Regulations in clinical research
ICH-GCP
Clinical studies should be carried
out according to International Conference on Harmonisation (ICH) / WHO Good
Clinical Practice standards. This provides a unified standard for the European
Union (EU), Japan, and the United States, as well as those of Australia,
Canada, the Nordic countries and the World Health Organisation (WHO). Thus, any
country that adopts this guideline technically follows this same standard.
I have gathered some links which you
may find useful if you plan to do clinical research.
The International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH) is a unique project that brings together the regulatory
authorities of Europe, Japan and the United States and experts from the
pharmaceutical industry in the three regions to discuss scientific and
technical aspects of product registration.
The purpose is to make
recommendations on ways to achieve greater harmonisation in the interpretation
and application of technical guidelines and requirements for product
registration in order to reduce or obviate the need to duplicate the testing
carried out during the research and development of new medicines. The objective
of such harmonisation is a more economical use of human, animal and material
resources, and the elimination of unnecessary delay in the global development
and availability of new medicines whilst maintaining safeguards on quality,
safety and efficacy, and regulatory obligations to protect public health. This
Mission is embodied in the Terms of Reference of ICH.
The main task of the EMEA is to
·
Provide the Member States and the
Community institutions with the best possible scientific advice on questions
concerning quality, safety and efficacy of medicinal products for human and
veterinary use.
·
Establish a multinational scientific
expertise through the mobilisation of existing national resources in order to
achieve a single evaluation via a centralised or decentralised marketing
authorisation system.
·
Organise speedy, transparent and
efficient procedures for the authorisation, surveillance and, where
appropriate, withdrawal of products in the European Union.
·
Advise companies on the conduct of
pharmaceutical research.
·
Reinforce the supervision of
existing medicinal products in coordinating national pharmacovigilance and
inspection activities.
·
Create the necessary databases and
telecommunication facilities to promote a more rational drug use.
The mission of FDA's Center for Drug
Evaluation and Research is to assure that safe and effective drugs are
available to the American people. The information below provides an
understanding of how CDER works to accomplish this mission as it relates to new
drug development and review. See the
CDER Handbook.
·
New Drug Development Process- An
interactive chart that provides an overview of the new drug development
process, with an emphasis on preclinical research and clinical studies
conducted by the drug's sponsor.
·
Investigational New Drug (IND) Review
Process- An interactive chart that provides an overview of
CDER's investigational new drug application process, including how CDER
determines if the product is suitable for use in clinical trials.
·
New Drug Application (NDA) Review
Process- An interactive chart that provides an overview of
CDER's new drug application review process, including how CDER determines the
benefit:risk profile of a drug product prior to approval for marketing.
OHSR operates within the Office of
the Deputy Director for Intramural Research (DDIR), National Institutes of
Health (NIH). The NIH is part of the U.S. Public Health Service (PHS) which is,
in turn, an agency within the Department of Health and Human Services (DHHS).
The OHSR was established to help IRP investigators understand and comply with
the ethical guidelines and regulatory requirements for research involving human
subjects. OHSR's overall goal is to promote and support the IRP's efforts to
conduct innovative research which protects the rights and promotes the welfare
of human subjects. Have a look at the following sites.
·
Department of Health and Human
Services (DHHS) regulations for the protection
of human subjects, 45 CFR 46
of human subjects, 45 CFR 46
Standard
operating procedures for clinical investigators ( WHO GCP SOP)
This document sets out the
objectives of Standard Operating Procedures and defines the Investigators'
responsibilities when undertaking a clinical study supported by TDR. It provides
instructions for planning, performing, documenting and reporting clinical
studies, and also provides a useful glossary of terms.
(Ref: http://www.vadscorner.com/internet29.html)
The purpose of audits
An audit is the
examination of the financial report of an organisation - as presented in the
annual report - by someone independent of that organisation. The financial
report includes a balance sheet, an income statement, a statement of changes in
equity, a cash flow statement, and notes comprising a summary of significant
accounting policies and other explanatory notes.
The purpose of an
audit is to form a view on whether the information presented in the financial
report, taken as a whole, reflects the financial position of the organisation
at a given date, for example:
Are details of what is
owned and what the organisation owes properly recorded in the balance sheet?
Are profits or losses
properly assessed?
When examining the
financial report, auditors must follow auditing standards which are set by a
government body. Once auditors have completed their work, they write an audit
report, explaining what they have done and giving an opinion drawn from their
work. With some exceptions, all organisations subject to the Corporations Act
must have an audit each year. Other organisations may require or request an
audit depending on their structure and ownership or for a special purpose.
What don't auditors do?
Audit other
information provided to the members of the organisation, for example, the
directors' report.
Check every figure in
the financial report – audits are based on selective testing only.
Judge the
appropriateness of the organisation's business activities or strategies or
decisions made by the directors.
Look at every
transaction carried out by the organisation.
Test the adequacy of
all of the organisation's internal controls.
Comment to
shareholders on the quality of directors and management, the quality of
corporate governance or the quality of the organisation's risk management
procedures and controls.
What can't auditors do?
Predict the future –
The audit relates to a specific past accounting period. It does not judge what
may happen in the future, and so cannot provide assurance that the organisation
will continue in business indefinitely.
Be there all the time
– The audit is carried out during a defined timeframe, and auditors are not at
the organisation all the time. The prime purpose of the audit is to form an
opinion on the information in the financial report taken as a whole, and not to
identify all possible irregularities. This means that although auditors are on
the look-out for signs of potential material fraud, it is not possible to be
certain that frauds will be identified.
How is the audit conducted?
The organisation's
management prepares the financial report. It must be prepared in accordance
with legal requirements and financial reporting standards.
The organisation's
directors approve the financial report.
Auditors start their
examination by gaining an understanding of the organisation's activities, and
considering the economic and industry issues that might have affected the
business during the reporting period.
For each major
activity listed in the financial report, auditors identify and assess any risks
which could have a significant impact on the financial position or financial
performance, and also some of the measures (called internal controls) that the
organisation has put in place to mitigate those risks.
Based on the risks and
controls identified, auditors consider what management does has done to ensure
the financial report is accurate, and examine supporting evidence.
Auditors then make a
judgement as to whether the financial report taken as a whole presents a true
and fair view of the financial results and position of the organisation and its
cash flows, and is in compliance with financial reporting standards and, if
applicable, the Corporations Act.
Finally, auditors
prepare an audit report setting out their opinion, for the organisation's
shareholders or members.
What do auditors do, specifically?
Auditors discuss the
scope of the audit work with the organisation – the directors or management may
request that additional procedures be performed. Auditors maintain independence
from management and directors so that tests and judgments are made objectively.
Auditors determine the type and extent of the audit procedures they will
perform, depending on the risks and controls they have identified. The procedures
may include: asking a range of questions - from formal written questions, to
informal oral questions - of a range of individuals at the organisation
examining financial
and accounting records, other documents, and tangible items such as plant and
equipment making judgments on significant estimates or assumptions that
management made when they prepared the financial report obtaining written confirmations
of certain matters, for eg, asking a debtor to confirm the amount of their debt
with the organization testing some of the organisation's internal controls watching
certain processes or procedures being performed.
Clinical audit is a
process that has been defined as "a quality improvement process that seeks
to improve patient care and outcomes through systematic review of care against
explicit criteria and the implementation of change".
The key component of
clinical audit is that performance is reviewed (or audited) to ensure that what
should be done is being done, and if not it provides a framework to enable
improvements to be made. It had been formally incorporated in the healthcare
systems of a number of countries, for instance in 1993 into the United
Kingdom's National Health Service (NHS), and within the NHS there is a clinical
audit guidance group in the UK.
One of first ever
clinical audits was undertaken by Florence Nightingale during the Crimean War
of 1853-1855. On arrival at the medical barracks hospital in Scutari in 1854,
Nightingale was appalled by the unsanitary conditions and high mortality rates
among injured or ill soldiers. She and her team of 38 nurses applied strict
sanitary routines and standards of hygiene to the hospital and equipment; in
addition, Nightingale had a talent for mathematics and statistics, and she and
her staff kept meticulous records of the mortality rates among the hospital
patients. Following these changes the mortality rates fell from 40% to 2%, and
the results were instrumental in overcoming the resistance of the British
doctors and officers to Nightingale's procedures. Her methodical approach, as
well as the emphasis on uniformity and comparability of the results of health
care, is recognised as one of the earliest programs of outcomes management.
Another notable figure
who advocated clinical audit was Ernest Codman (1869–1940). Codman became known
as the first true medical auditor following his work in 1912 on monitoring
surgical outcomes. Codman's "end result idea" was to follow every
patient's case history after surgery to identify errors made by individual
surgeons' on specific patients. Although his work is often neglected in the
history of health care assessment, Codman's work anticipated contemporary
approaches to quality monitoring and assurance, establishing accountability,
and allocating and managing resources efficiently.
Whilst Codman's
'clinical' approach is in contrast with Nightingale's more 'epidemiological'
audits, these two methods serve to highlight the different methodologies that
can be used in the process of improvement to patient outcome.
Types of audits
- Standards-based
audit - A cycle which involves
defining standards, collecting data to measure current practice against
those standards, and implementing any changes deemed necessary.
- Adverse
occurrence screening and critical incident monitoring - This is often used to peer review cases which have
caused concern or from which there was an unexpected outcome. The
multidisciplinary team discusses individual anonymous cases to reflect
upon the way the team functioned and to learn for the future. In the
primary care setting, this is described as a 'significant event audit'.
- Peer
review - An assessment of the quality
of care provided by a clinical team with a view to improving clinical
care. Individual cases are discussed by peers to determine, with the
benefit of hindsight, whether the best care was given. This is similar to
the method described above, but might include 'interesting' or 'unusual'
cases rather than problematic ones. Unfortunately, recommendations made
from these reviews are often not pursued as there is no systematic method
to follow.
- Patient
surveys and focus groups
- These are methods used to obtain users' views about the quality of care
they have received. Surveys carried out for their own sake are often
meaningless, but when they are undertaken to collect data they can be
extremely productive.
Clinical
audit comes under the Clinical Governance umbrella and forms
part of the system for improving the standard of clinical practice.
Clinical Governance is a system through
which NHS organisations are accountable for
continuously improving the quality of services; it ensures that there are clean
lines of accountability within NHS trusts and
that there is a comprehensive programme of quality improvement systems. The six
pillars of clinical governance are:
·
Clinical Effectiveness
·
Research & Development
·
Openness
·
Risk Management
·
Education & Training
·
Clinical Audit
Clinical
audit was incorporated within Clinical Governance in the 1997 White Paper,
"The New
NHS : Modern, Dependable", which brought together
disparate service improvement processes and formally established them into a
coherent Clinical Governance framework.
Preparing for audits.
In the mid-1950s, the
National Cancer Institute (NCI; Bethesda, Maryland) began funding the
Cooperative Group Program. Throughout the next 25 years, there was no on-site
verification of protocol compliance and validation of the data submitted by
participating members of these cooperative groups. In contrast, the US Food and
Drug Administration (FDA; Washington, DC) required that pharmaceutical
companies perform on-site validation of the clinical trial data involving
testing of investigational new drugs. In 1979, it was discovered that
scientific fraud had occurred at one institution1 that was a prominent member
of a major NCI-funded cooperative group. As a result of that event, in 1981 the
NCI implemented a requirement that all entities funded by the NCI must have a
system in place for on-site auditing of clinical trial data and protocol
compliance. Verification of administrative requirements, such as oversight by
an institutional review board (IRB) and documentation of written informed
consent, was also implemented as part of this auditing process.
Over the subsequent 25
years, the process has been refined and supplemented with additional
requirements such as the auditing of consent form contents and the handling of
investigational drugs in institutional pharmacies. Audits by various entities
(the NCI, the FDA, pharmaceutical firms, etc) are a fact of life,2 and
fortunately, the process has rarely uncovered instances of scientific fraud.
The more important benefit of auditing is that the scrutiny applied by external
review of those involved in clinical investigation often results in better
compliance with trial requirements and greater accuracy in data collection, to
the benefit of all clinical research. Audits also serve as a hands-on
educational process for both physicians as well as clinical research associates
(CRAs), both when being audited and when invited to be the auditor at another
site in their cooperative group.
The announcement that an
audit will be conducted in the near future always creates dread and anxiety in
those persons to be visited, especially in those closest to the data collection
process—the CRAs. In this article, we provide some hints for audit preparation
and ways to avoid deficiencies. We draw on our experience with the Cancer and
Leukemia Group B (CALGB) audit process for our frequently asked questions.
Because all NCI-funded cooperative groups have similar audit programs, the
information can be generalized for any such audits, though there may be minor
variations depending on the cooperative group involved.
What areas will be audited?
A document that should
be part of the training of all new CRAs and all clinical investigators is the
Audit Guidelines of the NCI Clinical Trials Monitoring Branch.3 This document
provides the standards that all cooperative group auditors must follow. When an
audit is scheduled, a review of this document will help the site staff
understand what items will be reviewed and how deficiencies will be assessed
and graded. There are three main areas of review: (1) IRB oversight and consent
contents; (2) handling of investigational drugs, including a visit to the
pharmacy; and (3) patient case review. In the latter, there are six subcategories
of review: (1) consent form signing, dating, and filling in blanks; (2)
protocol eligibility; (3) protocol-directed treatment, including (when
applicable) compliance with radiation therapy and surgery technique; (4)
verification of treatment response (or lack thereof) and patient outcome; (5)
toxicity grading and recording; and (6) accuracy of data recording and
submission, and the fulfillment of special requirements (when applicable) such
as submission of blood or urine samples, quality-of-life questionnaires,
pathology specimens, etc.
Which patients and studies will be audited?
This varies with each
cooperative group, but the NCI requires review of at least several studies
involving investigational drugs, and studies representing a cross-section of
protocols on which the site has enrolled patients. In the CALGB, an effort is
also made to include at least one patient entered by each participating
physician at the site, and to include some studies involving complex treatments
(such as for acute leukemia) and combined-modality treatment.
Is there any source of information regarding
audit preparation?
Each cooperative group
maintains a set of policies regarding how audits are conducted, all in
accordance with the NCI Audit Guidelines. In the CALGB, there is discussion of
audit preparation at CRA workshops, and once yearly at the main group meeting,
an “Audit Preparation Workshop” is held. The slide presentations for this
workshop are also available to group members on the CALGB Web site. Other
groups have similar training sessions for both group members to be audited and
those who will be conducting an audit.
What physical facilities and staff should be
arranged?
Depending on the size
of the audit team, a room should be reserved that is large enough for the team
and the local staff. At a few CALGB audits, only a desk and chair in an office
have been set aside for a team of six people, which is obviously insufficient.
A CRA experienced with both the case report forms and the local medical records
should be immediately available to assist in finding items to be reviewed and
answering questions the auditors may have. Some cooperative groups do not want
any local staff on hand during an audit, but at CALGB audits, a local staff
person is required to stay with the audit team all day. A senior physician
should also make time available for the exit interview at the end of the audit.
What will be audited regarding the IRB?
All studies on the
Audit Patient List will have an assessment of compliance in submitting the
protocol to the IRB for initial review, annual renewals (by each 365-day interval
since the previous approval), review of all relevant
amendments/revisions/updates within the NCI-required 90 days after
implementation, and timely submission and review of all reportable local
serious adverse events and those broadcast by the relevant group or other
research entity (e.g., NCI, pharmaceutical firms). The CALGB auditors have
found that contemporaneous updating of such IRB documents with chronological
filing in specific loose-leaf binders allows one to be certain that all such
items are easy to locate (for both local staff and auditors) and that nothing
is missing.
Not only will the
studies listed on the Audit Patient List be reviewed for compliance with IRB
requirements, but in some groups (including CALGB), several unannounced closed
studies are also audited for continued fulfillment of IRB review requirements.
What will be audited regarding consent form
contents?
Review of the details
of a sample of the local consent forms is required by the NCI. A minimum of
three forms must be reviewed, but most sites have a sufficiently large patient
accrual so that twice this number are reviewed. Some groups require that the
signed consent form be submitted to the group headquarters for review during
patient registration. At that time, any deficiencies are identified for
correction. Other groups depend on the audit process to monitor compliance with
consent form contents. There are many requirements for consent form content
specified in Federal government documents, but the NCI requires two items to be
identical to the protocol-specific Model Consent Forms (approved by the NCI
staff and/or the central IRB before a new study can be activated); they are:
(1) all the risks listed in the Model Consent Form must be in the local consent
form; none can be omitted; (2) all the alternatives and associated explanations
in the Model Consent Form must be present. It is worthwhile to check all local
consent forms to be certain such items are not omitted.
One error that occurs
commonly is the failure to complete fill-in-the-blank items on a consent form.
If the local consent form has additional items such as patient initials on
every page, names and phone numbers, and yes/no responses for special items
such as blood sample collection, then they must be completed. It is a simple
task to be certain that these items are completed at the time a patient signs
the original consent form. No patient should be registered until local staff
members have verified that all such items have been completed.
What will be reviewed at the pharmacy or other
drug preparation site?
Since 1983, the NCI
has required that cooperative group audits include a review of the handling of
investigational drugs. The Audit Guidelines3 and the NCI Web site4 have
information regarding the requirements for such handling, as well as the “Dos
and Don'ts.” Others5 have also published guides on preparation for this aspect
of audits. The pharmacist should assemble all Drug Accountability Record Forms
(DARFs) relevant to the audit and all invoices for all incoming and return
shipments, and arrange them in chronological order for auditor review. Someone
familiar with the investigational drugs must be available on the day of the
audit and plan on meeting with the audit team. In-stock investigational drug
supplies should be checked to ensure that the containers are properly labeled
as to drug and study, and that the amount of remaining stock corresponds to the
figures on the DARF.
The CALGB Pharmacy
Committee has prepared a checklist (Table 1)that can be a useful guide for
pharmacists in making sure deficiencies are minimized prior to the actual
audit. One error seen repeatedly in audits is that excess drug supplies are
kept well after they are needed (i.e., the study has closed to new patient accrual
and no patients are being treated, or the drug has expired), and only a few
days prior to the audit, they are returned to the NCI. The pharmacy staff
should have a system in place whereby shelf stocks are assessed on a monthly or
quarterly basis, at which time the return of unused drug supplies is
accomplished.
How should the local records be prepared for
the patient case review?
The work of the
auditors is greatly facilitated if the important items regarding protocol
compliance and patient management have color-coded adhesive tabs applied for
ease of identification. For example, one color would indicate pre-enrollment
and eligibility items, another color would indicate each treatment cycle and
toxicity assessment, and still another color to represent the salient
radiographic reports regarding response, etc. Importantly, each tab must be
identified. In some audits, the local staff members have appended such
color-coded tabs, but nothing was identified. The local records thus have
multiple colored tabs, but without identification, it is still difficult for
the auditors to find particular items.
Some institutions now
have electronic medical records, and nothing on paper is available for review.
In such cases, it is worthwhile to print the most important items for review
(e.g., pathology reports, initial physician evaluations, operative reports).
The site staff should then have a computer screen available for each auditor or
team, with a local staff member sitting adjacent who is qualified to locate
items in the system as they are needed. The auditors could then, for example,
request the baseline set of blood test results, and they would be immediately
brought up on the screen. The same process can be used to review electronic
records of radiographs. Computed tomography scans are now recorded on disc and
not on film in most hospitals. In the CALGB, the auditors rarely review the
normal radiographic studies (e.g., a screening brain magnetic resonance imaging
study), but the auditors do want to review the serial scans done on a patient
whose assessable tumor is being evaluated for treatment response. Thus,
relevant films (or discs) should be made available in such instances. Again, if
electronic records are to be reviewed, a qualified local person must be
available to assist with the process.
(ref: http://jop.ascopubs.org/content/2/4/157.full)
Typical audit finding and How can they be avoided
Informed Consent
Process &Documentation
• Accurate and
Complete Study Records
• Determination and Documentation
that Eligibility
Criteria are Satisfied
• Adverse Event Review
and Reporting
• Drug /Devicet
Accountability
• Protocol Adherence
• Poor Regulatory
Regulatory Site Documentation
• Failure to Address
Monitor Findings
• Sponsor‐Investigator Trials
Informed Consent Process and
Documentation
• Incorrect consent
version
• No source
documentation of consent process and fact
That subject was
provided a copy of consent
• Consent not dated by
subject
• Check boxes left
blank; pages not initialed by subject
• No HIPAA Authorization
• Original consent missing
• Notre‐consented consented when required required
– Long lag time
between signed consent and start of
participation
Accurate and Complete Study Records
• Discrepancies between between CRFs and medical
records/source
documents
• Incomplete CRFs
• No documentation of
PI review of CRFs
• Improper Error
Correction
– NO WHITEOUT; NO PENCIL
Determination and Documentation
that Eligibility Criteria are Satisfied
• Eligibility check lists
incomplete
• No source
documentation confirming eligibility
criteria
• Failure to conduct
all tests needed to satisfy
eligibility criteria
• No documentation
documentation that PI has reviewed and
signed eligibility
checklist
• No documentation of sponsor
waiver of eligibility
requirement or waiver
by PI when protocol specifically states that
no waivers are allowed
Adverse Event Review and Reporting
• Conflict between CRFs
and source
documentation, e.g.,
AE noted in medical
record but not on CRF,
or vice versa
• AEs not signed/graded/attributed
in a timely
manner
• Failure to follow
reporting requirements
Drug/Device Accountability
• No documentation
that oral drug was
provided to subject
and/or returned by
subject with pill
count
• Poor documentation
regarding drug diaries
• Poor prescription
practices
Protocol Adherence
• Changes made in protocol
without first
obtaining IRB approval
for reasons other than
immediate patient safety
• No documentation of reason
for missed tests,
schedule changes, etc.