33868 volunteers need to be randomized (estimated 254 COVID-19 cases observed) to detect the vaccine efficacy with point estimate at least 50% and lower bound of 95% confidence interval greater than 30%. 

Sample Size for COVID-19 Vaccine Phase 3 Study

Vaccine development for COVID-19 is at historic speed. Several companies have already had vaccines in the early phase of clinical trials. Leading the pack are AstraZeneca / Oxford University and Moderna / NIH who are targeting July for starting the late-stage phase 3 studies. Phase 3 study is pivotal in demonstrating that the vaccine is safe and effective in the general population including those at high risk of contracting COVID-19 and those with underly diseases.

There are quite some discussions about the sample size of the phase 3 study - the sample size for phase 3 study should be adequate to provide sufficient statistical power to demonstrate the vaccine's efficacy in preventing the COVID-19 infection and also adequate for regulatory agencies to assess the safety of the vaccine - sample size should be big enough so that the rare event (if any) can be observed. The sample size is being proposed to be at least 30,000 volunteers.

• FDA Shouldn't Authorize Coronavirus Vaccines Unless They're Tested on at Least 30,000 People: Experts
• Vaccine experts want the FDA to commit to 30,000 people in Covid-19 vaccine trials
• Lawmakers ask FDA to outline COVID-19 vaccine approval process
• Opinion: Here’s why the FDA may approve a Covid-19 vaccine before the November elections, according to Jefferies’ biotech-research team

For pivotal clinical trials, the sample sizes depend on the study design and the primary efficacy endpoint; and estimated based on assumptions.

The study design will be traditionally randomized, double-blinded, placebo- or active-controlled, parallel-group design (not human challenge design even though it has been pushed by some people) - see a previous post "Human Challenge Study Design for Covid-19 Vaccine Clinical Trials?".

• Human challenge trials with live coronavirus aren’t the answer to a Covid-19 vaccine
• Human Challenge Study Design for Covid-19 Vaccine Clinical Trials?

The primary efficacy endpoint is the incidence of symptomatic COVID-19. Moderna has finalized the study design for its phase 3 study and it says that the study will include 30,000 volunteers and the primary and secondary efficacy endpoints as the following:

"The primary objective of the trial, which is set to start in July, is to assess the ability of mRNA-1273 to prevent symptomatic COVID-19 disease. Secondary endpoints will assess the ability of mRNA-1273 to prevent hospitalization and infection with SARS-CoV-2."

•  Fauci: Moderna’s Phase 3 Covid-19 Vaccine Trial Of 30,000 Individuals Will Begin In July
• Moderna finalizes design of phase 3 COVID-19 vaccine trial ahead of July start
• Exclusive: U.S. plans massive coronavirus vaccine testing effort to meet year-end deadline

AstraZeneca/Oxford's COVID-19 vaccine enters phase 2/3 clinical trial. Their proposed sample size is much smaller than 30,000 subjects mentioned by US experts. We can also notice that they propose to use the vaccine against meningococcal bacteria as the control (instead of placebo). 

"Researchers at the University of Oxford have begun enrolling subjects in a phase 2/3 clinical trial of AstraZeneca-partnered COVID-19 vaccine AZD1222. The next stage of the program, which follows a 1,000-subject phase 1, is set to enroll 10,260 people in the U.K. to generate results to support the first shipments to customers in September."

"Once the vaccine moves into phase 3, the researchers will limit enrollment to people age 18 years and older. Adult participants in the phase 2 and 3 trials will be randomized to receive one or two doses of AZD1222 or a vaccine against meningococcal bacteria that will serve as the control.

The use of an active vaccine as a control is intended to ensure participants are unable to tell whether they received AZD1222 based on side effects such as soreness at the injection site. In the absence of such effects across both groups, participants could determine whether they had received the vaccine and make behavioral changes that skew the results of the study. "

Baseline on the study registration on clinicaltrials.gov "A Phase 2/3 Study to Determine the Efficacy, Safety and Immunogenicity of the Candidate Coronavirus Disease (COVID-19) Vaccine ChAdOx1 nCoV-19", we can see the following:

• The study consisted of different sub-groups (different age groups and different duration of the follow-up period).
• The primary efficacy endpoint is the number of biologically confirmed (PCR positive) symptomatic cases of COVID-19
• The primary safety endpoint is the occurrence of serious adverse events (SAEs) throughout the study duration.

It is not clear what the assumptions are used for estimating the sample size (30,000 subjects for Moderna's phase 3 study or 10,260 subjects for AstraZeneca/Oxford's phase 3 study). Perhaps the sample size is more based on the experiences rather than the calculation based on the solid assumptions.
In order to estimate the sample size, we will need to know the incidence rate of symptomatic COVID-19 in the control group (subjects who receive a placebo or a none anti-COVID-19 vaccine) and then the effect size (how much reduction in the incidence rate of symptomatic COVID-19 in the vaccine group (subjects who receive COVID-19 vaccination) - both of these are difficult to obtain.

• Estimating COVID-19 Prevalence in Symptomatic Americans
• COVID-19 Cases in U.S.

The incidence rate of symptomatic COVID-19 can vary significantly depending on the timing, the location, and the prevention and COVID-19 control strategies (i.e., stay-at-home, quarantine, social distance).

Back in January and February, the incidence rate of symptomatic COVID-19 would be very high. But now the COVID-19 situation in China has been under control. It is no longer feasible to test the efficacy of the COVID-19 vaccine in China. There are reports that COVID-19 vaccine researchers in China are looking for foreign sites to recruit the volunteers to test the efficacy of their vaccine candidate.

In the US, the incidence rate of symptomatic COVID-19 would be very high in New York and New Jersey in March/April time, now the states with high incidence rates have shifted to the southern states such as Texas, Arizona, North Carolina.

For phase 3 study to demonstrate the efficacy against the COVID-19, a sufficient number of subjects need to be included in the study so that (hopefully) a sufficient number of symptomatic COVID-19 cases can be observed (more in the control group and less in COVID-19 vaccine group). If subjects are recruited in areas with a high incidence rate, it will be quicker to accrue the number of symptomatic COVID-19 cases. Ironically, with strict COVID-19 prevention/control strategies, by the time the phase 3 studies start, the situation may be under the control and the incidence rate may be too low to accrue enough symptomatic COVID-19 cases. In the article below, a drop in coronavirus cases was listed as one of the biggest risks for Moderna's phase 3 study.

Here Are the 3 Biggest Risks for Moderna Right Now

"3. A drop in coronavirus cases

Of course, a drop in coronavirus cases is great news for everyone. But in order for Moderna and other vaccine makers to test their investigational products, the virus must be actively circulating. In an outbreak situation, the vaccine or placebo is administered to a group of healthy volunteers. If a high number of placebo participants get sick and those who received the vaccine don't, it's likely the vaccine is working. But if the virus is hardly present, it would be impossible to draw such a conclusion.

In the U.S., coronavirus cases recorded by the Centers for Disease Control and Prevention are cumulative, so they will continue to grow. And some states are still seeing spikes. But nationally, the number of people seeking medical attention for symptoms has been on the decline. If the trend continues, it may present difficulties for Moderna and rivals conducting trials in the U.S. to prove vaccine efficacy.

That doesn't mean the vaccine is doomed, but testing it could become more complicated. If virus circulation drops considerably, researchers may conduct a "challenge" trial. That means healthy volunteers are immunized, then exposed to the virus. There also is the possibility of conducting trials in other areas where the virus is on the rise. At this point, Moderna hasn't said it would turn to either of these alternatives."

The primary efficacy endpoint of "biologically confirmed symptomatic cases of COVID-19" belongs to the count data. Given the incidence rate is very low among the general population, the data can be assumed to follow a Poisson distribution or negative binomial distribution. The sample size calculation will then need to be based on Poisson rates or negative binomial rates. 

Hypothetically, the statements about the sample size for phase 3 COVID-19 vaccine studies can be something like this assuming 50% reduction in symptomatic CIVID-19 cases in the vaccine group:

Assuming that the incidence rate (Poisson mean) of subjects with symptomatic COVID-19 case is 0.003 (0.3%) in control group and 0.0015 (0.15%) in COVID-19 vaccination group, 32,673 subjects needs to be randomized to have 80% statistical power to detect the treatment difference."

In the US, we saw the rise in coronavirus cases - it is bad, really bad, but ironically it is good for vaccine clinical trials - it is easier and quicker to accrue a sufficient number of symptomatic COVID-19 cases and it requires less sample size for phase 3 studies to demonstrate the difference between vaccinated and control groups. As Dr. John Skerritt from the Department of Health, Australia said about the COVID-19 pandemic: "Do not waste a good crisis". 

The fate of confirmatory clinical trials for Remdesivir for treatment of COVID-19

Remdesivir, as the first highly touted drug to treat COVID-19 patients, has now been approved for emergency use authorization in several countries. The focus of fighting COVID-19 seems to shift to the safe and effective vaccine development. Unfortunately, the efficacy of Remdesivir has not been confirmed due to the flaws in the study design (for example, no placebo control) or due to the issues in the study conduct (for example, early discontinuation of the study resulted in underpowered studies) .

• Despite the Hype, Gilead’s Remdesivir Will Do Nothing to End the Coronavirus Pandemic
• Remdesivir alone is not enough, researchers conclude in first major Covid-19 trial of the drug
• Data Monitoring for the Chinese Clinical Trials of Remdesivir in Treating Patients with COVID-19 During the Pandemic Crisis
• Gilead to end coronavirus drug trials, adding to access worry: researchers

In a previous post, six pivotal studies were listed for Remdesivir. These six studies were also listed in the article by Singh et al Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies.

The table below listed the status (fate) of these studies.

 

Protocol Title	Study Features	Fate of Studies
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe COVID-19	Gilead Sciences Phase III, initially planned for 400 subjects, then increased to 2400, and then 6000 subjects Two  arms: Standard of care + Remdesivir for 5 days, Standard of care + Remdesivir for 10 days	Enrolment was stopped early after 397 subjects were randomized.   Results were published in NEJM (Goldman et al “Remdesivir for 5 or 10 Days in Patients with Severe Covid-19“ Conclusion: “In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined.” It is noted that the study design was flawed and should have included a third arm with Standard of Care without Remdesivir.
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate COVID-19 Compared to Standard of Care Treatment	Gilead Sciences Phase III, initially planned for 600 subjects, then increased to 1600 subjects Three arms: Remdesivir for 5 days, Remdesivir for 10 days, Standard of care	The study is active, but not recruiting new patients. The enrolment has stopped. The results have not been published yet. Gilead announces results in a press release “Gilead Announces Results From Phase 3 Trial of Remdesivir in Patients With Moderate COVID-19” Study Demonstrates 5-Day Treatment Course of Remdesivir Resulted in Significantly Greater Clinical Improvement Versus Treatment with Standard of Care Alone Data Add to Body of Evidence from Prior Studies Demonstrating Benefit of Remdesivir in Hospitalized Patients with COVID-19 Also see the articles “More evidence remdesivir helps some coronavirus patients”  “Gilead's remdesivir shows modest improvement in moderate COVID-19 patients” “A slice of half-baked remde­sivir da­ta takes a dark turn — but we're still wait­ing for a de­fin­i­tive study”
A Phase 3 Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Mild and Moderate 2019-nCoV Respiratory Disease.	Capital Medical University/Chinese Academy of Medical Sciences Phase III, 308 Subjects Two arms: Remdesivir, placebo Mainland China only	The study was suspended (The epidemic of COVID-19 has been controlled well at present, no eligible patients can be recruited).  The results have not been published yet.  See “Second trial testing Gilead's remdesivir in COVID-19 suspended in China”
A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Severe 2019-nCoV Respiratory Disease.	Capital Medical University Phase III, 453 Subjects Two arms: Remdesivir, placebo Mainland China only	The study was terminated after 237 patients were enrolled and randomly (158 in remdesivir and 79 in placebo) (The epidemic of COVID-19 has been controlled well in China, no eligible patients can be enrolled at present.) Results were published at Lancet Wang et al “Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial” Conclusion: “In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.”
A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults	National Institute of Allergy and Infectious Diseases (NIAID) Phase II, planned 440 Subjects (protocol specified 394 subjects), actual enrolment: 1063 subjects at the time of DMC review) Two arms: Placebo, Remdesivir with additional arms to be added Multi-National: US, Japan, South Korea, Singapore	The study was stopped after the interim analyses.  Results were published in NEJM by Beigel et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report Conclusion: “Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection.” The results from this study were the basis for FDA to issue Emergency Use Authorization for Remdesivir. Subsequently, several other countries followed suit. It is disappointing that the study was stopped after inconclusive or not convincing results from the interim analyses. There was no mention if there was a pre-specified stopping rule and whether the boundaries for stopping the study had been crossed.  Also see: Inside the NIH’s controversial decision to stop its big remdesivir study
Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults	Institut National de la Santé Et de la Recherche Médicale, France Phase III, 3100 Subjects Four arms: Remdesivir, Lopinavir/ritonavir, Interferon Beta-1A, Hydroxychloroquine, Standard of care France Only	F Ongoing. Continue to enroll new patients

Neutralizing Antibodies: Active Immunization and Passive Immunization Against Covid-19

Generally speaking, a person achieves immunity to disease through the presence of neutralizing antibodies, or proteins produced by the body that can neutralize or even destroy toxins or other disease carriers.  Active immunization is the process of vaccination to prevent an infectious disease by activating the body’s production of antibodies that can fight off invading bacteria or viruses.

The neutralizing antibodies (so-called because they stop the virus from being able to infect cells) can also be obtained from outside the body and can be given the recipients as a therapy for the prevention or treatment of a disease. Passive immunization is the process of administering the antibodies against a particular infectious agent.

An easy example is the antibodies against the rabies. In order to get immunity against rabies virus, we can receive rabies vaccine. Usually 2-3 weeks after the administration of the rabies vaccine (usually several courses), the neutralizing antibodies against rabies will develop in recipient’s body – this is called vaccine-induced active immunity. However, rabies antibodies can also be obtained from the human plasma donated by people in plasma collection centers scattered throughout the United States. The pooled plasma can be fractionated, and rabies antibodies can be obtained – these products are called RIG (Rabies Immune Globulin or hyperimmune globulin against rabies). The RIG can be given to the people to obtain so called ‘passive immunity’. If someone had potential exposure to rabies (for example, bite by wild animals) and had no record of rabies vaccination, the RIG should be immediately given to achieve the passive immunity for short period protection.

The same process of active immunity and passive immunity applies to the Covid-19 situation. Below is a table to compare the active immunity vs. passive immunity in Covid-19 situation:

Active Immunity	Passive Immunity
Relies on neutralizing antibodies against SARS-CoV-2 (the virus causing Covid-19)
active immunity results when exposure to a disease organism triggers the immune system to produce antibodies to SARS-CoV-2	passive immunity results when receiving a therapy containing neutralizing antibodies against SARS-CoV-2
Neutralizing antibodies are generated by our own immune system	Neutralizing antibodies are manufactured or obtained outside the body and then given to the recipients
Active Immunity can be obtained in two ways: Natural Immunity: obtaining immunity because of infection with Covid-19 (whether it is symptomatic or asymptomatic) Vaccine-Induced Immunity: obtaining immunity by receiving the vaccine (vaccination) that won’t make someone sick, but will trigger the body to make neutralizing antibodies), which is known as vaccine-induced immunity	passive immunity is provided when a person is given neutralizing antibodies. Antibody-containing blood products: convalescent plasma obtained from Covid-19 recovered patients Hyperimmune products (containing concentrated neutralizing antibodies) Manufactured antibody products
It will take a while for the body to generate neutralizing antibodies	Off-the-shelf, ready to use
Immunity (once obtained) will be longer	Immunity will be shorter
Companies who are working on vaccines: see previous post “Coronavirus Vaccine Tracker - Developing Vaccines Against Covid-19 “	Key players in the field (examples only): Convalescent plasma – Mayo Clinic Hyperimmune globulin – Grifols Neutralizing antibodies cocktail - Regeneron, Eli Lilly, Sorrento Therapeutics
Clinical trials in ‘healthy’ volunteers	Clinical trials in Covid-19 patients
Clinical trials to demonstrate the effect in prevention (prevent from symptomatic Covid-19)	Clinical trials to demonstrate the effect in treatment (speed up the recovery of the symptomatic Covid-19 patients and decrease the mortality)
The development process is longer	The development process is shorter
Larger sample size for clinical trials required for demonstrating the efficacy in prevention of Covid-19	Smaller sample size for clinical trials required for demonstrating the efficacy in the treatment of Covid-19

References:

• What to Know About Active Vs. Passive Immunity—And Why Both Matter With COVID-19
• Explainer: What are antibody therapies and who is developing them for COVID-19?
• A coronavirus vaccine is still months away, but an antibody treatment could be closer
• Coronavirus Antibody Therapies Raise Hopes—and Skepticism
• "Immunity passports" in the context of COVID-19
• CDC: Immunity Types
• CDC: Rabies 
• China begins phase 1 clinical trials of neutralizing antibody treatment for COVID-19

Coronavirus Vaccine Tracker - Developing Vaccines Against Covid-19

Ultimately, to win the battle against the Covid-19, we will rely on a safe and effective available in very large quantities. Pharmaceutical companies (large or small), biotech companies, academic, and governmental agencies have all rushed into the vaccine development field to fight the Covid-19. We hope that some vaccines will eventually become the winners.

The New York Times has a website for "Coronavirus Vaccine Tracker". The tracker grouped the vaccines into four categories:

• Genetic Vaccines developed by Moderna, BioNTech/Pfizer, Inovio, ...
• Viral Vector Vaccines developed by Oxford/Astrazeneca, CanSinoBIO, Johnson and Johnson,...
• Protein-Based Vaccines developed by Novavax, GSK, Baylor College of Medicine,...
• Whole-Virus Vaccines developed by Sinovac, Sinopharm,...

So far, some vaccines have gone beyond the pre-clinical stage and progressed into the clinical trial stage. Below is a timeline for those vaccines already in human trials: 

Also, this map shows where coronavirus vaccines are being tested around the world.

However, vaccine development is a lengthy process consisting of phase 1 -> phase 2 -> phase 3 clinical trials before the vaccine can be approved for use. In phase 3 study, the candidate vaccine must be demonstrated to be safe in the general public (with different age groups including the population with underly conditions)

With so many clinical trials initiated or to be indicated, there may be a shortage of volunteers for these studies. The extreme measures to control the Covid-19 (guarantee, stay-at-home, face-masks,...) are necessary to prevent the virus spread, however, it will lower the incidence rate of Covid-19 - consequently, the phase 3 studies for vaccines will require larger sample size with more participants in order to have the adequate statistical power and accumulate a sufficient number of Covid-19 infection cases to establish the efficacy of the candidate vaccine. The phase 2 study will include around 1000 volunteers and the phase 3 study will be even bigger with tens of thousands of volunteers. For those vaccines already in the clinical trial stage: the University of Oxford's phase 1/2 trial had a sample size of 1,090 participants. Moderna's vaccine candidate is being tested in phase 2 study with 600 participants. Its phase 3 study is planned to start this July and will include 30,000 participants to test if the vaccine is safe in general population and if the vaccine is effective in preventing symptomatic Covid-19.


Can we really expect to have a safe and effective Covid-19 vaccine available in a year? It is unlikely, but some people are cautiously optimistic. Read the panel discussions below:

Can a Vaccine for Covid-19 Be Developed in Record Time?

A discussion moderated by Siddhartha Mukherjee

Should Drug Safety (or Pharmacovigilence) Group be Provided with the Randomization Schedule for Blinded Studies?

To avoid the conscious and unconscious bias in safety and efficacy assessment, clinical trials are usually designed as double-blinded studies whenever the blinding is feasible. Double-blind indicates that the treatment assignments are concealed to the investigator and the study participants. The blinding is usually extended to the entire study team including the sponsor, CRO, and vendors. If too many study participants are unblinded during the study, the study integrity will be compromised.

However, not everybody is blinded to the treatment assignment. On the Sponsor side, the clinical trial material (CTM) management group is usually unblinded and has full access to the treatment assignments - because they need to make sure that the correct drugs (active or control) are packaged, labeled, shipped, and dispensed. CTM group will track the inventory at the study sites to make sure the study materials are available at all open sites.

The drug safety group or pharmacovigilance group (PVG) may also request for full access to the treatment assignment and they claim the full access to the treatment assignment is needed for serious adverse event reporting.

It is true that the regulations require the drug safety group to report the 'serious and unexpected suspected adverse reaction (SUSAR)' to regulatory agencies, investigators, and IRBs/ECs.

• 21CFR 312.32 IND safety reporting
• Directive 2001/20/EC of the European Parliament and of the Council
• Breaking the Blind in Clinical Trials & Reporting to Health Authorities, Investigators & IRBs/Ethics Committees
• Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
• Safety assessment in Clinical Trials and Beyond

Code of Federal Regulation regarding IND Safety Reporting says:

"(i) Serious and unexpected suspected adverse reaction. The sponsor must report any suspected adverse reaction that is both serious and unexpected. The sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the drug and the adverse event, such as:

(A) A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome);

(B) One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture);

(C) An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group."

EU has similar regulations. According to EU directive "on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use"

Article 17 Notification of serious adverse reactions 1. (a) The sponsor shall ensure that all relevant information about suspected serious unexpected adverse reactions that are fatal or life-threatening is recorded and reported as soon as possible to the competent authorities in all the Member States concerned, and to the Ethics Committee, and in any case no later than seven days after knowledge by the sponsor of such a case, and that relevant follow-up information is subsequently communicated within an additional eight days. (b) All other suspected serious unexpected adverse reactions shall be reported to the competent authorities concerned and to the Ethics Committee concerned as soon as possible but within a maximum of fifteen days of first knowledge by the sponsor. (c) Each Member State shall ensure that all suspected unexpected serious adverse reactions to an investigational medicinal product which are brought to its attention are recorded. (d) The sponsor shall also inform all investigators.

It is true that the drug safety group needs the treatment assignment information to assess the causal relationship of a SUSAR event to the study drug. If a SUSAR occurs in a placebo group, the event will then not be required to be reported.

Unlike the STM group, the drug safety group only needs the treatment assignment for individual subjects at the time when a SUSAR is reported. It is concerning that the drug safety group is given full access to the treatment assignment for all subjects. Drug safety group personnel sometimes can accidentally communicate the treatment assignment information outside the drug safety group (to the investigator and to the blinded study team) and causing the accidental unblinding of the subject.

I just read the FDA’s review document for a Merck product and noticed the review comments mentioning that drug safety staff should be blinded during the study. Given the potential accidental unblinding caused by drug safety staff, it is prudent to restrict drug safety staff’s access to the randomization codes for ongoing blinded studies.  

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000MedR.pdf

However, the drug safety group should be given emergency access to the randomization codes. In the situation a SUSAR is reported, drug safety personnel who are handling the SUSAR reporting can log into the interactive response technology (IRT) including interactive web response (IWR) and interactive voice response system (IVR) systems, and obtain the randomization information and treatment assignment for the individual subject with SUSAR reported. 

In summary, the drug safety group or PVG should not be given full access to all randomization codes, but should be provided in a controlled way the access to treatment information for individual subjects who have SUSAR reported. 

Binding Antibodies, nonneutralizing antibodies (n-NAbs), and Neutralizing Antibodies (NAbs)

Last Monday, Moderna announced the positive results from its phase I clinical trial for its mRNA vaccine against Covid-19. The study was listed under clinicaltrials.gov as "Phase I, Open-Label, Dose-Ranging Study of the Safety and Immunogenicity of 2019-nCoV Vaccine (mRNA-1273) in Healthy Adults". This phase I study contains 9 cohorts with 3 different vaccine doses (25 mcg, 100 mcg, and 250 mcg) in three different age groups (18-55, 56-70, and 71 or above years of age). The announced results were from three dose groups in 18-55 years of age. The phase I study was the first step to test the safety and the immunogenicity (i.e. vaccine's ability to trigger an immune response in the body) of the vaccine, but the released preliminary results caused a strong reaction from the wall street.

The immunogenicity data indicated that the binding antibodies were detected in all 45 subjects in three dose groups in 18-55 years of age and the neutralizing antibodies were detected in all 8 subjects in the first four subjects in 25 mcg and 100 mcg groups. It is worth discussing what the difference is between the binding antibodies and the neutralizing antibodies.

Moderna Announces Positive Interim Phase 1 Data for its mRNA Vaccine (mRNA-1273) Against Novel Coronavirus

"Immunogenicity data are currently available for the 25 µg and 100 µg dose level (ages 18-55) after two doses (day 43) and at the 250 µg level (ages 18-55) after one dose (day 29). Dose dependent increases in immunogenicity were seen across the three dose levels, and between prime and boost within the 25 µg and 100 µg dose levels. All participants ages 18-55 (n=15 per cohort) across all three dose levels seroconverted by day 15 after a single dose. At day 43, two weeks following the second dose, at the 25 µg dose level (n=15), levels of binding antibodies were at the levels seen in convalescent sera (blood samples from people who have recovered from COVID-19) tested in the same assay. At day 43, at the 100 µg dose level (n=10), levels of binding antibodies significantly exceeded the levels seen in convalescent sera. Samples are not yet available for remaining participants.

At this time, neutralizing antibody data are available only for the first four participants in each of the 25 µg and 100 µg dose level cohorts. Consistent with the binding antibody data, mRNA-1273 vaccination elicited neutralizing antibodies in all eight of these participants, as measured by plaque reduction neutralization (PRNT) assays against live SARS-CoV-2. The levels of neutralizing antibodies at day 43 were at or above levels generally seen in convalescent sera."

Moderna reports positive data on early-stage coronavirus vaccine trial, shares surge

"Moderna’s closely watched early-stage human trial for a coronavirus vaccine produced Covid-19 antibodies in all 45 participants, the biotech company announced Monday, sending the company’s shares surging nearly 20%."

"The vaccine also produced neutralizing antibodies against Covid-19 in at least eight participants, the company said. Experts have said neutralizing antibodies appear to be important in acquiring protection."

Vaccines are examples of antigens in an immunogenic form, which are intentionally administered to a recipient (usually healthy volunteers) to induce the memory function of adaptive immune system toward the antigens of the pathogen invading that recipient. In Covid-19 situation, vaccines are developed against the SARS-Cov-2 (the pathogen (the virus) that caused Covid-19. In phase I studies, besides the safety, we want to see if administering the vaccines can generate the antibodies (first binding antibodies, then neutralizing antibodies). Phase I study can fail if there is a safety issue or if no or not enough antibodies are generated in recipients. 

Binding Antibodies: 
Not all antibodies that bind a pathogenic particle are neutralizing. Binding antibodies, or non-neutralizing antibodies (n-NAb), bind specifically to the pathogen (SARS-Cov-2 virus), but do not interfere with their infectivity. that might be because they do not bind to the right region. Non-neutralizing antibodies can be important to flag the particle for immune cells, signaling that it has been targeted, after which the particle is processed and consequently destroyed by recruited immune cells.

Binding antibodies are produced at high levels throughout the life of an infected individual but are characterized by their inability to prevent viral infection. Even though they do not have impact on virus' infectivity, binding antibodies are useful as diagnostic indicators of whether an individual is infected or not.

Neutralizing Antibodies (NAb):
Neutralizing antibodies on the other hand can neutralize the biological effects of the antigen without a need for immune cells. In some cases, non-neutralizing antibodies or insufficient amounts of neutralizing antibodies binding to virus particles can be utilized by some virus species to facilitate uptake into their host cells.

Binding antibodies and neutralizing antibodies are similarly discussed in therapeutic protein products or biological products including monoclonal antibody (mAb) drug. In vaccine studies, immunogenicity is a good thing and is what we want to see. In biological products (protein therapy or mAb), the immunogenicity is a thing we try to avoid - developing the anti-drug antibody will have impact on the efficacy and safety of a biological product or mAb.

Binding antibodies and neutralizing antibodies are measured with different assays (i.e., binding antibody assay and neutralization assay). According to FDA guidance "Immunogenicity Testing of Therapeutic Protein Products — Developing and Validating Assays for Anti-Drug Antibody (ADA) Detection"

"Screening assays, also known as binding antibody assays, are used to detect antibodies that bind to the therapeutic protein product. The specificity of ADA for the therapeutic protein product is usually established by competition with a therapeutic protein in a confirmatory assay. ADAs are characterized further using titration and neutralization assays. Titration assays characterize the magnitude of the ADA response. It is important to characterize this magnitude with titration assays because the impact of ADA on pharmacokinetics, pharmacodynamics, safety, and efficacy may correlate with ADA titer and persistence rather than incidence (Cohen and Rivera 2010). Neutralizing antibodies (NAbs) refer to those ADA with the ability to interfere with interactions between the therapeutic protein product and its target. Neutralization assays assess ADA for neutralizing activity. It is important to characterize neutralizing activity of ADA because the impact of ADA on pharmacokinetics, pharmacodynamics, safety, and efficacy may correlate with NAb activity rather than ADA incidence"