Development Phases of Clinical Trails and Regulations

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Phases Of Clinical Trails

Development Phases of Clinical Trails and Regulations

Phases of Clinical Trails

What are the 4 phases of Clinical Trails?

The development of new drugs has four phases of clinical trials on humans. These trials can only occur following extensive modelling of the effects of drugs and testing in animals.

What are Phase 1 Clinical Trails?

Clinical Trails Phase 1 trials

• First time that the drug is given to humans (clinical trials on humans).

• Provide data on the safety and tolerability of a range of doses and assess maximum tolerated dose (MTD) and toxicity of a drug used for the first time in humans.

• Provide data on pharmacokinetics and pharmacodynamics of the drug.

• Often designed to start at a single low dose, which is gradually i depending on the side effects until the MTD is reached.

• Usually only involve small numbers of participants (20–100), and are usually undertaken in healthy volunteers unless it is unethical (e.g. cytotoxic drugs must be tested in cancer patients).

Clinical Trails Phase 2 (Clinical Trails Gov)

• Usually the first time that the drug is given to a patient with the disease state it is thought to treat (with the exception of anti-cancer drugs). Often called proof-of-concept studies.

• Assess efficacy and define therapeutic dose range and dosing regimen for a specific indication, with minimal side effects.

• Provide further information on safety, pharmacokinetics, and pharmacodynamics in the presence of the disease process.

• Provide information on the doses that should be tested in phase III studies. • Relatively small numbers of patients (50–300) are studied under close supervision, usually by specialized investigators.

• Phase II studies can be subdivided into phase II a and phase II b studies:

• Phase II a studies assess the dose required

• Phase II b studies assess the efficacy at specific doses.

• Phase I and phase II studies may be combined in one protocol to assess both efficacy and toxicity.

Clinical Trails Phase 3

• Assess treatment outcomes in a variety of patients approximating to the population of patients who will receive the drug once it is launched.

• May compare new treatments with existing treatments.

• May use a placebo arm if there is no current treatment protocol.

• Aim to demonstrate long-term safety, tolerance, and potential superiority to current licensed treatments.

• Undertaken in large numbers of patients (100<2000), often in multiple centres across the globe.

Clinical Trails Phase 4

• Performed after a product licence is obtained (i.e. post marketing).

• May be stipulated by the regulatory authority.

• Aim to investigate the incidence of relatively rare ADRs or to compare drugs with comparative treatments, maybe to extend the range of approved indications.

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Phases Of Clinical Trails

Clinical trial regulations

Clinical trials form a fundamental part of the research, development, and licensing of new medicines.

Research is done into how the drug will interact in humans is necessary to ensure that safe and effective medicines are licensed as new treatments.

It is an exciting and varied role at the cutting edge of modern research with trials ranging across all therapeutic specialities.

Clinical trial pharmacists are therefore needed to have a wide clinical knowledge and an experts special knowledge of the regulations that clinical trials have to follow.

New regulations were introduced in 2004 to help regulate the field of clinical trials in human subjects.

The European Clinical Trials Directive (2001/20/ EC) was implemented across the EU in 2004 and transposed into local law (Statutory Instrument (SI)1031 in the UK).

Its primary aim is to ensure that patient safety is paramount in all clinical trials.

Its secondary aim is to ensure the integrity of the data that is collected so that the decisions that are made based on the outcomes of the trial are representative of the true effects of the medicine and not due to bias in the trial.

All clinical trials involving investigational medicinal products (IMPs unlicensed drugs in a clinical trial) have to follow the principles outlined as good clinical practice (GCP).

This is a defined quality standard devised by the International Conference on Harmonisation which provides guidelines on how clinical trials should be conducted and defines the roles and responsibilities of clinical trial having sponsors, clinical research investigators, and also monitors.

In addition, all medicines used as IMPs in a clinical trial must have been manufactured and released according to good manufacturing practice (GMP).

GCP aims to ensure that the safety of the patient and the integrity of the data collected are paramount at all times.

The guidelines include protection of the human rights of subjects in a clinical trial and provide assurance of the safety and efficacy of the newly developed compounds.

Everyone involved in running a clinical trial (clinicians, nursing staff, pharmacists, radiologists, etc.) must have GCP training to ensure that they complete their role to the required standard.

A new European Regulation (No 526/2014) has been approved which will repeal both the Clinical Trials Directive and the GCP Directive; however, this is not expected to come into effect until 2017 at the earliest.

Licensing of a clinical trial

Before a clinical trial starts, the following authorizations/approvals must be obtained: • Clinical trial authorization from a competent authority in the UK this is the MHRA:

• The competent authority must consider the application within 60days (maximum). This application can run in parallel with the ethics opinion.

• This application outlines the design and outcomes of the trial so that the competent authority can assess whether the trial is safe to conduct.

• The competent authority must notify the sponsor within 35days if there are grounds for refusal.

• A favourable opinion from one ethics committee, if the trial is deemed ethical to complete.

• Permission from the NHS trust for the trial to take place within that trust (often called Trust Management Approval (TMA) or Research and Development (R&D) Approval) for each site. This now also includes an opinion on the suitability of the local investigator and facilities (this used to be obtained from the local research ethics committee).

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Clinical Trails Documentation

• AEudraCT number must be obtained from the EudraCT database. The EudraCT number is a unique number allocated to each trial by the competent authority. The EudraCT database registers details of all trials approved in the EU.

• The MHRA enforces these standards in the UK by performing inspections of GCP and GMP. The MHRA is also responsible for ensuring that suitable safety monitoring occurs in all clinical trials.

• There is no distinction between commercial and non-commercial trials.

• New guidance has been issued relating to ‘Risk-adapted approaches to Clinical Trials’. This is to allow for reduced requirements when certain criteria are known relating to the medication being used in the trial. Any reduction in requirements should be clearly documented in writing to the competent authority with a rationale why they are not required.

The sponsor still has a responsibility to show that the medication was suitable for use and only certain adaptations are permitted. These are often called ‘type A’ trials.

• All clinical trials will follow a protocol which will contain detailed information about the design of the trial and the drugs involved. All processes and requirements outlined in the trial must be followed as the protocol will have been written in compliance with GCP to ensure the study follows the required regulations.

European Clinical Trials

Directive The Clinical Trials Directive provides regulations that need to be followed for all clinical trials to ensure patient safety.

The Clinical Trials Directive was first implemented in 2004 and there have been three subsequent amendments to ensure that it covers current requirements and has been expanded to include blood products used in a clinical trial.

Phases Of Clinical Trails

The latest amendment was completed in 2009 and was transposed in the UK in SI 2009/1164. There are some specific requirements within the Directive that are particularly relevant to pharmacy or are in areas where pharmacists can help ensure compliance:

• Trials have to be under the control of a named sponsor. The sponsor is the person legally responsible for the conduct of a clinical trial.

This is usually the chief executive of the body registered as the sponsor (this can be a pharmaceutical company or a clinician in a hospital trust or university department). This person is responsible for ensuring that the required systems are in place and that all the regulations are complied with.

• All staff involved in clinical trials must have evidence of suitable training, including GCP, in their continuing professional development log.

• All sites that manufacture, label, or assemble clinical trial materials must hold an Investigational Medicinal Product Manufacturing Authorization (MIA(IMP)).

• Hospitals or healthcare centres with patients who are participating in a clinical trial fall under the Section 37 exemption within SI 1030. This allows a pharmacist (or a person under their authorization) to reconstitute, assemble, or label a clinical trial material without this licence. This does not allow pharmacies to manufacture a drug. Definitions of what constitutes manufacture and what is reconstitution are available from the MHRA.

• An individual in the pharmacy department will be named as the responsible pharmacist for clinical trials within that hospital or trust. This pharmacist must liaise with the trust’s R&D department to ensure that the trials are valid and acceptable.

They are also the contact person for any pharmaceutical company or investigator who wishes to run a clinical trial within that hospital.

• Clinical trial protocols must be made available to the pharmacy department in advance of consideration by an ethics committee, so that the practical details, such as doses and method of administration, packaging, labelling, and study documentation appropriate for each individual trial, can be checked.

The protocol must specify the duration of and responsibility for the storage of all pharmacy records relating to the trial.

Failure to comply with UK law transposed from the EU Clinical Trials Directive is a criminal offence.

• On completion of a clinical trial, the sponsor must notify the competent authority within 90 days of the conclusion of the trial.

• If the trial terminates early, the sponsor must notify the competent authority within 15 days.

• The competent authority can suspend or terminate any trial if there are doubts about the safety or scientific validity.

In summary, the Clinical Trials Directive sets standards to ensure the following:

• Safety of clinical trial participants

• Quality assurance of clinical trials and IMPs

• An appropriate regulatory approval system for clinical trials in the EU.

• Ethics committees were established on a statutory basis.

• Appropriate requirements for the manufacture, import, and labelling of IMPs

• Manufacture and labelling of clinical trial drugs are compliant with GMP

• Adequate safety monitoring of patients participating in trials

Procedures for reporting and recording ADRs. A new Clinical Trials Regulation has been approved by the EU (No 536/2014) which is planned to come into effect in 2017.

The main changes that will result from this regulation are:

• direct transposition into UK law, therefore no scope for interpretation which should result in more consistency across trials run in all European countries

• formalization of the risk adaptive approach already introduced in the UK by the MHRA

• i requirement for retention of documentation relating to clinical trials to 25 years.

There do not appear at the time of publication to be any major pharmacy relevant changes; however, clarification of certain clauses is still being developed.

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