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

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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

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).

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

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6

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)
7

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.
8

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.
11

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
12

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.
13

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 biosimilar
medicinal 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. 15

• 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.
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 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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• Fee
For 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.
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(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.
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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.
23

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)
27

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.
29

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.
32

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).
33

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.
34

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.
35

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.
36

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.
37

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.
38

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.
39

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).
40

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.
41

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.
42

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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