11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription

11

Prescription (legal) status

Categories vary country by country

• NP („OTC”)• POM• Subcategories

Prescription

22

EU Directive

Main categories• NP• POM

renewable/non-renewable prescriptions

special medical prescr.

restricted medical prescr., reserved for use in spec. areas

33

EU Directive

A medicinal product is NP, if it does not meet the criteria of POM

(Very important!)

(In many countries just the opposite is applied)

44

EU Directive

When POM?• danger, even used correctly, if without

medical supervision• frequently used incorrectly presenting

danger• APIs with activity/ADRs still be

studied• parenterals

55

EU Directive

POM, sub-category specialist’s prescription

• narcotic/psychotropic substance

• if used incorrectly, abuse/misuse

• novel active principle, precautionary

66

EU Directive

POM, sub-category restricted use

• can be used in hospitals only

• can be diagnosed in hospitals only

• specialist’s supervision (e.g. ADRs)

77

EU Directive

(SUB)CATEGORIZATION

• Taking into account single and max. daily doses, strength, dosage-form, pack unit

• Annually updated published list of POM (sub)categories

88

EU Guideline

Goal:

To help MAHs when applying to change the classification

(i.e., to harmonize the swithches!)

• POM/NP criteria

• switch application criteria

99

Guideline NP or POM?

Direct danger: even if used correctly

• Toxicity

• Serious and existing less serious ADRs

• Interactions with commonly used drugs

1010


Indirect danger:

• Masking conditions that would require medical attention. NP: time-limit must be set

• Wider use increase resistance, particularly in general population

1111


Risk and consequences of incorrect use

• If used according to indications (too many contra-indications, precautions, warnings, etc. May lead to incorrect use

• If the opposite: off-label or longer use

1212


Self-assessment/diagnosis• Symptoms can be correctly assessed by

patients (may vary country by country!)• Natural course of disease, duration or

re-occurrence of symptoms may be self-assessed

• Contraindications, etc. can be understood by the consumer

1313


• The way patient info is written

• „If not POM, must be less dangerous”

• Layman’s terms used?

• Explanation of use?

• Explanation when should not be used?

1414

Good question - who is „Patient”?

1515

Summarising the legal status

Ailment Treatm. ADR Dr’s diagn. Med.Att. Status

Minor any NS none no NP

Major single NS yes no NP/POM

Major long NS yes rare NP/POM

Major long S yes rare NP1/POM

Major any any yes yes NP2/POM

1if the patient can be informed…

2the smallest pack size

1616

In case of rigid systems...

The NP/POM choice may cease to exist!

Rigid systems:

• Drugs are officially classified either NP or POM (NP may be prescribed but not vice versa!)

• If NP no reimbursement

1717

Professional switches?

• It must be realised: this is a semi-political matter!

• If no consensus between reimbursement-policy makers and DRAs, affordability problems may occur!

1818

The second issue:

OTC distribution channels in the country

and/or

1919

The third issue:

Patients, their perception to medication, knowledge on drugs, etc.

(Average patient does not exist!)

2020

Back to the registration: Accompanying sheets

• SmPC (Summary of Product Characteristics = Data Sheet) for professionals

• PIL for patients• Label• (Assessment

Report written by the DRA)

Medi

cine

2121

Issuance of the MA

• Civil Service authoritative text (what is contained is binding!)

• The Accompanying Sheets annexed

STAMP

2222

Actual marketing (in many countries)?

Pricing and reimbursement negotiations!

• MA: risk/benefit• Pricing,

reimbursement: cost/benefit

2323

MA withdrawn (deletion from the Register)

• Applies to „the product”!

• Who may initiate:

• MAH - without specifying any reason (!)

• Medical Boards, DRA - with good reason (risk/benefit)

• Civil Service authoritative decision

2424

Withdrawal/Recall from the market

• It applies to a given batch of the medicine!

• Decided by the DRA, MAH may initiate it

• In Hungary: DRA informs by telefax the Nat. Publ. Health Serv., and central health-care organs

• Then “info-cascade” in the counties

2525

European Union

• The present marketing authorisation rules and procedures

2626

Certain EU terms

• Sources of law:

Regulation

Directive

• Brussels: Commission, DGs DG Enterprise, DG SANCO

• London: European Medicines Agency (EMA)

2727

EMA

• Established in 1995

• Both 2 DGs pharmacists until now

• Task: centralised MA procedure, ADR monitoring, guidance, appeal procedures

• Committees (one per member state)

28

EMA Committees

• C’ttee of Human Medicinal Prodcts CHMP• C’ttee of Veterinary Medicinal Products

CVMP• C’ttee of Orphan Medicinal Products COMP• Herbal Medicinal Products C’ttee HMPC• Pediatric Committee PDCO• C’ttee of Advanced Therapy Medicinal

Products CAT

28

2929

MA procedures in the EU

Procedures• Centralised CP• Decentralised DP• Mutual recognition

MRP• National

3030

Centralised MA procedure

• Mandatory: biotech substances, HIV/AIDS, cancer, diabetes, neurodegenerative diseases, orphan drugs (5:100,000), somatic cell- and tissue therapy medicinal products

• Possible:

new active substances

“high-tech products”

new, “important” indication

blood products

3131

Centralised procedure

• One single application to EMA• CHMP-assessment (2 rapporteurs from MSs)• 210 days dead-line, then EMA issues

Accompanying Sheets (SmPC, PIL) and Assessment Report in all languages

• MSs: 15-day possibility for „serious risk to public health” appeal

• Then signature by the Commission in Brussels: MA valid for the whole EU

• If negative: banned for the whole EU!

3232

Decentralised procedure

• Possible: any product for which CP is not mandatory

• “Referens MS (DRA)”, RMS where the first application is submitted (“lead market”) and

• Concerned MS (DRA) CMS where to submit later

3333

Decentralised procedure

• Application dossiers sent to RMS and CMSs, validation

• RMS: preliminary MA issued (time-frame!), Accompanying Sheets and Assessment Report (also in English)

• Discussion with to CMSs = final MA = national MAs in RMS and CMSs

• Opposing opinions: appeal (see CP)• Any changes: similar procedure

3434

Mutual recognition• (When the MA has already been issued in

one MS)• The Firm requests an AR (in English) from

the national competent authority (it is the RMS then)

• It, together with the full documentation submitted to CMSs asking a „recognition” of the AR (time-frames!)

• Opposing opinions: appeal (see CP, the decision is binding)

• Any changes: similar procedure

3535

EU registration collaborations

• Many Working Groups and Committees under EMEA and Commission

• EMEA CHMP Q, S, E, Herbal Medicines, Pharmacovigilance, Heads of Agencies, etc. Working Parties

• Commission Pharmaceutical Committee

36

Back to the general regulatory affairs concerning registered

drugs on the market

3737

Post-marketing surveillance

• GMP (manufacturers), GDP (wholesalers), GCP (CT sites), GLP (safety study laboratories)

• Drug Adverse effect monitoring (Pharmacovigilance)

• Mandatory Quality defect reporting national system

3838

Pharmacovigilance

Doctors and Marketing Authorisation Holders must report (to the DRA)

• serious• unexpected (not listed in the information for

professionals)

side effects (=adverse drug reactions, ADRs),

level of seriousness, time-frames may be specified in the law

39

A little story: what happens to these ADR reports?

• ADR Data Banks at national, regional (e.g. European Union) and global (e.g. WHO ADR Monitoring Centre in Uppsala, Sweden)

• All ADR data put into the Banks• From time-to-time, professionals review similar

data• If the connection between taking a drug and the

ADR is possible: it is called a signalsignal and national ADR centres, professional societies, etc. signalised: monitor this ADRs of this drug strictly

• If the connection becomes proven (many cases!): it comes to the information material of the drug

40

A signal generation story (WHO Uppsala Monitoring Centre)

• Spontaneous reports ot the Data Bank• Data „mining” with softwares• Signal generation review • If causality probable: signal message to

the National Monitoring Centres• If proven later: part of the information

material of that drug

41

Signal to the hydroalcoholic extract of a medicinal plant:

Teucrium chamaedrys

42

Signal generation example 1

• Teucrium chamaedrys: the hydroalcoholic (alcohol-water) extracts of the herb are extremely bitter. It is frequent component of reductant (anti-obesity) tees

• There were more than 20 data on hepatic adverse reactions (jaundice, hepatitis) in the WHO database

• In cases when the patients, after recovery, drank the tee again, the same symptoms were recurring very quickly (in 2 days, the note at the registration was: rarely possible!)

43


• How to start the review?• If the quick recurrence is true, that would mean

an immunological mechanism• Literature search: can liver damage be caused

via immunological mechanism? • Answer: yes!• Literature search: the main components of the

plant are diterpenoids and fenyl-ethanoid glycosides, they are free radical scavengers

44

Signal generation example 3• But these are small molecules, too small for an

immune response. Could they modify human proteins by binding on them? (E.g. an alkylating mechanism)?

• Literature search: – the tsructure of the plant components: there is no

alkílating agent among them– but, if free radical scavengers, they perhaps will be

metabolised via oxidation• Literature search: what could be oxidised

metabolites of these components? There is a furane ring on the side chain of one of the triterpenoids (the tecurin-A)

45


• Literature search: the oxidative metabolism of the furane ring is:

• Irodalmazás: this epoxid can alkylate the human epoxid hydrolase enzyme, the resulting modified protein is „foreign”, there will be antibody formation against it…

O

CYP450

OO

46

Signal generation example 5• But the extracts of the plant are widely used in various products

as amarum. If this is the basis of the adverse effect, why is it so rare?

• The place of oxidative metabolisms is the liver. Perhaps is there something in the liver to react with the epoxide, other that the mentioned enzyme?

• Literature search: the epoxidesaz epoxidok prefer reaction with „soft” (according to the Pearson classification) nucleofils

• Is there such compound in the liver? Yes! The

γ-L-glutamyl-L-cysteinil-glycin (glutathion)

-HN-CH-CO-NH-

CH2-SH

47


• Now we already know why only the anti-obesity tees caused the (relatively high number of the) adverse effects

• Glutathion: extreme diurnal changes in the organism! When fasting, its level goes almost to zero! And people whi take anti-obesity tees are fasting…

• The signal is ready!WHO Signal, March 2006, pp. 8-17

4848

National mandatory quality defect reporting system

• Wholesalers, marketing authorisation holders must report to the DRA drug quality defects, pharmacies even suspected ones

• Prerequisite: at least organoleptic checking of incoming drugs mandatory

4949

You may say that no quality defect can never be identified

by organoleptic checking – is it true?

5050

„the same” tablets in the same package unit

5151

„the same” coated tablets

5252

One ointment, if check the inside…

5353

the same ointment

5454

Drug assessment for registration:

multidisciplinary business!

5555

There is sThere is still a big mistake!till a big mistake!

• In certain Universities it is presumed that assessment of medicines can be taught by simply teaching chemistry, analysis, technology, pharmacology, some clinical sciences, etc.

• That is not true! That is not true!

5656

Big mistake!Big mistake!

Medicine evaluation means the recognition of the links between data generated under different scientific disciplines

5757

Big mistake!Big mistake!• E.g. if a medicine (registration

application) is evaluated by chemists, analysts, pharmacists, pharmaco-logists/toxicologists and clinicians separately, this a wrong evaluation!

• It is also the message of the EU Directive!

5858

Examples to indicate the spirit Examples to indicate the spirit of interdisciplinary medicine of interdisciplinary medicine

evaluationevaluation

Naturally, this topic can not be covered in a few minutes. However, it may be indicated by a few examples

5959

Penicillin powder for injection in Penicillin powder for injection in vialsvials

• Quality Dossier: water content not more than 2.5 % — what shall I check during evaluation of this medicine?

• As a requirement per se : may be acceptable

• The anal. method (not Karl Fischer) seems to be O.K.

• However, a good assessor tends to be anxious to check:

6060

Penicillin powder for injection in vials - topics to check

The main decomposition route is hydrolysis• Water content in the samples for stability

studies (much less than 2.5 %?)

• Water content in clinical trial samples (the

same question, for the sensitisation potential of decomposition products, chiefly the penicillin-polymers is higher)

6161

Penicillin powder for injection in vials, 2

• By the way, is there any data in the clinical trial reports about the time between reconstitution of the injection solution and the administration (hydrolysis! Was it required

to use the solutions within a specified time?)• Was the decomposition rate after

reconstitution determined? And its temperature dependence?) (If not, can I

evaluate the clinical safety at all?)

6262

Penicillin powder for injection in vials, 3

• Is there anything in the SmPC about the quick use after reconstitution?

• Is this issue addressed when the possibility of administration after mixing with a slow infusion is discussed from the medical point of view?

6363

Next example: CYPNext example: CYP450450

metabolism, 2metabolism, 2• Is the interaction issue reflected in

the clinical trial plans? (was the concomitant medication studied, or was it “carefully avoided”? Oxydator-phenotype classification of trial subjects? Patient exposure high enough?)

6464

Next example: CYPNext example: CYP450450

metabolism, 3metabolism, 3• Does the SmPC and the PIL reflect

the significance of the issue and the clinical data?

• By the way, let us go back to the chemical part and check whether the whole issue was reflected in the purity (related substances qualification) part

6565

CYP450 metabolism… 4

CH3–CH2-O

NH-C-CH3

O

NH-C-CH3

O

Cl

fenacetin intermedier-product: p-chloro-acetanilid

6666

CYP450 metabolism, 5

CH3–CH2-O

NH-C-CH3

O

NH-C-CH3

O

Cl

fenacetin intermedier-product: p-chloro-acetanilid

CH3–CH-O CH3–CH2-O

OH

NH-C-CH3

O

N-C-CH3

OHO

fenacetin CYP450 metabolism

6767

How to facilitate the multidisciplinary drug

assessmentElectronic submissions!

6868

Importance of electronic submissions

• Huge paper submissions

vs. a few CD - handling, archiving, etc...

this is true. PLUSPLUS:

• EU procedures: more fast-track recognition than assessment!

6969

Paper submission:

330,000pages per

application

7070

Electronic submissions for registration

Past:

Present/future:

7171

Electronic applications

1000 - 3000 hyperlinks connect the related text parts of chemical - pharmaceutical - preclinical - clinical - SmPC/PIL etc.

7272

Electronic dossier assessment: navigation, 1

METABOLISM: Expert Report: CYP450 interaction possibilitiesCYP450 interaction possibilities

Preclin. Dossier?

Clin. Expert Report?

Clin. Dossier, CT Protocol design?

CT results

SmPC?

SmPC: expiry date/ expiry date/ spec. Storagespec. Storage

Ch/Ph Expert Report

Ch/Ph Dossier, Stability results, statistical CI

7373

Electronic dossier as-sesment: navigation, 2

Ch/Ph Dossier: Impurity ProfileImpurity Profile

Ch/Ph Expert Report

Tox. Expert Report (discusseddiscussed?)

Tox. Dossier (same profilesame profile?)

Clin. Dossier (same profilesame profile?)

7474

The Essence of Hyperlinking

“If Regulatory Affairs comprise an art of recognising If Regulatory Affairs comprise an art of recognising interdisciplinary relations when reviewing dossiers, interdisciplinary relations when reviewing dossiers, hyperlinks may be taken as ‘Materialization’ of hyperlinks may be taken as ‘Materialization’ of these interdisciplinary relationsthese interdisciplinary relations” TLP, 1998

(Quoted in: Witzel et al.: Damos Experience Report, Lorenz GmbH, Frankfurt, 1998)

7575

Different hyperlinking needs: review structure

External or internal

assessors?

C’ttee/Peer review?

Rapporteurs?

Or concrete Q/A’s to/from experts?

Quality assessment connected to laboratory analyses?

REVIEW SOFTWARE INTRANET?

7676

Different hyperlinking needs: DRA structure

Highly specialised review

units (e.g., Quality, GMP,

Toxicology, Pharmacology,

Clinical, SPC/PIL,

Registration sections)

or

more concentrated expertise (such as Qua-lity, GMP, Biomedical and Registration)?

7777

The next registration issue

We are living in a World where the human beings are the same everywhere!

Why do not we collaborate in drug registration?

7878

Drug registration: an international business

• It became as international as the drug development

• Apart from the European Union where the system of Community medicine registration exists, there are many related international collaborations

7979

Content

• Why collaboration?

• Why regional collaboration?

• Which collaboration technique to be chosen?

8080

Content

• Why collaboration?• Why regional collaboration?


8181

“Every State is responsible for its public health issues” -

why collaboration?

8282

Fact:

Drug development became an international business

8383

Medicine development is a global business...

8484

To answer this challenge, DRAs should also go beyond frontiers (They

are doing so!)• GMP, GLP, GCP inspections over the

globe? Or information sharing (e.g. WHO

Certification Scheme…)recognition? (If you do not require such data, this is recognition without information! )

• Information on foreign drug/CT app-rovals/rejections (Are you not interest-ed?)

• PhV (Are you satisfied with your country’s reports, if any, alone?)

8585

Next argument

• Is Q-S-E assessment based on science? YES

• Is science international? YES

• Then?

8686

Next argument• Drugs are for patients to cure diseases

• Are patients and diseases different in different countries?

• ICH assessment: mostly not, in a few per cent yes

• Exaggerated! Pharmacogenetic and pharmacokinetic differences in the same population

8787

Concrete example (Drug Y)

• No pharmacokinetic differences between Caucasian, Japanese and Black races

• Combined effects of gender, age smoking within the same race: the Creatinine Clearence in young smoking males 3 times higher than that in elderly non-smoking females

B.K. Malhotra, 2001

8888

Further argument

• If new medicines of proven high efficacy appear, is there a public health interest to make them available as soon as possible?

• It were very difficult to answer “no”!

• But let us discuss it in more detail, it is a hot topic!

8989

Thus, all DRAs benefit the international collaboration when

registering drugs...

…by using/taking into account• literature data• foreign DRA decisions (e.g. WHO channel)• foreign registration and GMP certificates (e.g.

WHO Certification Scheme…)• foreign PhV data

in a non-structured way!

9090

Entering into collaboration

The national DRA will have access to these and even more data/information in a structured way!

9191

Content


• Why regional collaboration?• Which collaboration technique to be

chosen?

9292

Why regional collaboration,1

Sometimes: all DRAs did it before!

See countries before splitting into new States

9393

Why regional collaboration, 2

Many do exist successfully!

1999 Geneva WHO/CIOMS Meeting on Regional Harmonisation: many identified

• Latin America (at least 2)• Africa• Middle East• South-East Asia...

9494

Changing drug selection, medical practice...

……problems not experienced elsewhereproblems not experienced elsewhere

• Hungarian example: the antipyretic aminophenazone shifted to paracetamol, resulting in a “few” deaths due to intoxication

• the same rapid action expected by patients/parents

• high alcohol consumption in Hungary

9595

Benefits of a regional collaboration

Apart from the psychological factor, should every country repeat evaluations (QC analyses, CTs, etc.) done in another country?

9696

Regional collaboration- counter-arguments

“We are more clever (knowledgeable, professional, etc.) than those in another countries”

(No comment!)

9797

Regional collaboration- counter-arguments

(The psychological factor)

The Hungarian ice-hockey team example

(Who would be the leader?)

9898

Regional collaboration - counter-arguments

Too many collaborations!

• Financing

• Time

(However - see benefits - the more the DRA can afford it the more benefits, also saving resources, are gained! See CADREAC, PERF...)

9999

Content


• Why regional collaboration?


100100

Collaboration techniques, examples, evaluation

• Supranational as EU. General. “Forced” collaboration, limited sovereignty, i.e. Community Procedures, etc. It would be more than premature for SEE.

• Global technical, see ICH. Surely not a SEE goal

101101

Collaboration techniques, examples, evaluation (cont’d)

• Mandatory special such as former EFTA Conventions like PIC (GMP), or OECD (GLP), or Eu.Pharm. Mandatory recognition in special areas. Not worth-wile and may not be acceptable

102102

Collaboration techniques, examples, evaluation (cont’d)

• Not mandatory but information and expertise-sharing such as EFTA Schemes (e.g. Pharmaceutical Evaluation Report Scheme, PER). Shared info on registered medicines and the results of the evaluation, arguments for acceptance-rejection, common guidelines, etc. Consider it!

103103

How to build up a regional collaboration, 1

• Common meetings. Will needed

• Agreement between DRAs, it communicated to industry

• Start with info sharing ondrugs registered/refused, reason

CTs authorised refused, reason

Laws/regulations/guidelines issued

Implementation experiences, problems

Still nothing mandatory

104104


If it works:

• Extension to collaborative development of

technical guidelines

procedural guidance

105105


If it works, extension to

• Common drug evaluation

personnel changes, study tours

participation in each other’s drug evaluation

joint inspection teams

Still nothing is mandatory!

106106


If it works, possible extension to

• Mutual recognition” (in the EU meaning) of marketing authorisation, inspections

still retaining the ultimate national responsibility for decision!

STEPWISE APPROACH, EXISTING FORMS, NO LEGAL OBLIGATION, IT WOULD BE WORTH OF TRYING!

107107

Hungarian international drug registration collaborations

• European Pharmacopoeia• Pharmaceutical Inspection Cooperation

Scheme (PIC-S)• OECD GLP Working Party...• WHO International Pharmacopoeia,

guidelines…• European Union…

108

Exam topic

109

Registration of drugs

• Different kinds of drug authorisations for use: the 3 levels according to WHO

• Medicine use possibilities, other than registered ones• Registration as product characterisation plus legal and

professional sides• The 3 main elements of the professional side• Characterisation of the content of an application (CTD)• The flow of the registration process of a new drug• The CJD issue• Prescription statuses, their reason, switches between these

statuses• Accompanying info for professionals and patients• Deletion from the register versus batch recall

110

Registration of generics and the European Union marketing

authorisation routes• Description of the application types (from fill

application to generics)• Patent protection and data exclusivity• Doha declaration• What is a generic drug. Ho9w to establish

equivalence• Discuss the EU Community procedures (3) in

short• The European Medicines Agency• International (global and regional) registration

collaborations

111

Levels of proof for the use of drugs

• List the levels of proof and their order

• Explain the clinical terminology

Documents

11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription