Crown Regulatory Affairs Post-Graduate Certificate 2016 - Spain Regulatory Affairs - Professor Peivand Pirouzi

http://www.crownacademy.ca

All unauthorized reproduction is prohibited.1

PHARMACEUTICAL REGULATORY

AFFAIRS IN SPAIN

May, 2015

Professor: Peivand Pirouzi, Ph.D., MBA

Post-Graduate Certificate in Regulatory Affairs and Drug Submission

Crown Medical Research and Pharmaceutical Sciences

College of Canada

http://www.crownacademy.ca/


All unauthorized reproduction is prohibited.

European Union / EMA

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European Union

Founded in 1957

Now has 28 Member States

The euro is the single currency of 18 European countries

Single wide-market of over 500 million consumers.





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European Medicines Agency (EMA) :

Decentralised agency of the European Union, located in London.

The Agency is responsible for the scientific evaluation of medicines

developed by pharmaceutical companies for use in the European

Union. It began operating in 1995.

EMA works closely with:

28 European Union Member States

European Economic Area countries (Norway, Iceland and

Liechtenstein).





4Europe in 12 lessons (2014) . 2014, European Commission, Directorate-General for Communication.





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Spain Government System

• The system of government in Spain takes the form of a parliamentary monarchy.

• Central State power is divided in:– legislative (Constitutional Court),

– executive (National Parliament-Congress),

– judiciary.

• After elections, the leader of the party of government becomes the president.

• Spain has four different levels of Government:– Central (Parliament)

– Autonomous Regions (17), each with its own Parliament and Government

– Provinces (50)

– Municipalities (Council headed by Mayor)

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Regulatory Overview

• Law 29/2006 (26 July 2006) on guarantees and

the rational use of medicinal products and

medical devices.

• Royal Decrees which develop Law 29/2006 on

particular regulatory issues.

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Regulatory Authorities

A. Ministry of Health: Rule on all healthcare issues.

B. AEMPS - Agency on Medicinal Products and Medical Devices (Agencia Española de Medicamentos y Productos Sanitarios)– Grant, modification, revocation of manufacturing and

marketing authorisations.

– Authorisation of clinical trials.

– Promotion, control and supervision of medicinal products in the market.

– Enforcement of the regulations. Pharmacopeia.

– Guarantee the supply of medicinal products.

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• DGFPS - General Directorate for Pharmacy and

Medical Devices.

– Public funding and price setting.

– Establishing special conditions for the prescription and

sale of medicinal products in the National Healthcare

System (NHS).

• Regional governments of the Autonomous

Communities,

– Implement measures on medicinal products in their

territories.

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Medicinal products must be authorised for marketing by one of the following:

• AEMPS - Agency on Medicinal Products and Medical Devices – Responsible for national marketing authorisations (MAs),

decentralized and mutual recognition procedures• EMEA - Agency for the Evaluation of Medicinal Products (EU Level)

– Responsible for the centralised procedure, mandatory for:• Medicinal products developed by recombinant DNA technology

and/or controlled expression of genes coding.

• Orphan medicinal products.

• Medicinal products which contain a new active ingredient, not as yet authorised in the EU, relating to:

– AIDS;

– cancer;

– a neurodegenerative disease;

– diabetes; and

– auto-immune diseases and other immune dysfunctions, and viral diseases.

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Pricing and funding

• Prices regulated under Article 90 of Law 29/2006.

• DGFPS regulates the price of medicinal products sold in Spain and financed by NHS.– Laboratory selling price. Base on:

• Manufacturing costs (incl. administrative and marketing costs).

• Research and development costs.

• Profit element.

• Adjusted by correcting mechanism such as:– Therapeutic use

– Cost of financing for similar therapeutic medicinal products

– Modulating factor of the lowest price of the medicinal product which is being financed in Europe

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Pricing and funding

– Public retail price.laboratory selling price

+

annually updated commercial margins (fixed by resolution of the Ministry of Health) for wholesalers

and pharmacies

+

value added tax (VAT).

In case of OTC excluded from financing by NHS, the laboratory notifies its selling price to the Ministry of Health.

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Pricing and funding

• Reimbursement is by a system of reference pricing.– Reference prices are the maximum amount the

NHS will fund for each medicinal product in a group.

– Group : the total of financed medicinal product's presentations that have the same active ingredient and identical administration route (at least one must be a generic or biosimilarmedicinal product or its main AI been authorised within Spain or the EU for ten years – RD 177/2014).

– Reimbursement is normally paid by the NHS to the pharmacist. 14




Manufacturing. Authorisation process.

Application (Royal Decree 1564/1992)

– Made to AEMPS in Spanish through the online application.

– AEMPS may authorize certain parts of the scientific-technical documentation to be filed in another language.

Conditions (Article 6, 15 and 16, Royal Decree 824/2010)

– Personnel requirements. • Sufficient technically qualified personnel.

• Technical Director manufacturing.

• QC responsible.

– Material and technical requirements.

– Quality requirements. GMP and MA conditions.

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• NO Restrictions on foreign applicants Key stages and timing

– AEMPS makes a reasoned decision within 90 days of the application.

– If all requirements are met, AEMPS grants the authorisation. Entered in the ‘Registry of Pharmaceutical Laboratories’.

– If applicant fall, it is communicated and have 15 days to provide the relevant information. If the AEMPS does not communicate a decision within three months of the application's submission, the application is dismissed.

– Right of appeal to AEMPS and then to a court. 16





Key stages and timing (cont.)During the application, the AEMPS:

– Inspects the premises.

– Informs the applicant of remediable defects, and gives the applicant a period in which to remedy those defects.

The AEMPS can also:

– Request additional documentation.

– Require pending information to be provided within ten days (the application is set aside if the information is not provided).

– Hear statements from the applicant.

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• FeeFor 2014, the fee payable for an authorisation to begin activity as a pharmaceutical laboratory is EUR 5,857.78 (CAN$7,944.43).

Period of authorisation and renewals.

Authorisations are granted for an indefinite period.

• Monitoring compliance– Health authorities of the Autonomous Communities have power to

inspect, supervise and fine.

– If there is reasonable suspicion of an imminent and serious risk to health. AEMPS and the Autonomous Communities can impose measures, such as:

• putting into quarantine;

• suspending medicinal products from manufacturing, import, marketing, export, advertising and use;

• provisionally closing establishments, centres and services; and

• suspending the elaboration, prescription, dispensing or supply of medicinal products under research.

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Packaging and labelling

• Labels and leaflets contain to guarantee proper

identification and correct use of medicinal products is set

out in:

– Law 29/2006.

– Royal Decree 1345/2007.

– DGFPS Circular 29/1994.

– AEMPS' Circular 2/2000 (modified by Circular 1/2002).

• The text and other features of the packaging and leaflet:

– Are part of the MA, authorised by AEMPS.

– Must be written in Spanish.

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Clinical trials

• Regulated by Royal Decree 223/2004 on clinical trials.

• Authority– AEMPS is the authority responsible for approval of clinical trials.

– Requires a favourable opinion from the Ethics Committee on Clinical Investigation (1)

– Requires the approval of the centres where CT are carried out.

• Consent

– A participant in a clinical trial must consent to participation after having understood, the objectives, risk, inconveniences, conditions and right to withdraw.

– Consent documented in specific form.

• Trial Pre-conditions: – Sponsors are responsible for obtaining insurance to cover any harm that could

arise to trial subjects as a consequence of the trial

• Procedural requirements– The trial must be performed according to the trial protocol, legal and ethical

regulations, and good clinical practices.

20(1) Independent organisation accredited by health authorities of the Autonomous communities and the AEMPS.




Clinical trials

• Timing

– 10 days from application. If meets

requirements, AEMPS inform the application is

admitted.

– 60 days from admission. Approval granted if

AEMPS does not oppose.

– 15 days from refusal.

• If AEMPS refuses to authorise, the applicant has this period

to modify its application or make any necessary statements.

• AEMPS makes and express decision on the revised

application, which is final.21




Clinical trials

• Timing– Trials requiring AEMPS' prior written authorisation and subject to

special procedure. • Trials where the AEMPS has notified objections to the sponsor.

• Trials that refer to products requiring a qualification as products under clinical investigation. Pharmaceutical forms of active ingredients which are:

– Used or combined differently form the authorised form;

– Used to treat an unauthorised symptom; or

– Gain more information on the authorised use.

– If no response to application within 60 days, the application is deemed refused

• Trials that are undertaken with medicinal products relating to:– gene therapy;

– somatic cell therapy;

– medicinal products containing genetically modified organisms,

– Time limit is 90 days.

• For medicinal products relating to:– xenogeneic cell therapy.

– No time limit to either authorise or reject the clinical trial.

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Sales and marketing

Prescription and OTC medicinal products must be sold in

pharmacies.

Retail outlets only can sell non medicinal products (food

supplements, some type of medical devices with

conditions)

Prohibited sale of prescription-only medicines by post and

by telematic procedures.

Approved telematic sale of non-prescription medicinal

products (RD 879/2013), through website of legally

authorised pharmacy.

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Traditional herbal medicines

• Plants, plant mixtures and preparations obtained from plants with therapeutic or preventive use are subject to laws governing magisterial formulae, officinal preparations or pharmaceutical specialties.

• Plants traditionally considered as medicinal plants that are offered without reference to therapeutic, diagnostic or preventive properties, can be freely sold to the public but only at authorised establishments.

• A list of the permissible traditional plants is established by the Committee on Herbal Medicinal Products (HMPC) of the EMEA.

• Ministry of Health has published a list of plants whose sale to the public is restricted or prohibited due to their toxicity (Order SCO/190/2004).

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Marketing

• Application for MA– Must be made in Spanish to AEMPS, and signed by the

applicant and the laboratory's technical director.

– In some circumstances, an application must be made to EMA.

Conditions (Article 10, Law 29/2006)

– Achieve the established quality requirements.

– Be safe (that is, in normal conditions of use it does not produce toxic or unwanted effects disproportionate to the benefit obtained).

– Have shown its efficacy for the therapeutic purposes for which it is offered.

– Be correctly identified and accompanied by the required information (accessible and comprehensive for the patient).

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Marketing

Key stages and timing (Royal Decree 1345/2007)– 210 days for AEMPS to decide whether to grant or refuse the

application.• If the application is not complete, AEMPS gives the applicant ten days to

provide the required documentation. This interrupts the 210-day period.

• If this information is not provided, AEMPS informs the applicant and, after three months, the application expires.

• The Committee for the Evaluation of Medicinal Products for Human Use, an official body of AEMPS, issues a non-binding report during the 210-day period.

• AEMPS makes a final decision on the application within ten days of the Committee's report.

– AEMPS' decision sets out the medicinal product's marketing conditions, including the text, labelling and packaging requirements to comply with the Summary of Product Characteristics (Technical Deed).

– At the same time, the product is also entered into the Registry of Medicinal Products (Registry). 26




Marketing

• Fee

– EUR 20,529.17 for MA and entry in the

Registry for medicinal product

(CAN$27,843.13)

– EUR 8,350.71 for MA and entry in the Registry

for generic medicinal product

(CAN$11,325.83)

– EUR 2,319.51 for renewal fees

(CAN$3,146.08)

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Marketing

• Period of authorisation and renewals– MA are granted for an initial period of 5 years.

– MA can be renewed following a re-evaluation of the risk-benefit relation.

– Renewal is for indefinitive period except if, for pharmacovigilance reasons justify it being submitted to a new renewal procedure.

– The MA holder must annually declare to AEMPS its intention to market the medicinal product .

– The MA expires if:• its holder does not effectively market the product within

three years or

• once on the market, the product is no longer available or being produced for three years. 28




Marketing

• Post-marketing commitments and pharmacovigilance obligations– MA holder must:

• Maintain the conditions of the MA.

• Notify of any porduct’s withdrawal form the market.

• Inform health authorities of the Autonomous communities of any adverse reaction caused by the medicinal product.

• Continually update the information relating to the safety of the product.

• Execute pharmacovigilance plans and risk management programs,

• Carry out continuing assessments of the risk-benefit relation of the medicinal product, etc.

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Marketing

MA Authorizations Compliance Monitoring

By AEMPS and the health authorities of the

Autonomous Communities in their territories

(similar to manufacturing authorisation)

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Marketing• Abridged procedure = not required to provide the

results of pharmacological or toxicological tests or clinical trials– The application is made with the consent of a MA holder of

a medicinal product with the same qualitative and quantitative composition and identical pharmaceutical form.

– The active ingredient (AI) of the medicinal product has a clearly established medicinal use of at least ten years in the EU, with known efficacy and an acceptable level of security established by a detailed scientific bibliography.

– The medicinal product is a generic of a reference medicinal product authorised under EU regulations for a minimum period of eight years. The generic however cannot be marketed in Spain until ten years have elapsed since the initial MA was granted (or 11 years if a relevant new indication is subsequently authorised).

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Marketing

• Mandatory mutual recognition of MA granted by EU member states.

If an application for MA of a medicinal product has already been examined by another member state's health authority:

– AEMPS suspends examination of the application until it receives a report from that health authority.

– Within the following 30 days, AEMPS must either:• Grant the authorisation.

• Start a consultation period in which representations of the applicant and the relevant member states are obtained.

• If AEMPS still refuses to accept the application, a Commission conciliation procedure starts, following which the Commission issues a final decision.

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Marketing

Parallel imports (RD1785/2000

• Requirements for Authorization in Spain of medicinal products from EU member states:

– Technical requirements. • Have a MA in the member state of origin. Be entered in the

AEMPS`Registry of Medicinal Products

• Meet requirements on labelling, packaging, conditioning material, repackaging.

– Be Qualified as distributor or manufacturer

– Information Requirements• Notify the Spanish holder of the MA. Provide if requested a sample of

repackaged product to verify not damage to the trade mark’s reputation.

• Keep for at least two years following expiring date of the imported product, data on every product batch for the health authorities.

• Inform AEMPS when stop importation

• Notice to AEMPS if intends to export products to other EU states (there medicinal products listed as to be at risk of non-availability).

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Advertising

• Regulated by:– Law 29/2006, RD 1416/1994, DGFPS Circular 6/95.

– Autonomous Communities regional codes.

• Members of ‘Farmaindustria’ - main Spanish association of research-based pharma companies- , also complaint with :

– Conduct of Conduct for the Promotion of Medicinal Products.

– Codes of the European Federation of Pharmaceutical Industries and Association (EFPIA).

– Code of the International Federation of Pharmaceutical Manufacturers (Code).

• General public. – Authorization for medicinal products (usually OTC).

– Non-prescription products, don’t need authorization.

• Health professionals. – Notification to Autonomous Community's health authority by the company.

– Advert must satisfy requirements set in the legislation.

• Legal provisions and the ‘Code’ are also applied to Internet advertising.

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Patents

• An invention can be protected by a patent if it – Is new.

– Involves an inventive step.

– Is capable of an industrial application.

• Regulated by– Law 11/1986 (modified by Law 10/2002, which brought into force Directive

98/44/EC on the legal protection of biotechnological inventions).

– Royal Decree 2245/1980.

• Authority– Patent rights can be obtained by an application to the Agency of Patents

and Trade Marks 7Oficina Española de Patentes y Marcas (OEPM)

• Fee (e.g. 2009)– EUR91.69 (about CAN$124) for the patent application.

– EUR664.51 (about CAN$898.925) for the report.

– Annual fees from the third year following the date of registration of the patent.

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Patents

• Process and timing – Obtain registration lasts between 30 and 36

months. A rejection can be appealed before the administrative courts.

– Patent rights last 20 years from the date the application (if renewal fees are paid and the patent is not revoked)

– Patents cannot be extended beyond a term of 20 years, except for medicinal products.

– Patent rights for medicinal products can be extended by a supplementary protection certificate (SPC), for a period of up to five years (1).

(1) Equal to the period between the date when the patent application was lodged, and the date when the first marketing authorisation was granted in the EU, minus a period of five years. Regulation (EEC) No. 1768/92.

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Patents• Revocation

– A patent is revoked when any of the following occur:

• The invention does not meet one of the patentability requirements.

• The invention is not described sufficiently clearly and completely so as to be carried out by an expert.

• The purpose of the patent exceeds the description in the patent application.

• The patent owner was not entitled to apply for a patent.

– Civil and Criminal proceedings against patent infringer are also regulated by Law.

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Trade marks

Product brands can be protected by registration as trade marks, provided:

• The trade mark cannot:– incur in the prohibitions contained in Law17/2001

– mislead as to the therapeutic properties or the nature of the medicinal product;

– be confused with a Spanish official denomination or an international common denomination;

– be confused with another medicinal product in the market, or a cosmetic product, or food sold in pharmacies;

– have been used by a medicinal product that was annulled within the previous five years.

Generic medicinal products are identified by the abbreviation EFG following their denomination or by trade mark.

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Trade marks• Authority. Applications addressed to:

– Autonomous Community where the applicant is domiciled, or has its industrial or commercial establishment, or

– OEPM, when the applicant is not domiciled in Spain

• Fee– In 2009 was EUR154.38 (CAN$208,87).

• Process and timing – Between eight and 20 months

– Registration is valid for 10 years

– Can be extended for successive 10 years periods on payment of a renewal fee (EUR178.73 -CAN$241.82).

• Revocation– A trade mark can be revoked by a court's final judgment.

– Civil and Criminal proceedings against patent infringer are also regulated by Law.

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Trade marks• Spain is party to the following international conventions:

– Council of Europe Convention on the counterfeiting of medical products and similar crimes involving threats to public health. CETS No.: 211 (Medicrime convention).

• Ratified by 4 countries. Ratified by Spain on August 5, 2013.

• Signed by19 countries.

• International tool which criminalizes counterfeiting and the production and distribution of medical products put on the market without approval or in violation of safety standards.

– WIPO Paris Convention for the Protection of Industrial Property 1883.

– Patent Cooperation Treaty 1970.

– Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure 1977.

– WTO Agreement on Trade-Related Aspects of Intellectual Property Rights 1994 (TRIPS).

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Product liability

• Regulations– Civil Code, which applies to contractual or extra-

contractual (that is, tortious) liability.

– Royal Decree 1/2007, 16 November 2007, which harmonises product liability rules for defective products.

• Liability– The manufacturer and importer are liable for damage

caused by a defect in a product which they have manufactured or imported.

– Other persons involved in the manufacture, import or sale of the defective products (or other operation relating to the marketing of the defective product) can be liable for damage attributable to them.

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Product liability

• Regulations– Civil Code, which applies to contractual or extra-contractual (that

is, tortious) liability.• Limitation periods are 15 years contractual liability and one year for

extra-contractual.

– Royal Decree 1/2007, 16 November 2007, which harmonises product liability rules for defective products.

• Limitation period of three (3) years from the day on which the claimant suffers the damage. Ten (10) years from the date on which the product which caused the damage was put into circulation.

• Liability– The manufacturer and importer are liable for damage caused by

a defect in a product which they have manufactured or imported.

– Other persons involved in the manufacture, import or sale of the defective products (or other operation relating to the marketing of the defective product) can be liable for damage attributable to them.

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References

• Hector Jausas and Maria Cedó . Medicinal product regulation and product liability in Spain: overview. Life Sciences. Multijurisdictional guide 2014-2015. ( Law stated as 1 May 2014)

• Europe in 12 lessons (2014) . 2014, European Commission, Directorate-General for Communication.

• European Union. Official website. http://europa.eu/index_en.htm

• European Medicines Agency. Official website. http://www.ema.europa.eu

• Agencia Española de Medicamentos y Productos Sanitarios. (Spanish Agency of Medicines and Health Products). http://www.aemps.gob.es/

• Living and working in Spain. David Hamsphire.

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Education

Crown Regulatory Affairs Post-Graduate Certificate 2016 - Spain Regulatory Affairs - Professor Peivand Pirouzi