Drug registration and approval process in US, Europe / Regulatory Filing Requirements - US Vs Europe

The path a drug travels from a lab to patient is usually long, and every drug takes a unique route. Most drugs that undergo preclinical (animal) testing never even make it to human testing and review by the FDA. The drugs that do must undergo the agency's rigorous evaluation process, which scrutinizes everything about the drug--from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured. 

Drug Approval Process In United States

In United states USFDA controls the drug-approval process and is tasked with reviewing new drugs, biologics and medical devices before companies can sell them.

Drugs intended for human use are evaluated by FDA’s Center for Drug Evaluation and Research (CDER) to ensure that drugs marketed in the United States are safe and effective. Biological products are evaluated by FDA’s Center for Biologics Evaluation and Research.

A pharmaceutical company seeking FDA approval to sell a new prescription drug must complete a five-step process: discovery/concept, preclinical research, clinical research, FDA review and FDA post-market safety monitoring.

First, the company must conduct laboratory tests and try the drug on animals and then people to make sure it works and is safe.

 The FDA doesn’t actually test the drug itself before making a decision. The agency does, however, inspect the facilities where the drug will be manufactured as part of the approval process. It is the responsibility of the company seeking approval to market a drug to conduct laboratory and animal tests on the safety and effectiveness of a proposed new drug and then to submit that information to FDA for review process by CDER Physicians, Statisticians, Chemists, Pharmacologists and other scientist. 

  

 The drug approved by USFDA and can be marketed in the United states. USFDA will continue to monitor the drug post -approval. 

FDA Drug Approval Process Infographic (Horizontal) - https://www.fda.gov/drugs/information-consumers-drugs/fda-drug-approval-process-infographic-horizontal

FDA Drug Approval Process Infographic (Vertical) -https://www.fda.gov/drugs/information-consumers-drugs/fda-drug-approval-process-infographic-vertical

Different types of drug applications that can be submitted to FDA

Investigational New Drug (IND): Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines.

New Drug Application (NDA): When the sponsor of a new drug believes that enough evidence on the drug's safety and effectiveness has been obtained to meet FDA's requirements for marketing approval, the sponsor submits a new drug application (NDA) to FDA. The application must contain data from specific technical viewpoints for review, including chemistry, pharmacology, medical, biopharmaceutics, and statistics. If the NDA is approved, the product may be marketed in the United States.

Abbreviated New Drug Application (ANDA): An Abbreviated New Drug Application contains data that provides for the review and ultimate approval of a generic drug product. Generic drug applications are called "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.  Instead, a generic drug applicant must scientifically demonstrate that its product is bioequivalent (performs in the same manner as the innovator drug). Once approved, an applicant may manufacture and market the generic drug product.

Biologic License Application (BLA): Biological products are approved for marketing under the provisions of the Public Health Service Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product. A biologics license application is a submission that contains specific information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology and the medical affects of the biologic product. If the information provided meets FDA requirements, the application is approved and a license is issued allowing the firm to market the product. 

Drug Approval Process in Europe

To protect public health and ensure the availability of high quality, safe and effective medicines for European citizens, all medicines must be authorised before they can be placed on the market in the EU. The European system offers different routes for such an authorisation.

The European medicines regulatory system is based on a network of around 50 regulatory authorities from the 30 EEA countries (27 EU Member States plus Iceland, Liechtenstein and Norway), the European Commission and EMA.

EMA and the Member States cooperate and share expertise in the assessment of new medicines and safety information. They also rely on each other for exchange of information in the regulation of medicine, for example regarding the reporting of side effects of medicines, the oversight of clinical trials and the conduct of inspections of medicines’ manufacturers and compliance with good clinical practice (GCP), good manufacturing practice (GMP), good distribution practice (GDP), and good pharmacovigilance practice (GVP). This works because EU legislation requires that each Member State operates to the same rules and requirements regarding the authorisation and monitoring of medicines.

Routes of Drug Registration Process in EU: 

Centralized Procedure: The centralised procedure allows the marketing of a medicine on the basis of a single EU-wide assessment and marketing authorisation which is valid throughout the EU. Pharmaceutical companies submit a single authorisation application to EMA. The Agency’s Committee for Medicinal Products for Human Use (CHMP) or Committee for Medicinal Products for Veterinary Use (CVMP) then carries out a scientific assessment of the application and gives a recommendation to the European Commission on whether or not to grant a marketing authorisation. Once granted by the European Commission, the centralised marketing authorisation is valid in all EU Member States. The use of the centrally authorised procedure is compulsory for most innovative medicines, including medicines for rare diseases.

National Procedure: The national procedure only one member state is involved. The documents submitted to an authority are very specific to that particular authority and evaluation of the application is carried out by the same member state. The evaluation time for an application for a national marketing authorization is 210 days from the receipt of the application.

When a company wants to authorise a medicine in several Member States, it can use one of the following procedures:

Decentralised procedure: Where companies can apply for the simultaneous authorisation of a medicine in more than one EU Member State if it has not yet been authorised in any EU country and does not fall within the scope of the centralised procedure.

 Mutual-recognition procedure: Where companies that have a medicine authorised in one EU Member States can apply for this authorisation to be recognised in other EU countries. This process allows Member States to rely on each other’s scientific assessments.

Rules and requirements applicable to pharmaceuticals in the EU are the same, irrespective of the authorisation route for a medicine.

A European Public Assessment Report, or EPAR, is published for every human or veterinary medicine that has been granted or refused a marketing authorisation following an assessment by EMA. For a medicine that is authorised by a Member State, details on the assessment of the medicine are also available in a Public Assessment Report.

The role of the European Commission in Drug Approval

The European Commission plays an important role in the regulation of medicines in the EU. On the basis of scientific assessments carried out by EMA, it grants or refuses, changes or suspends marketing authorisations for medicines that have been submitted via the centralised procedure. It can also take EU-wide action when a safety issue has been identified for a nationally authorised product and when harmonised regulatory measures in all MSs are considered necessary following assessment by EMA’s PRAC. The European Commission can also take action concerning other aspects of medicine regulation.

The role of the European Medicines Agency (EMA) in Drug Approval

EMA is responsible for the scientific evaluation, primarily of innovative and high-technology medicines developed by pharmaceutical companies for use in the EU. EMA was established in 1995 to ensure the best use of scientific resources across Europe for the evaluation, supervision and pharmacovigilance of medicines.

The EMA has seven scientific committees that carry out its scientific assessments.

EMA’s scientific committees

Committee for Medicinal Products for Human Use (CHMP)

Pharmacovigilance Risk Assessment Committee (PRAC)

Committee for Medicinal Products for Veterinary Use (CMVP)

Committee for Orphan Medicinal Products (COMP)

Committee on Herbal Medicinal Products (HMPC)

Committee for Advanced Therapies (CAT)

Paediatric Committee (PDCO)

The role of National competent Authorities in Drug Approval

The national competent authorities (NCAs), responsible for the regulation of human and veterinary medicines in the EU, coordinate their work in a forum called Heads of Medicines Agencies (HMA). The heads of the NCAs work closely with EMA and the European Commission to maximise cooperation and ensure the European medicines regulatory network functions efficiently. The HMA meets four times per year to address key strategic issues for the network, such as the exchange of information, IT developments and sharing of best practices, and to streamline mutual recognition and decentralised procedures.

Regulatory submission pathways and requirements for US and Europe are entirely different from one another, Similarities and differences in drug approval process in US and Europe is detailed below.

Particulars	US	Europe
General Information
Regulatory Agency	USFDA	EMA National Agencies
Application	IND NDA ANDA BLA	MAA [Article 8(3) Full Application, Article 10(1) Generic, Article 10(3)Hybrid(mixed)Application, Article 10(4) Biosimilars, Article 10(a) well established use, Article 10(b) Fixed combination products, Article 10(c) Informed consent/Duplicate]
Registration Process	One Registration Process	Multiple Registration Process Ø Centralized Procedure (European Community) Ø Decentralized Procedure (Atleast 2 member states) Ø Mutual Recognition Procedure (Atleast 2 member states) Ø National Procedure (1 member states)
Approval Timeline	10 Months (Standard review)	210 Days –CHMP opinion Centralized procedure 210+67(EC Decision: Granting/Refusing)=277 days CHMP Opinion (Ensure that medicinal  products have a positive risk - benefit balance in favour of patients/users) EC Decision – Granting/Refusing
Administrative Part
Debarment Certification	Applicable	Not Applicable
Agent letter of appointment	Applicable	Not Applicable
Environmental  Assessment Report	Applicable	Applicable
Pharmacovigilance	Not Applicable	Applicable
Specifying Medicinal product name in Braille format	Not Applicable	Applicable
Quality
Number of batches	3 batches	3 batches
Container closure  DMF Requirements	Applicable	Not applicable
API DMF Requirements	DMF (Type II)	ASMF/CEP
Number of API lots for Submission batches	A minimum of two lots of the drug substance should be used to prepare the three primary batches of drug product.	No specific requirements
Executed BMR	Applicable (Part of Dossier Filing)	Not part of Dossier filing
Blank (Commercial ) BMR	Applicable (Part of Dossier Filing)	Not part of Dossier filing
Stability Data Requirements	Minimum 6 Month data – Accelerated, Long term & Intermediate (if applicable)	Minimum 6 Month data – Accelerated, Long term & Intermediate (if applicable)
Container orientation For primary batches of liquids, solutions, semi-solids, and suspensions	Product should be place in worst case and non-worst case scenarios (Up right/Inverted or Vertical/Horrizontal)	No such requirements
Antimicrobial Effectiveness testing (AET) Requirements	Applicable (One Batch)	Applicable (One Batch)
Special stability studies conducted to confirm the quality of the constituted drug products (for example, parenterals and/or powders reconstituted with diluents and/or drug admixtures)	Applicable (One Batch)	Applicable (One Batch)
API DMF requirements	Type – II DMF	CEP ASMF
Miscellaneous
Initial Screening	Applicable (60 Days)	Screening will be done only for administrative part
Fee Requirements	Applicable	Applicable
Faster Approval Pathways	Accelerated Approval Priority Review Fast Track Break through Therapy	Accelerated Approval Conditional Marketing Authorization
Goal Date	Applicable	Not applicable
Time Slot booking Requirements for dossier filing	Not Applicable	Applicable
Types of Queries	IR/DRL/CRL	Day 50/Day 100/Day 120/Day 180

   

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