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Des sources du savoir aux médicaments du futur

Jacques Fleurentin
Jean-Marie Pelt
Guy Mazars

3. Médicaments du XXIe siècle

Franco-chinese dossier: regulations on plant-based medical products in France and China

Antoine Sawaya, Yves Frances, Jean-Pierre Reynier et Guy Balansard


Following the cooperation agreement in the field of medicine and health between the government of the French Republic and the government of the People's Republic of China, a « Franco-chinese Herbal Group » has been set up.
The objective of this group is to establish a list of medicinal plants from the traditional Chinese Pharmacopoeia, which could be proposed to the French Health Products Agency with a view to include them eventually in the French Pharmacopoeia and in the Agency's list of plants (Instructions Booklet N° 3).
The group is made up of pharmacological, galenical, toxicological and clinical experts from both parties. It officially meets twice a year. Plants proposed must comply with quality and safety criteria required for herbal medicinal products in France. Traditionnal usage must be acknowledged.
The development of herbal medicinal products is difficult in Europe because differents reglementary rules exist in the differents european member states. The basis of harmonisation should be established on the assessment of quality objectives and using safety and efficacy data already available. Don't give a legal status to herbal medicine provide abuses and accidents.

Texte intégral

1. The franco-chinese herbal group

1A cooperation agreement in the field of medicine and health was concluded on 15 May 1997 between the Government of the French Republic represented by the Minister of Foreign Affairs, Mr. Hervé de Charette, and the Government of the People's Republic of China represented by the Health Minister, Mr. Chen Minzhang.

2Under article 2 of the agreement, which was published in the Official Journal of 17 April 1998 (decree N° 98.282 of 8 April 1998), cooperation between the two parties is to give priority to:

  1. Public Health
  2. Medicine oncology (radiotherapy, radiophysics) cardiology, surgical specialties
  3. Scientific cooperation on infectious diseases, notably tuberculosis, hepatitis B and AIDS
  4. Emergency medicine
  5. Health insurance
  6. Pharmacy
  7. Training of health professionals and notably the francophone network of physicians' training.

3Furthermore, under article 4, to ensure the implementation of the agreement, both parties are to set up a joint working group which is to meet yearly to examine and develop specific action plans. This group is to evaluate on a regular basis the implementation of the agreement.

4The joint working group met on 9 and 10 November 1998 at the Chinese Health Ministry in Beijing.

5The official conclusions of the meeting specify, in the appendix relating to cooperation in the field of pharmacy, that future cooperation with regard to medicinal products is to be structured around the following themes:

  • the exchange of information
  • training
  • herbal medicines
  • participation in scientific events

6The AFSSAPS and the SDA (State Drug Administration), whose responsibility is to implement the pharmaceutical chapter of the agreement, have set up a "Franco-Chinese Herbal Group".

7The objective of this group is to establish a list of medicinal plants from the traditional Chinese Pharmacopoeia, which could be proposed to the French Health Products Agency with a view to include them eventually in the French Pharmacopoeia and in the Agency's list of plants (Instructions Booklet N° 3).

8The initial work of the Franco-Chinese Herbal Group has led to the pre-selection of a few dozen Chinese plants. In order to better study these plants, they have been divided into four categories:

9Plants of category I

10Species and drugs used in France and included in the Agency's Instructions Booklet N° 3 (Herbal Medicinal Products) and in the list of plants of the Pharmacopoeia.

11Plants of category II

12Plants included in the French Pharmacopoeia but not included in the Agency's Instructions Booklet.

13Plants of category III

14Chinese species closely related to French or European species, for which analogies need to be found.

15Plants of category IV

16Chinese species for which additional chemical, pharmacological and toxicological information is needed.

17The group is made up of pharmacological, galenical, toxicological and clinical experts from both parties. It officially meets twice a year.

18The conclusions of the meetings are discussed by the French Health Products Agency's Herbal Medicinal Products Working Group before being presented to the Marketing Authorization Commission for its opinion.

19Plants proposed must comply with quality and safety criteria required for herbal medicinal products in France. Traditional usage must be acknowledged.

2. Authorisation request for placing on the market a new medicine (France and European Community)

20The marketing authorisation for a new medicine (French acronym for the procedure A.M.M.) is subjected to a rigorous procedure imposing to the Pharmaceutical Company to submit an application to the Authorisation Commission, following the standard regulations laid down in the "European Format" (see Appendices A and B).

21After examining the application, the Commission can establish:

  • the pharmaceutical properties of the drug proposed;
  • the benefit / risk ratio when using the medicine for specific indications, i.e. its efficacy and safety of use. This calls for a comparison with the other medicines to be used for the same indications.

22The efficacy is assessed for each individual indication and in relation to the groups of patients (ordinary patients, patients with a risk factor increased because of specific physiological conditions, as in the case of old-age people or infants, or pathological conditions, such as kidney or liver failure).

23The best therapeutic modalities have to be clearly defined: best dosage to achieve the best benefit / risk ratio, optimal conditions for a prescription (distribution of dosages, form of administration). The choice of dosages and therapeutic modalities is generally based on data supplied by human pharmacology and clinical trials. The effectiveness has to be assessed on the basis of clinical criteria having medical significance and accepted by specialists.

24The results of clinical trials will be examined in relation to the quality of the experimental procedure and the application of good clinical practice.

25Safety of use is assessed on the basis of the analysis of toxicological studies carried out on animals and focussing on the organs targeted by the drugs concerned, and experiments in mutagenesis, carcinogenesis and the reproductive functions.

26The adverse responses observed must be examined in relation to their gravity and the frequency of occurrence in the various groups of patients, as compared with the reference medicines available.

27The clinical assay, in this case, refers to a systematic survey of the impact of the drug on man, taking into account voluntary patients and healthy people, and the safety of use.

28Generally, the clinical trials are divided in 4 stages. It is difficult to separate these stages clearly and opinions vary as for the modalities and methodology to follow these 4 stages.

29The various stages can be defined as follows:

• Stage I

30First tests applied to a new active substance on man, involving in most cases on healthy volunteers. The objective is to obtain a primary assessment of the safety of use and set up a preliminary pharmaco-kinetic / pharmaco-dynamic profile of the active substance on man.

• Stage II

31Therapeutic pilot trials. The idea is to evidence the activity and evaluate the short-term safety of use of the active substance on patients suffering from a disease or an ailment that should be treated with the active substance.

32These tests are carried out with a limited number of people and, often, at the end of the stage, following a comparative protocol (for instance: as opposed to placebo treatment). The purpose of this stage is also to determine the appropriate dosage and posology and, if possible, to clearly establish the dosage / response relationship to provide an optimal basis for therapeutic testing applied to a higher number of patients.

• Stage III

33Tests with larger and, if possible, diversified groups of patients, to determine the long- and short-term safety of use / efficiency ratio, and to assess the global and relative therapeutic value of one or several forms of the active substance. The most frequent type and profile of the adverse responses and the specific properties of the drug (e.g. interaction between drugs having clinical significance, factors likely to influence results, such as old age, etc) should be investigated. The tests will be preferably carried out following a controlled double-blind randomised protocol, versus one or several reference substances. However, other types of tests are admissible, especially for long- term surveys on the safety of use. Generally speaking, the conditions applied to tests must be as close as possible to the standard conditions of use.

• Stage IV

34Trials carried out after launching the drug on the market; however, we observe that there is some persistent divergence of opinions concerning the features of this stage. The stage-IV tests are carried out on the basis of the information contained in the summary of the characteristics of the substance as they appear in the marketing authorisation. The purpose of experiments, for instance, is to have proper drug monitoring or to assess the therapeutic benefit or therapeutic strategies. While taking the circumstances into account, the stage-IV tests should be carried out in a way similar to that applied for the clinical trials before placing the substance on the market, as described above (including at least a protocol). Clinical tests carried out after releasing the substance on the market with a view to examining new indications, new forms of administration or new combinations are to be considered as tests for a new medicine.

35The clinical assay is based essentially on a comprehensive and well- structured testing protocol developed with the utmost. It should contain at least the information mentioned in appendices C1 and C2.

3. The development of herbal medicinal products in the European Union

36The European goal for the next ten years is to define the rules for submission of herbal medicines abridged dossier.

37It should be necessary to precise:

  • The quality objectives who are needed by applicants;
  • Toxicology data existing and there who would be provided;
  • The difficulty to realize clinicals trials with herbal medicines because the lack of particular protection and the difficulty to patent.

Quality objectives

38Origin of plant (botanical identification, geographical origin and conditions of production),

39The various steps necessary to obtain the medicinal product,

40The control procedures of the finished product with relevant chemical defined substance if the therapeutic constituant is unknown,

41Stability test under ICH conditions.

Toxicological data

42They are very often made a long time ago without GLP conditions. Most of time we have no data on mutagenicity, cancerogenicity and the effects on reproduction organs.

43On the other hand we have vigilance data on a long time with numerous population of patients traditionnally treated. With regard to the pathology, authorities must fix clearly the required studies for each plant before submission.

Proof of efficacy

44European authorities have to defined clearly the acceptable indications for each plant may be in e concertation procedure and in a specific working group.

45In this case if it is considered as a traditional use more efficacy data are not suitable.

46If the applicant hope a specific indication, he should have to give the proof of efficacy on the same basis that a new active ingredient.

Traditional herbal medicine list

47The European Authorities could provide to Pharmaceutical Industry a list of traditional herbal medicine on the following basis:

48Using the available bibliographic data;

49Taking into account the traditional family use of the plants;

50Describing the pharmacological effects of the plants and if they are known these principal active constituants;

51Giving the necessary proof level for one specific indication comparing with drugs already on the market.


52What are the risks if herbal products will not have not a medicine label?

53Lack of quality, with dramatical confusion in the botanical identification,

54Unknown mix of plant and chemical ingredient,

55Difficulties to have a good pharmacovigilance.

56Don't give a legal status to herbal medicine provide abuses and accidents and lead users to a lack of confident in his health system.

What are the benefits?

57It is hoped that plant based medicinal products will replace for certain indication linked to minor pathologies some medicines likely to be more active which may be addicting or cause iatrogenic pathologies.

58As a conclusion and in reply to the critics of this type of medicinal product, it can be said that there are no major or minor medicines, only major or minor pathologies requiring adequate medicines.


Appendix A

Standard format for applications submitted for marketing in the EEC
(National and EC procedures)
According to the Notice to requesters for an authorisation for placing on the market medicines for human application in the Member States of the European Community prepared by the Committee for Proprietary Medicinal Products, Brussels 1989

General plan

Part I: Summary of the file

I A Administrative information

I B Summary of the characteristics of the product

I C Specialist reports about chemical,

pharmaceutical, biological, toxicological,

pharmacological and clinical documentation

Part II:Chemical, pharmaceutical and biological documentation

II A Composition

II B Form of presentation

II C Raw material control

II D Intermediary product control

II E Finished product control

II F Stability

II Q Others informations

Part III: Toxicological and pharmacological documentation

III A One-time administration toxicity

III B Repeated administration toxicity

III C Reproduction survey

III D Muta-genetic potential

III E Carcino-genetic / onco-genetic potential

III F Pharmaco-dynamics

III G Pharmaco-kinetics

III H Local tolerance

III Q Other information

Part IV: Clinicol documentation

IV A Clinical pharmacology

IV B Clinical experimentation

IV C Other information

Part V: Specific information

V A Presentation

V B Samples

V C Manufacturing authorisation(s)

V D Authorisation(s) for placing on the market

Appendix B

Part IV: Clinical documentation

Part IV A: Clinical pharmacology

• Pharmaco-dynamics (Summary, detailed description of the assay, results including the characteristics of the population studied, efficiency, clinical and biological tolerance, conclusion, bibliography)

• Pharmaco-kinetics in healthy volunteers, patients, particular groups of patients

Part IV B: Clinical experience

• Clinical survey: a summary, a detailed description of the protocol and the analytical methods, the final results (characteristics of the population studied, results in terms of efficiency, clinical and biological results regarding the safety, statistical assessment of results, data tabulated over patients), a discussion and a conclusion should possibly be provided for each survey

• Experimentation after placing on the market (Pharmaco-vigilance and reports about adverse effects and undesirable occurrences)

• Published and non-published experience

Part IV C: Other information

Appendix C1

1. General information

• title of the project;

• name of the investigator (or investigators) clinically in charge of the assay and names of other possible contributors and their qualifications ("medical doctor", "biochemist", "nurse", "statistician", etc.);

• name of the promoter, if necessary;

• hospital / department / medical team that will be in charge of carrying out the assay (affiliations, addresses).

2. Justification and purpose

• purpose of the assay;

• reason for carrying it out;

• state of the issue and its context, with reference to the pertinent literature.

3. Ethics

• general ethical considerations relative to the assay;

• describing the way involved people will be informed and the way their consent will be obtained;

• possible reasons for not asking them their enlightened consent.

4. General schedule

• describing the schedule of the assay, i. e.: planned duration, date of beginning and ending;

• justifying the schedule, especially by taking into account the results of the surveys regarding the safety of active substances or medicines, the evolution of the involved disease and the duration planned for the treatment.

5. General conception

• describing the type of assay (controlled assay, pilot assay, for example) and the stage it refers to;

• describing the drawing lots method, including the procedures and the practical dispositions;

• describing the assay conception (for instance, parallel groups, cross-reference protocol) and the blind assay (double blind, blind assay);

• describing the other steps implemented to minimise external influences.

6. Selection of patients

• describing the involved people (patients, healthy volunteer), including age, gender, ethnic group, prognosis factors, etc;

• describing precisely the pre-inclusion criteria;

• exhaustive inclusion, exclusion and assay output criteria.

7. Treatment

• precise description of the utilised medicine(s) (commercial forms and non "galenic form reserved to assays") and posology justification;

• describing the treatment administered to reference group(s) or administered during the control period(s) (placebo, other medicines etc.);

• form of administration, dosages, posology, duration of administration of the assessed medicine containing the active substance and (or) reference medicines;

• regulation for using combined treatments;

• steps implemented to assure the safety in stocking and administering medicines;

• necessary steps to assure and control the full respect of prescriptions (verification of the observance of the treatment).

8. Assessment of the efficiency

• defining the assessment criteria;

• describing the methods for measuring and recording the effects;

• dates and duration of the recording of these responses;

• describing the analysis and (or) particular tests to carry out (pharmaco-kinetical, clinical, biological, radiological tests, etc.)

Appendix C2

9. Evénements indésirables

• methods for recording the adverse occurrences;

• provisions to take in case of complications;

• information about where is stocked the blind code and about the way to release it in case of an emergency;

• notification terms of adverse occurrences, specifying who is liable and who is the recipient of the notification, and the notification times.

10. Adverses occurences

• detailed and precise scheme of the different stages and procedures aiming at a control and monitoring of the assay as efficient as possible;

• further information and instructions concerning the forecast gaps compared with the protocol;

• distributing and co-ordinating the tasks and responsibilities within the research team;

• instructions given to the staff, including the description of the assay;

• addresses, phone numbers etc., enabling the staff members to contact the research team at any time;

• considerations in terms of confidentiality, if necessary.

11. Processing of the results

• procedures for collecting, structuring and processing of the results regarding the effects of the experimented medicine(s) and the adverse occurrences;

• procedures for managing the file of all the participants to the test. Information have to ensure an easy identification of every patient or healthy volunteer. A copy of the observance notebook must be enclosed.

12. Assessment

• describing precisely the utilised method for assessing the results;

• recording and computing method of the effects of the medicines;

• describing the way of taking in account and analysing the exclusions and test outputs;

• quality control of methods and assessment procedures.

13. Statistics

• detailed description of the utilised statistical methods;

• number of patients planned for the testing. Ground for the choice of the size of the sample, including assessment or computing of the statistical value of the test and its clinical justification;

• describing the team in charge of the statistical analysis;

• niveau de signification choisi;

• regulation to follow in case of cessation of the test.

14. Financing, report, consulting, authorisations ou notifications, insuring, etc.

The way various issues that may have a direct or indirect impact on the accomplishment and results of the assay should be specified in the protocol The essential provisions in this respect are listed in the points 8 to 10: the financing of the assay, the insurance and civil liability issues and the labelling are involved.

15. Résumé, suppléments

A general summary and appropriate additional information will have to appear in the protocol (for example, information given to the patients, instructions for the research team, description of particular procedures).

16. Bibliographic references

The list of pertinent bibliographic references quoted in the protocol will have to be enclosed.


Agence Française de Sécurité Sanitaire des Produits de Santé 143 - 147, boulevard Anatole France 93285 Saint-Denis Cedex – France

Centre Hospitalier Régional et Universitaire de Marseille, Service Médecine Interne chemin des Bourrely 13915 Marseille Cedex 20

Université de la Méditerranée (Aix-Marseille II) 27, Boulevard Jean Moulin 13385 Marseille Cedex 5 - France

© IRD Éditions, 2002

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