drug licensing

Question 1

Who is responsible for processing drug regulations in Europe?

Answer 1

European Medicines Agency.

Question 2

Who formulates the standards required for drug licensing to be achieved?

Answer 2

European Commission.

Question 3

What is the role of the EMA in processing drug licensing requests?

Answer 3

The EMA’s primary role is to protect the health and safety of humans and animals via the evaluation of medicines intended for such use. They scientifically evaluate all applications and co-ordinate a safety monitoring system.

Question 4

What are National Health Authorities?

Answer 4

These are smaller authorities which exist in different nations which are responsible for drug regulation in that place. They liaise with the EMA on EU-wide regulatory issues, but are responsible for the advice and assessment of applications within their own place, e.g. the UK has the MHRA.

Question 5

What are Marketing Authorisation Applications?

Answer 5

This is the application a pharmaceutical company may make before receiving approval to license to the public. These can be submitted via a centralised route, decentralised route, mutual recognition route, or a national procedure route.

Question 6

What is the centralised procedure/route?

Answer 6

This is a single application with the assessment co-ordinated by the EMA where the CHMP will likely carry out a scientific evaluation. The European Commission will ultimately make the decision based on EMA recommendation. Once approved, the authorisation is valid in all EU Member States. It is mandatory for advanced therapies (orphan drugs) and certain disease areas, e.g. cancer, virology, neurodegenerative diseases.

Question 7

What is the decentralised procedure/route?

Answer 7

This is a simultaneous submission to reference member states (RMS) and concerned member states (CMS). The application is received by the RMS, who then may pass it on to CMS.

Question 8

What is the Mutual Recognition Procedure?

Answer 8

This is used when a drug already has Marketing Authorisation in a member-state (e.g. not new products). It is therefore used to expand the use of nationally approved products to more CMS.

Question 9

What is the National Procedure?

Answer 9

This is an application for marketing authorisation to the national health authority of a particular state.

Question 10

What would be included in a Marketing Authorisation Application?

Answer 10

The labelling information (e.g. patient information leaflet, the packaging), any information from additional follow-up studies, the risk management plan, and the paediatric investigation plan (compliance, waivers).

Question 11

What do the CHMP review in the evaluation of MAA’s?

Answer 11

They look at the benefit:risk ratio, the risk management plan, the product information, and assess whether there is any need to carry out any further safety/efficacy studies before approval.

Question 12

What are the key responsibilities of the MHRA?

Answer 12

The MHRA ensure that the safety, quality, and efficacy of all medicines is maintained. They also carry out inspections (GCP, pharmacovigilance), as well as governs clinical trials and completes MAAs when received. Also enforce laws, e.g. detect illegal medicine supply.

Question 13

What does legislation of authorisation of medicinal products include?

Answer 13

Their manufacture, import, distribution, sale, supply, advertising, labelling, pharmacovigilance.

Question 14

Give examples of drugs which do not require a marketing authorisation.

Answer 14

Drugs may be known as ‘specials’ when they are ordered by a doctor/physician/nurse for treatment of a particular individual. For example, vitamin D supplements, midodrine tablets (used for orthostatic hypertension when fludrocordisone is not effective). However there must be sufficient evidence that there will be efficacy/safety.

Question 15

Who is the regulatory body governing drug approval in the US?

Answer 15

The Food and Drug Administration (FDA), in particular the Centre for Drug Evaluation and Research (CDER).

Question 16

How are the FDA involved in the clinical trial/drug licensing process

Answer 16

The FDA has mandatory consultation during each phase of development, including meetings or documentation. They may put clinical trials on hold until Sponsor’s respond to questions. After a successful phase 3 trial, the sponsor may then submit a MAA to the FDA.

Question 17

How is the FDA licensing process different to the EMA process?

Answer 17

Although similar, the FDA hold advisory committee meetings which members of the public can attend, as well as competing pharmaceutical companies. This allows external expertise to be noted, as well as the FDA’s own receive. This helps with the opinion of if a drug should be licensed or not. A review is undertaken after this committee meeting regarding the labelling and inspection of manufacture, before action is taken.

Question 18

What is accelerated approval?

Answer 18

Accelerated approval may be given in situations where the treatment has demonstrated a huge therapeutic benefit over standard, or in the absence of a standard treatment for life-threatening diseases (e.g. advanced metastatic cancer, Alzheimer’s disease). However, if confirmatory studies do not exhibit the same benefit, then the drug may be withdrawn.

Question 19

What is Orphan Drug Legislation?

Answer 19

Orphan Drugs refer to treatments used in rare diseases. Separate legislation has been produced to encourage the research, development, and approval of drugs for rare diseases.

Question 20

What is defined as a rare disease?

Answer 20

In the EU, this is classed as less than 5 in 10,000 patients. In the US, this is classed as a disease affecting less than 200,000 patients.

Question 21

Why might researchers be encouraged to look at rare diseases?

Answer 21

The EU offers incentives to drug companies/researchers for development of orphan drugs, e.g. scientific advice on protocols, fee reductions, access to grants, and 10-year marketing protection. These drugs will also be monitored by the Committee for Orphan Medicinal Products.

Question 22

What is the required structure used for MAAs or NDAs?

Answer 22

Applications should produce a Common Technical Document (CTD) consisting of modules 2,3,4,5 which concerns the table of contents, the introduction, the clinical overview and summary, the non-clinical overview and summary, the quality overall summary, quality, the non clinical study reports and the clinical study reports.

Question 23

What happens in the MAA is successful?

Answer 23

After MAA authorisation, there must be approval for the SmPC and USPI regarding the labelling and detailed description of the intended use (including PK/PD effects, adverse events, precautions, dosage).

Question 24

Why is a risk management plan necessary within an MAA? What does it aim to do?

Answer 24

Risk management plans are required to ensure there are effective means to reduce/prevent the risks associated with the medicinal product. Remember, all medicinal products have risks. It should characterise the safety profile of the drug, state how it would be characterised further after approval and licensing to public, and how these risks may be minimised, etc.

Question 25

What should be included in the Risk Management Plan?

Answer 25

The RMP should include: the safety specification, the clinical trial exposure, the target population, the populations not tested in trials, the identified and potential risks, the measures that will be taken to minimise safety risks.

Question 26

What is the Yellow Card Scheme?

Answer 26

The Yellow Card Scheme is a system for self-reporting of side effects from drugs via an electronic system or postal of completed form. Healthcare professionals may also submit side effect forms. The information is centralised to the EU EudraVigilance database. Adverse events can also be compiled into MedDRA, where medical terminology is used.

Question 27

How are adverse events categorised in MedDRA?

Answer 27

Events are categorised into system organ class (e.g. gastrointestinal disorders), then high level group terms (e.g. gastrointestinal signs and symptoms), then high level terms (e.g. nausea and vomiting), then preferred term (nausea), then the lowest level term (e.g. how the symptoms may be communicated in practice - feeling queasy).

Question 28

What is signal detection in adverse event reporting?

Answer 28

From the Yellow Card Scheme there may be thousands of reports. Signal detection is an alert from any available data source that a drug may be associated with an unanticipated hazard, or that a known hazard is quantitatively different from expectations. It is hard to find a valid signal. Statistical methods rely on the number of ADR combinations being more than expected.

Question 29

How are signal detections analysed?

Answer 29

Millions of reports are received each year and the data must be reduced based on duplicate forms and grouped into same drug classes (some people may provide different names for the drugs). Then the number of adverse events reported can be calculated and compared against the expected number of adverse events. A Bayesian shrinkage model can be used to incorporate the ratios and the p-values. Heat maps are also produced to demonstrate a qualitative view of the prevalence of adverse events within system organ classes (as categorised by MedDRA)

Question 30

What is the Green Card Scheme?

Answer 30

The Drug Safety Research Unit will identify people who have been prescribed new medicines and collects clinical data on these patients. The data is submitted by practitioners via a Green Form.

Question 31

What are the disadvantages to spontaneous reporting schemes?

Answer 31

There will be under-reporting therefore you cannot know how significant the adverse event is. There is approximately 95% of false positive reports.

Question 32

What are the advantages to spontaneous reporting schemes?

Answer 32

You may be able to detect events which you were unable to detect in clinical trials, due to a small sample size. You will theoretically be able to control the risk more, due to an easier way of knowing and assessing the risks.

Question 33

What are the relevant actions which may take place after assessing benefit-risk ratio after marketing authorisation and public licensing?

Answer 33

Marketing approval may be revoked, or suspended. No action may be taken. There may be requirements for the product information to be altered, e.g. not suitable in specific population, or warnings that this side effect may be experienced.

Question 34

What was the Vioxx disaster?

Answer 34

Vioxx was a drug intended to treat osteoarthritis in adults. However, a year after marketing approval, studies showed that the risk of heart attacks was doubled with administration of Vioxx. The company Merck voluntarily withdrew its marketing approval.

Question 35

What are gaps in knowledge of safety and efficacy of a drug at the point of licensing?

Answer 35

Before a drug is licensed, safety and efficacy have been demonstrated in phase 3 trials. However, there is lack of external validity, e.g. we do not know what the safety and efficacy will be like in the general population. Usually trials are set up so that specific populations receive the drug, however when the drug is prescribed to other groups, there may be different reactions. As a result, the benefit-risk ratio may go down, therefore this needs to be managed as best possible. This is often done with a risk management plan and via schemes such as Yellow and Green card schemes. However, further gaps in knowledge exist when drugs are taken and prescribed off-license. This is due to the lack of communication, e.g. physicians may identify a significant benefit of a drug which was not already known, however fail to report it to higher regulatory agencies, and just continue to use the drug in these other beneficial ways.