Discovery & Approval
DRUG
<<The CTD, one of the multidisciplinary guidelines of ICH, is catagorised into five modules. Module 1 is not part of CTD, is a region specific. Modules 2 comprises a brief introduction and information related to quality, safety, (non-clinical studies) and efficacy (clinical studies). While Module 3, 4 and 5 comprise the individual study report; quality, non-clinical and clinical study reports. They are intended to be common for all regions. (Hill, R., & Rang, H. P. (2013)
CTD is now strongly recommended format of the application subsmisson of NDA to FDA.
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Only one drug being approved.
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Apprx cost: 1.15 biliions
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75% chance of success
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requires 1.15-3 years
NDA (New Drug Application)
After clinical phase III, if the drug shows its safety and demonstrate a good efficacy, then NDA is submitted to FDA for approval the drug onto the market. CTD is part of the NDA submisstion process.
Overview of FDA NDA process Flow Chart
FDA Review
FDA stuffs from different offices of CDER review the NDA. The review might take the suggestion from committes and experts. The review process take about 12 months in general.
Reference
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Ng, R. (2003) Regulatory Applications, in Drugs: From Discovery to Approval, John Wiley & Sons, Inc., Hoboken, NJ, USA. doi: 10.1002/0471722804.ch8
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ICH, 'M4 : The Common Technical Document' available from http://www.ich.org/products/ctd.html
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Morton.D (2015), ''patents 2015-update", retrieved from http://moodle.vle.monash.edu/pluginfile.php/3521645/mod_resource/content/0/patents%202015%20Update.pdf
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Hill, R., & Rang, H. P. (2013). Drug discovery and development : Technology in transition (2nd ed.). Edinburgh ; New York: Elsevier.
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USP, 2015 ‘USP Excipient Verification & Supplier Qualification Processess’ available from http://www.usp.org/usp-verification-services/usp-verified-excipients/usp-excipient-verification-supplier-qualification-processes
CTD
(Common Technical Document)
The agreement to assemble all the Quality, Safety and Efficacy information in a common format (called CTD - Common Technical Document ) has revolutionised the regulatory review processes, led to harmonised electronic submission that, in turn, enabled implementation of good review practices. For industries, it has eliminated the need to reformat the information for submission to the different ICH regulatory authorities.
(Ng.R, 2003)
Large-Scale Manufacturing
After FDA has reviewed the NDA application, if the application is approved......
In large-scale manufacturing step
100% chance of getting success!!!!
Large-scale Manufacturing Time
Phase IV- Post Marketing Surveillance
NO!
NO!
NO!
NO!
NO!
There is another last essential step.....
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Begin after marketing approval (Orlando.L, 2014)
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Known as : Post-market approval/ surveillance trials (Ng.R, 2003)
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Aim: to monitor the efficacy and side effects of the drug in real-life situation.
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How:
(i) Constract the drug efectiveness in the market with established treatment, side
effects, patient’s quality of life, and cost-effectiveness. ( involved approx. 10,000 subjects)
(ii) Report any adverse effects regulatory authorities
(iii) If serious, doctors and patients are notified, the drug might recall.
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Time: 0.5 years +
This is
The End
When submitting a new drug to FDA by NDA application, FDA is likely to construct a pre-approval inspection (PAI) to ensure the facility has adequate procedures and controls to manufacture the drug regulated under GMP.
If PAI is not satisfactory, FDA can hold the approval of NDA application.
If PAI has made some comments on the application, FDA issues "FDA 483/ Notice of inspectional observation. If there are more serious issue, FDA sends "warning letters"
Deficiencies need be corrected and fixed in the short time!!!!
Form 483
warning letter
Click any circle icon to see their website
Example of warning letter to Actavis Laboratories UT, Inc. (formerly Watson Laboratories, Inc.) for issuing 'NDA 022206 RAPAFLO® (silodosin) Capsule for oral use'
Click to see the full document
Mergers and acquisitions affect your supply chain for excipients and you will need to register an alternate suppler immediately after the product is launched.
According to the US Pharmacopeia and National Formulary, excipients are defined as “any component, other than active substance(s), intentionally added to the formulation of a dosage form”. The purposes of adding excipients into the formulation are controlling the release of drug substances in the body, enhancing drug dissolution, stability, bioavailability and etc. (Ng.R 2003) To solve this issue, I need to find an alternate supplier for the excipients and the supplier needs to provide the information regarding to safety and quality issues such as excipients are manufactured which compliance with GMP (Good Manufacturing Practices) ,testing of excipients compliance with USP-NF, EP and/or JO monographs, meeting the acceptable limits for impurities and contaminations. (USP, 2015)
Q & A
Example of NDA approval for recent Onivyde drug on 22/10/15 for Merrimack Pharms Inc.
Click to see the full document
Magnesium Sulfate in 5% Dextrose injection of Hospira Inc was recalled on 3/6/15 due to incorrect baracode in the primary bag labeling. The barcode was mislabeled with the barcode for Heparin Sodium 2000 USP units/1000 mL in 0.9% Sodium Chloride Injection. Adminstration of inccorect treatment to pateint that can result in life-threatening seizures, stroke, cerebral hemorrhage and maternal death, and attendant risks to the fetus, including fetal demise