Chapter 1. The Marketing Authorization Procedure: "Marketing Authorization"
Section 1.1. Who is concerned by the AMM?
Medicines, before being introduced on the European or French market, must receive a marketing authorization (L5121-8 public health code).
A medicine is (L 5111-1 of the Public Health Code or European Community Directive 65/65 / EEC of 26 January 1965Article 1):
- a substance or composition presented as possessing curative or preventive properties with regard to diseases, or
- a substance or composition that can be administered for the purpose of establishing a medical diagnosis, or
- a substance or composition that can be administered for the purpose of restoring, correcting or modifying organic functions.
Section 1.2. Key steps in drug design
From a general point of view, here are the main stages of a drug's life, from conception to commercialization.
The purpose of preclinical trials This includes testing the tolerance of molecules in vitro in animals, performing toxicological tests and studying the pharmacokinetics of molecules (basically, how fast molecules act, are absorbed, or are eliminated).
The clinical research splits into three major phases:
- phase I :
- trials in human patients, on a small cohort of healthy volunteers.
- these tests aim in particular to test the tolerance in patients of the molecules.
- phase II :
- trials in human patients, on a larger cohort of sick volunteers (but without other pathologies).
- these tests aim in particular to establish a benefit / risk ratio of the molecule and to define the doses of effectiveness.
- phase III :
- trials in human patients, on a large cohort of sick volunteers under real conditions.
- these tests are intended in particular to verify the effectiveness (study in double blind") And security in the long run.
During the phase of marketing, a mechanism of pharmacovigilance »(L5121-22 of the public health code et al.) is in place: potential side effects are collected from health professionals and may lead to observational studies.
In addition, interventional studies (called phase IV) may be carried out, in particular if the MA requires it because of the small number of patients during clinical trials (L5121-8-1 Public Health Code).
Finally, during the marketing phase, secondary clinical studies can be conducted on the initiative of the manufacturer to test his drug on another pathology, a new population, as part of a new therapeutic strategy, etc. to have a new indication authorized.
Section 1.3. Procedures and modalities
1.3.1. Different possible procedures
To obtain a marketing authorization, it is possible to choose different ways:
- national procedure :
- only of course for one country
- centralized procedure :
- covers 27 European countries;
- may be mandatory for certain drugs (eg biotechnologies or new substances in certain areas such as cancer or HIV);
- mutual recognition procedure :
- an MA obtained in a reference country can be recognized by other countries;
- decentralized procedure :
- close to the mutual recognition procedure, but no MA has yet been obtained;
- files are filed in all countries, but studied only by a reference country.
The submission of an AMM file is made to the competent authorities (French, European, etc.) in a format that is fortunately harmonized (CTD format).
The AMM file contains particulars:
- administrative (this depends on the competent authorities);
- quality (manufacturing process, raw material used, product stability, etc.);
- on preclinical trials;
- on clinical research;
- on the information to be included on the packaging and the leaflet for the use of patients (annexed).
1.3.3. Decision making
On this basis, the competent authorities may grant marketing authorization on the basis of quality, efficacy and safety information: benefit / risk ratio is then established taking into account other available treatments (L5121-9 Public Health Code).
The decision is important because it fixes the name, the form of the drug, the mode of administration, the dosage, the therapeutic indications, the prescriber, the duration of the treatment ... All of these elements will fix indirectly the price and therefore the profitability of the drug.
Section 1.4. Data protection of the AMM
The AMM file is not public for a certain period, the so-called period of Data protection ».
During the period of Data protection Regulatory authorities can not:
- nor disclose the record
- nor authorize another company to refer to a MA of a third party to obtain an authorization.
The duration of the period of Data protection Is 8 + 2 + 1 years old (EC Regulation n ° 726/2004, art. 14 (11)):
- 8 years protection is granted, during which period no one can access or refer to the AMM file (R5121-28 public health code);
- 2 years additional protection period during which it is possible to refer to the AMM file, but during which it is not possible to obtain marketing authorization on this basis (L5121-10-1 public health code);
- 1 year additional protection (compared to the previous 2 years), if during the 8-year period a new therapeutic indication is granted and that this brings a significant advantage (L5121-10-1 public health code).
1.4.2. End of the protection of the AMM file and existence of a patent
If the AMM file is accessible and a third party obtains a new MA on this basis (end of period 8 + 2 + 1), this does not mean that it will not be a counterfeiter if a patent exists and is in force.
These two issues need to be clearly distinguished.
1.4.3. Protection and extension of range
If after obtaining a marketing authorization, a new therapeutic form or a new dosage is authorized (via a secondary clinical study), this does not mean that a new MA is granted.
Thus, an extension of range does not make it possible to extend the duration of protection of a marketing authorization (R5121-41-1 public health code or Directive 2001/83 / EC of the European Parliament and of the Council of 6 November 2001, art 6.1).
1.4.4. Protection and orphan disease
An orphan disease does not affect more than 5 people out of 10,000 in the Community (or that the marketing of a medicinal product does not generate sufficient profits to justify an investment) and that there are still no medicines that have been authorized (at least with comparable effectiveness) (Regulation No 141/2000 of the European Parliament and of the Council of 16 December 1999Article 3 (1)).
If a marketing authorization is requested for an orphan disease, then there is a guarantee that no other marketing authorization (even a marketing authorization extension) will be granted for a similar medicine (Regulation No 141/2000 of the European Parliament and of the Council of 16 December 1999Article 8.1) during 10 years.
This period of 10 years can be reduced to 6 years, if it establishes before the end of the 5th year that the disease is no longer an orphan disease as previously defined (Regulation No 141/2000 of the European Parliament and of the Council of 16 December 1999Article 8.2).
Nevertheless, this 10-year exclusivity can be reduced if (Regulation No 141/2000 of the European Parliament and of the Council of 16 December 1999Article 8.2):
- the holder agrees;
- the registrant can not produce his medicine in sufficient quantity;
- a new applicant demonstrates that their drug is safer, more effective or clinically superior.
1.4.5. Protection and pediatric orphan disease
The 10-year period mentioned for orphan diseases in the previous section is 12 years if the MA application includes results from all studies conducted according to an approved pediatric investigation plan (EC Regulation No. 1901/2006 of the European Parliament and of the Council of December 12, 2006art 37).
It should be noted that if a CCP exists, there are special provisions for pediatric studies (see below).
Section 1.5. Pricing and reimbursement
The price of the drug is fixed during a negotiation between industry and the Economic Committee of Health Products (or CEPS, in the absence of agreement, the CEPS unilaterally fixes the price). The price, set by ministerial decree (L5123-1 public health code), considers :
- prices of other drugs with the same therapeutic aim;
- expected sales volumes;
- conditions of use;
- progress compared to existing treatments (or AMSR, improvement in actual benefit).
Depending on the actual benefit (SMR), it is decided whether the drug is, in whole or in part, taken over by social security. Other drugs are not included in this assessment.
The final decision on reimbursement falls within the competence of the Ministers responsible for Health and Social Security (L162-17-2-1 social security code).
The SMR can be:
- important: reimbursement from 65% to 100% (the maximum rate is granted to irreplaceable and expensive drugs);
- moderate: 30% reimbursement;
- low: reimbursement at 15%;
- insufficient: not reimbursed.
Section 1.6. Generic and bio-similar
A generic is a drug with the same qualitative and quantitative composition of active substance and with the same pharmaceutical form as a reference medicine (L5121-1 public health code, 5 ° a or Directive 2001/83 / EC of the European Parliament and of the Council of 6 November 2001art 10.2 b).
In addition, bioequivalence between the generic and the reference medicine has been proven.
Section 1.7. Simplified procedure for the AMM
The MA application for a generic is simplified.
Thus, the applicant is not required to provide results:
- pharmacological and toxicological tests;
- clinical trials.
Only pharmaceutical data corresponding to the quality of the raw materials and the manufacturing process are required.
In addition, it must be shown that the credits are similar to a medicinal product which has obtained a marketing authorization for at least 10 years (Directive 2001/83 / EC of the European Parliament and of the Council of 6 November 2001, art 10.1) via a bioequivalence study (ie equivalent behavior in the body: absorption, distribution metabolism and elimination).
Section 1.8. Possible differences
It is therefore possible to have a different presentation (eg syrup vs. pill) or different excipients.
It is also possible to have a different therapeutic indication (ie list of pathologies for which the drug can be used, Council of State, July 23, 2003, No. 246716).
Section 1.9. Pricing
The price is determined as for a standard drug, but it will be lower than the reference medicine because the search costs are lower.
Chapter 2. Supplementary Certificates of Protection or CCP
Section 2.1. Principle
The CCPs were created to take into account the particularly long duration required to obtain the MA and to prevent protection from being lost even before the beginning of the marketing of the drug.
Section 2.2. Applicable texts?
The existence of the CCP is foreseen by:
- the Council Regulation No 1768/92 of 18 June 1992 :
- for the CCPs issued after on 2 January 1993 (Article 23 of the Regulation) if the patent relates to a drug (Article 2 of the Regulation), its method of production or its use (Article 2 of the Regulation together Article 1.c);
- the Regulation (EC) No 1610/96 of the European Parliament and of the Council of 23 July 1996 :
- for the CCPs issued after on 8 February 1997 (Article 23 of the Regulation) if the patent relates to a plant protection product (Article 2 of the Regulation);
- the articles L611-2 CPI and L611-3 CPI :
- for the CCPs issued before January 2, 1993.
In other words, the provisions of the CPI are no longer usable today ...
Section 2.3. Autonomous title
A CCP is an autonomous title, it does not extend the duration of a patent (even if the existence of the patent is a prerequisite): it confers a clean and attached protection to this CCP.
Section 2.4. Condition for granting CCPs
To obtain a CCP, you must:
- ask for it
- have a patent in force (and not an application) covering one of the elements mentioned above according to the applicable text;
- Article 3.a of the Council Regulation No 1768/92 of 18 June 1992 or
- Article 3.a of the Regulation (EC) No 1610/96 of the European Parliament and of the Council of 23 July 1996 ;
- have a current marketing authorization covering a specialty of this medicine (ie the brand name of a medicine) covered by the patent or if the patented medicinal product or phytosanitary product has been the subject of a marketing authorization
- Article 3.b of Council Regulation No 1768/92 of 18 June 1992 or
- Article 3.b of Regulation (EC) No 1610/96 of the European Parliament and of the Council of 23 July 1996);
- not having already asked for a CCP
- Article 3.c of the Council Regulation No 1768/92 of 18 June 1992 or
- Article 3.c of the Regulation (EC) No 1610/96 of the European Parliament and of the Council of 23 July 1996);
- that this marketing authorization is the first in the Community
- Article 3.d of Council Regulation No 1768/92 of 18 June 1992 or
- Article 3.d of Regulation (EC) No 1610/96 of the European Parliament and of the Council of 23 July 1996);
Section 2.5. Scope of protection
The protection conferred by the SPC is limited to the specialty covered by the WMA (L611-3 CPI or Article 4 of Council Regulation No 1768/92 of 18 June 1992 or Article 4 of Regulation (EC) No 1610/96 of the European Parliament and of the Council of 23 July 1996).
In addition, it is not possible to obtain a larger CCP (CJEU C-518/10 of 25 November 2011) or more restricted (CJEU C-322/10 of 24 November 2011) the claim for the patent concerned (exact concordance): if the claim is A1 + A2, it is not possible to have a CCP on A1 + A2 + A3 (even if the MA would be granted for A2 + A2 + A3) or A1 only.
Section 2.6. Term of protection
The CCP provides protection of a duration that can not exceed (Article 13 of Council Regulation No 1768/92 of 18 June 1992 or Article 13 of Regulation (EC) No 1610/96 of the European Parliament and of the Council of 23 July 1996):
- 5 years from the expiry of the patent;
- and the time difference between the date of the first marketing authorization and the date of filing of the patent which is subtract 5 years.
To summarize, the term of protection granted by the CCP is:
- if the MA is granted more than 10 years after the filing of the patent application: 5 years ;
- if the MA is granted faster than 10 years, the duration of 5 years is reduced accordingly.
2.6.2. Starting point of the deadline
The question that arose was whether what was referred to date of first marketing authorization »:
- the date of the decision granting the marketing authorization
- the date of notification of that decision or
- the date of grant.
This can be important ...
The CJEU had the opportunity to comment on the subject (CJEU C-471/14, 6 October 2015) and stated that date of first marketing authorization Was the date of notification of this decision.
1) Negative duration?
Because of the calculation method previously mentioned, it is quite possible that the duration of a CCP is negative.
Although the patentee is usually not interested in obtaining a CCP of negative duration, he may exceptionally wish to do so, especially if he intends to benefit from a pediatric extension mentioned below.
The CJEU indicated that this was entirely possible (CJEU C-125/10, December 8, 2011).
2.6.3. Pediatric extension
If the holder of a CCP provides the results of the studies carried out according to a pediatric investigation plan (in part or in full on the 0 to 18 age group) approved in his MA or complementary MA application, this one has the right to an extension of 6 months of its CCP (EC Regulation No. 1901/2006 of the European Parliament and of the Council of December 12, 2006, art. 36.1).
Nevertheless, this extension is not possible:
- if the medicinal product is designated in the AMM as targeting an orphan pediatric disease (additional protection of the MA is already granted, see above) (EC Regulation No. 1901/2006 of the European Parliament and of the Council of December 12, 2006art 36.4);
- if the marketing authorization is granted an additional one-year protection granted in the event of a new therapeutic indication (see above) (EC Regulation No. 1901/2006 of the European Parliament and of the Council of December 12, 2006, art. 36.5).