Good Clinical Practice Journal

Below are the titles of articles published in the Good Clinical Practice Journal Volume 7 Issue 3 (June 2000).

Copies of back issues and individual articles are available direct from the publisher � please contact us for further information.

"Opinion"
by Anna Bingham

As discussed by Hanka Meutgeert, a new European Regulation for orphan medicinal products (OMPs) has come into effect in the last couple of weeks. In conjunction with other regulations and incentives such as the Food and Drug Administration's orphan drug approval procedure and the European Medicines Evaluation Agency's agreement to drop its review fees for OMP applications, the development of drugs for small patient populations has never been better. Although there are obvious benefits associated with this regulatory modification, potentially negative outcomes do exist. In the (dull) light of there being few International Conference on Harmonisation guidelines specific to life-threatening disease treatment development, early phase toxicology and safety guidelines and the Data and Safety Monitoring Board (DSMB) together form solid regulatory building blocks. However, it appears that interim analyses and the intervention of Ethics Committees are the most effective monitors of these trials on a local basis. To ensure that these, the most vulnerable of patients, are protected from exploitation, it is imperative that participants are appropriately informed before, during and after treatment, and that they are given the freedom to exercise their rights - without penalty. The development of new treatment modalities for life-threatening diseases and conditions where little, if any, treatment options exist, present similar ethical dilemmas. Drug development is poised between fundamental human needs, scientific progress and the protection of the individual from unnecessary risk. Communication channels are considered central to efficient and effective trial design and conduct; it is down to the individual investigators and sponsors alike to help ensure that the scientific gain to population exposure ratio runs at an optimum. Unnecessary exposure of patients to "drug failures" is the main underlying concern linking this issue's articles.

Given the levels and complexity of regulatory bureaucracy, the question arises as to how is it that some products reach Phase III or even IV before it is identified that the trial drug is either unsafe or lacks sufficient efficacy. GlaxoWellcome, for example, did not abandon gavestine , its glycine antagonist, until Phase III, after it failed to show a benefit over placebo in acute ischaemic strokes. GlaxoWellcome is not alone in its failure to accurately predict the therapeutic potential and physiological activity of therapeutic chemical entities in a timely manner. Contraindication studies for approved drugs may prevent patients from receiving the "best treatment" option(s). Britannia's lung surfactant, pumacant, for example, also proceeded to Phase III prior to termination - causing much distress to the patients and parents involved. Not to mention the recent media explosion regarding the baby ventilator trial that continued for 4 years before a "no-go" agreement was reached, amid serious parental accusations following a high number of deaths. Yes of course the story was hyped-up by the press, but the public's response was real and impassioned and demonstrates the importance (and failings) of the informed consent process, despite detailed guideline specifications. The use of resources in terms of finance and exposure of subjects in late phase studies must be efficient and justifiable. Pulling the plug on a trial is the last straw and ideally should never happen - but it does for a number of reasons. Premature trial termination is one of the most tangible options when dealing with drug failure and can be enforced either on a site-specific level by an investigator or by regulatory powers (ie, the DSMB) on a more extensive level. Implemented correctly in response to predetermined endpoints and objectives, premature termination of studies can be a positive learning experience from which many can benefit. In their article, Ann Marinus and Denis Lacombe discuss the networking role of the European Organisation for Research and Treatment of Cancer (EORTC), which was set up specifically to combat inefficiencies in the conduct and execution of cancer trials within Europe. However, unlike cancer trials, for which recruitment periods can spill over into years, the proportion of patients to trials for rare conditions are such that patients perceive that they are in competition with one another to "win" the opportunity to be first in line for new therapies. However, patient groups are desperate to be enrolled on to trials because they provide new hope and, hence, this increases concern over exploitation. Indeed, they are easily persuaded onto trials and so the patient information and informed consent procedures must be closely monitored. Meutgeert discusses the value of patient organisations and refers to them as "central to two-way communication between researchers and patients". She also mentions the positive effect that researcher-patient interaction can have on both parties. In view of the motivational side effect of such interactions perhaps the anonominisation of patients encouraged by traditional guidelines should be updated to incorporate changes in patient attitudes, thereby bringing them in line with the associated trend towards increasing patient involvement in treatment decisions. Perhaps introducing patient opportunities to communicate directly with sponsors will help to ensure that they remain fully informed and may provide the sponsor with an insight into the reality of living with the condition and through treatment. In addition to enhancing the patient's control over his or her illness, this information may help provide better treatment programmes and motivate research staff by retaining the focus on the real endpoint - people! In terms of introducing immediate improvements in current practice, we should review protocols to ensure that prospective sequential or interim analyses are built in to secure the achievement of accurate trial outcomes, thus, avoiding broad population exposure to toxic or ineffective medications. In their, Genevieve Decoster and Debra Barker debate this issue in their discussion on the rationale for discontinuing a trial. Supported by Nigel Crossland's article, they stress the importance of site exit meetings, but identify the real end of a clinical trial as being the point at which the full trial results are published and accessible within the public domain - regardless of the outcome. In their opinion, the publication of negative clinical results is important to help eliminate the unnecessary repetition of negative outcomes and, hence, the waste of resources. Even if the publication of negative results achieves little else, the trial participants deserve access to the overall results to which they contributed. Please do not hesitate to respond to any of the point(s) discussed and/or comment on the "new look" of the Journal. It is important that we continue to receive feed back because your opinion matters.

"Improving the effectiveness of audits"
by Nigel Crossland

Abstract
To facilitate compliance with Good Clinical Practice (GCP), audits should be regarded as opportunities for future improvement of clinical research programmes. Audits should be planned and their results considered as part of a proactive quality assurance programme. These programmes should incorporate a system that can provide learning and training in GCP so that everyone can learn from each individual audit.

"Exploring the multi-facets of ending a clinical trial"
by Genevieve Decoster and Debra Barker

Abstract
ICH GCP site close-down guidelines and prospective provision for early termination are essential elements of well designed and conducted studies. Regardless of the outcome, all trial data represent a positive contribution to disease treatment and knowledge and, hence, publication is the true endpoint of clinical trials.

"Cancer clinical trials in Europe: issues and challenges, the academic point of view of the EORTC"
by Ann Marinus and Denis Lacombe

Abstract
Data management for cancer clinical trials differs from other medical studies in the time over which clinical trials in oncology are spread. All Phase III trials are run over several years and trials have a lifetime follow-up. Keeping pace with the most recent up-to-date regulations in an ongoing trial is a major challenge.

"The importance of sharing information in clinical trials for rare disorders"
by Hanka Meutgeert

Abstract
There are thousands of patients waiting for researchers to find an effective treatment for their particular disease. In most cases the patients do not suffer from the diseases that most modern medicines target. For diseases with no known effective treatment options, patients will give anything to be enrolled in new trials. They perceive trials to be their only opportunity to change something about their situation and the natural course of their disease.

These issues require good communication skills on the part of both the doctors and scientists involved in conducting clinical trials.