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Since the first scientific breakthrough of the migraine drug, Schuma Cootassages, the first scientific breakthrough in the early 90s, startan drugs have led and driven the growth of the global market for anti migraine drugs. In 2005, the global anti migraine drug market reached US $3 billion 500 million. In recent years, there has been no breakthrough in the advent of migraine drugs, and the 7 stark drugs, which have been listed on the market, have suffered a patent cliff successively, and the global market for anti migraine drugs is declining. In 2015, there was no drug sales exceeding $one billion in migraine brand drugs. Therefore, it is urgent to anticipate the emergence of new anti migraine leader varieties.
In addition, the pathomechanism of anti migraine drugs has not been fully elucidated, so there is no cure for migraine. Tetanus is the only drug for migraine, but it can not be used for prophylactic treatment in intermission. There are still unmet clinical needs.
Based on the current pathological mechanism of migraine and the cognition of the drugs listed on the market, we should think deeply about how we should face the development of migraine drugs with the new requirements. Fortunately, FDA released the new Migraine: Developing Drugs for Acute Treatment in February 2018 for our reference. The author combed the contents of the guide based on the original text, so as to facilitate readers to understand the essence of the guide.

Guide introduction

1. guide description
This guideline is intended to assist applicants in the clinical development of prescription drugs for acute migraine, but not for class OCT drugs.
This guide does not involve the development of drugs to reduce the frequency of migraine attacks. Guidelines for the development of such drugs will be released separately in the future.
This guideline presents the overall development plan for FDA support for the treatment of acute migraine prescription drugs and the design ideas of current clinical trials.
2. migraine characteristics
Migraine is a chronic neurovascular disease characterized by frequent recurrent episodes of moderate to severe headaches, often accompanied by nausea, light and / or sound sensitivity. Migraine is usually pulsatile, unilateral, and aggravated by physical activity. In adults, migraine attacks usually last for 4 to 72 hours.
3. Diagnosis and classification of  migraine
The International Headache Society (IHS) points out that migraine should be diagnosed in combination with at least 5 episodes.
Migraine has two main subtypes: migraine without aura (common migraine) and threatened migraine (classic migraine). Premonitory migraine is characterized by typical local neurological symptoms or sometimes accompanied by headache. These local neurological symptoms do not exist in migraine without aura. Some patients may have two subtypes of migraine simultaneously.
Drugs for the treatment of migraine include drugs for acute migraine attacks (treatment of acute migraine) and drugs that reduce the frequency of migraine attacks (preventive treatment). This guide covers only the development of drugs for treating acute migraine attacks.

4. development plan
(1) the population of the subjects
Phase I clinical trials can recruit healthy adult volunteers or migraine sufferers. However, it is important to note that as migraine patients are mainly women, it is also important to recruit women of childbearing age at the early stage of development (that is, at the beginning of II clinical trials).
Since the peak period of migraine is adolescence, and the incidence of young children is not uncommon, FDA requires pediatric medication research for children. Since the applicant needs to submit the paediatric research program within 60 days after the end of the II clinical trial meeting, the applicant is encouraged to begin the discussion of the pediatric clinical development plan at the early stage of development.
(2) effectiveness consideration
Normally, at least two fully and well controlled trials are required to support the approval of new molecular entities.
For the approved acute migraine treatment, a separate good controlled trial can be used to support the approval of new subsets of treatment (for example, for Paediatrics) and new drug delivery drugs.

(3) security considerations
Acute migraine can be treated with long term and intermittent treatment. Therefore, the safety data required for the approved drug delivery for acute migraine should be consistent with the requirements of chronic treatment drugs, including at least a long-term safety test, during which patients can be treated with trial drugs for all acute migraine attacks.
Since phase III clinical trials are usually in the outpatient clinic, the I and II clinical trials are conducted under strict medical supervision, which is the best opportunity for the drug to obtain the vital signs and laboratory data. These tests should include vital signs, hematology, serum chemistry, urine analysis and 12 lead electrocardiogram. For the tested drugs and main metabolites, the vital signs and electrocardiogram should be assessed around the expected Cmax. In most short-term II and III outpatient trials, vital signs and laboratory assessments should be conducted at baseline and after treatment. The long-term safety data of phase III clinical trials should be obtained at appropriate intervals, taking into account the results of non clinical studies and the experience of early human drug use for trial and other drugs.
The new molecular entity should follow the security proposal in the ICH Industry Guide “E1A The Extent of Population Exposure to Assess Clinical Safety: For.” For long-term safety databases, adult patients should have at least two migraine attacks per month. Safety experience should be established at the relevant dose and frequency.
Additional non clinical studies (such as assessing coronary artery vasoconstriction in vitro) and safety studies in dangerous groups, such as patients with known coronary artery disease, may be needed if the drug has a potential adverse vascular impact. It is suggested that the relevant departments should be consulted at the early stage of the development plan.

(4) other considerations
The study of Pediatrics
Migraine is a relatively common disease among children. There is reason to believe that migraine in adults and paediatric populations is completely different, and that effective drugs for adults are not effective for children. Therefore, it needs to be studied in the pediatric population.
Migraine is rarely seen in children under 6 years of age, so research on this age group is usually waived. Pediatric studies should be aimed at assessing patients aged between 6 and 17. Because the characteristics of the disease change with the changes in adolescence, pediatric studies should include a sufficient number of patients to describe the safety and effectiveness of the entire age of Pediatrics.
The diagnosis of migraine should be based on the IHS standard. It is recommended that the applicant refer to the pediatric research Equality Act, which is revised on the basis of the FDA reauthorization act 2017, to review the initial pediatric research plan submitted.
Before the trial of clinical efficacy, the pharmacokinetic characteristics of drugs in the pediatric population should be evaluated and compared with the pharmacokinetic characteristics of drugs in adults. This helps to select the right dose for pediatric efficacy and safety studies. Consideration should also be given to designing suitable formulations for the corresponding age groups.
The following two options can be considered for pediatric effectiveness study:
(1) separate the 12 to 17 year old paediatric patients and the 6 to 11 year old paediatric patients for validity study.
(2) a separate effectiveness study for patients aged 6 to 17 should be recruited to a sufficient number of patients aged 6 to 11 and 12 to 17 years old to fully assess the effectiveness (and safety) of the drug in each subgroup, but not to be statistically significant in each subgroup.
Due to the high rate of placebo response in children’s migraine research, we should consider adopting an enrichment strategy to increase the chance of proving the effects of drugs. In some pediatric clinical trials, the successful method was to give all patients a single blind placebo during a migraine attack, and then randomly assigned to a trial drug or placebo at a time of only 30 minutes.
The proportion of patients who received pain relief after 2 hours should be the primary endpoint. Pediatric research does not need to assess pain and other symptoms (i.e., common primary endpoints). Migraine related symptom assessment should be used as a secondary endpoint. Other secondary endpoints of the above adult clinical trials should also be evaluated and the I error rate should be controlled again.
A long-term pediatric safety study should be carried out for a year. In general, if the drug has been approved for adults, the paediatric safety database should include at least 200 patients to treat migraine attacks per month for 6 months, and 75 patients treat at least one migraine attack per month for 1 years.
The study should assess the effects of treatment on growth, cognition and endocrine development. Before conducting a long-term pediatric safety study, a single species (usually rats) should be studied for toxicological studies of young animals.

(4) other considerations
The study of Pediatrics
Migraine is a relatively common disease among children. There is reason to believe that migraine in adults and paediatric populations is completely different, and that effective drugs for adults are not effective for children. Therefore, it needs to be studied in the pediatric population.
Migraine is rarely seen in children under 6 years of age, so research on this age group is usually waived. Pediatric studies should be aimed at assessing patients aged between 6 and 17. Because the characteristics of the disease change with the changes in adolescence, pediatric studies should include a sufficient number of patients to describe the safety and effectiveness of the entire age of Pediatrics.
The diagnosis of migraine should be based on the IHS standard. It is recommended that the applicant refer to the pediatric research Equality Act, which is revised on the basis of the FDA reauthorization act 2017, to review the initial pediatric research plan submitted.
Before the trial of clinical efficacy, the pharmacokinetic characteristics of drugs in the pediatric population should be evaluated and compared with the pharmacokinetic characteristics of drugs in adults. This helps to select the right dose for pediatric efficacy and safety studies. Consideration should also be given to designing suitable formulations for the corresponding age groups.
The following two options can be considered for pediatric effectiveness study:
(1) separate the 12 to 17 year old paediatric patients and the 6 to 11 year old paediatric patients for validity study.
(2) a separate effectiveness study for patients aged 6 to 17 should be recruited to a sufficient number of patients aged 6 to 11 and 12 to 17 years old to fully assess the effectiveness (and safety) of the drug in each subgroup, but not to be statistically significant in each subgroup.
Due to the high rate of placebo response in children’s migraine research, we should consider adopting an enrichment strategy to increase the chance of proving the effects of drugs. In some pediatric clinical trials, the successful method was to give all patients a single blind placebo during a migraine attack, and then randomly assigned to a trial drug or placebo at a time of only 30 minutes.
The proportion of patients who received pain relief after 2 hours should be the primary endpoint. Pediatric research does not need to assess pain and other symptoms (i.e., common primary endpoints). Migraine related symptom assessment should be used as a secondary endpoint. Other secondary endpoints of the above adult clinical trials should also be evaluated and the I error rate should be controlled again.
A long-term pediatric safety study should be carried out for a year. In general, if the drug has been approved for adults, the paediatric safety database should include at least 200 patients to treat migraine attacks per month for 6 months, and 75 patients treat at least one migraine attack per month for 1 years.
The study should assess the effects of treatment on growth, cognition and endocrine development. Before conducting a long-term pediatric safety study, a single species (usually rats) should be studied for toxicological studies of young animals.

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