UNIT-I:
Licensing
authorities-roles and responsibilities
ICH
GCP
( Note : throughout the syllabus, in
some topics you will find the serial numbers like 3.1 , 4.1 , 5.1…..so on etc which is extracted from the guidelines of
ICH, GCP,FDA etc and it is mandatory to present because it gives authentication
of the data. During examination, a student need not to mention the serial
numbers.)
3. INSTITUTIONAL REVIEW
BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
3.1 Responsibilities
3.1.1 An IRB/IEC should safeguard
the rights, safety, and well-being of all trial subjects. Special attention
should be paid to trials that may include vulnerable subjects.
3.1.2 The IRB/IEC should obtain the
following documents:
trial protocol(s)/amendment(s),
written informed consent form(s) and consent form updates that the investigator
proposes for use in the trial, subject recruitment procedures (e.g.
advertisements), written information to be provided to subjects, Investigator's
Brochure (IB), available safety information, information about payments and
compensation available to subjects, the investigator’s current curriculum vitae
and/or other documentation evidencing qualifications, and any other documents
that the IRB/IEC may need to fulfil its responsibilities.
The IRB/IEC should review a proposed
clinical trial within a reasonable time and document its views in writing,
clearly identifying the trial, the documents reviewed and the dates for the
following:
- approval/favourable opinion;
- modifications required prior to its
approval/favourable opinion;
- disapproval / negative opinion;
and
- termination/suspension of any
prior approval/favourable opinion.
3.1.3 The IRB/IEC should consider
the qualifications of the investigator for the proposed trial, as documented by
a current curriculum vitae and/or by any other relevant documentation the
IRB/IEC requests.
3.1.4 The IRB/IEC should conduct
continuing review of each ongoing trial at intervals appropriate to the degree
of risk to human subjects, but at least once per year.
3.1.5 The IRB/IEC may request more
information than is outlined in paragraph 4.8.10 be given to subjects when, in
the judgement of the IRB/IEC, the additional information would add meaningfully
to the protection of the rights, safety and/or well-being of the subjects.
3.1.6 When a non-therapeutic trial
is to be carried out with the consent of the subject’s legally acceptable
representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the
proposed protocol and/or other document(s) adequately addresses relevant
ethical concerns and meets applicable regulatory requirements for such trials.
3.1.7 Where the protocol indicates
that prior consent of the trial subject or the subject’s legally acceptable
representative is not possible (see 4.8.15), the IRB/IEC should determine that
the proposed protocol and/or other document(s) adequately addresses relevant
ethical concerns and meets applicable regulatory requirements for such trials
(i.e. in emergency situations).
3.1.8 The IRB/IEC should review both
the amount and method of payment to subjects to assure that neither presents
problems of coercion or undue influence on the trial subjects. Payments to a
subject should be prorated and not wholly contingent on completion of the trial
by the subject.
3.1.9 The IRB/IEC should ensure that
information regarding payment to subjects, including the methods, amounts, and
schedule of payment to trial subjects, is set forth in the written informed
consent form and any other written information to be provided to subjects. The
way payment will be prorated should be specified.
3.2 Composition, Functions and
Operations
3.2.1 The IRB/IEC should consist of
a reasonable number of members, who collectively have the qualifications and
experience to review and evaluate the science, medical aspects, and ethics of
the proposed trial. It is recommended that the IRB/IEC should include:
(a) At least five members.
(b) At least one member whose
primary area of interest is in a nonscientific area.
(c) At least one member who is
independent of the institution/trial site.
Only those IRB/IEC members who are
independent of the investigator and the sponsor of the trial should
vote/provide opinion on a trial-related matter.
A list of IRB/IEC members and their
qualifications should be maintained.
3.2.2 The IRB/IEC should perform its
functions according to written operating procedures, should maintain written
records of its activities and minutes of its meetings, and should comply with
GCP and with the applicable regulatory requirement(s).
3.2.3 An IRB/IEC should make its
decisions at announced meetings at which at least a quorum, as stipulated in
its written operating procedures, is present.
3.2.4 Only members who participate
in the IRB/IEC review and discussion should vote/provide their opinion and/or
advise.
3.2.5 The investigator may provide
information on any aspect of the trial, but should not participate in the
deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
3.2.6 An IRB/IEC may invite
nonmembers with expertise in special areas for assistance.
FDA
Roles and Responsibilities
The
main role of the Thai FDA is to protect consumer,s health, especially, to
ensure safety, quality and efficacy of health products within its remit. These
include: foods, drugs, psychotropic substances, narcotics, medical devices,
volatile substances, cosmetics and hazardous substances available in the
country. This has to be implemented in accordance with national legislation and
international agreements as follows:
- Drug Act, B.E. 2510 (1967)
- Psychotropic Substances Act B.E. 2518 (1975)
- Food Act, B.E. 2522 (1979)
- Narcotics Act, B.E. 2522 (1979)
- Medical Devices Act, B.E. 2531 (1988)
- The Emergency Decree on Prevention of Abuse of Volatile
Substances, B.E. 2533 (1990)
- Cosmetics Act, B.E. 2535 (1992)
- Hazardous Substances Act, B.E. 2535 (1992)
- The Single Convention on Narcotic Drugs 1961,
commentary on the protocol amended in Geneva on March 25, 1972.
- The International Convention on Psychotropic
Substances, 1971.
- The International Code on Marketing of Breast Milk
Substitute, 1981
- The United Nations Convention against Illicit Traffic
in Narcotic Drugs and Psychotropic Substances, 1988.
By
law, certain important issues are decided by committees, whose members, all
experts in their fields, are appointed by the Minister of Public Health.
Currently, there are six committees : Drugs, Food, Cosmetics, Narcotics, Psychotropic
Substances and Medical Devices.
There
are two committees whose members are appointed by the other ministries. They
are the Committee on the Prevention of Abuse of Volatile Substances appointed
by two ministers (Industry and Public Health), and the Hazardous Substance
Committee appointed by three ministers (Public Health, Industry and
Agriculture).
At
the national level, the Cabinet appoints three committees: the National Drug
Committee, the National Food Committee and the National Chemical Safety
Committee. The national committees are mainly assigned policy and development
issues and collaborative action with other agencies to facilitate the
implementation of the food, drug and chemical safety program as well as the
control system.
The
roles and responsibilities of the FDA may be grouped into five main areas:
1.
Pre-marketing control
This
includes control of manufacturing facilities, product quality and advertising
before product-launch to the market. In each case, compliance is required with
the relevant legislation and regulations.
2.
Post-marketing control
The
aim of this activity is to investigate manufacturing facilities and product
quality and to ensure that they maintain compliance with previously-approved
standards and with legislation and regulations. For example, samples of
products are regularly inspected and taken to check for compliance and quality.
Previously-approved products are revisited periodically to ascertain the
consistency of manufacturing and product standards over time.
3.
Surveillance program for consumers' safety
The
aim of this Program is to detect any adverse effects or unexpected outcomes
from consumer use of products. Research and epidemiological data on adverse
effects, including technical information, is collected, summarized, interpreted
and reported. There are also operational centers, such as the Adverse Product
Reaction Monitoring Center (APRMC) and the International Program on Chemical
Safety (IPCS). Information is exchanged with other agencies at local and
international level.
4.
Consumer Education
Consumers
are supplied with sufficient, accurate information to enable them to choose
products wisely. Access to such information, provided by the FDA, is available
from many sources: television, radio, newspaper, leaflets, internet, and so on.
FDA,s campaigns on priority topics have been regularly conducted in department
stores, schools and villages in many parts of the country. There are many
sources for consumers to use so that they can obtain further useful information
and be in a better position to protect themselves.
5.
Technical Support and Cooperation with other agencies
The
FDA has conducted many interesting seminars and workshops, with participants
from both public and private sectors. On the other hand, officials from the
Thai FDA are sent to join seminars and conferences, both local and abroad. As a
result, with a widened perspective, they can work more effectively at home. The
Good Manufacturing Practice (GMP) program is another example demonstrating
successful cooperation with other organizations, in this case, with
universities and drug manufacturers. In relation to cooperation in terms of
research and development, the FDA is continually supportive of such endeavor, and
some research projects are partly or wholly funded by the agency.
EU
Clinical Trial Directive
General Information
Clinical
trials are investigations in humans intended to discover or verify the effects
of one or more investigational medicinal products ("IMPs").
Requirements
for the conduct of clinical trials in the EU are provided for in "
Directive 2001/20/ECpdf of the European Parliament and of the Council of 4
April 2001 on the approximation of the laws, regulations and administrative
provisions of the Member States relating to the implementation of good clinical
practice in the conduct of clinical trials on medicinal products for human
use" (" the Clinical Trials Directivepdf ").
The
Clinical Trials Directive is concretised further by " Commission Directive
2005/28/ECpdf of 8 April 2005 laying down principles and detailed guidelines
for good clinical practice as regards investigational medicinal products for
human use, as well as the requirements for authorisation of the manufacturing
or importation of such products" (Good Clinical Practice - " the GCP
Directivepdf ").
Clinical
trials performed in the European Union are required to be conducted in
accordance with the Clinical Trials Directive. If the clinical trials are
conducted outside the EU, but submitted in an application for marketing
authorisation in the EU, they have to follow the principles which are
equivalent to the provisions of the Clinical Trials Directive (cf. Annex I,
point 8 of the " Directive 2001/83/ECpdf of the European Parliament and of
the Council of 6 November 2001 on the Community code relating to medicinal
products for human use" - " the Community Code for medicinal
productspdf ").
Guidelines
There
are a number of guidelines further specifying various aspects of clinical
trials, and in particular:
The information to be submitted to the
competent authorities and to the ethics committees
The requirements on safety monitoring and
the reporting of adverse reactions
The requirements regarding Good Clinical
Practice, including the documentation, of the clinical trials
The specific requirements regarding the
products and the clinical trials
The inspections of competent authorities
and the applicable procedures
These
guidelines have been published by various bodies:
By the European Commission: In this case,
they are published in Volume 10 of "EudraLex - The rules governing
medicinal products in the European Union"
By the European Medicines Agency
("EMA") These guidelines concern in particular:
Inspection procedures and guidance for
GCP inspections conducted in the context of the Centralised Procedure
Requirements relating to the quality,
safety and efficacyof products, as well as specific types of products. Volume 3
of EudraLex
Moreover, the Heads of Medicines Agencies
have established a Clinical Trials Facilitation Group ("CTFG") (in
which the Commission and EMA are observers), in order to discuss ongoing
technical issues.
Clinical trial application
The
Clinical Trials Directive harmonises the rules in the EU for the approval of a
clinical trial conducted in a Member State. As regards national competent
authorities, the details are set out in the 'Commission Detailed guidance on
the request to the competent authorities for authorisation of a clinical trial
on a medicinal product for human use, the notification of substantial
amendments and the declaration of the end of the trial (CT-1)' published in
EudraLex Volume 10.
EudraCT
A
European database - EudraCT - contains all ongoing or completed clinical trials
falling within the scope of Directive 2001/20/EC, i.e. with at least one
investigator site in the EU (incl. the European Economic Area) and commencing
after implementation of Directive 2001/20/EC by the Member States. This
database gives the competent authorities of the Member States, the EMA and the
Commission the necessary information to communicate on clinical trials and to
maintain oversight of clinical trials and IMP development. This provides for
enhanced protection of clinical trial subjects and patients receiving IMPs.
More information, including a user manual for EudraCT is available on the
EudraCT Supporting Documentation web page.
Paediatric
clinical trials that form part of a Paediatric Investigation Plan (PIP) but are
conducted in third countries will also be included in the near future
(paediatric clinical trials with sites in the EU/EEA are already included).
Transparency of information
related to clinical trials
Union
legislation provides that certain information contained in EudraCT is to be
made accessible to the public. This public accessibility concerns clinical
trials with paediatric as well as non-paediatric participants. It englobes
protocol-related information and result-related information. And it covers both
negative and positive results.
To
implement the legislation further, the Commission has issued a set of
guidelines, which are accessible via chapter V of EudraLex, Volume 10.
These
guidelines consist of three "mother guidelines" (Guideline
2008/C168/02; Guideline 2009/C28/01, Guideline 2012/C302/03), setting out the
principles, responsibilities, and procedural aspects. The "mother
guidelines" are further concretised by way of a number of very detailed
"daughter guidelines".
With
regard to protocol-related information, this information is public under
clinicaltrialsregister.eu, which is part of the public database EudraPharm.
With
regard to result-related information, this information is presently not
contained in EudraCT at all. Therefore, prior to making anything public, the
necessary guidelines had to be adopted and published. These are published in
EudraLex, Volume 10. Programming of the relevant databases is currently
ongoing. More information is available here.
For all
additional information, reference is made to the applicable guidelines in
chapter V of EudraLex Volume 10.
Safety reporting
The
Clinical Trials Directive introduces rules on safety reporting in the context
of a clinical trial. Further details are set out in 'the Commission Detailed
guidance on the collection, verification and presentation of adverse
event/reaction reports arising from clinical trials on medicinal products for
human use (‘CT-3’)' published in EudraLex Volume 10. Regarding suspected
unexpected serious adverse reactions (SUSARs), this guidance provides inter
alia the rules for reporting directly to the national competent authority. In
order to obtain the national address for the direct reporting, click on the
relevant Member State:
Revision of the Clinical trials Directive
Adoption
of the proposal for a "Clinical Trials Regulation"
On 17
July 2012, the Commission has adopted a "Proposal for a Regulation of the
European Parliament and of the Council on clinical trials on medicinal products
for human use, and repealing Directive 2001/20/ECpdf(767 KB) Choose
translations of the previous link" (hereinafter "Clinical Trials
Regulation") .
The
proposal has been submitted to the European Parliament and the Council who
engage in ordinary legislative procedure. You find an overview of this procedure
here. To follow the proposal in the different steps of the procedure, please
consult the "legislative observatory" of the European Parliament or PreLex, the EU-database on
interinstitutional procedures.
Preparation of the Commission
proposal
In its
Communication of 10 December 2008 to the European Parliament, the Council, the
European Economic and Social Committee and the Committee of the Regions on
“Safe, Innovative and Accessible Medicines: a Renewed Vision for the
Pharmaceutical Sector”, the Commission announced that an assessment would be
made of the application of the Clinical Trials Directive.
This
assessment would consider, in particular, various options for improving the
functioning of the Clinical Trials Directive with a view to making legislative
proposals, if appropriate, while taking the global dimension of clinical trials
into account.
In 2009,
a public consultation document along this line was published herepdf(134 KB).
The responses have been published here. A summary document of the responses is
available herepdf(61 KB).
A
'roadmap' of the Commission impact assessment, setting out the main structure
and the next steps, was made available here.
On 9
February 2011, a public consultation on a concept paper on the revision of the
'Clinical Trials Directive' 2001/20/ECpdf(94 KB) has been launched. The concept
paper presented:
- a
'preliminary appraisal' of which option appeared to be the most suitable one to
address some of the key concerns of the Clinical Trials Directive, on the basis
of the current state of the impact assessment; and
- the
main figures used to evaluate the impacts of the different policy options.
(Ref : http://ec.europa.eu/health/human-use/clinical-trials/)
EU
Clinical Trials Directive
The European Union Clinical Trials
Directive (2001/20/EC) provides a framework which sets out how clinical trials
investigating the safety or efficacy of a medicinal product in humans must be
conducted. It includes medicinal trials with healthy volunteers and small scale
or pilot studies.
The Directive aims are to:
- Provide greater protection to subjects participating in
clinical trials
- Ensure quality of conduct
- Harmonise regulation and conduct of clinical trials
throughout Europe
EU
Good Clinical Practice Directive
Good Clinical Practice is a set of
internationally recognised ethical and scientific quality requirements which
must be observed for designing, conducting, recording and reporting clinical
trials that involve the participation of human subjects.
The International Conference on Harmonisation Guidance on Good
Clinical Practice (Topic E6) (CPMP/ICH/135/95) is an international
standard for GCP.
The Good Clinical Practice Directive 2005/28/EC
supplements the Clinical Trials Directive, strengthening the legal basis for
requiring Member States to comply with the principles and guidelines of good
clinical practice, as set out in the ICH-GCP guidelines.
The
Medicines for Human Use (Clinical trials) Regulations 2004
- Establishment of ethics committees on a legal basis
- Each Clinical Trial must have an identified Sponsor who
takes responsibility for its initiation, conduct and management
- Phase 1 pharmacology studies in healthy volunteers
require authorisation by the Medicines and Healthcare products Regulatory
Agency (MHRA)
- Investigational medicinal products (IMPs) must be
manufactured to Good Manufacturing Practice
(GMP) standards and the manufacturer must have a manufacturing licence
- The MHRA is empowered to carry out statutory
inspections of the sponsor, researchers, facilities and manufacturing
organisations for GCP, GMP and pharmacovigilance to help ensure required
standards are maintained
Failure to comply with the UK
Clinical Trials Regulations 2004 can lead to penalties of fines and/or a
custodial sentence for non-compliance. A summary of the regulations is
available here
Amendments
to the Regulations
There have been various amendments
to the Medicines for Human Use Clinical Trials Regulations as listed below:
(Ref : http://www.cardiff.ac.uk/racdv/resgov/clintrials/directives/)
Data
Protection Act
The Data Protection Act 1998 (DPA)
is a United Kingdom Act of Parliament which defines UK law on the processing of
data on identifiable living people. It is the main piece of legislation that
governs the protection of personal data in the UK. Although the Act itself does
not mention privacy, it was enacted to bring UK law into line with the EU data
protection directive of 1995 which required Member States to protect people's
fundamental rights and freedoms and in particular their right to privacy with
respect to the processing of personal data. In practice it provides a way for
individuals to control information about themselves. Most of the Act does not apply
to domestic use, for example keeping a personal address book. Anyone holding
personal data for other purposes is legally obliged to comply with this Act,
subject to some exemptions. The Act defines eight data protection principles.
It also requires companies and individuals to keep personal information to
themselves.
Data protection principles
Schedule 1 to the Data Protection Act lists the data protection principles
in the following terms:
- Personal
data shall be processed fairly and lawfully and, in particular, shall not
be processed unless –
(a) at least one of the conditions in Schedule 2 is met, and
(b) in the case of sensitive personal data, at least one of the
conditions in Schedule 3 is also met.
- Personal
data shall be obtained only for one or more specified and lawful purposes,
and shall not be further processed in any manner incompatible with that
purpose or those purposes.
- Personal
data shall be adequate, relevant and not excessive in relation to the
purpose or purposes for which they are processed.
- Personal
data shall be accurate and, where necessary, kept up to date.
- Personal
data processed for any purpose or purposes shall not be kept for longer
than is necessary for that purpose or those purposes.
- Personal
data shall be processed in accordance with the rights of data subjects
under this Act.
- Appropriate
technical and organisational measures shall be taken against unauthorised
or unlawful processing of personal data and against accidental loss or
destruction of, or damage to, personal data.
- Personal
data shall not be transferred to a country or territory outside the
European Economic Area unless that country or territory ensures an
adequate level of protection for the rights and freedoms of data subjects
in relation to the processing of personal data.
(Ref
: http://ico.org.uk/for_organisations/data_protection/the_guide/the_principles)
Regulations
relating to electronic signatures
An electronic signature, or e-signature, is
any electronic means that indicates either that a person adopts the contents of
an electronic message, or more broadly that the person who claims to have
written a message is the one who wrote it (and that the message received is the
one that was sent). By comparison, a signature is a stylized script associated
with a person. In commerce and the law, a signature on a document is an
indication that the person adopts the intentions recorded in the document. Both
are comparable to a seal.
Increasingly,
encrypted digital signatures are used in e-commerce and in regulatory filings
as digital signatures are more secure than a simple generic electronic signature.The
concept itself is not new, with common law jurisdictions having recognized
telegraph signatures as far back as the mid-19th century and faxed signatures
since the 1980s.
In many
countries, including the United States, the European Union and Australia,
electronic signatures (when recognised under the law of each jurisdiction) have
the same legal consequences as the more traditional forms of executing of
documents.
Enforceability of electronic
signatures
In 1996
the United Nations published the UNCITRAL Model Law on Electronic Commerce.The
model law was highly influential in the development of electronic signature
laws around the world, including in the US.
The U.S.
Code defines an electronic signature for the purpose of US law as "an
electronic sound, symbol, or process, attached to or logically associated with
a contract or other record and executed or adopted by a person with the intent
to sign the record." It may be an electronic transmission of the document
which contains the signature, as in the case of facsimile transmissions, or it
may be encoded message, such as telegraphy using Morse code.
In the
United States, the definition of what qualifies as an electronic signature is
wide and is set out in the Uniform Electronic Transactions Act
("UETA") released by the National Conference of Commissioners on
Uniform State Laws (NCCUSL) in 1999. It was influenced by ABA committee white
papers and the uniform law promulgated by NCCUSL. Under UETA, the term means
"an electronic sound, symbol, or process, attached to or logically
associated with a record and executed or adopted by a person with the intent to
sign the record." This definition and many other core concepts of UETA are
echoed in the U.S. ESign Act of 2000.[10] 47 US states, the District of
Columbia, and the US Virgin Islands have enacted UETA. Only New York,
Washington State, and Illinois have not enacted UETA, but each of those states
has adopted its own electronic signatures statute.
Canadian
law (PIPEDA) attempts to clarify the situation by first defining a generic
electronic signature as "a signature that consists of one or more letters,
characters, numbers or other symbols in digital form incorporated in, attached
to or associated with an electronic document", then defining a secure
electronic signature as an electronic signature with specific properties.
PIPEDA's secure electronic signature regulations refine the definition as being
a digital signature applied and verified in a specific manner.
In the
European Union, the EU Directive on Electronic Signatures or the EU Electronic
Signatures Directive was published in the EC Official Journal, as Directive
1999/93/EC of the European Parliament and of the Council of 13 December 1999 on
a Community framework for electronic signatures (OJ No L 13 p. 12 19/1/2000).
In
India
The Information Technology Act 2000
(also known as ITA-2000, or the IT Act) is an Act of the Indian Parliament (No
21 of 2000) notified on October 17, 2000. This act is being opposed by Save
Your Voice campaign and other civil society organizations in India.
Provisions
Information technology Act 2000
consisted of 94 sections segregated into 13 chapters. Four schedules form part
of the Act. In the 2008 version of the Act, there are 124 sections (excluding 5
sections that have been omitted from the earlier version) and 14 chapters.
Schedule I and II have been replaced. Schedules III and IV are deleted.
Information Technology Act 2000
addressed the following issues:
Legal Recognition of Electronic Documents
Legal Recognition of Digital Signatures
Offenses and Contraventions
Justice Dispensation Systems for Cybercrimes
Declaration
of Helsinki 2000 amendment and financial disclosure Law
A. Introduction
1. The World Medical Association has
developed the Declaration of Helsinki as a statement of ethical principles to provide
guidance to physicians and other participants in medical research involving
human subjects. Medical research involving human subjects includes research on
identifiable human material or identifiable data.
2. It is the duty of the physician
to promote and safeguard the health of the people. The physician’s knowledge
and conscience are dedicated to the fulfillment of this duty.
3. The Declaration of Geneva of the
World Medical Association binds the physician with the words, ‘‘The health of
my patient will be my first consideration,’’ and the International Code of
Medical Ethics declares that, ‘‘A physician shall act only in the patient’s
interest when
providing medical care which might
have the effect of weakening the physical and mental condition of the
patient.’’
4. Medical progress is based on
research which ultimately must rest in part on experimentation involving human subjects.
5. In medical research on human
subjects, considerations related to the well-being of the human subject should
take precedence over the interests of science and society.
6. The primary purpose of medical
research involving human subjects is to improve prophylactic, diagnostic and therapeutic
procedures and the understanding of the aetiology and pathogenesis of disease. Even
the best prove prophylactic, diagnostic, and therapeutic methods must continuously
be challenged through research for their effectiveness, efficiency,
accessibility and quality.
7. In current medical practice and
in medical research, most prophylactic, diagnostic and therapeutic procedures involve
risks and burdens.
8. Medical research is subject to
ethical standards that promote respect for all human beings and protect their health
and rights. Some research populations are vulnerable and need special
protection. The particular needs of the economically and medically
disadvantaged must be recognized. Special attention is also required for those
who cannot give or refuse consent for themselves, for those who may be subject
to giving consent under duress, for those who will not benefit personally from
the research and for those for whom the research is combined with care.
9. Research Investigators should be
aware of the ethical, legal and regulatory requirements for research on human subjects
in their own countries as well as applicable international requirements. No
national ethical, legal or regulatory requirement should be allowed to reduce
or eliminate any of the protections for human subjects set forth in this
Declaration.
B. Basic principles for all medical research
10. It is the duty of the physician
in medical research to protect the life, health, privacy, and dignity of the
human subject.
11. Medical research involving human
subjects must conform to generally accepted scientific principles, be based on
a thorough knowledge of the scientific literature, other relevant sources of
information, and on adequate laboratory and, where appropriate, animal
experimentation.
12. Appropriate caution must be
exercised in the conduct of research which may affect the environment, and the welfare
of animals used for research must be respected.
13. The design and performance of
each experimental procedure involving human subjects should be clearly formulated
in an experimental protocol. This protocol should be submitted for
consideration, comment, guidance, and where appropriate, approval to a
specially appointed
ethical review committee, which must
be independent of the investigator, the sponsor or any other kind of undue influence.
This independent committee should be in conformity with the laws and
regulations of the country in which the research experiment is performed. The committee
has the right to monitor ongoing trials. The researcher has the obligation to
provide monitoring information to the committee, especially any serious adverse
events. The researcher should also submit to the committee, for review, information
regarding funding, sponsors, institutional affiliations, other potential
conflicts of interest and incentives for subjects.
14. The research protocol should
always contain a statement of the ethical considerations involved and should indicate
that there is compliance with the principles enunciated in this Declaration.
15. Medical research involving human
subjects should be conducted only by scientifically qualified persons and under
the supervision of a clinically competent medical person. The responsibility
for the human subject must always rest with a medically qualified person and
never rest on the subject of the research, even though the subject has given consent.
16. Every medical research project
involving human subjects should be preceded by careful assessment of predictable
risks and burdens in comparison with foreseeable benefits to the subject or to
others. This does not preclude the participation of healthy volunteers in
medical research. The design of all studies should be publicly available.
17. Physicians should abstain from
engaging in research projects involving human subjects unless they are confident
that the risks involved have been adequately assessed and can be satisfactorily
managed. Physicians should cease any investigation if the risks are found to outweigh
the potential benefits or if there is conclusive proof of positive and beneficial
results.
18. Medical research involving human
subjects should only be conducted if the importance of the objective outweighs the
inherent risks and burdens to the subject. This is especially important when
the human subjects are healthy volunteers.
19. Medical research is only
justified if there is a reasonable likelihood that the populations in which the
research is carried out stand to benefit from the results of the research.
20. The subjects must be volunteers
and informed participants in the research project.
21. The right of research subjects
to safeguard their integrity must always be respected. Every precaution should be
taken to respect the privacy of the subject, the confidentiality of the
patient’s information and to minimize the impact of the study on the subject’s
physical and mental integrity and on the personality of the subject.
22. In any research on human beings,
each potential subject must be adequately informed of the aims, methods,
sources of funding, any possible conflicts of interest, institutional affiliations
of the researcher, the anticipated benefits and potential risks of the study
and the discomfort it may entail. The subject should be informed of the right
to abstain from participation in the study or to withdraw consent to participate
at any time without reprisal. After ensuring that the subject has understood
the information, the physician should then obtain the subject’s freely-given
informed consent, preferably in writing. If the consent cannot be obtained in
writing, the non-written consent must be formally documented and witnessed.
23. When obtaining informed consent
for the research project the physician should be particularly cautious if the subject
is in a dependent relationship with the physician or may consent under duress.
In that case the informed consent should be obtained by a well-informed
physician who is not engaged in the investigation and who is completely independent
of this relationship.
24. For a research subject who is
legally incompetent, physically or mentally incapable of giving consent or is a
legally incompetent minor, the investigator must obtain informed consent from
the legally authorized representative in accordance with applicable law. These
groups should not be included in research unless the research is necessary to promote
the health of the population represented and this research cannot instead be
performed on legally competent persons.
25. When a subject deemed legally
incompetent, such as a minor child, is able to give assent to decisions about participation
in research, the investigator must obtain that assent in addition to the
consent of the legally authorized representative.
26. Research on individuals from
whom it is not possible to obtain consent, including proxy or advance consent,
should be done only if the physical/mental condition that prevents obtaining
informed consent is a necessary characteristic of the research population. The
specific reasons for involving research subjects with a condition that renders
them unable to give informed consent should be stated in the experimental protocol
for consideration and approval of the review committee. The protocol should
state that consent to remain in the research should be obtained as soon as
possible from the individual or a legally authorized surrogate.
27. Both authors and publishers have
ethical obligations. In publication of the results of research, the
investigators are obliged to preserve the accuracy of the results. Negative as well
as positive results should be published or otherwise publicly available. Sources
of funding, institutional affiliations and any possible conflicts of interest
should be declared in the publication. Reports of experimentation not in accordance
with the principles laid down in this Declaration should not be accepted for
publication.
C. Additional principles for medical research combined with
medical care
28. The physician may combine
medical research with medical care, only to the extent that the research is
justified by its potential prophylactic, diagnostic or therapeutic value. When
medical research is combined with medical care, additional standards apply to
protect the patients who are research subjects.
29. The benefits, risks, burdens and
effectiveness of a new method should be tested against those of the best
current prophylactic, diagnostic, and therapeutic methods. This does not
exclude the use of placebo, or no treatment, in studies where no proven
prophylactic, diagnostic or therapeutic method exists.
30. At the conclusion of the study,
every patient entered into the study should be assured of access to the best
proven prophylactic, diagnostic and therapeutic methods identified by the
study.
31. The physician should fully
inform the patient which aspects of the care are related to the research. The
refusal of a patient to participate in a study must never interfere with the patient–physician
relationship.
32. In the treatment of a patient,
where proven prophylactic, diagnostic and therapeutic methods do not exist or have
been ineffective, the physician, with informed consent from the patient, must
be free to use unproven or new prophylactic, diagnostic and therapeutic
measures, if in the physician’s judgement it offers hope of saving life,
reestablishing health or alleviating suffering. Where possible, these measures
should be made the object of research, designed to evaluate their safety and
efficacy. In all cases, new information should be recorded and, where
appropriate, published. The other relevant guidelines of this Declaration should
be followed.
(ref: http://www.who.int/bulletin/archives/79%284%29373.pdf)
Guidelines
and codes of practice; Regulation
of drug preparation and packaging
Introduction
FDA ensures the quality of drug
products by carefully monitoring drug manufacturers' compliance with its
Current Good Manufacturing Practice (CGMP) regulations. The CGMP regulations for drugs contain
minimum requirements for the methods, facilities, and controls used in
manufacturing, processing, and packing of a drug product. The regulations make sure that a product is
safe for use, and that it has the ingredients and strength it claims to have.
The approval process for new drug
and generic drug marketing applications includes a review of the manufacturer's
compliance with the CGMP. FDA inspectors
determine whether the firm has the necessary facilities, equipment, and skills
to manufacture the new drug for which it has applied for approval. Decisions regarding compliance with CGMP
regulations are based upon inspection of the facilities, sample analyses, and
compliance history of the firm. This information is summarized in reports which
represent several years of history of the firms.
FDA can issue a warning letter or
initiate other regulatory actions against a company that fails to comply with
Current Good Manufacturing Practice regulations. Failure to comply can also lead to a decision
by FDA not to approve an application to market a drug.
This web page provides links to
resources to help drug manufacturers comply with the Current Good Manufacturing
Practice regulations.
Federal Regulations
Code of Federal Regulations (CFR). The final regulations published in the
Federal Register (daily published record of proposed rules, final rules,
meeting notices, etc.) are collected in the CFR. The CFR is divided into 50 titles which
represent broad areas subject to Federal regulations. The FDA's portion of the CFR interprets the
Federal Food, Drug and Cosmetic Act and related statutes. Section 21 of the CFR contains most
regulations pertaining to food and drugs.
The regulations document the actions of drug sponsors that are required
under Federal law.
21 Code of Federal Regulations Part 210.
Current Good Manufacturing Practice in Manufacturing Processing,
packing, or Holding of Drugs.
21 Code of Federal Regulations Part 211.
Current Good Manufacturing Practice for Finished Pharmaceuticals.
Federal Register Notices for Proposed Changes and Final Changes to
CGMP. The Office of Compliance, Division
of Manufacturing and Product Quality web page provides links to in-process
changes in CGMP regulations announced in the Federal Register.
Guidance Documents
Guidance documents represent the
Agency's current thinking on a particular subject. These documents are prepared
for FDA review staff and drug sponsors to provide guidelines for the
processing, content, and evaluation of applications, and for the design,
production, manufacturing, and testing of regulated products. They also provide consistency in the Agency's
regulation, inspection and enforcement procedures. Because guidances are not regulations or
laws, they are not enforceable. An alternative
approach may be used if it satisfies the requirements of the applicable
statute, regulations, or both.
Guideline on the Preparation of Investigational New Drug Products (Human
and Animal) (PDF - 795KB) (Issued
11/1992, Posted 3/2/1998). This guidance
provides practices and procedures for preparing investigational new drug
products that comply with certain section of the Current Good Manufacturing
Practice (CGMP) regulations for finished pharmaceuticals (Title 21 of the Code
of Federal Regulations, Parts 210 and 211.)
Guidance for Industry: Investigating Out-of-Specification (OOS) Test
Results for Pharmaceutical Production (PDF - 98KB). 10/2006 This guidance provides the Agency’s current thinking
on how to evaluate suspect, or out of specification (OOS) test results. For
purposes of this document, the term OOS results includes all suspect results
that fall outside the specifications or acceptance criteria established in new
drug applications.
CDER Manual of Policies and
Procedures (MaPPs)
MaPPs are approved instructions for
internal practices and procedures followed by CDER staff to help standardize
the new drug review process and other activities. MaPPs define external activities as well. All MaPPs are available for the public to review
to get a better understanding of office policies, definitions, staff
responsibilities and procedures.
4723.1 Standing Operating
Procedures for NDA/ANDA Field Alert Reports (PDF - 15KB). (Issued 10/30/1998, posted 11/02/1998). This MaPP establishes a system for evaluating
new drug application (NDA) and abbreviated new drug application (ANDA) Field
Alert Reports and provides instructions to the responsible CDER units for
handling those reports.
Compliance Policy Programs and Guidelines
Compliance References. This web
site from the Office of Regulatory Affairs provides links to compliance policy
guides, regulatory procedures manuals, and other compliance related
information. Chapter 4 of the Compliance
Policy Guide covers human drugs.
Compliance Program Guidance Manual.
These programs and instructions are for FDA field inspectors.
Consistent Application of Current Good Manufacturing Practice
Determinations. FDA cannot approve
applications to market new drugs from companies who have been cited for Current
Good Manufacturing Practice violations.
Similarly, disapproval of any drug marketing application based upon CGMP
deficiencies must also lead to regulatory and/or administrative action against
other products produced under the same conditions.
(Ref : http://www.fda.gov/drugs/developmentapprovalprocess/manufacturing/ucm090016.htm)
EMEA
The European
Medicines Agency (EMA) is a European
Union agency for the evaluation of medicinal
products. From 1995 to 2004, the European Medicines Agency was known
as European Agency for the
Evaluation of Medicinal Products.
Roughly
parallel to the U.S. Food and Drug Administration (FDA), but
without FDA-style centralisation, the European Medicines Agency
was set up in 1995 with funding from the European
Union and the pharmaceutical industry, as well as indirect subsidy
from member states, in an attempt to harmonise (but not replace) the work of
existing national medicine regulatory bodies. The hope was that this plan would
not only reduce the €350 million annual cost drug companies incurred by having
to win separate approvals from each member state but also that it would
eliminate the protectionist tendencies of states
unwilling to approve new drugs that might compete with those already produced
by domestic drug companies. The EU is currently the source of about one-third
of the new drugs brought onto the world market each year.
Based in
London, the EMA was born after more than seven years of negotiations among EU
governments and replaced the Committee for Proprietary Medicinal Products and
the Committee for Veterinary Medicinal Products, though both of these were
reborn as the core scientific advisory committees.
The European Medicines Agency
operates as a decentralised scientific agency (as opposed to a regulatory
authority) of the European Union and its main responsibility is the protection
and promotion of public and animal health, through the evaluation and
supervision of medicines for human and veterinary use. More specifically, it
coordinates the evaluation and monitoring of centrally authorised products and
national referrals, developing technical guidance and providing scientific
advice to sponsors. Its scope of operations is medicinal products for human and
veterinary use including biologics and advanced therapies, and herbal medicinal
products.
The agency is composed of the
Secretariat (ca. 600 staff), a management board, six scientific committees
(human, veterinary and herbal medicinal products, orphan drugs, paediatrics and
advanced therapies) and a number of scientific working parties. The Secretariat
is organised into five units: Directorate, Human Medicines Development and
Evaluation, Patient Health Protection, Veterinary Medicines and Product Data
Management, Information and Communications Technology and Administration. The
Management Board provides administrative oversight to the Agency: including
approval of budgets and plans, and selection of Executive Director.
The Board includes one
representative of each of the 27 Member States, two representatives of the
European Commission, two representatives of the European Parliament, two
representatives of patients’ organisations, one representative of doctors’
organisations and one representative of veterinarians’ organisations. The
Agency decentralises its scientific assessment of medicines by working through
a network of about 4500 experts throughout the EU. The EMA draws on resources
of over 40 National Competent Authorities (NCAs) of EU Member states.
MRECs
MREC was established on 2002. The
objective of MREC secretariat is to provide independence guidance. Advice and
decision on health research/specific protocol involving human subjects
conducted by staff of MOH or involving MOH facilities. MREC Secretariat is
acting as an independent ethics committee for non- MOH institutions. MREC
Secretariat is composed of scientist and non-scientist and constituted and
operated under director general Of Health Malaysia Authority.
Research involving human subjects
requires prior ethics review and approval by the MOH Research and Ethics
Committee (MREC)
- A human subject (in the context of research) is “a
living individual about whom an investigator obtains either data through
intervention (eg. Clinical trial) or interaction (eg. Questionnaire in
health survey) with the individual, or identifiable private information”
- Submission to MREC for ethics review and approval is
conducted online at www.nmrr.gov.my
Submission
Form & Procedure
It is the responsibility of the investigator to apply to MREC for
approval to conduct research involving human subjects if the research is
conducted in Ministry of Health Malaysia facilities or institutions.
No research can commence until the investigator has written and dated
approval from the MREC.
All investigators must register their research online in the NMRR
(National Medical Research Register, www.nmrr.gov.my) to open an account and
obtain a password to access the NMRR.
Study documents, any corrections and amendments, are to be submitted
online in the NMRR. Please access the NMRR for instructions on how to submit
such documents.
The NMRR will automatically generate a notification of receipt of study
documents to the investigator.
Review
Procedure
- MREC Secretary will schedule complete application for
MREC meeting. Study documents will be circulated online to MREC members
before scheduled meeting.
- MREC members will conduct online review and submit
recommendations and comments to NMRR before schedule meeting.
- MREC members at meeting shall review and discuss all
members’ recommendations and comments. Investigator will be invited to
present study at scheduled meeting and will be queried if there are
issues.
- MREC members present at meeting will decide on study
and decision will be communicated to investigator: Decision may be:
- study is approved / rejected
or revision required.
- changes to study documents
are needed. Corrected documents must be submitted by investigator.
- MREC Chairperson will decide whether corrected
documents need to be reviewed at MREC meeting or by selected MREC members.
If meeting is required, steps 1 to 4 above are repeated.
- If corrected documents are reviewed by selected MREC
members, the corrected documents are circulated online to those members.
Members will conduct online review and submit their recommendations and
comments.
- Based on the recommendations and comments of the MREC
members, the MREC Chairperson will decide on the study and decision will
be communicated to investigator as in step 4 above.
Expediated
Review
- A study qualifies for expedited review if it satisfies
the following criteria:
- Modification or amendment of approved protocol:
- administrative revisions such
as correction of typographical errors.
- addition or deletion of
non-procedural items such as addition of study personnel names,
laboratories, etc.
- research activity with
minimal risk.
- minor changes to approved
research activities that do not increase risk to subjects.
- Protocols involving interviews of a non-confidential
nature not likely to be detrimental to the status or interests of
subjects, and not likely to offend the sensibilities and sensitivities of
subjects.
- Those that involve collection of small volumes of blood
samples (less than 20 mls) at any one time and not too often (not more
than 3 times foe whole duration of study, and not more than twice a week)
by venipuncture, finger prick, heel prick, etc.
- Those that involve collection of biological samples by
non-invasive means (e.g. collection of body fluids or excreta, collection
of hair or nail clippings).
- Collection of data through non-invasive procedures (not
involving general anesthesia or sedation) routinely used in clinical
practice and using medical devices approved by national regulatory
authorities.
- Research involving data, documents or specimens that
have already been collected or will be collected for ongoing medical
treatment or investigation.
- Continuing review of research previously approved with
no modification to original protocol and studies that have taken place,
and no identifiable additional risk to subjects.
- The MREC Secretary will review all submissions and if a
study satisfies the above criteria, the MREC Chairperson will be notified.
The Secretary will select 2 scientific and 1 non-scientific MREC members
to review the study.
- Study documents will be circulated online to selected
MREC members who will review the documents and submit their
recommendations and comments online.
- The MREC Chairperson will examine the recommendations
and comments of the reviewers, and decide on the study. If the Chairperson
is unable to decide or if recommended by the reviewers, the study will be
scheduled for a MREC meeting. The decision will be communicated to the
investigator.
- A study may be consider for waiver of informed consent
if it satisfies the following criteria:
- The study design involves no
more than minimal risk.
- Medical records and
biological specimens taken in the course of clinical care may be used
for research without consent of the patients/subjects only if the
research poses minimal risk, that the rights or interests of the
patients will not be violated, that their privacy and confidentiality or
anonymity are assured, and that the research is designed to answer an
important question and will be impractical if the requirement of
informed consent is to be imposed. Refusal or reluctance of individuals
to agree to participate is not evidence of impracticability sufficient
to warrant waiving informed consent.
- Study involves the collection
or use of existing data, documents, records, pathological specimens, or
diagnostics if these sources are publicly available or if the
information is recorded by the investigator in such a manner that
subjects cannot be identified, directly or through identifiers linked to
the subjects.
- Study design to investigate,
evaluate or examine public service programmes.
- On receipt of an application for waiver of informed
consent, the MREC Secretary will select 2 scientific and 1 non-scientific
MREC members to conduct a preliminary review.
- Study documents will be circulated online to selected
MREC members who will review the documents and submit their
recommendations and comments online.
- The MREC Chairperson will examine the recommendations
and comments of the reviewers and decide on the study. If the Chairperson
is unable to decide or if recommended by the reviewers, the study will be
scheduled for a MREC meeting. The decision will be communicated to the
investigator.
MREC
Requirements
- All blood samples must be stated in mls and
teaspoons/tablespoons per visit and for the whole study.
- Assent is required for studies involving subjects aged
7 to less than 18 years. (Ref: Malaysian Guidelines for Research Involving
Minors)
- Patient information sheet should state whether
investigational product contains porcine, bovine or other animal products.
- MREC decision and approval is final for all local
studies if the subjects are patients from Ministry of Health Malaysia
hospitals or facilities. Any subsequent changes to the protocol, patient
information sheet, informed consent form, and other supporting documents,
as instructed by other ethic committees, will result in the MREC’s
approval becoming null and void.
(ref : http://www.nih.gov.my/mrec/index.php/menuer-subpro)
Ethics
committees – history structure regulation impact of ICH GCP
1.27
Independent Ethics Committee (IEC)
An
independent body (a review board or a committee, institutional, regional,
national, or supranational), constituted of medical professionals and
non-medical members, whose responsibility it is to ensure the protection of the
rights, safety and well-being of human subjects involved in a trial and to
provide public assurance of that protection, by, among other things, reviewing
and approving / providing favourable
opinion on, the trial protocol,
the suitability of the investigator(s), facilities, and the methods and
material to be used in obtaining and documenting informed consent of the trial
subjects.
The
legal status, composition, function, operations and regulatory requirements
pertaining to Independent Ethics Committees may differ among countries, but
should allow the Independent Ethics Committee to act in agreement with GCP as
described in this guideline.
2.6
A
trial should be conducted in compliance with the protocol that has received
prior institutional review board (IRB)/independent ethics committee (IEC)
approval/favourable
1.42
Opinion (in relation to Independent Ethics Committee)
The
judgement and/or the advice provided by an Independent Ethics Committee (IEC).
3. INSTITUTIONAL REVIEW
BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
3.1
Responsibilities
3.1.1
An IRB/IEC should safeguard the rights, safety, and well-being of all trial
subjects. Special attention should be paid to trials that may include
vulnerable subjects.
3.1.2 The IRB/IEC should obtain the following
documents:
trial
protocol(s)/amendment(s), written informed consent form(s) and consent form
updates that the investigator proposes for use in the trial, subject
recruitment procedures (e.g. advertisements), written information to be
provided to subjects, Investigator's Brochure (IB), available safety
information, information about payments and compensation available to subjects,
the investigator’s current curriculum vitae and/or other documentation
evidencing qualifications, and any other documents that the IRB/IEC may need to
fulfil its responsibilities.
The
IRB/IEC should review a proposed clinical trial within a reasonable time and
document its views in writing, clearly identifying the trial, the documents
reviewed and the dates for the following:
- approval/favourable opinion;
- modifications required prior to
its approval/favourable opinion;
- disapproval / negative opinion;
and
- termination/suspension of any
prior approval/favourable opinion.
3.1.3 The IRB/IEC should consider the qualifications
of the investigator for the proposed trial, as documented by a current
curriculum vitae and/or by any other relevant documentation the IRB/IEC
requests.
3.1.4 The IRB/IEC should conduct continuing review
of each ongoing trial at intervals appropriate to the degree of risk to human
subjects, but at least once per year.
3.1.5 The IRB/IEC may request more information than
is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of
the IRB/IEC, the additional information would add meaningfully to the
protection of the rights, safety and/or well-being of the subjects.
3.1.6 When a non-therapeutic trial is to be carried
out with the consent of the subject’s legally acceptable representative (see
4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or
other document(s) adequately addresses relevant ethical concerns and meets
applicable regulatory requirements for such trials.
3.1.7 Where the protocol indicates that prior
consent of the trial subject or the subject’s legally acceptable representative
is not possible (see 4.8.15), the IRB/IEC should determine that the proposed
protocol and/or other document(s) adequately addresses relevant ethical
concerns and meets applicable regulatory requirements for such trials (i.e. in
emergency situations).
3.1.8 The IRB/IEC should review both the amount and
method of payment to subjects to assure that neither presents problems of
coercion or undue influence on the trial subjects. Payments to a subject should
be prorated and not wholly contingent on completion of the trial by the
subject.
3.1.9
The IRB/IEC should ensure that information regarding payment to subjects,
including the methods, amounts, and schedule of payment to trial subjects, is
set forth in the written informed consent form and any other written
information to be provided to subjects. The way payment will be prorated should
be specified.
3.2
Composition, Functions and Operations
3.2.1 The IRB/IEC should consist of a reasonable
number of members, who collectively have the qualifications and experience to
review and evaluate the science, medical aspects, and ethics of the proposed
trial. It is recommended that the IRB/IEC should include:
(a) At least five members.
(b) At least one member whose
primary area of interest is in a nonscientific area.
(c) At least one member who is
independent of the institution/trial site.
Only
those IRB/IEC members who are independent of the investigator and the sponsor
of the trial should vote/provide opinion on a trial-related matter.
A
list of IRB/IEC members and their qualifications should be maintained.
3.2.2 The IRB/IEC should perform its functions
according to written operating procedures, should maintain written records of
its activities and minutes of its meetings, and should comply with GCP and with
the applicable regulatory requirement(s).
3.2.3 An IRB/IEC should make its decisions at announced
meetings at which at least a quorum, as stipulated in its written operating
procedures, is present.
3.2.4 Only members who participate in the IRB/IEC
review and discussion should vote/provide their opinion and/or advise.
3.2.5 The investigator may provide information on
any aspect of the trial, but should not participate in the deliberations of the
IRB/IEC or in the vote/opinion of the IRB/IEC.
3.2.6 An IRB/IEC may invite nonmembers with
expertise in special areas for assistance.
3.3
Procedures
The IRB/IEC should establish,
document in writing, and follow its procedures, which should include:
3.3.1 Determining its composition (names and
qualifications of the members) and the authority under which it is established.
3.3.2 Scheduling, notifying its members of, and
conducting its meetings.
3.3.3 Conducting initial and continuing review of
trials.
3.3.4 Determining the frequency of continuing
review, as appropriate.
3.3.5 Providing, according to the applicable
regulatory requirements, expedited review and approval/favourable opinion of
minor change(s) in ongoing trials that have the approval/favourable opinion of
the IRB/IEC.
3.3.6 Specifying that no subject should be admitted
to a trial before the IRB/IEC issues its written approval/favourable opinion of
the trial.
3.3.7
Specifying that no deviations from, or changes of, the protocol should be
initiated without prior written IRB/IEC approval/favourable opinion of an
appropriate amendment, except when necessary to eliminate immediate hazards to
the subjects or when the change(s) involves only logistical or
administrative aspects of the trial (e.g., change of
monitor(s), telephone number(s)) (see 4.5.2).
3.3.8 Specifying that the investigator should promptly
report to the IRB/IEC:
(a) Deviations from, or changes
of, the protocol to eliminate immediate hazards to the trial subjects (see
3.3.7, 4.5.2, 4.5.4).
(b) Changes increasing the risk
to subjects and/or affecting significantly the conduct of the trial (see
4.10.2).
(c) All adverse drug reactions
(ADRs) that are both serious and unexpected.
(d) New information that may
affect adversely the safety of the subjects or the conduct of the trial.
3.3.9 Ensuring that the IRB/IEC promptly notify in
writing the investigator/institution concerning:
(a) Its trial-related
decisions/opinions.
(b) The reasons for its
decisions/opinions.
(c)
Procedures for appeal of its decisions/opinions.
6.12
Ethics
Description of ethical considerations relating to the trial.
Recent
development with regard to the INDIA/ USA / EU Clinical Trial directive
INIDA
Studies involving non-CE marked medical devices carried out in the UK may be
regulated as clinical investigations under the Medical Devices Regulations 2002
and require approval from the UK Competent Authority.
Studies involving non-CE marked
medical devices carried out in the UK may be regulated as clinical
investigations under the Medical Devices Regulations 2002 and require approval
from the UK Competent Authority.
This page provides guidance on how
to notify the MHRA of proposed clinical investigations involving non-CE marked
medical devices. Please see the links at right-hand side of this page to
guidance documents contained on this website. Please note that investigations
of In Vitro Diagnostic Medical Devices are regulated as performance evaluations
and guidance on the requirements for these is included in our Guidance Note 18
which can be found on our registration
of medical devices page.
Prior to submitting a notification
to the Competent Authority, you are advised to ensure that you have the
information necessary to demonstrate compliance with all the relevant essential
requirements except for those that are the subject of the investigation. A
significant percentage of the grounds for objection that have been raised have
resulted from the failure to supply the necessary data within the 60 day time
period allowed by the Regulations. Details of the information required are
provided in the guidance documents to the right of this page. Please prepare
your notification to the MHRA online by using the Integrated
Research Application System (IRAS) (external link). IRAS
is a UK-wide system that streamlines the process for applying for permissions
and approvals to conduct health and social care research, including clinical
investigations of medical devices. It allows users to enter the information for
the relevant permissions and approvals once, instead of having to complete
several separate application forms for each review body. Filters are used to
ensure that data is collected and collated appropriately to the type of study
and the approvals and permissions required. IRAS captures the information
needed by the MHRA offering the facility for users to print out the completed
PCA1 and PCA2 forms and sterilization proforma for signing before making a
notification to the MHRA in the usual way.
Notifications will only be accepted
by the MHRA once the signed forms, necessary supporting documentation and the
appropriate fee have been received by the Agency.
Your notifications should be submitted in the following format:
- The documentation should be sent by recorded delivery.
- All information must be in English. If any part of the
supporting data consists of material in another language, this must be
translated. One copy of the original document in its original language
should accompany the application.
- One hardcopy of the full submission and eight
rewritable CD-ROMs are required.
- The hardcopy copy of the proposed clinical
investigation, must be presented and collated with all pages in their
correct numbered sequence, including reprints, diagrams, tables and other
data. The method of reproduction used must allow for legible presentation
of the text and any relevant drawings with their captions. All papers
should be provided in a folder or bound with dividers separating
individual documents.
- All documents must be arranged on the CDs as separate
attachments. Please include a document index on each CD and ensure that
all documents are named appropriately ie clinical investigation plan,
investigator’s brochure, patient information, patient consent, essential
requirements checklist, summary of pre-clinical data, sterilization
validation report, risk analysis, instructions for use etc.
- Please provide:
- Eight rewritable CD-ROMS,
each containing a full set of the supporting documentation
- One hardcopy of the full
set of supporting documentation
- The hardcopy and all CDs must
contain identical information
- When paying by bank transfer, please provide a copy of
the payment transaction receipt, otherwise include the cheque with the
submission.
(ref: http://www.mhra.gov.uk/Howweregulate/Devices/Clinicaltrials/)
USA
Clinical Trials
Adherence to the principles of good clinical practices (GCPs), including
adequate human subject protection (HSP) is universally recognized as a critical
requirement to the conduct of research involving human subjects. Many
countries have adopted GCP principles as laws and/or regulations. The
Food and Drug Administration’s (FDA’s) regulations for the conduct of clinical
trials, which have been in effect since the 1970s, address both GCP and
HSP. These FDA regulations and guidance documents are accessible from
this site. International GCP guidance documents on which FDA has
collaborated and that have been adopted as official FDA guidance are also be
found here. Finally, this site includes links to other sites relevant to
the conduct of clinical trials, both nationally and internationally.
Bioresearch Monitoring
FDA’s bioresearch monitoring (BIMO) program conducts on-site inspections of
both clinical and nonclinical studies performed to support research and
marketing applications/submissions to the agency. Links to the compliance
programs for each inspection type and contact information for each Center’s
BIMO program are also accessible from this site.
EU
Current status on EU legislation on
clinical trials:
The revision of the Clinical Trials Directive
Directive 2001/20/CE, adopted on the 4th
of April 2001 has entered its final phase. The Commission has finalised its new
proposal on the 17th of July 2012
(COM2012/312 FINAL) after years of legislative work. The legislative proposal
will now be discussed in the European Parliament and in the Council. It is
expected to come into effect in 2016.
What’s new in the
proposal:
Fostering
EU's attractiveness in clinical research:
Commission proposes to
revamp rules on trials with medicines
Boosting clinical research in Europe
by simplifying the rules for conducting clinical trials isnwhat today's
proposal from the Commission is about. Clinical trials are tests of medicines
in humans and give patients access to most innovative treatments. At the same
time, clinical research with over 20 billion Euros of investment per year in
the EU makes a significant contribution to the growth policy of the Europe 2020
agenda. Clinical trials are vital to develop medicines and to improve and
compare the use of already authorised medicines. The data generated in clinical
trials are used by researchers in publications, and by pharmaceutical companies
applying for marketing authorizations. Once implemented, the measures proposed
today will speed up and simplify the authorisation and reporting procedures,
while maintaining the highest standards of patient safety and robustness and
reliability of data. The measures will also better differentiate the
obligations according to the risk-profile of the trial, and improve
transparency including on trials done in third countries.
John Dalli, European Commissioner
for Health and Consumer Policy, said:
"the proposal significantly
facilitates the management of clinical trials, while maintaining the highest
standards of patient safety and the robustness and reliability of trial data.
800 million euros per year could be saved in regulatory costs and boost
research and development in the EU, thus contributing to economic growth."
The proposed Regulation, once
adopted, will replace the 'Clinical Trials Directive' of 2001. It has
ensured high level of patient safety, but its divergent transposition and
application led to an unfavourable regulatory framework for clinical research.
According to the European Commission, this has contributed to a to a decrease
of 25% of clinical trials conducted in the period between 2007 and 2011: in
2007, more than 5000 clinical trials were applied for in the EU while by 2011
the number had dropped to 3800.
The new legislation proposed by the
Commission will take the form of a Regulation. This will ensure that the rules
for conducting clinical trials are identical throughout the EU. In particular,
it will make it easier to conduct multinational clinical trials in Europe. Some
concrete proposals are:
• An authorisation procedure for
clinical trials which will allow for a fast and thorough assessment of the
application by all Member States concerned and which will ensure one single
assessment outcome.
• Simplified reporting procedures
which will spare researchers from submitting largely identical information
on the clinical trial separately to various bodies and Member States.
• More transparency on
whether recruitment for participating in a clinical trial is still ongoing, and
on the results of the clinical trial.
• The possibility for the Commission
to conduct controls in Member States and other countries to make sure the
rules are being properly supervised and enforced.
(ref : http://www.esicm.org/research/eu-directives)