Clinical trial management
Encyclopedia
A clinical trial
is the application of the scientific method
to human health. Since such trials require the use of human test subjects and can severely impact the well-being of the subjects, as well as treatments of other people and large amounts of capital for those performing the trial, the proper management of clinical trials is crucial.
s has become the most delay-ridden aspect of the drug discovery and development
process. When implemented effectively, clinical trial
recruitment (CTR) initiatives can be highly successful. Time lines can be dramatically reduced and recruitment targets can be met ahead of schedule; every day saved in the progression to marketing authorization can equate to millions of pounds made in patent-protected sales revenue.
However, great care is needed in the development of a CTR program. Considerable ethical scrutiny is applied to all patient recruitment materials and initiatives. For example, in 2002 the European Commission issued guidelines for consultation which require patient advertising
and details of recruitment initiatives to be submitted to appropriate ethics committees. Unfortunately, there is no simple code of established practice, no unified regulatory body and no recourse to appeal. If an ethics committee doesn't like what a CRO has planned, the CRO can't use it. In Europe, this aspect has yet to be effectively addressed.
Enhancing CTR is obviously an area in which great caution is required. Some investigating doctors, for example, question the need for extra activities as, they claim, there are sufficient numbers of suitable patients among those already attending their clinics. However, practical experience has shown that this is an over-estimation of the number of patients that physicians will be able to recruit and it is estimated that only about 10% of a physician’s patients will actually wish to enroll in a clinical trial.
Perhaps more importantly, there are also objections raised from within the industry. These usually centre on a highly cautious approach to the ethics and legitimacy of patient-facing initiatives. Some nervousness is understandable given the strict controls that govern DTC marketing but for clinical research there is a critical need for increased patient understanding and education. The signs are that the caution of the industry is slowly giving way to a new openness and confidence.
A review of recent press coverage also highlights a deep skepticism of industry involvement in clinical research. If not approached ethically, a firm’s CTR campaign can leave them wide open to aggressive media
criticism and adverse advocacy relationships. The key point to remember is that the objective of all this work is ultimately to improve care for the patient. A strenuous effort to maintain this focus throughout clinical development will ultimately allow pharma companies to reap considerable rewards.
Over the past several years these problems have been addressed in the US, where clinical research receives more and more active support of government bodies, advocacy groups, charities and patient groups. This provides a collaborative environment and ensures that there is always an independent counterpoint when the integrity of industry-sponsored studies is attacked.
The American public sees a vast amount of government-sponsored education, designed to maximize understanding of clinical trials. A quick look at Cancer.gov and ClinicalTrials.gov, both run by the National Institutes of Health
, illustrates just how much work is being done. This in turn is supported by private efforts such as Centerwatch.com, which currently offers a 300-page book on informed consent
for patients.
Additionally, patient groups and organizations have formed new initiatives to increase education about and participation in clinical trials for specific diseases. For example, people with Parkinson's disease
can use PDtrials
to find up-to-date information on Parkinson’s trials currently enrolling participants in the U.S. and Canada and search for specific Parkinson’s trials using criteria such as location, trial type, and symptom. Other disease-specific services exist for recruiting patients with other conditions as well.
A recently announced US public-private partnership
, designed to improve trial recruitment, demonstrates how support for industry research can be broadened. The initiative created a $6 million fund, which the contributing pharma companies and National Cancer Institute will use to accelerate patient recruitment for Phase I and II cancer studies. Naturally, the credibility of the public bodies involved enhances the effectiveness of the scheme.
(ECG) changes to qualify for randomization
. A quick pilot study would have alerted the sponsors before committing to major cost.
The basic risks that are associated with clinical Trial are:
Technology is playing an increasingly important role in reducing risks while also driving down costs.
. Across the EU
, as well as in Australia
, Canada
, and USA, ethics committees' practices may vary enormously so that, when planning a multinational study, good local knowledge is crucial. Even inside the borders of the same country or state there is often inconsistency, especially since the demise of single central approval for multicenter studies. Theoretically, local research ethics committees (IRBs) are expected to follow Department of Health guidelines, but, if they choose not to do so, there is apparently no redress, so one may be presented with unexpected delays in particular centers because of widely varying IRBs' practices. There is a move toward rationalization in the form of a two-level approval process. A central committee will review the study and, if approved, pass it on to local committees for ratification
. Within the U.S., the Institutional Review Board
(IRB) has clearly defined responsibilities and reporting lines. In Australia, central approval is still possible, and the ethics committee sees itself more as a partner in research than as a regulator; a very rapid start-up of studies is possible.
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
is the application of the scientific method
Scientific method
Scientific method refers to a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge. To be termed scientific, a method of inquiry must be based on gathering empirical and measurable evidence subject to specific principles of...
to human health. Since such trials require the use of human test subjects and can severely impact the well-being of the subjects, as well as treatments of other people and large amounts of capital for those performing the trial, the proper management of clinical trials is crucial.
Recruitment
Over the last ten years, getting patients and doctors into clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s has become the most delay-ridden aspect of the drug discovery and development
New product development
In business and engineering, new product development is the term used to describe the complete process of bringing a new product to market. A product is a set of benefits offered for exchange and can be tangible or intangible...
process. When implemented effectively, clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
recruitment (CTR) initiatives can be highly successful. Time lines can be dramatically reduced and recruitment targets can be met ahead of schedule; every day saved in the progression to marketing authorization can equate to millions of pounds made in patent-protected sales revenue.
However, great care is needed in the development of a CTR program. Considerable ethical scrutiny is applied to all patient recruitment materials and initiatives. For example, in 2002 the European Commission issued guidelines for consultation which require patient advertising
Advertising
Advertising is a form of communication used to persuade an audience to take some action with respect to products, ideas, or services. Most commonly, the desired result is to drive consumer behavior with respect to a commercial offering, although political and ideological advertising is also common...
and details of recruitment initiatives to be submitted to appropriate ethics committees. Unfortunately, there is no simple code of established practice, no unified regulatory body and no recourse to appeal. If an ethics committee doesn't like what a CRO has planned, the CRO can't use it. In Europe, this aspect has yet to be effectively addressed.
Enhancing CTR is obviously an area in which great caution is required. Some investigating doctors, for example, question the need for extra activities as, they claim, there are sufficient numbers of suitable patients among those already attending their clinics. However, practical experience has shown that this is an over-estimation of the number of patients that physicians will be able to recruit and it is estimated that only about 10% of a physician’s patients will actually wish to enroll in a clinical trial.
Perhaps more importantly, there are also objections raised from within the industry. These usually centre on a highly cautious approach to the ethics and legitimacy of patient-facing initiatives. Some nervousness is understandable given the strict controls that govern DTC marketing but for clinical research there is a critical need for increased patient understanding and education. The signs are that the caution of the industry is slowly giving way to a new openness and confidence.
A review of recent press coverage also highlights a deep skepticism of industry involvement in clinical research. If not approached ethically, a firm’s CTR campaign can leave them wide open to aggressive media
Mass media
Mass media refers collectively to all media technologies which are intended to reach a large audience via mass communication. Broadcast media transmit their information electronically and comprise of television, film and radio, movies, CDs, DVDs and some other gadgets like cameras or video consoles...
criticism and adverse advocacy relationships. The key point to remember is that the objective of all this work is ultimately to improve care for the patient. A strenuous effort to maintain this focus throughout clinical development will ultimately allow pharma companies to reap considerable rewards.
Over the past several years these problems have been addressed in the US, where clinical research receives more and more active support of government bodies, advocacy groups, charities and patient groups. This provides a collaborative environment and ensures that there is always an independent counterpoint when the integrity of industry-sponsored studies is attacked.
The American public sees a vast amount of government-sponsored education, designed to maximize understanding of clinical trials. A quick look at Cancer.gov and ClinicalTrials.gov, both run by the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
, illustrates just how much work is being done. This in turn is supported by private efforts such as Centerwatch.com, which currently offers a 300-page book on informed consent
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...
for patients.
Additionally, patient groups and organizations have formed new initiatives to increase education about and participation in clinical trials for specific diseases. For example, people with Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
can use PDtrials
PDtrials
PDtrials is an initiative to increase education and awareness about Parkinson's disease clinical research. The initiative is led by the Parkinson's Disease Foundation, and involves a collaboration between a number of Parkinson's organizations in the U.S...
to find up-to-date information on Parkinson’s trials currently enrolling participants in the U.S. and Canada and search for specific Parkinson’s trials using criteria such as location, trial type, and symptom. Other disease-specific services exist for recruiting patients with other conditions as well.
Public-private partnership
The nature of American healthcare provision no doubt motivates patients to seek free or subsidized medication, but the investment, approach and partnerships in the US are demystifying clinical trials and generating considerable goodwill toward industry-driven research.A recently announced US public-private partnership
Public-private partnership
Public–private partnership describes a government service or private business venture which is funded and operated through a partnership of government and one or more private sector companies...
, designed to improve trial recruitment, demonstrates how support for industry research can be broadened. The initiative created a $6 million fund, which the contributing pharma companies and National Cancer Institute will use to accelerate patient recruitment for Phase I and II cancer studies. Naturally, the credibility of the public bodies involved enhances the effectiveness of the scheme.
Study designs and methods
A common pitfall is insufficiently rigorous evaluation of study designs and methods. A "straw poll" during a clinical project management training course revealed that virtually all clinical protocols have at least one amendment during the study. The reasons appear to cover the full range, from reliance on well-established designs without allowing newer, more creative ideas to be considered and, at the other extreme, not testing new methods for the current application. For example, in a recent angina study, treadmill exercise testing was used as the primary efficacy criterion. This is, of course, extremely well validated methodology, but, in this case, the patients were elderly, so the exercise protocol was substantially modified to reduce the physical demand. The problem was that with such a mild exercise protocol, less than half the patients recruited showed sufficient electrocardiogramElectrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
(ECG) changes to qualify for randomization
Randomization
Randomization is the process of making something random; this means:* Generating a random permutation of a sequence .* Selecting a random sample of a population ....
. A quick pilot study would have alerted the sponsors before committing to major cost.
Risk management
All research and development must involve some risk. Some of the risks are typically encountered in the main stages of a typical clinical trial.The basic risks that are associated with clinical Trial are:
- Enrollment of the subject at the sites within the projected time line
- Failure of the molecule e.g. efficacy ,
- Safety of the subjects e.g. number of SAEs reported to the enrolled subjects(Since DSMB analyse the trial data different time intervals during the study and if they find any risk associated to the patients safety at any time the trial may be terminated.
- Helping subject and sites comply with the complex demands of the clinical protocol.
- Reducing subject early withdrawal and lost to follow up
Technology is playing an increasingly important role in reducing risks while also driving down costs.
Risk distribution
Delivering the results on time, to the required standard, may have a lower risk in phase I than in later phases, mainly because subjects are healthy and not potentially complicated patients, and thus, recruitment can be predicted with some confidence. However, first administration to humans is something of a leap into the unknown, and safety problems are always to be considered. What is possibly less obvious is the risk of any early-phase design errors to later phases and to the whole drug project. Once phase III is imminent, perhaps there is a degree of confidence emerging, as much more is known about the drug. The requirement for phase III, therefore, may be seen as accumulating data to enable a product license application. In fact, the great expansion of activity dictated by phase III studies introduces even more complexity and a new set of risks. The application of the drug to a more realistic clinical setting means that we will not necessarily by studying "clean" patients. Patients will often have other diseases on top of that under study and will only be under observation for a small proportion of the time. Attention to clinical protocol design, thus, is at least as critical as in phases I-II.Key tasks and external agencies
The most common reason for late tasks and projects is that they are started late. Before patients can be screened for entry, a well-established set of start-up tasks must be completed, and of these, some are relatively easy to plan, and others are less predictable. Those relying on internal agreements (e.g., drug supplies, protocol sign-off), can be expedited by instilling the right culture of negotiation between departments and individuals. But what of the external elements, particularly regulatory and ethics approvals? The former is, fortunately, reasonably easy to plan, because, in most countries, there are clear limits to the time and effort required to meet regulatory requirements. Much more difficult is the matter of approval of ethical standardsEthics
Ethics, also known as moral philosophy, is a branch of philosophy that addresses questions about morality—that is, concepts such as good and evil, right and wrong, virtue and vice, justice and crime, etc.Major branches of ethics include:...
. Across the EU
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
, as well as in Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
, Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
, and USA, ethics committees' practices may vary enormously so that, when planning a multinational study, good local knowledge is crucial. Even inside the borders of the same country or state there is often inconsistency, especially since the demise of single central approval for multicenter studies
Ratification
Ratification is a principal's approval of an act of its agent where the agent lacked authority to legally bind the principal. The term applies to private contract law, international treaties, and constitutionals in federations such as the United States and Canada.- Private law :In contract law, the...
. Within the U.S., the Institutional Review Board
Institutional review board
An institutional review board , also known as an independent ethics committee or ethical review board , is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the...
(IRB) has clearly defined responsibilities and reporting lines. In Australia, central approval is still possible, and the ethics committee sees itself more as a partner in research than as a regulator; a very rapid start-up of studies is possible.
See also
- Contract research organizationContract research organizationA contract research organization, also called a clinical research organization, is a service organization that provides support to the pharmaceutical and biotechnology industries in the form of outsourced pharmaceutical research services...
- Clinical trials management systems
- Clinical data management systemClinical data management systemA clinical data management system or CDMS is a tool used in clinical research to manage the data of a clinical trial. The clinical trial data gathered at the investigator site in the case report form are stored in the CDMS...
- Data clarification formData clarification formA Data Clarification Form or Data Query Form is a questionnaire specifically used in clinical research. The DCF is the primary data clarification tool from the trial sponsor or Contract Research Organization towards the investigator to clarify discrepancies and ask the investigator for...
- Clinical trialClinical trialClinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
- Good clinical practiceGood clinical practiceGood Clinical Practice is an international quality standard that is provided by International Conference on Harmonisation , an international body that defines standards, which governments can transpose into regulations for clinical trials involving human subjects.Good Clinical Practice guidelines...