REGULATORY AFFAIRS

1064 #{149}J Clin Pharmacol 1988;28:1064-1070

The Drug Regulatory Affairs System in theFederal Republic of Germany

Karlheinz Schmitt -Rau

A bout 140,000 different pharmaceutical prepara-tions were on the market in Germany when, in

1976, after several years of hard and cumbersomenegotiations and debates the “Law for the Reorgani-sation of Drug Legislation” (Arzneimittelgesetz,AMG, “Drug Law”) passed the German “Bundes-tag.” This large number of drugs was partly due tothe fact that almost everything that is able to influ-ence state and condition of the human or animalbody could now be considered to be a drug.1 One ofthe main reasons, however, has certainly been thelack of adequate legislation controlling develop-ment, manufacture and marketing of drugs beforethis law became effective. Before 1961 the industrialmanufacture, which was about 85% of total manu-facture,2 was entirely unregulated. The first DrugLaw (Law about Commercialization of Drugs) of1961 (AMG 1961) was a first attempt to reorganisethe German drug market:

-Proprietory Medicinal Preparations (Arzneispe-zialit#{228}ten) became subject to registration with theFederal Health Office (Bundesgesundheitsamt,BGA).

.-Manufacture of drugs became subject to permis-

sion by the local health authorities (“Lander”).-Industrial manufacture and commercialization

came under the supervision of the local healthauthorities.

Registration, however, was only a formal proce-dure at that time. No authority was given to the BGAas far as the review of a drugs development docu-mentation and the assessment of its quality, safetyand efficacy was concerned.

A complete revision of the drug regulatory systemin the Federal Republic of Germany, however, be-came mandatory after the “Directive 65/65/EEC”had passed the Council of the European EconomicCommunity”. This finally lead to the Drug Law of1976, which was amended twice (1983 and 1986)since then.

From Du Pont de Nemours (Deutschland) GmbH Du Pont de NemoursStral3e 1 D-6230 Bad Homburg v,d,H.

Important features of this new Drug Law were:

-Preventive control of drugs in terms of quality,safety and efficacy, need for approval by BGAprior to commercialization.

-Review of “old drugs” (drugs already on the mar-ket, when the law became effective) and reregis-tration by 1989 on basis of new drug law.

-Protection of man during clinical trials.-Risk monitoring of approved drugs.-Supervision of development, clinical trials, man-

ufacture, quality control, import and marketing ofpharmaceutical preparations.

REGULATORY BODIES IN THE FRG ANDTHEIR RESPONSIBILITIES

Due to the political organization of West Germany asa federal republic, tasks and responsibilities re-quired by drug legislation are split between federalauthorities and the health authorities of the differ-ent German states (“Lander”).

The federal authorities are the Federal Health Of-fice (Bundesgesundheitsamt, BGA) and the Paul-Ehrlich-Institut (PEI). The responsibilities of thePaul-Ehrlich-Institut are limited to sera, vaccines,test allergens, test sera and test antigens. Both insti-tutions are under the supervision of the Ministryof Youth, Family, Women and Health (BMJFFG).(Fig. 1)

The main tasks of the different authorities in-volved in the drug regulatory process are shown inTable I.

The separation of responsibilities as compiledhere clearly shows that enforcement of drug legisla-tion is the duty of the “Lander” and not of the BGAor the PEI. To coordinate work of local health au-thorities and to achieve uniform enforcement of thelaw regular meetings have been established of a“Working Group of the Executive Medicinal Offi-cials of the States” (Arbeitsausschul3 der LeitendenMedizinalbeamten der Lander).

THE DRUG REVIEW PROCESS

The kind of chemical/pharmaceutical, preclinicaland clinical data needed to get approval of a drug

Figure 1. System of Regulatory Affairs Authorities.

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REGULATORY AFFAIRS 1065

needs not to be reviewed in detail here. Guidelineshave been issued by the European Community (forreview see 3) and the German authorities.4 Theoverall format is identical to the European format asoutlined in the “Notice to Applicants”5 and by Sauerand Hankin.3 The procedure of drug review processis shown in Figure 2. Different to for instance the USIND and NDA systems, where manifold contacts be-tween company and agency take place during the

TABLE IResponsibilities of Different Authorities Involved

In the Regulatory Process

BGA/PEI

-Review and assessment of New Drug Applications-Approval or rejection of NDAs-Revocation/withdrawal of approvals-Prolongation of approvals-Registration of homeopathic drugs-Deposition of preclinical documentation prior to clinical

trials-Monitoring of drug risks

Local Health Authorities

-Decide about manufacturing license, withdraw license-Inspect pharmaceutical companies for compliance with

regulations-Issue certificates (WHO. GMP. GLP, PlC)-Take samples of finished drugs to check for compliance

with registered features (quality, ingredients, labeling)-Supervise commercialization of drugs and drug

advertisement-Classify products as drug or non-drug-Allow import and issue import licenses-Initiate and supervise recalls of product in cases of

violations of drug law

development of a drug, influencing progress of de-velopment, giving advice to the company, the Ger-man system does not foresee regular discussions be-tween applicant and BGA. The product has to bedeveloped pharmaceutically, preclinically, andclinically according to the relevant EEC directives.A submission is then made containing the completeinformation gathered during the developmentphase.

The entire approval procedure is to be finishedwithin 4, in “exceptional” cases within 7 months.During the time the applicant prepares his answer tothe deficiency letter, the clock stops. The review isdone within the BGA by own pharmaceutical, phar-macological, toxicological and clinical experts, whobelong to the staff of the different departments of the“Institute of Drugs” (Institut f#{252}rArzneimittel). (Fig.3) In the case of New Chemical Entities an expertcommission has to be heard prior to approval. Theseexperts are appointed by the ministry upon proposalof the professional associations of pharmacists, phy-sicians, dentists and the pharmaceutical industry.BGA is not bound in its decisions to the vote of thecommission, in the case, however, that BGA’s deci-sion differs from the commission’s vote, BGA has tojustify its decision. Experience during the last tenyears has shown that in the majority of cases BGAand the commission came to similar assessments.6

Once the application has been filed with the BGA,communication between company and agency is re-stricted to written exchange of information untilfinal approval or rejection of the application. Ac-cording to J. Schuster of “Institute of Drugs” at theBGA the agency recognizes the need for direct com-munication and discussion with the applicant, ithas, however, “to consider and balance the follow-ing two factors:

1. the agency must assess hundreds of applicationsfor drug approvals each year [. . . ]. Thus, becauseof the workload, personalization of the discussion[. . .] is impossible.

2. [ . . . ] written communication can cause both,small and large misunderstandings. When there arelarge misunderstandings, fundamental discussion ofthe application can produce mutual understanding[. . . ]. When principles are abstracted from the in-dividual cases, discussions about similar cases canbe avoided. The approval agency must carefullyconsider in which cases discussions can be useful.Many of the smaller misunderstandings can be re-solved by a short telephone call.”7

More than 6000 different pharmaceutical prepara-tions (including different strengths/different galenicforms of the same active) have been approved be-

Phase I

-Ei-

Phase II

Review in DifferentDepartments

Letter of

Deficiency

ApprovalCommission

Approval

Hearing

Rejection

Figure 3. BGA and Structure of the Institute of Drugs.

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1066 #{149}J CIln Pharmacoi 1988;28:1064-1070

Figure 2. Review Procedure for NCE’s.

tween 1980 and 1987. A considerable number to the question on what reasons BGA may reject an(around 600) has been rejected by BGA. A similar application for approval of a drug to be used innumber of applications has been withdrawn by the humans.applicant during the same period of time.6 This leads This is clearly defined in para 25 AMG:

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“The competent federal authority may only refuseto grant the marketing authorization if

1.the documents submitted are incomplete2. the drug has not been sufficiently tested pursuant

the presently prevailing level of scientific find-ings

3. the drug does not show the adequate quality pur-suant to the acknowledged pharmaceutical prac-tise

4. the therapeutic efficacy attributed to the drug bythe applicant [. . . ] is lacking or is unsufficientlysubstantiated taking into consideration the pre-vailing level of scientific knowledge

5. there is reason to suspect that under correct usethe drug has harmful effects that exceed thebounds considered justifiable in the light ofknowledge available in medical science.”

All the rejections since 1980 occurred on one ormore of these reasons.

Unfortunately, the time needed for approval of adrug has considerably increased in the last years,despite the legal requirement to come to a decisionwithin 4 to 7 months.

Due to the second amendment to the Drug Law in1986 rendering more difficult the approval proce-dure for generic drugs thousands of applications forgenerics were filed before this amendment becameeffective, leading to a back up of approximately 7000applications at the BGA. Since BGA has to reviewapplications in the order of receipt this leads to asituation where therapeutically valuable drugs cannot be approved in due time, thus impairing medicalprogress. Drug Law gives the possibility for the pre-ferred review for such preparations.

Nevertheless, only very few applicants can be de-cided within the defined time frame at present.

Measures have been undertaken in the meantimeto improve the situation: a third amendment to theDrug Law has passed the Bundestag introducing thepossibility of an external expert review of genericdrugs, thus taking away a considerable amount ofBGA’s workload. A fourth amendment being inpreparation will bring additional improvements. Be-sides that organizational changes and increase ofstaff at BGA will hopefully shorten the review timeof NDAs in near future.

CLINICAL TRIALS WITH NEW DRUGS

It has already been mentioned that a system compa-rable to the US IND or the UK CTX system does notexist in the Federal Republic of Germany. No formalapproval by a health authority is needed before aclinical trial can be started. That does, however, notmean that clinical trials can be performed without

any control and supervision. Although no approvalis needed a very stringent and effective system existsto ensure protection of patients/volunteers in clini-cal research. Companies or persons violating theseregulatiofis are liable to prosecution.

The legal basis for the conduction of clinical trialsis given in paragraphs 40 to 42 of the Drug Law.Besides that the “Guidelines for Orderly Conductionof Clinical Trials with Drugs.” (Richtlinien zur ord-nungsgemal3en Durchfuhrung von klinischenPrufungen mit Arzneimitteln, Clinical Trials Guide-lines)8 as well as EC guideline 75/318/EEC and rec-ommendation 83/571/EEC have to be considered.National “Guidelines for Evaluation of Drugs” (Arz-neimittelprUfrichtlinien) exist as drafts only at themoment.4

Before a clinical trial can be started the results ofthe pharmacological and toxicological evaluationmust be available for deposition with the BGA, forinformation of the responsible clinical investigators,for writing a benefit/risk assessment, for writing thestudy protocol, for review by the ethics committee.

Deposition of pharm/tox data with the BGA: Thedocumentation submitted to the BGA before start ofclinical trials is not reviewed by the agency, but keptthere to facilitate taking of evidence in case of severeADR’s during the trial.

In such cases-if suspicion exists that the person/company responsible for the clinical trial has nottaken serious enough their obligations-the attor-ney of state may ask for access to these data. Lawrequires that the tests have been carried out com-plying with the prevailing level of science, e.g. theyhave to comply more or less with the requirementsas given in the respective EC-guidelines (75/318/EEC etc.)

Information of investigators: A principle investi-gator has to be nominated to the authorities. Thisinvestigator has to be informed by the companyconducting the clinical trial about results of thepharmacological/toxicological tests and the poten-tial risks arising from the results of these tests for thepatients/volunteers participating in the trial.

Benefit/risk evaluation: A clinical trial may onlybe conducted if the potential benefit outweighs therisk. This benefit/risk assessment has to be fixed inwriting and is subject to control of the supervisingauthorities.

Ethics committee: The approval of a clinical trialby an ethics committee is not mandatory, the Clini-cal Trial Guidelines, however, strongly recommenduse of ethics committees before start of the trial.

Study protocol: The Clinical Trial Guidelines givea very detailed description of what kind of informa-tion has to be included in a study protocol: objectiveand justification of the trial, characteristics of the

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drug, study design, inclusion/exclusion criteria,number of patients, kind of treatment allowed/notallowed, concomitant medication, methods usedand their validation, monitoring of side effects, pa-tient compliance, time frames, criteria for stoppingthe trial, name, qualification and responsibilities ofthe physician in charge of the trial, signature of thephysician, are only the most important criteriamentioned there. Besides this, a detailed case reportform has to be developed, containing all informationnecessary to answer the questions formulated in thestudy protocol.

Further key requirements of the Clinical TrialsGuidelines and/or the Drug Law are:

#{149}the necessity to monitor the clinical trials for com-pliance with the protocol,

#{149}the need to monitor all serious side effects/ADRs,#{149}the need for reconciliation of clinical trials sup-

plies,#{149}the need for detailed and comprehensible final re-

ports,#{149}the documentation of all data generated during

the trials for at least ten years,#{149}the existence of a patient insurance and of patient

informed consent.

Besides this, the trial has to be notified to the localhealth authorities (Lander), which are responsiblefor monitoring and supervision of clinical trials. Ex-perience shows that this task is taken very seriouslyby the Lander authorities. Regular inspections andaudits of pharmaceutical companies as well as clini-cians and conducting clinical trials have becomemore common to enforce the requirements of DrugLaw and Clinical Trial Guidelines. Non-compliancewill result in halting of the trial and can be consid-ered as a criminal act to be punished by imprison-ment.

POST MARKETING SURVEILLANCE

Post marketing surveillance regulations in the Fed-eral Republic of Germany may be divided in thosedescribing the tasks directed to the pharmaceuticalindustry and those of the different authorities in-volved. An excellent review on that subject hasbeen published recently by A. Bertelsmann of BGA.9

Tasks of the pharmaceutical industry

The pharmaceutical companies are obliged to reporteach case of suspected adverse drug reaction theyget knowledge of to the BGA. They have to report“immediately”. To fulfill this requirement thepharmaceutical companies have the task to observethe use of their drugs after registration. This refers to

the prescribing practises of the physicians as well asto the reaction of patients/drug consumers. Theyhave to observe whether misuse or abuse of theirdrugs occur. Measures have to be taken by the com-panies to guarantee correct and timely monitoringand reporting of ADRs:

#{149}short and effective communication lines have tobe installed within the company to ensure fastprocessing of ADRs, written procedures shouldexist (alarm plans, recall plans),

#{149}sales representatives (Pharmaberater) have theobligation to collect information about drug risksand to forward it to the company,

#{149}literature has to be evaluated for drug risks#{149}experience reports have to be submitted 2 years

after registration as well as with the application forprolongation of approval every five years. In thesereports experts have to re-assess the benefit riskratio of a drug marketed.

#{149}a “drug safety nominee” (Stufenplanbeauftragter)must be available in each company. This person,who has to have a specific qualification is person-ally responsible for all monitoring, collection, as-sessment and reporting of drug risks to the agency,as well as for coordination of measures to be takeninternally, if a serious ADR should occur.

Tasks of the authorities

Main tasks of the authorities-BGA and Paul Ehr-lich Institute-is the monitoring and assessment ofdrug risks as well as the coordination of measuresnecessary to avert such risk (together with the su-pervising “Lander” authorities).

They have to cooperate with WHO, the regulatoryagencies of other countries and the drug commis-sions of the physicians and the pharmacists.

A major source of BGA’s knowledge about drugrisks results from spontaneous reporting of sus-pected undesired effect in connection with the useof drugs. Such spontaneous reports normally comefrom the drug commissions of the health professionsas well as from pharmaceutical industry (see pre-vious). They are recorded and evaluated by theagency.

Recording is performed using international codingsystems like lCD (International Classification of Dis-ease), ATC (Anatomical Therapeutic Chemical Clas-sification System) and ADR (Adverse Reaction Ter-minology). Besides this BGA participates in interna-tional ADR monitoring and recording programs suchas the WHO International Monitoring of Adverse Re-actions to Drugs of WHO Collaboration Center andthe CIOMS (Council for International Organizationof Medical Science).

REGULATORY AFFAIRS IN THE FEDERAL REPUBLIC OF GERMANY

REGULATORY AFFAIRS 1069

TABLE II

Catalogue of Measures to be Undertakenby the ResponsIble AuthorIty in Case

of Potential Drug RIsks

Measure AuthorIty

Get expert external opinions BGAInitiate research BGAGive recommendations for health

professionals BGARequest labeling changes (add warnings

etc. to pack insert) BGARequest change of pack sizes BGAWithdraw, suspend registration BGA

intensify monitoring Lander (local)Recall of products Lander

Sale on prescription MinistrySale in pharmacy only MinistryDecision about scheduling Ministry

The evaluation and assessment of suspected drugrisks is done in the Department “Arzneimittelver-kehr” of the Institute of Drugs (Fig. 3). Criteria forassessment whether a suspected adverse drug reac-tion may be considered as serious are the CriticalTerms of WHO. Important as well in the review ofsuch a case is the question whether a drug is anentirely NEW Chemical Entity or a preparationknown to the medical community. According to theresult of the assessment measures can be taken bythe BGA to minimize potential drug risks.

The legislative body has issued an ordinance thatregulates the enforcement of such measures and thecooperation/coordination of the different author-ities involved as well as the involvement of thepharmaceutical industry. Since the measures thatcan be taken may differ according to the seriousnessof an ADR this ordinance is known as “Stufenplan”(“graduated plan”).

Normally the action of BGA proceeds in two steps:

Step 1: Indication exists about the possibility of adrug risk. Exchange of information between BGAand pharmaceutical company, notification of otherauthorities involved.

All pharmaceutical companies marketing a drugwith the ingredient under suspicion have to com-ment on a list of questions-adapted to the actualcase-covering:-registration conditions of the drugin third countries,-side effects observed,-resultsof the Phase IV studies,-marketing data,-risk as-sessment by the pharmaceutical company.

Step 2: The result of information exchange hasdemonstrated that there is a well founded suspicion

that a drug appears to be an actual risk for the healthof patients. In that case BGA has two options, de-pendent on the type of drug risk:

1. A hearing takes place. During that hearing BGAexperts, experts of the pharmaceutical industry andindependent experts present and discuss their scien-tific findings. Based on the information gatheredduring that hearing BGA decides about measures.

2. Not in all cases a hearing is necessary. In thatcases BGA sends a letter to all companies marketingthe drug in question telling that they intend to im-pose conditions on further marketing of the drug, i.e.change in labelling, mentioning additional side ef-fects in the pack inserts a.s.o.

The pharmaceutical companies have four weeksto react and give their comments on the plannedmeasures for consideration by BGA.

Dependent on the seriousness of the drug risk acatalogue of potential measures exist (Table II)

In 1986 BGA had to deal with a total of 71 cases ofdrug risks involving 6400 drugs and 2220 pharma-ceutical companies.6 Registration was suspended forthree drugs, one drug had to be withdrawn. In 300cases the pharmaceutical companies gave up mar-keting licenses voluntarily.

REVIEW OF OLD PRODUCTS

It was already mentioned earlier that a major part ofdrugs on the market in the Federal Republic of Ger-many has never been subject to review according torequirements of new Drug Law and EEC guidelinesas far as quality, safety and efficacy are concerned.

These products had to be notified to the BGA afterthe new Drug Law had become effective in 1978 andobtained preliminary approval valid until December31 1989. By this date at the latest applications forre-registration will have to be submitted by thepharmaceutical companies, consisting primarily of apharmaceutical/chemical documentation provingthe quality of the preparations. No toxicological orclinical data will have to be submitted as the BGAhas to ensure that commissions are installed whosetasks is the review of available material about safetyand efficacy of these “old products” respectively theactive ingredients of these products. The pharma-ceutical companies may then refer in their re-regis-tration applications to the monographs about theseactive ingredients issued by the commissions. Infact, 14 review commissions have been installed be-tween 1978 and 1985 (Table III). Almost 3000 chemi-cal compounds covering more then 10,000 differentpreparations have been reviewed in the meantimeand monographs have been published for thesecompounds, either as final monographs or as drafts.

1070 I J ClIn Pharmacoi 1988;28:1064-1070

SCHMITI’-RAU

TABLE Ill

Review Commissions

CommissIon Special FIeld

Bi angiology, cardiology, nephrologyB2 rheumatologyB3 neurology, psychiatryB4 endocrinology, gynecologyB5 gastroenterology, metabolism

B6 infectious diseases, oncology, immunology,pulmology

B7 dermatology, hematologyB8 balneologyB9 dentistry810 infusion and transfusionC anthroposophical therapiesD homeopathic therapiesE phytotherapyF animal drugs

Format of these monographs is based more or less onthe technical data sheet of the EEC, giving informa-tion about indications, contraindications, side ef-fects, interactions, pharmacology a.s.o. A lot of sup-port is provided to these review commissions by thepharmaceutical industry as far as data supply (liter-ature, clinical trials results) is concerned. On theother hand the work of the commissions not alwayslead to favourable results for certain compounds. Acouple of substances got “negative monographs” be-cause of an unfavourable benefit/risk ratio or lack ofefficacy. Thus chances are low for preparations con-taining these compounds to take the hurdle of re-registration after 1989.

CONCLUSION

An attempt was made to give an overview over thedrug regulatory system of the Federal Republic ofGermany. It is obvious that due to limitation of spaceonly a few highlights can be reviewed in such anarticle. Thus the paper concentrates on five topics:

the regulatory bodies in the FRG;the review process;the clinical trial regulations;the post marketing surveillance system; andthe review of old drugs

Drug regulatory systems are dynamic systems. Sois the German one. From almost no regulations sometwenty years ago a well developed system could be

established being not least the result of permanentcooperation of authorities, health professional socie-ties, pharmaceutical industry and consumer protec-tion associations.

If the development of the regulatory system wasoriented more nationally in the past this haschanged considerably within the last years. “Eu-rope” and the common market have become a morerealistic goal for the very near future. Harmoniza-tion of the different regulatory systems within theEEC member countries has to be accomplished. Thishas consequences for the FRG and its regulatorybodies as well. BGA actively participates in the dif-ferent supranational drug registration proceduresestablished by the EEC to support mutual under-standing between the different national regulatoryagencies. Certainly these supranational procedureswill not be the last steps towards a further harmoni-zation. Development will proceed to a more sophis-ticated, more effective pan European system. It is tooearly at present to say how this will look like. It isclear, however, that doing Regulatory Affairs in Eu-rope will remain challenging also in the future.

The author wishes to thank Dr. K, P. Klein of Du Pont de Ne-

mours (Deutschland) GmbH, Clinical Research for his construc-

tive criticism of this paper as well as Mrs. M. Krokel for her help

with the manuscript.

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