Good Clinical Practice Journal
Good Clinical Practice Journal |
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Below are the titles of articles published in the Good Clinical Practice Journal Volume 6 Issue 3 (May/June 1999).
Copies of back issues and individual articles are available direct from the publisher � please contact us for further information.
"GCP and Computer Validation"
by Dr Michael Hamrell
Abstract
The increasing use of computers in clinical research has required clinical researchers to increase their
awareness of GCP requirements. The recent ICH GCP guideline as well as other guidance documents
issued by the FDA address some of the important issues for computer systems. These include the principles
of computer validation, electronic records and signatures, and understanding security issues and concerns
regarding this technology.
"A standard procedure for patient information sheet and informed consent"
Abstract
The place of written informed consent is pivotal to the approval, initiation and completion of a clinical trial.
For some time the informed consent process has been widely identified as a major cause of delays in
commencing a clinical trial. One key obstacle has been the failure of sponsors/investigators to communicate
to ethics committees, that trial information and consent procedures will be adequately presented to patients.
A working group chaired by Alison Palmer has recently released a standardised documentation that should
provide assistance to sponsors, ethics committees and patients.
"FDA GCP - a practical approach"
by Dr Galen Neher
Abstract
The Federal Agency of the US Food and Drug Administration (FDA) established US GCP over a number of years in response
to inspection findings that cast doubt on the validity of some clinical trials. Because they were instituted over time,
the US GCP regulations (FDA GCP) are not a single document, being located in various sections of Chapter 21 of the Code
of Federal Regulations. Despite the fact that ICH GCP is now the most accepted GCP standard throughout the world, and
has been published as a guideline in the Federal Register as an official FDA guideline, it is only a guideline and so
investigators, nurses, ethical review boards and monitors all need to have complied with FDA GCP regulations when the
inspector comes to call.
"Does anyone really like statistics?"
Fiona Jones interviews Patricia Jones, biostatician
Abstract
The biostatistician now enjoys a high profile within the pharmaceutical industry and is involved at every stage
of a clinical trial. Fiona Jones interviewed Patricia Collins, biostatistician with a leading CRO, and was
persuaded that statistical input, especially in the early phases, is vital in ensuring the accuracy and reliability
of the trial results.
"Globally harmonised research needs established research ethics"
by Dr Rachel Babbedge
Abstract
Nobody has come up smelling of roses in the Fiddes fraud affair. Cavalierly corrupt Californian doctor
Robert Fiddes rose to fame last week an article published in the New York Times revealed how he had,
over the course of 8 years, fabricated patient records, deceived patients and received millions of dollars
from his pharmaceutical company sponsors for whom he in return provided contaminated data for 91 of
their clinical development plans.1 Fiddes, who is now serving a fifteen year jail sentence, founded the
Southern California Research Institute in 1987 and, up until his arrest, worked for almost every major
pharmaceutical company in the business. At the time of his arrest, Fiddes had done work for 42 companies
using 91 different protocols.
The antihero Fiddes took on the might of regulators, trial monitors and expert ethics panels and showed them wanting. When one reads the full account in the NY Times, the scale and destructiveness of the fraud is breath-taking. Subsequent articles ricocheting in last week's US press provided an illuminating picture of exasperatingly inattentive monitoring and torturously slow regulators. (Most who work in clinical trials in the States will sadly find the account quite easy to believe.) Interestingly, however, none of the reports has yet commented on the vital role of the ethics committee in the whole of the clinical trial process.
According to ICH GCP, the Institutional Ethics Committee (known as Independent Review Board (IRB) in the United States) is solely responsible for approving the choice of the principal investigator for each trial. In addition, under the guidelines, ethics committees have (arguably) the right to request information about payments to the investigator (Editor's own chosen interpretation of Section 3.1.2 , 3.1.3 and 3.3.8 where "any new information that may influence the patient should be brought to the knowledge of the ethics committee.) I choose to interpret the guidelines in this way because, to me, the logic of asking ethics committees to review payments to study subjects is flawed if there is no obligation on the part of investigators also to declare the amount of money they expect to receive for recruiting the subjects. If money is believed to be such a persuasive factor, driving vulnerable patients into making self destructive decisions, surely doctors can't themselves be entirely immune to its allure. Indeed, the trial investigator stands to make far more money out of a well-lubricated industrial drug study than any trial subject. Perhaps it would be a step forward to admit that not only patients but doctors are vulnerable to incentivisation and should be protected by ethics.
With an estimated 7,500 projects under development by pharmaceutical companies world-wide, the clinical trial arena is exploding. Ethics committees are being required to oversee hospitals that have moved from conducting the occasional clinical 3 - 4 patient trial, to being "medical juggernauts" conducting multiple studies that are held together precariously by hundreds of over-worked research co-ordinators. The committees have had to try to adapt very fast. How could they have prepared for these changes?
Ethics committees came out of the Declaration of Helsinki. Section 1.2 of the 1975 document states that "The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor, provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed."
This territory of the ethics committee has provided the framework for the description of their role under ICH GCP. With ICH GCP already set to provide a world-wide clinical research gold standard, it is time to ask the question, is the ethical "backbone" of ICH, the Declaration of Helsinki, going to be strong enough to support such globalisation?
In an attempt to answer this question, one might start by comparing the model of international discussion and consensus that led to the generation of the guidelines of ICH with that of the Helsinki. ICH started as a joint initiative between the regulatory agencies and the research-based industry in the European Union, Japan and USA. It has subsequently had close links with the WHO, which regulates clinical research performed in 184 developing countries. The ICH Secretariat who generate all documents as they reach different stages of consensus, is co-ordinated by the international industry association, the IFPMA. ICH's world-wide consultation has meant that its principles can be applied equally in countries as varying as Taiwan, France and Paraguay.
The Declaration of Helsinki, on the other hand, was constituted by the World Medical Association (WMA) in Geneva. By itself, the WMA is quite a small organisation which brings together representatives from individual national medical associations. The final wording was adopted at a meeting of the full Assembly in Helsinki in 1964. It has been amended several times over the last 35 years, in 1975 and 1989 and in 1996 in the Republic of South Africa (SA) (after the WMA had been relieved of its NGO status, having ventured into SA at the time when sanctions were being imposed). The amendment in 1996 was very minor, with the addition to section II, "where every patient should be (including control group), entitled to best proven diagnostic and therapeutic methods - this does not exclude placebo where no other treatment exists" being the only significant revision. Now in 1999, the Declaration is being revised again. This time amendments promise to be major. The first reports of what the WMA's working party on medical ethics has come up with have generated concern most notably amongst patient/consumer organisations. An amendment dealing with the issue of "best standard of care" has raised particular passion. When research is increasingly being performed in a large scale global fashion with investigators recruiting patients from sites all over the world, the issue of what constitutes the best standard of care available starts to get complicated. For example, if a trial is being performed using sites in Western Europe as well as Brazil, is the "best standard of care" to be given to control/test study populations the best standard of care available in Brazil or in Europe?
The panel who have been drafting the latest amendments met last year in Ottawa in Canada. Although representatives from many major wealthy countries attended the meeting, there was no-one from a Southern developing country present. The Declaration of Helsinki must have at its heart the aim of research to serve people rather than to use them. If the document is to serve as a standard to protect individuals from being used, then those working on the text will need to ensure that they include contributions from all nations, not just a few.
On an optimistic note, the final wording of the revised Declaration has not yet been adopted. Discussions about the likely impact of particular revisions are still ongoing and this itself is an important part of the ethical review process. As long as discussions continue then there may be a chance for some of the critical areas that remain poorly monitored in clinical research to be tackled in a reasonable patient-protecting way.
On a final note, I return to Robert Fiddes. According to Dr Frank Wells, on the Council of the British Medical Association, founder of the unique Medicolegal Investigations company which investigates suspected trial fraud, there will always be the one or two percent of individuals who will try to buck the system. "There are people" he says, "driven by greed and arrogance who simply do not believe that anyone would dare to report them." These individuals will exist no matter how we legislate. So there is a need for vigilance. As a result of globalisation of the research "gold standard" of ICH GCP, data generated in accordance with ICH will in the future be acceptable world-wide. Corrupt studies will not only influence the drugs marketed within contained national boundaries, they will impact a worldwide marketplace. The his-and-hers BMW cars and weekend Ferrari purchased by Robert Fiddes with money from false trials are a reminder that, if fraud is not spotted early enough, catastrophic consequences can follow at racing speed. The mantle has fallen upon ethics committees to protect the rights of human subjects, there must be an international gold standard to protect the rights of a globalised patient population.
References
* New York Times, Tuesday May 18th (Late Edition) Column 6 page 2