Typical Cases of Special Approval for New Drugs

Typical Cases of Special Approval for New Drugs (Exempt from Registration Clinical Trials) ---- Caffeine Citrate Injection

       Caffeine citrate injection (Approval No.: H20130109) is the only drug approved internationally for the treatment of apnea in premature infants. Apnea in premature infants is a potentially disabling and fatal condition, and there has been a lack of effective therapeutic drugs in past medical practices in our country. After a comprehensive review of global clinical data, the CDE adopted a review strategy exempting registration clinical trials for rapid approval, providing timely new treatment options for the life-saving of such patients.

This article discusses the results of the product's exemption from registration clinical trials and rapid approval from four aspects: clinical need, supporting evidence, further requirements after marketing, and risk control, hoping to help understand the CDE's review logic and evaluation criteria.
1. Need: Urgent Clinical Need
Disease Background
Apnea is a common clinical symptom in newborns, especially in premature infants, particularly those with extremely low birth weight (<1000 grams), where approximately 90% experience apnea. Brief pauses in breathing (5 to 10 seconds) are normal in premature infants, but repeated and prolonged episodes can lead to hypoxemia, resulting in hypoxic brain injury, intracranial hemorrhage, respiratory failure, pulmonary hemorrhage, and even death. Apnea is a critical condition that requires urgent treatment. Current treatment measures for apnea in premature infants include non-drug and drug therapies. Non-drug treatments include gentle skin stimulation for infants with mild intermittent apnea, oxygen supplementation for long-term and frequent apnea, and ventilation via oxygen bags and masks or intubation and positive pressure ventilation. If apnea persists repeatedly, drug treatment must be implemented.
Current Treatments
Caffeine citrate formulations, including injections and oral solutions, were approved in France on December 31, 1997, for the treatment of apnea in premature newborns. It received orphan drug status in the United States in September 1998 and FDA marketing approval on September 21, 1999. Currently, in Europe and the United States, caffeine citrate formulations have become the first-line drug for treating apnea in premature infants. Pediatric textbooks abroad list caffeine citrate formulations as the primary drug for treating apnea in premature infants. Caffeine citrate injection and oral solution have also been explicitly included in the current World Health Organization's core essential medicines list and the essential medicines list for children, becoming one of the commonly used drugs in neonatal intensive care units (NICUs) abroad.
Clinical Need
Currently, there are no approved drugs for the treatment of apnea in premature infants in our country. Although naloxone, naloxone combined with theophylline, and doxapram are used clinically to treat apnea in premature infants, they are considered empirical medications and lack evidence-based medical support. Especially for theophylline, which is the most widely used, the safety range is narrow, requiring close monitoring of blood drug concentrations. Therefore, there is a significant urgent need for this product in the field of neonatal treatment in our country. In light of the above situation, after thorough discussions with neonatal experts, the import of this product was approved for the indication of treating primary apnea in premature newborns. For newborns who have not received relevant treatment before, the recommended dosing regimen is: a loading dose of caffeine citrate 20 mg/kg body weight, administered slowly via intravenous infusion (30 minutes) using an infusion pump or other quantitative infusion device. After a 24-hour interval, a maintenance dose of 5 mg/kg body weight is given, administered as a slow intravenous infusion (10 minutes) every 24 hours; or via oral administration (e.g., through a nasogastric tube), with a maintenance dose of 5 mg/kg body weight given every 24 hours.

2. Supporting Evidence: Very Sufficient
Efficacy and Safety
       A multicenter, randomized, double-blind, controlled clinical study conducted in the United States evaluated the efficacy of caffeine citrate in 85 premature newborns (gestational age 28 to 33 weeks) with apnea, comparing the effects of caffeine citrate and placebo over a period of 10 to 12 days. The results showed that the number of days without apnea symptoms significantly increased in the caffeine citrate treatment group (3.0 days) compared to the placebo group (1.2 days; p=0.005); and the percentage of patients without apnea symptoms for 8 days or more was higher in the caffeine citrate group (22%) compared to the placebo group (0%), indicating a clear efficacy of caffeine citrate in treating apnea in premature newborns. No clinically significant differences were found between the two groups in terms of vital signs, weight, or laboratory test values during the double-blind and open-label study phases. The average daily weight gain was similar between the two groups. The number and percentage of adverse events between the groups showed no clinically significant differences. The number of infants who withdrew from double-blind treatment due to adverse events was similar between the two groups.
A large multicenter post-marketing placebo-controlled study conducted abroad (n=2006) observed the short-term and long-term (18-21 months) clinical effects of caffeine citrate in treating premature newborns. The results showed that caffeine citrate significantly reduced the incidence of bronchopulmonary dysplasia [Odds Ratio (95% Confidence Interval) 0.63 (0.52 to 0.76)], and significantly increased the survival rate without neurodevelopmental abnormalities [Odds Ratio (95% Confidence Interval) 0.77 (0.64 to 0.93)]. The tolerance of caffeine citrate was similar to that of the placebo. The number of infants experiencing tachycardia and tremors was similar between the two groups.
       The known pharmacological and toxicological characteristics of caffeine and other methylxanthines suggest potential adverse reactions of caffeine citrate, including stimulation of the central nervous system, such as irritability, restlessness, and tremors; as well as adverse effects on the heart, such as tachycardia, hypertension, and increased stroke volume. These adverse effects are dose-related, and plasma drug concentrations should be measured and doses reduced as necessary.
       
        Ethnic Differences
        Caffeine citrate is easily soluble in water. The citrate molecule is rapidly metabolized during infusion or absorption. Caffeine can take effect within a few minutes after the infusion begins. After oral administration of 10 mg caffeine/kg body weight to preterm newborns, the peak plasma caffeine concentration (Cmax) ranges from 6 to 10 mg/l, with the time to peak (tmax) averaging between 30 minutes to 2 hours. The extent of absorption is not affected by the feeding method. After administration, caffeine quickly distributes into the brain. The concentration of caffeine in the cerebrospinal fluid of preterm newborns is close to that in plasma. The average volume of distribution (Vd) of caffeine in infants (0.8 to 0.9 l/kg) is slightly higher than in adults (0.6 L/kg). Due to the immature liver enzyme system in preterm newborns, the metabolism of caffeine in their bodies is relatively limited, and the clearance of caffeine in newborns is almost entirely completed through renal excretion. A population pharmacokinetic study conducted in an Asian population indicated that the pharmacokinetic parameter values are comparable to those of other studies, including Caucasian populations. Considering that this product is almost not metabolized by the liver in preterm newborns, pharmacokinetic parameters from populations of newborn preterm infants in Japan, Singapore, etc., are comparable to those of Caucasian populations. Therefore, it can be considered that the pharmacokinetic differences between individuals and among preterm infants of different gestational ages are greater than the differences between races.

       Benefit and risk assessment
       From the analysis of clinical needs, apnea in preterm infants can lead to brain and systemic hypoxia and ischemia, even resulting in death. Currently, there are no approved drugs in this treatment area in China, thus there is an urgent clinical need for the treatment of apnea in preterm infants. This product has been widely used in Europe and the United States for the treatment of apnea in preterm infants for over 10 years, and no serious safety issues have been found. Pharmacokinetic studies in Asian and Caucasian newborns have shown no significant racial differences. Combined with the wide therapeutic safety window of this product and its low adverse reaction profile, the safety and efficacy of this product are basically clear. However, conducting pediatric research, especially clinical studies on preterm infants in China, is challenging. Foreign approvals are often based on data from dozens of cases, followed by large-sample post-marketing studies. Therefore, an exemption from clinical trials for this product is proposed. Considering that safety and efficacy can be guaranteed and risks can be controlled, it is possible to allow patients in China to receive treatment as soon as possible, with benefits outweighing risks.

Post-marketing requirements
       Post-marketing requirements: that is, after the product is marketed, open clinical trials using this product to treat apnea in preterm infants need to be conducted, with a recommended case number of no less than 200. The marketing of this product will provide the first clearly effective and acceptably safe treatment drug for the field of apnea treatment in newborn preterm infants in China.
Risk control
Restricted to use in the neonatal intensive care unit.
From the review of this product, we can see that the CDE's thinking is very clear: there is an urgent clinical need for this product, and the supporting data is relatively sufficient. The further requirement is data from 200 Chinese children, and risk control is to be used in the neonatal intensive care unit.
However, the shortcomings of this review summary are that the wording is somewhat awkward, which may be related to the translation level of the applicant manufacturer, reminding us that we need to improve the quality of document writing; otherwise, if the reviewers are unwilling to continue reading, the review cannot proceed smoothly.

Attached CDE original text: Overview of the review of caffeine citrate injection
Apnea is a common clinical symptom in newborns, especially in premature infants, particularly those with extremely low birth weight (<1000 grams), where approximately 90% experience apnea. Brief pauses in breathing (5 to 10 seconds) are normal in premature infants, but repeated and prolonged episodes can lead to hypoxemia, resulting in hypoxic brain injury, intracranial hemorrhage, respiratory failure, pulmonary hemorrhage, and even death. Apnea is a critical condition that requires urgent treatment. Current treatment measures for apnea in premature infants include non-drug and drug therapies. Non-drug treatments include gentle skin stimulation for infants with mild intermittent apnea, oxygen supplementation for long-term and frequent apnea, and ventilation via oxygen bags and masks or intubation and positive pressure ventilation. If apnea persists repeatedly, drug treatment must be implemented.
Caffeine citrate formulations, including injections and oral solutions, were approved in France on December 31, 1997, for the treatment of apnea in premature newborns. It received orphan drug status in the United States in September 1998 and FDA marketing approval on September 21, 1999. Currently, in Europe and the United States, caffeine citrate formulations have become the first-line drug for treating apnea in premature infants. Pediatric textbooks abroad list caffeine citrate formulations as the primary drug for treating apnea in premature infants. Caffeine citrate injection and oral solution have also been explicitly included in the current World Health Organization's core essential medicines list and the essential medicines list for children, becoming one of the commonly used drugs in neonatal intensive care units (NICUs) abroad.
Currently, there are no approved drugs for the treatment of apnea in preterm infants in China. Although naloxone, naloxone combined with aminophylline, and doxapram are still used clinically to treat apnea in preterm infants, they are considered empirical medications and lack evidence-based medical support. Especially for the most widely used theophylline drugs, the safety range is narrow, requiring close monitoring of blood drug concentrations. Therefore, there is a very urgent need for this product in the field of neonatal treatment in China.
In light of the above situation, after thorough discussions with neonatal experts, approval is granted for this product to be imported into China, with the indication for the treatment of primary apnea in preterm newborns. For newborns who have not received relevant treatment before, the recommended dosing regimen is: a loading dose of caffeine citrate 20 mg/kg body weight, using an infusion pump or other quantitative infusion device, administered slowly via intravenous infusion (30 minutes). After an interval of 24 hours, a maintenance dose of 5 mg/kg body weight is given, with the administration method being a slow intravenous infusion (10 minutes) every 24 hours; or through oral administration (for example, via a nasogastric tube), with a maintenance dose of 5 mg/kg body weight given every 24 hours.

The basis for supporting the marketing of this product in China is as follows:
Efficacy and Safety
A multicenter, randomized, double-blind, controlled clinical study conducted in the United States evaluated the efficacy of caffeine citrate in 85 premature newborns (gestational age 28 to 33 weeks) with apnea, comparing the effects of caffeine citrate and placebo over a period of 10 to 12 days. The results showed that the number of days without apnea symptoms significantly increased in the caffeine citrate treatment group (3.0 days) compared to the placebo group (1.2 days; p=0.005); and the percentage of patients without apnea symptoms for 8 days or more was higher in the caffeine citrate group (22%) compared to the placebo group (0%), indicating a clear efficacy of caffeine citrate in treating apnea in premature newborns. No clinically significant differences were found between the two groups in terms of vital signs, weight, or laboratory test values during the double-blind and open-label study phases. The average daily weight gain was similar between the two groups. The number and percentage of adverse events between the groups showed no clinically significant differences. The number of infants who withdrew from double-blind treatment due to adverse events was similar between the two groups.
A large multicenter post-marketing placebo-controlled study conducted abroad (n=2006) observed the short-term and long-term (18-21 months) clinical effects of caffeine citrate in treating premature newborns. The results showed that caffeine citrate significantly reduced the incidence of bronchopulmonary dysplasia [Odds Ratio (95% Confidence Interval) 0.63 (0.52 to 0.76)], and significantly increased the survival rate without neurodevelopmental abnormalities [Odds Ratio (95% Confidence Interval) 0.77 (0.64 to 0.93)]. The tolerance of caffeine citrate was similar to that of the placebo. The number of infants experiencing tachycardia and tremors was similar between the two groups.
The known pharmacological and toxicological characteristics of caffeine and other methylxanthines suggest potential adverse reactions of caffeine citrate, including stimulation of the central nervous system, such as irritability, restlessness, and tremors; as well as adverse effects on the heart, such as tachycardia, hypertension, and increased stroke volume. These adverse effects are dose-related, and plasma drug concentrations should be measured and doses reduced as necessary.
Ethnic Differences
Caffeine citrate is easily soluble in water. The citrate molecule is rapidly metabolized during infusion or absorption. Caffeine can take effect within a few minutes after the infusion begins. After oral administration of 10 mg caffeine/kg body weight to preterm newborns, the peak plasma caffeine concentration (Cmax) ranges from 6 to 10 mg/l, with the time to peak (tmax) averaging between 30 minutes to 2 hours. The extent of absorption is not affected by the feeding method. After administration, caffeine quickly distributes into the brain. The concentration of caffeine in the cerebrospinal fluid of preterm newborns is close to that in plasma. The average volume of distribution (Vd) of caffeine in infants (0.8 to 0.9 l/kg) is slightly higher than in adults (0.6 L/kg). Due to the immature liver enzyme system in preterm newborns, the metabolism of caffeine in their bodies is relatively limited, and the clearance of caffeine in newborns is almost entirely completed through renal excretion. A population pharmacokinetic study conducted in an Asian population indicated that the pharmacokinetic parameter values are comparable to those of other studies, including Caucasian populations. Considering that this product is almost not metabolized by the liver in preterm newborns, pharmacokinetic parameters from populations of newborn preterm infants in Japan, Singapore, etc., are comparable to those of Caucasian populations. Therefore, it can be considered that the pharmacokinetic differences between individuals and among preterm infants of different gestational ages are greater than the differences between races.
Benefit and risk assessment
From the analysis of clinical needs, apnea in preterm infants can lead to brain and systemic hypoxia and ischemia, even resulting in death. Currently, there are no approved drugs in this treatment area in China, thus there is an urgent clinical need for the treatment of apnea in preterm infants. This product has been widely used in Europe and the United States for the treatment of apnea in preterm infants for over 10 years, and no serious safety issues have been found. Pharmacokinetic studies in Asian and Caucasian newborns have shown no significant racial differences. Combined with the wide therapeutic safety window of this product and its low adverse reaction profile, the safety and efficacy of this product are basically clear. However, conducting pediatric research, especially clinical studies on preterm infants in China, is challenging. Foreign approvals are often based on data from dozens of cases, followed by large-sample post-marketing studies. Therefore, an exemption from clinical trials for this product is proposed. Considering that safety and efficacy can be guaranteed and risks can be controlled, it is possible to allow patients in China to receive treatment as soon as possible, with benefits outweighing risks.

Thus, post-marketing requirements are proposed, that is, after the product is marketed, open clinical trials using this product to treat apnea in preterm infants need to be conducted, with a recommended case number of no less than 200.

The marketing of this product will provide the first clearly effective and acceptably safe treatment drug for the field of apnea treatment in newborn preterm infants in China.