PRAAAPS2014

Ibrahim Mahamoud

Regulatory overview Medicinal products are mainly regulated by the Drug

Act (Arzneimittelgesetz) and the Facility Ordinance for Active Ingredients of Pharmaceuticals (Arzneimittel-und Wirkstoffherstellungsverordnung).

These address, for example, manufacturing, marketing, distributing and pharmacovigilance. Rules for advertising medicinal products are set out in the Healthcare Advertising Act (Heilmittelwerbegesetz).

Medicinal products for human use are subject to a marketing authorisation from :

the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte) (BfArM)

the Federal Agency for Sera and Vaccines (Paul-Ehrlich-Institut) (PEI), if not covered by the European centralised procedure.

Overview

Pricing and state funding

Manufacturing

Clinical trials

Marketing

Advertising

Packaging and labelling

Traditional herbal medicines

Patents

Trade marks

The regulatory authorities

Pricing and state funding The funding of public health insurance: A fixed contribution rate was introduced at

federal level. Every public health insurance fund will receive a lump sum for each insured person and an additional sum depending on the age and risk-level of the insured person. If the lump sum does not cover the insurer's costs, the public health insurance fund can impose additional contributions on each insured person with a maximum of 1% of the income liable to insurance deductions.

Public health insurance funds provide benefits (generally benefits in kind) and services. Therefore, the insured person does not have to pay for the services directly. Federal law largely covers the range of benefits offered by public health insurers. About 85% of the German population are covered by public health insurance. Insured persons can choose optional rates covering, for example, special forms of medical care, non-reimbursable pharmaceuticals, and so on.

Private insurance companies practise a cost-reimbursement principle where the insured person pays the medical bills and is reimbursed by the insurance company afterwards.

Pricing ,,,,,,,,,,, the pricing of drugs by manufacturers and dealers is still largely

unregulated, the Ordinance on Pharmaceutical Product Pricing (Arzneimittelpreisverordnung) sets permissible margins for wholesalers and pharmacists. The Ordinance applies only to prescription medicinal products.

The Fifth Social Security Code (Sozialgesetzbuch V) sets compulsory discounts for public health insurance funds and pharmacies (section 130, 130a, Fifth Social Security Code).

Retail prices for prescription drugs must be uniform across all pharmacies.

The Act on the Improvement of Economic Efficiency for the Provision of Medicinal Products (Gesetz zur Verbesserung der Wirtschaftlichkeit derArzneimittelversorgung) introduced further compulsory discounts for public health insurers.

In general, prescription medicinal products are reimbursed by public health insurance funds. The patients obtain a prescription from their physician and collect the medicinal product from the pharmacy. The reimbursement of medicinal products is then paid directly to the pharmacist by the public health insurance funds. The Ordinance on Pharmaceutical Product Pricing provides the relevant financial framework for prescription drugs that must be sold in pharmacies. The regulation allows the pharmacy or wholesalers to add on a fixed percentage charge to the freely calculated manufacturer's price, when selling the drug to final consumers or pharmacies respectively. About 65% of prescriptions are affected by this regulation.

The cost of medicinal products that are not "necessary and economic" or which are prescribed in cases of specific minor impairments of health is not reimbursed at all. Specific medicinal products, which are considered inefficient or which cannot provide the necessary proof of sufficient therapeutic benefits, are set out in a government "negative list".

Generally, over-the-counter (OTC) products are not refundable.

Manufacturing

Manufacturing - Application Authorisation is required for each production facility

located in Germany.

The competent authority is determined by the states and is usually the general regional government authority (Regierungspräsidium) or the local or regional public health authority (Gesundheitsamt).

Manufacturing ,,,Conditions The manufacturer must meet certain requirements set

out in the Facility Ordinance for Active Ingredients of Pharmaceuticals, relating to, for example, quality management, personnel, hygiene requirements, manufacturing processes and storage.

The Facility Ordinance for Active Ingredients of Pharmaceuticals complies with Directive 2003/94/EC on good manufacturing practice for medicinal products. ,,,, GMP

Restrictions on foreign applicants ,,, Manufacturing The legal requirements are equally binding on foreign

and domestic manufacturers.

Key stages and timing ,, Manufacturing

The authorisation application must be filed before the manufacturing process is started. In most cases, the public authority inspects the premises before delivering a manufacturing authorisation.

The application must be accompanied by several documents. The public authority only issues the authorisation if it is sure that the necessary safety and quality benchmarks are complied with.

The competent authority must decide on an application for a manufacturing authorisation within three months (section 17 paragraph 1, Drug Act). However, if the authority asks the applicant to remedy defects in the application, this time limit is interrupted (section 17 paragraph 3, Drug Act).

Manufacturing … Fee The competent authorities must fix fees on a case-by-

case basis.

Their decisions are made according to a legal framework that can vary between federal states.

Period of authorization and renewals ,,,Manufacturing

Usually, the competent authorities give an unlimitedaccreditation.

What powers does the regulator have to: Manufacturing

Monitor compliance with manufacturing authorizations? Impose penalties for a breach of a manufacturing authorization? The competent authorities , can monitor a manufacturer's

compliance with its manufacturing authorisation. They can enforce compliance using the Drug Act (section 64, Drug Act).

The public officers in charge of monitoring can, for example: Enter and inspect office premises and operating rooms. Review documents on the manufacture of the products. Demand all necessary information on the company's operations. Demand samples, if the authority considers this necessary for

monitoring.

,,, Manufacturing

Generally, premises inspections take place every two years.

they can suspend or withdraw the marketing authorisation (section 18, Drug Act). They can also stop the manufacturing or seize and withdraw medicinal products from the market (section 69, Drug Act).

However, they cannot impose fines or criminal penalties

Clinical trials

Legislation, regulatory authorities and authorizations (clinical trials) The conduct of clinical trials is regulated in the Drug Act

(section 40 pp). the Ordinance on Good Clinical Practices (GCP-Verordnung)

sets out details regarding the conduct of a clinical trial. Before starting a clinical trial, a trial protocol and other details

set out in the GCP-Verordnung must be submitted for parallel approval by the independent Ethics Committee and either the BfArM* or the **PEI (depending on the test product).

The trial can begin only if both voting bodies approve (section 40 paragraph 1, Drug Act). The competent authority of the relevant federal state must be notified of the clinical trials.

* Federal Institute for Drugs and Medical Devices ** Federal Agency for Sera and Vaccines

Consent from trial subjects,,, clinical trials Before including a trial subject in a clinical trial, the

trial subject must give its informed consent in writing. Before the consent can be obtained, the physician must explain the nature, intent, risks and importance of the clinical trial to the trial subject.

The trial subject must also give its consent to the purpose and extent of collection and use of personal data in the clinical trial.

Other conditions ,,, clinical trials The sponsor of the clinical trial must have its seat in the EU

or EEA, or have a legal representative in the EU or EEA.*(European Economic Area)

The clinical trial must have a superior audit manager who must be an approbated physician with a minimum of two years experience in clinical trials.

Patients participating in a trial must have specific insurance cover appropriate to the risks involved, which pays at least EUR500,000 (about US$737,000) for death or permanent inability to work.

Procedural requirements ,,, clinical trials All clinical trials must be conducted according to the

Good Clinical PractiGCPce () standard (section 40, Drug Act implementing Directive (EC) No. 20/2001 on the conduct of clinical trials). In addition, products to be tested must have a Good Manufacturing Practice (GMP) certificate.

Reporting and documenting the clinical trial by the sponsor and physicians are regulated in the GCP-Verordnung (section 12 pp).

Marketing

MarketingApplication Authorizations are granted by the BfArM* or PEI**,

depending on the product.Conditions Finished medicinal products can only be placed on the

market after authorisation (for pharmaceutical products) or registration (for homeopathic products). To be granted authorisation, pharmaceutical companies must provide proof of the pharmaceutical quality, efficacy and safety of the product.

* Federal Institute for Drugs and Medical Devices ** Federal Agency for Sera and Vaccines

Marketing …Key stages and timing The BfArM* accepts documentation submitted in electronic form, including CD-ROM

(see Ordinance on Submission of Application - Verordnung über die Einreichung von Unterlagen in Verfahren für die Zulassung und Verlängerung der Zulassung von Arzneimitteln).

It usually takes two and a half years to obtain a decision. The authorities dealing with the application can provide guidance before an application is filed. All government authorities must provide such information and assistance as is requested (both before and after the formal application is filed) (section 71c, Code on Administrative Procedure).

Fee The applicant must pay the costs of investigating the application and granting the

authorisation after the BfArM issues its decision. The BfArM fixes fees on a case-by-case basis according to the corresponding cost

ordinance.

* Federal Institute for Drugs and Medical Devices

Period of authorisation and renewals ,,,Marketing

The first authorisation is usually granted for five years and can be extended by applying to the same authority that granted it.

(Renewal is refused if the necessary requirements of quality, efficacy and safety are no longer fulfilled).

After the first renewal of the authorisation, no further renewal is needed unless the authority makes another decision, for example, due to security reasons.

If the application for renewal has been filed at least six months before the end of the five-year period, the marketing of the product can be continued until the authority issues a decision.

The renewal fee is between EUR1,410 (about US$2,078) and EUR4,757 (about US$7,012).

Advertising

AdvertisingLegislation and regulatory authority Title VIII of Directive 2001/83/EC regulating the advertising of medicinal

products for human use has been implemented. There are strict regulations on advertising campaigns that target the public. The regulations also make a distinction between advertising activities that are limited to healthcare professionals and those that are also addressed to potential patients.

For medical devices, advertising provisions are less restrictive (Healthcare Advertising Act, which applies to product-related promotional advertising).

A company can only advertise if a responsible person or company with a seat in the EU or EEA* has been expressly entrusted to assume the obligations arising from the Healthcare Advertising Act (section 13, Healthcare Advertising Act).

*European Economic Area

,,,, Advertising

There is a minimum standard for information in marketing strategies (for example, the product's side effects and specific warning notices).

Supervision of medicinal product advertising is the responsibility of the federal states.

Because of the increasing need for consistent supervision, a centralised co-ordination of supervision of the federal states has been set up (Zentralstelle der Länder fürGesundheitsschutz (ZLG)).

Restrictions…. Advertising Medicinal products cannot be advertised before the necessary

marketing approval is obtained (section 3a, Healthcare Advertising Act). Further, advertising prescription medicinal products to patients is prohibited (section 10, Healthcare Advertising Act).

The following issues, among other things, are prohibited: Misleading advertising. Gifts and other advertising giveaway. Promotional activities aimed at the general public must not

contain any advertising statements relating to prescription medicinal products or to (severe) diseases explicitly mentioned in the Healthcare Advertising Act (however, there are plans to reduce the list of severe diseases).

Packaging and labeling

Packaging and labelling Legislation and regulatory authority Title V of Directive 2001/83/EC on the Community code relating to medicinal

products for human use, regulating the labelling of medicinal products for human use and on package leaflets, has been implemented by the Drug Act (sections 10 to 12, Drug Act).

Labelling medicinal products used in clinical trials is regulated by the GCP Ordinance (section 5, GCP Ordinance).

The BfArM* has issued guidelines on labelling and on drafting text for labellingaccording to section 11 of the Drug Act (www.bfarm.de/cln_012/nn_1198876/SharedDocs/Bekanntmachungen/DE/Arzneimittel/natVerf/bm-zul-20061130-packungsbeilagen_2006-pdf.html).

* Federal Institute for Drugs and Medical Devices

Packaging and labelling ,,,, Information

Labelling of packages must contain, among other things (section 10, Drug Act):

The name or firm and the address of the pharmaceutical company.

The name and pharmaceutical form of the medicinal product.

The approval number, the description of charge, content of the package (weight, size or number of units), the method of application, the active ingredients, and the expiry date.

Depending on the individual case: "prescription only", "pharmacy medicines", "sample not for sale" and special precautions.

Other conditions ,, Packaging and labelling

The information for labelling must be well written, generally understandable, durable and in German language.

Traditional herbal medicines

Traditional herbal medicines Herbal medicinal products are deemed to be medicinal products

within the meaning of section 2 of the Drug Act and are subject to the same legal requirements.

there is a simplified re-registration procedure that allows reference to the tradition of a medicinal product as a criterion for efficacy of the product, which applies to a substantial number of traditional herbal medicinal products (section 109a, Drug Act).

A commission has been established under section 25, paragraph 7 of the Drug Act to consider documented evidence and reports, and to produce lists of fields for which this procedure can be applied. These lists were published in the Federal Gazette (Bundesanzeiger) (see www.bundesanzeiger.de) and contain about 1,000 substances.

Patents

Patents Medicinal products are capable of patent protection if

they are novel, involve an inventive step and are capable of industrial application.

Pharmaceutical inventions can be protected by substance claims, process claims or use claims.

The scope in terms of the prerequisite of novelty has recently been revised by the German Supreme Court.

Substance claims can relate to any of the following: An active compound of a pharmaceutical drug. A pharmaceutical composition containing an active compound. Interim products of a manufacturing process.

Directive 98/44/EC on the legal protection of biotechnological inventions (Biotech Directive) has been implemented in Germany, but the legislator used its remaining discretion to limit patent protection in this area. The basic rule is that plants and animal varieties, and essential biological processes for the production of plants or animals, are excluded from patent protection. However, the following can be protected:

Inventions that concern plants or animals not confined to a particular plant or animal variety.

Inventions that concern a microbiological or other technical process, or a product obtained by means of such process.

How is a patent obtained? .. The authority

Patent applications must be filed with either the:

German Patent and Trade Mark Office (DeutschesPatent- und Markenamt) (PTO) (www.dpma.de).

European Patent Office (Europäisches Patentamt) (EPO) (www.epo.org).

Both offices are in Munich.

Fee …. patent The fees for a German patent are: EUR40 (about US$60) for online filings. EUR60 (about US$88) for other filings. EUR350 (about US$517) for the examination.

EPO fees are: EUR100 (about US$148) for online filings. EUR180 (about US$266) for other filings.

Designation fee for one or more Contracting State designated (Article 79(2), EPC): EUR500 (about US$739). Between EUR1,405 (about US$2,076) and EUR1,565 (about US$2,312) for examination.

Fee for patent grant: EUR790 (about US$1,167) (including fee for printing the European patent specification up to 35 pages).

Process and timing ,,,patent The time frame for filing an application for a patent

depends on the technical field involved and the complexity of the invention.

According to the PTO, the procedure should be completed within two and a half years, if the request for inspection is filed within the first four months from the priority date and the fees are paid in time. ( in some cases this period can be extended)

the European patent grant procedure takes about three to five years from the date the application is filed.

Duration of protection ,,patent A patent is granted for a maximum 20-year term beginning on the day

following the filing of the application. A supplementary protection certificate can be obtained in some cases

to extend the duration of protection. Certificates are granted on a national basis according to the formal and material requirements set out in Regulation (EEC) No. 1768/92 concerning the creation of a supplementary protection certificate for medicinal products. The maximum extension period is five years. Under Regulation (EEC) 1901/2006 concerning medicinal products for paediatric use, this five year protection period can be extended for another six months, if both:

The studies conducted to obtain approval for the medicinal product comply with an agreed paediatric investigation plan.

The medicinal product is authorised in all EU member states (however, the interpretation of this condition is currently debated).

Renewal ,,,patent Renewal is not possible.

Trade marks the German Patent and Trade Mark Office

(DPMA)

the Office for Harmonisation in the Internal Market (OHIM)

Trade marks Marks comprising sufficient modifications of descriptive

indications can be registered as trade marks. This is especially true for marks in the pharmaceutical field. However, the scope of protection conferred is limited and does not extend to the generic name or International Nonproprietary Name.

Trade mark protection is excluded if a mark:

Lacks distinctive character in relation to the goods or services for which it claims protection.

Consists exclusively of signs used to describe the kind, condition, amount, or other features of the goods or services.

The law of trade marks is set out in the Trade Mark Act (Markengesetz).

How is a trade mark registered? The authority

Applications for German trade marks must be filed with the PTO (www.dpma.de)

applications for Community Trade Marks (CTMs) must be filed with the Office for Harmonisation in the Internal Market (OHIM) (http://oami.europa.eu).

Fee ,,, Trade marksThe PTO fees are: the German Patent and Trade Mark Office

(DPMA)

For up to three classes of registration: EUR300 (about US$443) or online filing EUR290 (about US$428).

For each additional class: EUR100 (about US$148). Accelerated examination: EUR200 (about US$295).

The OHIM fees are: Registration fee for up to three classes of registration: EUR1,050

(about US$1,551) or online filing EUR900 (about US$1,330). Registration fee for each additional class: EUR150 (about

US$222).

Process and timing ,,, trade marks

After filing, an application is examined by the relevant trade mark office. If no objections are raised, German trade marks are usually provisionally registered within 10 to 12 months.

An accelerated examination procedure is available, which usually enables registration within three to four months.

CTM* applications usually take about one year to provisionally register. If no opposition is filed, the trade mark is registered but is, under certain conditions, open to cancellation proceedings.

*Community Trade Marks

German trade marks and CTMs* are registered for an initial ten-year period. Registrations can be renewed indefinitely for further ten-year terms.

German trade marks and CTMs* can be cancelled if they are not used within five years of registration.

*Community Trade Marks

The regulatory authorities Federal Institute for Drugs and Medical Devices

(Bundesinstitut für Arzneimittel und Medizinprodukte) (BfArM)

Federal Agency for Sera and Vaccines (Paul-Ehrlich-

Institute) (PEI)

Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte) (BfArM)

T +49 228 99 307 30F +49 228 99 307 5207E poststelle@bfarm.deW www.bfarm.de

Main areas of responsibility. The BfArM regulates medicinal products (other than blood and vaccination products) for use on humans.

Authorising finished medicinal products (that is, products that have been manufactured and marketed in packaging ready for distribution to consumers), including post-marketing authorisation.

Registering homeopathic products. Recording and assessing risk. Controlling legal marketing of narcotic drugs and precursors

(that is, chemical substances used to manufacture drugs). Advising the federal government. The sub-departments (Abteilungen) are: Departments 1 to 5: approval procedures. Department 6: scientific service. Department 7: pharmacovigilance.

Federal Agency for Sera and Vaccines (Paul-Ehrlich-Institute) (PEI)

T +49 6103 77 0F +49 6103 77 1234E pei@pei.deW www.pei.de

Main areas of responsibility. The PEI authorises

the marketing and control of:

Immune biological drugs for human and veterinary use, in particular sera. Vaccines. In vitro diagnostics for the detection of specific pathogens. Allergens. Test sera and test antigens. Blood preparations. Bone marrow preparations. Gene transfer medicinal products. Somatic cellular therapeutics. Xenogenetic cellular therapeutics. Genetically manufactured blood fractions. The PEI has a test laboratory for In Vitro Diagnostics (PEI-IVD). This is a notified body

within the meaning of the IVD Directive and deals with products listed in Annex II of the IVD Directive. The objective of the PEI-IVD is to maintain the high level of safety of blood and blood products set out in the IVD Directive.