Why would it have been hard for AstraZeneca to discover blood clots in clinical trials?
Why would it have been hard for AstraZeneca to discover blood clots in clinical trials?
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The AstraZeneca vaccine went through rigorous Phase 3 testing and regulatory approval processes before being administered in the general public where it has been approved. In the reported Phase 3 trial data of more than 23,000 people, a total of 175 severe adverse events were reported (84 in the study group, 91 in the control group). Three events were considered possibly related to either the control or experimental vaccine. These events included one case of hemolytic anemia (in the phase 1/2 study control group), one case of transverse myelitis (in the study group 14 days after the second vaccine dose), and a case of high fever without another diagnosis (the patient information remains masked as part of the trial). Blood clots were not mentioned in the study published online on December 8, 2020. In clinical trials, it can be very difficult to identify uncommon side effects or serious adverse events (or reactions). When an event is uncommon, it can take a very large study group for it to be observed in research even once. Vaccine studies are designed to evaluate if the vaccine works, and if it is safe. COVID-19 vaccines were studied in clinical trials with thousands of participants before emergency use approval. Even with diverse and large study groups, it is possible that some side effects, reactions, or serious adverse events may not have been seen in the study population. Events that only occur in a few people out of a million or more can be very difficult to detect. In statistics there is a formula that is sometimes used to estimate how many people would need to be studied to detect a serious adverse reaction (SAR). The formula is called the rule of three. For example, if a medication were to cause a SAR in 1 person in every 1,000, then a company would need to study 3,000 people (the rule of 3) in order to have a 95% chance of observing or detecting even one case. For even more rare events that may occur in 1 person in every 10,000, a company would need to study 30,000 people to have a 95% chance of observing or detecting one case. For comparison, the type of rare blood clotting that was observed is estimated to occur in only a few people out of every million. To help understand more rare adverse effects, drugs and vaccines are studied even after they are approved for the public. Data collection continues for years. This Phase 4 study (or observation) continues as the sample size of the study population is much larger, currently in the many millions for the COVID-19 vaccines. Researchers are continuing to gather data and information about events that occur in people who have received the vaccine. In Epidemiology: An Introduction, a text by Kenneth Rothman, the author notes that a lot of the data around drug safety “comes from studies that are conducted after a drug is marketed.” For the COVID-19 vaccines, government agencies (like the U.S. Food and Drug Administration and others) are collecting data about possible adverse events. Suspected adverse events are reported to the agency, and the agency investigates further. A reported or possible association does not mean that a vaccine caused an event to happen. Trained researchers monitor and analyze data from these reports. They try to evaluate whether it is likely that the reaction was caused by the vaccine. To do so, they study the possible pathways that could cause the reaction to occur. They also compare the probability of the reaction in those who have been vaccinated to the probability of the reaction in those who have not. Now that many millions of people are being vaccinated with the new COVID-19 vaccines, it is not surprising that some rare events, like allergic reactions and blood clots, are being reported. Researchers now need to work to determine if the events are related to the vaccines and why. Many thousands of blood clots are diagnosed every year. Immobility, surgery, obesity, and smoking are some of the many risk factors. According to the European Medicines Agency, it is possible that blood clots could also be related to receiving the AstraZeneca COVID-19 vaccine. There has not been evidence of issues related to specific batches or a particular manufacturing site for the AstraZeneca vaccine. As of April 4, 2021, a total of 222 cases of thrombosis (169 cases of cerebral venous sinus thrombosis and 53 cases of splanchnic vein thrombosis have been reported) have been reported to EudraVigilance - the European system for managing information about serious adverse reactions to medicines. About 34 million people had been vaccinated in the European Economic Area and United Kingdom by this date. On April 7, 2021, the European Medicines Agency safety committee concluded “that unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (formerly COVID-19 Vaccine AstraZeneca).” The U.K. regulatory agency recommended alternatives to the AstraZeneca vaccine to be given to people under 30 years of age, following 79 reported cases of blood clotting and 19 deaths. As of April 16, 2021, the Australian regulatory agency is also conducting a review of the AstraZeneca vaccine following three reported instances of rare clotting, including one fatal case. AstraZeneca has not applied for regulatory approval in the United States, but another viral vector vaccine for COVID-19 made by Johnson & Johnson is also under review for rare blood clotting as of April 13, 2021. Regulatory agencies take vaccine safety seriously and often exercise an abundance of caution. COVID-19 vaccines have been credited with saving lives and reducing hospitalizations on a large scale.
The AstraZeneca vaccine went through rigorous Phase 3 testing and regulatory approval processes before being administered in the general public where it has been approved. In the reported Phase 3 trial data of more than 23,000 people, a total of 175 severe adverse events were reported (84 in the study group, 91 in the control group). Three events were considered possibly related to either the control or experimental vaccine. These events included one case of hemolytic anemia (in the phase 1/2 study control group), one case of transverse myelitis (in the study group 14 days after the second vaccine dose), and a case of high fever without another diagnosis (the patient information remains masked as part of the trial). Blood clots were not mentioned in the study published online on December 8, 2020. In clinical trials, it can be very difficult to identify uncommon side effects or serious adverse events (or reactions). When an event is uncommon, it can take a very large study group for it to be observed in research even once. Vaccine studies are designed to evaluate if the vaccine works, and if it is safe. COVID-19 vaccines were studied in clinical trials with thousands of participants before emergency use approval. Even with diverse and large study groups, it is possible that some side effects, reactions, or serious adverse events may not have been seen in the study population. Events that only occur in a few people out of a million or more can be very difficult to detect. In statistics there is a formula that is sometimes used to estimate how many people would need to be studied to detect a serious adverse reaction (SAR). The formula is called the rule of three. For example, if a medication were to cause a SAR in 1 person in every 1,000, then a company would need to study 3,000 people (the rule of 3) in order to have a 95% chance of observing or detecting even one case. For even more rare events that may occur in 1 person in every 10,000, a company would need to study 30,000 people to have a 95% chance of observing or detecting one case. For comparison, the type of rare blood clotting that was observed is estimated to occur in only a few people out of every million. To help understand more rare adverse effects, drugs and vaccines are studied even after they are approved for the public. Data collection continues for years. This Phase 4 study (or observation) continues as the sample size of the study population is much larger, currently in the many millions for the COVID-19 vaccines. Researchers are continuing to gather data and information about events that occur in people who have received the vaccine. In Epidemiology: An Introduction, a text by Kenneth Rothman, the author notes that a lot of the data around drug safety “comes from studies that are conducted after a drug is marketed.” For the COVID-19 vaccines, government agencies (like the U.S. Food and Drug Administration and others) are collecting data about possible adverse events. Suspected adverse events are reported to the agency, and the agency investigates further. A reported or possible association does not mean that a vaccine caused an event to happen. Trained researchers monitor and analyze data from these reports. They try to evaluate whether it is likely that the reaction was caused by the vaccine. To do so, they study the possible pathways that could cause the reaction to occur. They also compare the probability of the reaction in those who have been vaccinated to the probability of the reaction in those who have not. Now that many millions of people are being vaccinated with the new COVID-19 vaccines, it is not surprising that some rare events, like allergic reactions and blood clots, are being reported. Researchers now need to work to determine if the events are related to the vaccines and why. Many thousands of blood clots are diagnosed every year. Immobility, surgery, obesity, and smoking are some of the many risk factors. According to the European Medicines Agency, it is possible that blood clots could also be related to receiving the AstraZeneca COVID-19 vaccine. There has not been evidence of issues related to specific batches or a particular manufacturing site for the AstraZeneca vaccine. As of April 4, 2021, a total of 222 cases of thrombosis (169 cases of cerebral venous sinus thrombosis and 53 cases of splanchnic vein thrombosis have been reported) have been reported to EudraVigilance - the European system for managing information about serious adverse reactions to medicines. About 34 million people had been vaccinated in the European Economic Area and United Kingdom by this date. On April 7, 2021, the European Medicines Agency safety committee concluded “that unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (formerly COVID-19 Vaccine AstraZeneca).” The U.K. regulatory agency recommended alternatives to the AstraZeneca vaccine to be given to people under 30 years of age, following 79 reported cases of blood clotting and 19 deaths. As of April 16, 2021, the Australian regulatory agency is also conducting a review of the AstraZeneca vaccine following three reported instances of rare clotting, including one fatal case. AstraZeneca has not applied for regulatory approval in the United States, but another viral vector vaccine for COVID-19 made by Johnson & Johnson is also under review for rare blood clotting as of April 13, 2021. Regulatory agencies take vaccine safety seriously and often exercise an abundance of caution. COVID-19 vaccines have been credited with saving lives and reducing hospitalizations on a large scale.
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What our experts say
In statistics, there is a formula that is sometimes used to estimate how many people would need to be studied to detect a serious adverse reaction (SAR). The formula is called the rule of three. For example, if a medication were to cause a SAR in 1 person in every 1,000, then a company would need to study 3,000 people (the rule of 3) in order to have a 95% chance of observing or detecting even one case. For even more rare events that may occur in 1 person in every 10,000, a company would need to study 30,000 people to have a 95% chance of observing or detecting one case. For comparison, the type of rare blood clotting that was observed is estimated to occur in only a few people out of every million.
The AstraZeneca vaccine has gone through rigorous testing and regulatory approval before being administered in the general public where it has been approved. In Phase 3 trial data of more than 23,000 people, 175 severe adverse events were reported (84 in the study group, 91 in the control group). Three events were considered possibly related to either the control or experimental vaccine. Blood clots were not mentioned in the study published online on December 8, 2020.
Even with diverse and large study groups, it is possible that researchers may not uncover some side effects, reactions, or serious adverse events during clinical trials. Events that only occur in a few people out of a million or more can be very difficult to detect. When vaccines are given to millions of people, new and unseen side effects are likely to emerge that weren't seen in the smaller clinical trial groups.
To help understand rare adverse effects, scientists study drugs and vaccines even after they are approved for the public. Data collection continues for years. The sample size of the study population is much larger in these cases, currently in the many millions for the COVID-19 vaccines. Researchers are continuing to gather data and information about events that occur in people who have received the vaccine.
In Epidemiology: An Introduction, a text by Kenneth Rothman, the author notes that a lot of the data around drug safety “comes from studies that are conducted after a drug is marketed.” For the COVID-19 vaccines, government agencies (like the U.S. Food and Drug Administration and others) are collecting data about possible adverse events. Suspected adverse events are reported to the agency, and the agency investigates further. A reported or possible association does not mean that a vaccine caused an event to happen.
Trained researchers monitor and analyze data from reports of adverse events. They try to evaluate whether it is likely that the vaccine caused the reported event or reaction. To do so they study possible pathways that could cause the reaction to occur. They also compare the probability of the reaction in those who have been vaccinated to the probability of the reaction in those who have not.
Now that many millions of people are being vaccinated with the new COVID-19 vaccines, it is not surprising that some rare events, like allergic reactions and blood clots, are being reported. Researchers now need to work to determine if the events are related to the vaccines, and why.
Many thousands of blood clots are diagnosed every year. Immobility, surgery, obesity, and smoking are some of the many risk factors. According to the European Medicines Agency, it is possible that blood clots could also be related to receiving the AstraZeneca COVID-19 vaccine. There has not been evidence of issues related to specific batches or a particular manufacturing site for the AstraZeneca vaccine. As of April 4, 2021, a total of 222 cases of thrombosis have been reported to EudraVigilance—the European system for managing information about serious adverse reactions to medicines. About 34 million people had been vaccinated in the European Economic Area and United Kingdom by this date.
On April 7, 2021, the European Medicines Agency safety committee concluded “that unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (formerly COVID-19 Vaccine AstraZeneca).” The U.K. regulatory agency recommended alternatives to the AstraZeneca vaccine be given to people under 30 years of age, following 79 reported cases of blood clotting and 19 deaths. As of April 16, 2021, the Australian regulatory agency is also conducting a review of the AstraZeneca vaccine following three reported instances of rare clotting, including one fatal case.
AstraZeneca has not applied for regulatory approval in the United States, but another viral vector vaccine for COVID-19 made by Johnson & Johnson is also under review for rare blood clotting as of April 13, 2021. Regulatory agencies take vaccine safety seriously and often exercise an abundance of caution. COVID-19 vaccines have been credited with saving lives and reducing hospitalizations on a large scale.
In statistics, there is a formula that is sometimes used to estimate how many people would need to be studied to detect a serious adverse reaction (SAR). The formula is called the rule of three. For example, if a medication were to cause a SAR in 1 person in every 1,000, then a company would need to study 3,000 people (the rule of 3) in order to have a 95% chance of observing or detecting even one case. For even more rare events that may occur in 1 person in every 10,000, a company would need to study 30,000 people to have a 95% chance of observing or detecting one case. For comparison, the type of rare blood clotting that was observed is estimated to occur in only a few people out of every million.
The AstraZeneca vaccine has gone through rigorous testing and regulatory approval before being administered in the general public where it has been approved. In Phase 3 trial data of more than 23,000 people, 175 severe adverse events were reported (84 in the study group, 91 in the control group). Three events were considered possibly related to either the control or experimental vaccine. Blood clots were not mentioned in the study published online on December 8, 2020.
Even with diverse and large study groups, it is possible that researchers may not uncover some side effects, reactions, or serious adverse events during clinical trials. Events that only occur in a few people out of a million or more can be very difficult to detect. When vaccines are given to millions of people, new and unseen side effects are likely to emerge that weren't seen in the smaller clinical trial groups.
To help understand rare adverse effects, scientists study drugs and vaccines even after they are approved for the public. Data collection continues for years. The sample size of the study population is much larger in these cases, currently in the many millions for the COVID-19 vaccines. Researchers are continuing to gather data and information about events that occur in people who have received the vaccine.
In Epidemiology: An Introduction, a text by Kenneth Rothman, the author notes that a lot of the data around drug safety “comes from studies that are conducted after a drug is marketed.” For the COVID-19 vaccines, government agencies (like the U.S. Food and Drug Administration and others) are collecting data about possible adverse events. Suspected adverse events are reported to the agency, and the agency investigates further. A reported or possible association does not mean that a vaccine caused an event to happen.
Trained researchers monitor and analyze data from reports of adverse events. They try to evaluate whether it is likely that the vaccine caused the reported event or reaction. To do so they study possible pathways that could cause the reaction to occur. They also compare the probability of the reaction in those who have been vaccinated to the probability of the reaction in those who have not.
Now that many millions of people are being vaccinated with the new COVID-19 vaccines, it is not surprising that some rare events, like allergic reactions and blood clots, are being reported. Researchers now need to work to determine if the events are related to the vaccines, and why.
Many thousands of blood clots are diagnosed every year. Immobility, surgery, obesity, and smoking are some of the many risk factors. According to the European Medicines Agency, it is possible that blood clots could also be related to receiving the AstraZeneca COVID-19 vaccine. There has not been evidence of issues related to specific batches or a particular manufacturing site for the AstraZeneca vaccine. As of April 4, 2021, a total of 222 cases of thrombosis have been reported to EudraVigilance—the European system for managing information about serious adverse reactions to medicines. About 34 million people had been vaccinated in the European Economic Area and United Kingdom by this date.
On April 7, 2021, the European Medicines Agency safety committee concluded “that unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (formerly COVID-19 Vaccine AstraZeneca).” The U.K. regulatory agency recommended alternatives to the AstraZeneca vaccine be given to people under 30 years of age, following 79 reported cases of blood clotting and 19 deaths. As of April 16, 2021, the Australian regulatory agency is also conducting a review of the AstraZeneca vaccine following three reported instances of rare clotting, including one fatal case.
AstraZeneca has not applied for regulatory approval in the United States, but another viral vector vaccine for COVID-19 made by Johnson & Johnson is also under review for rare blood clotting as of April 13, 2021. Regulatory agencies take vaccine safety seriously and often exercise an abundance of caution. COVID-19 vaccines have been credited with saving lives and reducing hospitalizations on a large scale.
Context and background
Blood clots have been observed as a possible side effect from the AstraZeneca COVID-19 vaccine in a couple hundred people. Two-thirds of cases have happened in women, with most under 60 years of age experiencing blood clots within two weeks of vaccination. A small subset of cases have been fatal, although more evidence is still being gathered to understand underlying medical conditions and other potential contributing factors for these deaths.
The U.K. regulatory agency stated that more evidence is needed before confirming that these blood clots were caused by COVID-19 vaccination, and that 4 out of 1,000,000 people would normally be expected to develop this type of rare blood clotting, although exact rates are difficult to estimate due to rarity.
Phase 3 clinical trials rigorously test vaccines for safety in tens to hundreds of thousands of people. Some rare side effects only impact a couple people out of a million, so they're unlikely to be seen until a vaccine is rolled out in the general population.
Additionally, studying Phase 3 trial participants for a longer period may not have revealed more information about rare blood clots occurring in the first couple weeks after vaccination. Phase 4 trials and systems for on-going monitoring of vaccine safety are important for understanding more rare adverse reactions.
Dr. June Raine, head of the U.K. regulatory agency, has stated that the benefits of the AstraZeneca vaccine far outweigh the risks of hospitalization and death from COVID-19 for the vast majority of people, while suggesting that the risks may be more “finely balanced” in younger people and recommending alternative vaccines for people under the age of 30. Regulatory agencies in other regions are also reviewing the link between the AstraZeneca vaccine and the potential rare side effect of blood clotting.
Blood clots have been observed as a possible side effect from the AstraZeneca COVID-19 vaccine in a couple hundred people. Two-thirds of cases have happened in women, with most under 60 years of age experiencing blood clots within two weeks of vaccination. A small subset of cases have been fatal, although more evidence is still being gathered to understand underlying medical conditions and other potential contributing factors for these deaths.
The U.K. regulatory agency stated that more evidence is needed before confirming that these blood clots were caused by COVID-19 vaccination, and that 4 out of 1,000,000 people would normally be expected to develop this type of rare blood clotting, although exact rates are difficult to estimate due to rarity.
Phase 3 clinical trials rigorously test vaccines for safety in tens to hundreds of thousands of people. Some rare side effects only impact a couple people out of a million, so they're unlikely to be seen until a vaccine is rolled out in the general population.
Additionally, studying Phase 3 trial participants for a longer period may not have revealed more information about rare blood clots occurring in the first couple weeks after vaccination. Phase 4 trials and systems for on-going monitoring of vaccine safety are important for understanding more rare adverse reactions.
Dr. June Raine, head of the U.K. regulatory agency, has stated that the benefits of the AstraZeneca vaccine far outweigh the risks of hospitalization and death from COVID-19 for the vast majority of people, while suggesting that the risks may be more “finely balanced” in younger people and recommending alternative vaccines for people under the age of 30. Regulatory agencies in other regions are also reviewing the link between the AstraZeneca vaccine and the potential rare side effect of blood clotting.
Resources
- Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine (ChAdOx1-S [recombinant]) – COVID-19 Vaccine AstraZeneca (Other viral vaccines) (European Medicines Agency)
- If Nothing Goes Wrong, Is Everything All Right?Interpreting Zero Numerators (JAMA)
- Adverse Event Detection in Drug Development:Recommendations and Obligations Beyond Phase 3 (American Journal of Public Health)
- Human Regulatory Research and Development (EudraVigilance)
- Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK (Lancet)
- Why is it so hard to investigate the rare side effects of COVID vaccines? (Nature)
- Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations (US FDA)
- If Nothing Goes Wrong, Is Everything All Right? Interpreting Zero Numerators (JAMA)
- EU drug regulator: Unusual blood clot is 'very rare AstraZeneca side effect' (British Broadcasting Corporation)
- Australia reports first blood clot death 'likely' linked to AstraZeneca vaccine (Reuters)
- Australia to consider EU and UK findings over AstraZeneca COVID vaccine and blood clots (The Guardian)
- COVID: Under-30s offered alternative to Oxford-AstraZeneca jab (British Broadcasting Corporation)
- COVID: How does the Oxford-AstraZeneca vaccine work? (British Broadcasting Corporation)
- AstraZeneca Vaccine and Blood Clots: What Is Known So Far (New York Times)
- Recommendation to Pause Use of Johnson & Johnson’s Janssen COVID-19 Vaccine (U.S. CDC)
- Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine (ChAdOx1-S [recombinant]) – COVID-19 Vaccine AstraZeneca (Other viral vaccines) (European Medicines Agency)
- If Nothing Goes Wrong, Is Everything All Right?Interpreting Zero Numerators (JAMA)
- Adverse Event Detection in Drug Development:Recommendations and Obligations Beyond Phase 3 (American Journal of Public Health)
- Human Regulatory Research and Development (EudraVigilance)
- Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK (Lancet)
- Why is it so hard to investigate the rare side effects of COVID vaccines? (Nature)
- Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations (US FDA)
- If Nothing Goes Wrong, Is Everything All Right? Interpreting Zero Numerators (JAMA)
- EU drug regulator: Unusual blood clot is 'very rare AstraZeneca side effect' (British Broadcasting Corporation)
- Australia reports first blood clot death 'likely' linked to AstraZeneca vaccine (Reuters)
- Australia to consider EU and UK findings over AstraZeneca COVID vaccine and blood clots (The Guardian)
- COVID: Under-30s offered alternative to Oxford-AstraZeneca jab (British Broadcasting Corporation)
- COVID: How does the Oxford-AstraZeneca vaccine work? (British Broadcasting Corporation)
- AstraZeneca Vaccine and Blood Clots: What Is Known So Far (New York Times)
- Recommendation to Pause Use of Johnson & Johnson’s Janssen COVID-19 Vaccine (U.S. CDC)
