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Before a new drug can be marketed, pharmaceutical companies conduct a complex and lengthy series of toxicologic, pharmacologic, and clinical tests. During this evaluation process, the results of these tests are assessed by health authorities to verify the quality, efficacy, and safety of a medicinal product (1), and only then will it be made available to patients. A delay in the approval of a certain drug may constitute a significant problem in clinical practice. The actual procedure for drug evaluation is often not known by health professionals and, unfortunately, in most cases, only when a serious public health issue is raised does the matter receive significant attention. The evaluation and approval process of drugs in the European Union (EU), with particular emphasis on the field of rheumatology, will be described.

Development of a new drug

  1. Top of page
  2. Development of a new drug
  3. Procedures for authorizing medicines in Europe
  4. Guidelines for testing and evaluation of new drugs
  5. Comparison between regulatory systems
  6. REFERENCES

During drug development, basic research is directed towards the fundamental understanding of biology and disease processes. Then, the ideas formed from the basic scientific research enter into translational research, which is concerned with efficiently moving basic discoveries from concept into clinical evaluation, often focused on specific disease entities or therapeutic concepts (2). Although today's revolution in biomedical science has raised new hope for the prevention, treatment, and cure of serious illnesses, the current medical product development path is becoming increasingly challenging, inefficient, and costly (2). In response to the widening gap between basic biomedical knowledge and clinical application, after decades of investment in basic biomedical research, the focus is widening to include translational research—multidisciplinary scientific efforts directed at “accelerating therapy development” (i.e., moving basic discoveries into the clinic more efficiently). The critical path begins when candidate products are selected for preclinical and, subsequently, clinical development with phase I, II, and III testing. A new medicinal compound beginning phase I testing often represents the culmination of a decade of preclinical screening and evaluation; however, it is estimated to have only an 8% chance of reaching the market. The current cost of bringing a new medicine to market is estimated to be between 0.8 and 1.7 billion dollars (2).

Procedures for authorizing medicines in Europe

  1. Top of page
  2. Development of a new drug
  3. Procedures for authorizing medicines in Europe
  4. Guidelines for testing and evaluation of new drugs
  5. Comparison between regulatory systems
  6. REFERENCES

Medicinal products are widely regulated in Europe to safeguard public health, and to facilitate access of European patients to innovative drugs (3, 4). Legislation governing drug regulation in the European community is currently under review to take into account current scientific and technologic changes in drug development, and also the enlargement of the EU.

The types of new medicinal product investigations conducted by pharmaceutical companies are also regulated and include pharmaceutical, preclinical, and clinical tests. A registration dossier containing the results of these tests is submitted to the health authorities. The dossier consists of 4 parts: administrative data, chemical-pharmaceutical aspects, preclinical investigations, and clinical investigations, and each part is assessed separately by specialized teams of assessors.

The European Medicines Agency (EMEA) was formed in 1995 and is based in London, England. The EMEA coordinates the existing scientific resources of the Member States for the evaluation, supervision, and pharmacovigilance of medicinal products for both human and veterinary use throughout the EU (4). At present, the EMEA is comprised of representatives of the 25 member states of the EU, and 3 additional countries from the European Economic Area–European Free Trade Association.

The EMEA uses 3 types of procedures (centralized, mutual recognition, and decentralized procedures) for authorizing a drug (3, 4), and all 3 require a registration dossier. The centralized procedure is compulsory for all medicinal products developed by biotechnologic process; for new active substances indicated for the treatment of acquired immune deficiency syndrome, cancer, neurodegenerative disorder, or diabetes; and also for designated orphan medicinal products. The centralized procedure is optional for other innovative new medicines. Applications are made directly to the EMEA and are evaluated by the scientific Committee for Human Medicinal Products (CHMP) (4), which is composed of senior assessors nominated by the Member States, and a network of over 3,500 experts (5). On the basis of the CHMP report, the European Commission makes its decision whether to grant a community marketing authorization, which will be valid throughout the entire EU. After authorization, a scientific assessment report (European Public Assessment Report) for each medicinal product is published on the EMEA website (4).

The mutual recognition procedure is based on the principle of mutual recognition of national authorizations between Member States, and applies to the majority of conventional medicines. Under this procedure, a marketing authorization granted by one Member State is extended to one or more other Member States selected by the applicant (3).

In the decentralized procedure, a marketing authorization for a medicinal product is granted simultaneously in more than one Member State but, in contrast to the mutual recognition procedure, the medicinal product has not received any national marketing authorization at the time of application (3). There is also a national procedure for those applications for marketing authorization that would be restricted to a national level (2); however, its use has become limited. Examples of rheumatology medicinal products that have been authorized in Europe along with its corresponding authorization procedure are shown in Table 1. It should be noted that all biotechnology substances use the centralized procedure.

Table 1. Examples of rheumatology drugs authorized in Europe listed by the corresponding authorization procedure
  • *

    Different brand names and different indications.

Centralized procedure
 Adalimumab
 Celecoxib*
 Etanercept
 Infliximab
 Leflunomide
 Parecoxib
 Zoledronate
Mutual recognition procedure
 Alendronate
 Celecoxib*
 Dexketoprofen
 Etoricoxib
 Lumiracoxib
 Meloxicam
 Risedronate

The summary of product characteristics (SmPC) lists the available information of a medicinal product including therapeutic indications, dosing, warnings, contraindications, etc., in accordance with the information contained in the dossier (6), and is identical in all the Member States at the end the registration procedure. The EMEA, together with the network of national authorities, also carefully monitor all centrally authorized products once they are in use (4).

After the marketing authorization is granted, the drug can be further evaluated, and any new relevant information discovered is submitted to the health authorities for assessment. This information can lead to a change in the SmPC listing for therapeutic indications, adverse reactions, etc. Table 2 shows the different indications for etanercept since its authorization in the EU.

Table 2. Examples of different indications for etanercept since its authorization in the European Union*
Indication grantedDate of approval
  • *

    RA = rheumatoid arthritis; DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate.

RA in adults when inadequate response to DMARDsFebruary 3, 2000
Juvenile chronic arthritis in children when inadequate response to MTXFebruary 3, 2000
Psoriatic arthritis when inadequate response to DMARDs in adultsDecember 5, 2002
Ankylosing spondylitis in adultsJanuary 16, 2004
Combination with MTX for RA when inadequate response to DMARDs and for structural damageMay 15, 2004
Moderate to severe plaque psoriasis in adultsSeptember 29, 2004

Guidelines for testing and evaluation of new drugs

  1. Top of page
  2. Development of a new drug
  3. Procedures for authorizing medicines in Europe
  4. Guidelines for testing and evaluation of new drugs
  5. Comparison between regulatory systems
  6. REFERENCES

A coordinated licensing procedure needs common standards of quality evaluation, and safety and efficacy testing requirements. The work of the CHMP is supported by several working parties, one of which is the Efficacy Working Party whose main task is to prepare guidelines for the CHMP to increase coordination between the parties and, thus, to facilitate the assessment. Guidelines will also ensure consistency of the assessment between products in the same area and improve the transparency of the decisions concerning product licensing. Guidelines also give companies guidance when developing new medicinal products (7). Examples of several guidelines for drugs used to treat rheumatologic conditions are shown in Table 3.

Table 3. Examples of European Guidelines for drugs used to treat rheumatologic conditions*
  • *

    CHMP = Committee for Human Medicinal Products; EWP = Efficacy Working Party; NSAIDs = nonsteroidal antiinflammatory drugs.

CHMP/EWP/556/95 rev 1.Points to consider on clinical investigation of medicinal products other than NSAIDs for treatment of rheumatoid arthritis.
CHMP/EWP/784/97.Points to consider on clinical investigation of medicinal products used in the treatment of osteoarthritis.
CHMP/EWP/552/95 rev 1.Note for guidance on postmenopausal osteoporosis in women.
CHMP/EWP/438/04.Concept paper on the development of a CHMP points to consider on clinical investigation of medicinal products for the treatment of psoriatic arthropathy.
CHMP/EWP/422/04.Concept paper on the development of a CHMP points to consider on clinical investigation of medicinal products for the treatment of juvenile idiopathic arthritis.

On a more global scale, the CHMP (in addition to developing European guidelines) is also involved with the International Conference for Harmonization (ICH) process, which explores the possibility of worldwide development of drugs. The ICH also works to develop standardized general application requirements between Europe, Japan, and the United States (7). The CHMP also gives scientific advice to research-based companies during the development stage of new medicinal products (4).

Comparison between regulatory systems

  1. Top of page
  2. Development of a new drug
  3. Procedures for authorizing medicines in Europe
  4. Guidelines for testing and evaluation of new drugs
  5. Comparison between regulatory systems
  6. REFERENCES

The US Food and Drug Administration (FDA) and the European Medicines network share similar mandates, which include promoting and protecting public health, promptly evaluating therapeutic products, working collaboratively with outside experts, reducing the regulatory burden through international harmonization, providing regulatory and health information, and enhancing product development. The FDA is also a partner with the ICH and follows all the consensus document guidelines including those concerning clinical trial design, data collection, safety monitoring and reporting, and statistical analysis (8). Although the FDA and EMEA share similar objectives, their structures differ mainly in the fact that the FDA oversees a single nation, and the EMEA coordinates many European nations. In the FDA, drug evaluation applications are assessed by the FDA's own staff, compared with the EMEA, where the assessment is conducted by the national agencies of the Member States.

Both the FDA and the EMEA have similar evaluation processes from a scientific stand-point, although the final outcome of the benefit/risk assessment is not necessarily the same in all cases. Traditionally, new drug clinical investigations in the US compare the new agent with placebo, while in the EU there is increased emphasis on comparisons between the new agent and existing agents. However, in the current system where pharmaceutical companies frequently conduct a clinical program for submission in all regions, the main clinical requirement would be to demonstrate efficacy and safety, which is normally not associated with a unique study design concerning the choice of comparator. In any case, a 3-arm study using placebo and an active treatment as controls is preferable, when possible.

The signing of confidentiality arrangements in September 2003 has increased the level of cooperation between the EMEA and the FDA, particularly in the provision of parallel scientific advice to companies developing new medicines (5).

The evaluation of a new medicinal product of chemical or biologic origin is considered by Health Authorities as a process that requires the highest guarantee of quality, efficacy, and safety. The EU has developed a regulatory system to facilitate cooperation among the Member States, and the EMEA plays a prominent role.

REFERENCES

  1. Top of page
  2. Development of a new drug
  3. Procedures for authorizing medicines in Europe
  4. Guidelines for testing and evaluation of new drugs
  5. Comparison between regulatory systems
  6. REFERENCES
  • 1
    The European Agency for the Evaluation of Medicinal Products. Frequently asked questions. URL: http://www.emea.eu.int/pdfs/general/direct/faqs/FAQen.pdf.
  • 2
    US Food and Drug Administration. Innovation Stagnation: Challenge and Opportunity on the Critical Path to New Medical Technologies. URL: http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html
  • 3
    Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Official Journal of the European Union 30.4.2004.
  • 4
    Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. URL: www.emea.eu.int.
  • 5
    The European Medicines Agency. Tenth annual report of the European Medicines Agency. URL: http://www.emea.eu.int/pdfs/general/direct/emeaar/ar6149205en.pdf.
  • 6
    Guideline on Summary of product characteristics (The rules governing medicinal products in the European Union, The Notice to Applicants). URL: http://pharmacos.eudra.org/F2/eudralex/vol-2/c/spcGuidRev1-Oct2005.pdf.
  • 7
    Van Zwieten-Boot B. Preparation of guidelines for testing and evaluating new drugs in several therapeutic areas [newsletter]. Eur Soc Clin Phar 1999; 92: 23.
  • 8
    Hirschfeld S, Pazdur R. Oncology drug development: United States Food and Drug Administration perspective. Crit Rev Oncol Hemat 2002; 42: 13743.