Legislation Lecture 2:Licensing of Medicinal Products

Question 1

Marketing AuthorisationFormerly known as PRODUCT LICENCE (PL)

Answer 1

Needed for every Medicinal Product
Before being prescribed / sold.
Licensing body – Either or both of the Ministers
Functions carried out by MHRA
Usually submitted by Pharmaceutical Industry
But, anyone can submit a request.
Can take up to 210 days to go through process
Can take 30 days to inform approval granted

Sets out the rules for manufacturing, importing and wholesale dealing
It requires these activities to be subject to a licence
Establishes what the licencing authority must consider when assessing an application
Sets out requirements for Responsible Persons and Qualified Persons

Manufacturer’s or wholesale dealer’s license
Granted by licensing authority
Within 90 days
Remains in force until surrendered/revoked
Licensing authority may suspend/revoke/vary
28 day notice
Immediate suspension possible for safety reasons
Max 3 months + further 3 months…..

Question 2

Manufacturer’s licence.

Answer 2

Medicinal products manufactured in the UK must be produced on a site that holds an appropriate manufacturer’s licence (ML).

A person may not, except in accordance with a licence (a “manufacturer’s licence”)
(i)Manufacture, assemble or import from a state other than EEA state any medicinal product; or
Possess a medicinal product for the purpose of any activity in (i) above.
Marketing Authorisation issued by a competent authority
MHRA
Manufacturing license not needed by a person who imports a medicinal product for personal use.
Manufacturing license does not apply to the mixing of medicines.

The site is inspected by the MHRA Inspectorate to ensure that the following criteria and standards are met:
Appropriate facilities, equipment and suitably trained staff are available and maintained
All products are manufactured to the standards detailed by the EC Guide to Good Manufacturing Practice
Quality Assurance measures are built into each step of the manufacturing process to ensure the safety, quality & efficacy of the product
The site is inspected by the MHRA Inspectorate at least every two years

Question 3

Wholesale dealer’s licence

Answer 3

Any company or individual wishing to wholesale deal (defined as selling, supplying or procuring to anyone other than the end-user) medicinal products within the EU must hold a wholesale dealer’s licence (WDL)

Distributing by way of wholesale dealing is a reference to –
Selling or supplying it; or
Procuring or holding it or exporting to another EEA state for the purpose of sale or supply,
To a person who receives it for a purpose of –
Selling or supplying the product or
Administering it or causing it to be administered to one or more human beings, in the course of a business carried on by that person.

The licensing is primarily concerned with:
Identification of the Distributor
Suitability of the premises used for storage, distribution and stock control
Wholesalers are inspected before a WDL is granted, and at least once during the 5-year period of the licence
Wholesale dealer (GSL) available
Only deal in GSL medicines
RP needed to oversee process.

Question 4

Clinical trial authorisation

Answer 4

Needed by new products under development.
Needed before being tested on humans

Question 5

licensing

Answer 5

Manufacturer’s licence
Wholesale dealer’s licence
Clinical trial authorisation

(All are issued by MHRA)

Question 6

So No WDL needed if

Answer 6

1. It takes place on an occasional basis
2. The quantity of medicines supplied is small
3. The supply is made on a not for profit basis
4. The supply is not for onward wholesale distribution

Question 7

Product development

Answer 7

New Chemical Entity
Clinical trials
Marketing Authorisation
Production (Manufacturer’s Licence)
Distribution to patients (Wholesaler Dealer’s Licence)

Question 8

Development Process

Answer 8

Discovery: 5,000 to 10,000 molecules
Preclinical testing: approx. 250 molecules
Phase I: approx. 5 molecules
Phase II: approx. 2-3 molecules
Phase III: approx. 1-2 molecules
Phase IV: Post marketing trials)

Registration Approval: 1 molecule

Time - 10 years? (range: 4.2 to 25 years)

Cost – $2.5billion (2014 Scientific American)

Question 9

Clinical Trials

Answer 9

Phase 1 trials usually involve healthy people to find out how the medicine works in the body
Usually less than 100 people
Phase 2 trials look at how the drug works in a particular condition
Several hundred people
Phase 3 looks at how well the medicine works and how safe it is in the general population
Several hundred to several thousand people

Question 10

Clinical Trials Application

Answer 10

New legislation introduced May 2004
Emphasis shifted from controlling the product to authorisation of the trial
Trial approval by MHRA within 60 days
Regulation of healthy volunteer trials
Manufacturer’s trials licence required
Inspections for standards of Good Clinical Practice (GCP) & Good Manufacturing Practice (GMP)
Labelling requirements
Ethics committee system

Question 11

EvaluationSafety & Efficacy

Answer 11

Nature of the active ingredients
Dosage form
Nature of disease or condition treated
Type of Patient
Duration of treatment
More effective than placebo
Risk to Benefit ratio

Question 12

EvaluationQuality

Answer 12

Product’s physical, pharmaceutical & biological characteristics to ensure that each batch of the medicine is capable of performing reliably and consistently

Question 13

Granting of MA- marketing authority

Answer 13

Submission of necessary documentation
Fees
Validation
Ensure forms completed accurately
Assessment
Assessor determines whether there is sufficient information to evaluate the Safety, Quality and Efficacy of the product.
Assessor may seek further advice from CHM or EAG.
CHM / EAG may advise to license or refuse.
Applicant has the right of appeal.

Valid for 5 years initially
On renewal, unlimited period unless safety concerns.
On renewal, up to date data must be supplied
New medicines are usually POMs
Product must be on market within 3 years of granting of MA.
Subject to pharmacovigilance
‘Black triangle’ drugs
‘Yellow card’ reporting

All applications to the MHRA

Question 14

What are the Systems to Register Medicines

Answer 14

Centralised
Decentralised
Mutual Recognition
National

Question 15

Centralised

Answer 15

One single application is made to the EMA (used to based in London)
One single European Authorisation is granted by EMA
Certain medicines can only be licensed in this way to ensure that they are automatically available to every EU member state
Gene therapies
Medicines for HIV/AIDS, cancer, diabetes, Altzheimer’s
Orphan drugs (medicines for rare diseases, occurring in less than 5 in 10,000 people)

Question 16

Decentralised

Answer 16

The same application is submitted simultaneously in a number of member states
One state takes the lead in the application
Identical national licences issued in each state involved in the application

Question 17

Mutual recognition

Answer 17

First application is made to one or more EC Member State Authority
National/decentralised authorisation granted
Mutual recognition of this authorisation by other Concerned Member States Authorities
Each Member State issues an Authorisation

Question 18

Every MP must have

Answer 18

Summary of Product Characteristics (SPC) – formerly known as ‘Data Sheet’
Label (PJR)

Patient Information Leaflet (PIL)

Question 19

Summary of Product Characteristics (SPC)

Answer 19

Legal document containing factual information about an MP based on data generated during the development of the product
Name, strength and pharmaceutical form.
Qualitative and quantitative composition
Clinical particulars
Pharmacological properties
Pharmaceutical particulars
Name of UK MA holder
Number of UK MA

Question 20

Parallel Import Licence (PLPI)

Answer 20

Allows Medicinal Products with a Marketing Authorisation to be bought in one European Member State and sold in another.
Importer must hold:
Wholesale dealer’s licence (import)
Manufacturer’s license (repackage + re-label)

Conditions must be met that the product:
Is not a vaccine, toxin, blood product, radioactive isotope or homeopathic product
Is covered by a European MA & is a version of a product which already holds UK MA
Has the same therapeutic effect as the UK product
Must be made by, or under licence to the UK manufacturer or by a member of the same group of companies
Must be labelled and have PIL in English

Question 21

Manufacturer’s Specials Licence

Answer 21

Specials’ are products which have been specially manufactured or imported for the treatment of an individual patient after being ordered by a:
doctor
dentist
nurse independent prescriber
pharmacist independent prescriber
supplementary prescriber
Not all ‘prescribers’ can order a special (see PSNC website)

For a manufacturer to make an unlicensed MP (a “Special”), they must hold a Manufacturer’s “Specials” Licence
No advertising of products only of the service
Doctor takes responsibility for efficacy of product
Licence holder takes responsibility for quality of product
Inspected by MHRA as per ML

Question 22

Homeopathic medicines (Part VI)

Answer 22

Product Licence of right – before MA 1968 (including indications)
Homeopathic Certificate of Registration
Simplified Scheme
Safety and quality demonstrated
No medical claims or indications allowed
Restricted to products for oral & external use
Products must be sufficiently dilute to ensure safety
National Rules Scheme
Product can be registered with indications for relief or treatment of minor symptoms
Applications supported by data on safety and quality with appropriate labelling
Evidence that it has been used as a homeopathic treatment in the indication sought
From 30th April 2011 all herbal products are required to have a THR or an MA
1) Traditional Herbal Registration (THR)
Simplified registration scheme
Required to reach specific standards of safety and quality
2) Licensed herbal medicine (needs MA)
Quality, safety and efficacy has been demonstrated
See Pharm J Vol 286 (16.04.11) p465 – 468
RPS Guidance ‘The Traditional Herbal Medicine Registration Scheme’ (June 2011)