Drug Approval Process in US/ EU

In this post, i write about process by which drug approvals are made in big markets like US and Europe. The drugs are being developed over many years and have to cross many barriers to get marketed.
There are regulatory Authorities to regulate drug market to ensure safety and effectiveness of marketed drug.
IN US, Food and Drug Administration (FDA)
IN EU, European agency for the Evaluation of Medicinal products (EMEA)

In brief, key stages of drug development
1. Preclinical studies: to establish drug's merit to progress into clinical trials and it includes animal studies and API related studies and formulation (Tablet, capsule in small scale) Investigational new drug (IND) submitted to FDA CDER and FDA checks preclinical studies are perfomed whether in compliance with GLP or not, when clinical trial commences CDER start to monitor the trial.
2. Phase I: conducted with small group of people, to establish merits to progress into patients trials, for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
3. Phase II: conducted in larger group people, to further evaluate safety
4. Phase III: to provide pivotal trial evidence to prove safety and efficacy and FDA uses this data to decide whether to approve or not.
At the end of Phase III, Innovator/sponsor submit New drug application (NDA) FDA CDER checks and concludes the safety and efficacy established in clinical trials

Brief explanation of how process happeans
(Available at http://www.fda.gov/cder/handbook/develop.htm)

The NDA is evaluated based on the safety and efficacy established in clinical trials and scientifc dats. and Phase IV, this post marketing studies to access the drug's safety, effectiveness and monitored for unexpected health risks. CDER could put hold at any stage in this development cycle.
The above mentioned processes are when new drugs investigated for marketing approval and what is generic drugs? the generic drug applications are called Abbreviated New drug application (ANDA), No need to establish clinical trial data (safety and efficacy) generic drug manufacturers, generic drugs could enter the market after patent protection on formulation/product expired.
Orange book is FDA CDER's listing of approved products and corresponding patent protection, generic drug applications (ANDA) are evaluated for their bioequivalency with innovator/Sponsor product.

ANDA: FDA approved generic based on
1. contains same active agent as an approved (reference listed drug product)
2. should be identical dose, strength and route of administration
3. have same use/ indications
4. be bioequivalent
ANDA applicant has to file ANDA with any of one or more certifications for patent(s) listed in Orange Book (OB)
paragraph I ceritification: No patent information found in OB for which ANDA submitted,
Paragraph II certification: Listed patents are expired for which ANDA submitted,
Paragraph III: to seek approval after listed patent expiry
Paragraph IV: to challenge listed patent, saying Patent(s) listed are invalid, will not infringe to manufacture, use and sale.
Exclusivity:
Exclusivities are to protect the interest and benefit the innovator or generic applicants
Innovator's:
New Chemical entity: 5 years for first time approval of new chemical molecule
pediatric exclusivity: 6 months added to patent lifetime or existing exclusivity, but it will not stand alone.
3 years exclusivity for any significant changes, if new clinical studies conducted by innovator/ sponsor for new indication/dose etc.
generic applicant:
180 day's exclusivity: On filing ANDA with para IV certification and challenging innovator patent(s) listed in OB. First ANDA filing will get 180 days exclusivity on challenging and wining the case. it prevents other generic players from approval.

In EU, Drug approval process is regulated by European agency for the Evaluation of Medicinal products (EMEA), this agency give marketing authorization (MA) in european union (EU) member countries to market drug products. This is called centralized procedure.
In decentralized procedure/ Mutual reconization procedure: This applies to conventional drugs. Applications are made to individual member states selected by applicant.
In EU, two steps to get marketing Authorization,
1. Clinical trial Application
2. marketing Authorization Application (MAA)
Clinical trial Applications are approved in member state level and MAA approved at centralized level. Innovator/Sponsor submit clinical trial application in each member state where trials are to be conducted. In UK clinical trila applications are to be submited to medicine control agency (MCA).
Upon sucessful completion of clinical trials, MAA is to be submitted to EMEA in centralized procedure, four different MAAs are there, it depends on type of medicinal product.
In Mutual regonization procedure, if Once drug approved by any one member state, it is eligible to file MAA in other EU member states through Mutual regonization procedure.

Reference:
1. Drugs from discovery to approval by Rick Ng, PhD, published by John Wiley & Sons, Inc (2004)
2. Pharmaceutical project management 2nd edition, edited by Tony Kennedy
3. generic drug product development, leon shargel and Isadore Kanfer, Marcel Dekker (2005)
4. http://www.fda.gov/cder/about/smallbiz/generic_exclusivity.htm (Accessed 9th Aug 2008)
5. http://clinicaltrials.gov/ct2/info/understand (Accessed 9th Aug 2008)
6. http://www.fda.gov/cder/handbook/develop.htm (Accessed 9th Aug 2008)

Today i got interest to write many things on drug approval, snice i read first two books listed in reference. Please write comment on mistakes i made.