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Patient recruitment in clinical trials
Every new drug needs to go through the critical phase of
clinical trials before it is launched in the market. In the first of a two-part
series, Katya Naidu takes a look at the issues affecting patient recruitment
for clinical trials.
 Like
the right soldiers make a strong army, right patients determine the success
of a clinical trial. Moreover, testing on humans is a sensitive and a difficult
issue as it involves many legal and ethical issues. Even though a drug is passed
to the human stage only after it successfully completes in-vitro testing and
animal testing, the side-effects of a new drug are always unknown, making patient
recruitment and monitoring a very complex activity.
Patients or volunteers are the backbone of any clinical study and make a very
valuable contribution to the testing of the efficacy of a drug. However, such
people are scarce in nature. "Clinical studies are becoming larger, longer
and more complex. Today, more patients are required for clinical trials on new
drugs than ever before, like, over 5,300 patients and new drug applications,"
says Dr Suhasini Sharma, Chief Operating Officer, ICRI Research (P) Ltd (IRL).
She adds, "Patient recruitment consumes almost one third of the time and
drug development budget." It is also the most critical bottleneck in clinical
research. Of all clinical trials conducted globally, more than 80 percent are
delayed due to slow patient recruitment. This delay may cost the pharmaceutical
companies millions of dollars per day in terms of lost sales. Speeding up patient
recruitment in clinical trials can result in lower drug development costs, and
ultimately, new drugs that are more affordable to patients.
The subjects who are recruited depend on the stage
of a clinical trial. Like in Phase I trials, pharmacokinetic studies, bio-availability
and bio-equivalence studies are done which are performed on healthy human
volunteers. Whereas, trials from Phase II to Phase IV are done on patients,
where the efficacy of the drug on the disease is tested.
- In Phase I clinical trials, researchers test a new drug or
treatment for the first time in a small number of people (20-80), usually
normal, healthy volunteers, to evaluate its safety, determine a safe
dosage range, and identify side-effects
- In Phase II clinical trials, the drug or treatment is administered
to a larger group of people (100-300) to further assess its safety and
effectiveness
- In Phase III clinical trials, the drug or treatment is administered
to large groups of people (1,000-3,000) to further determine effectiveness,
monitor side-effects, compare it to commonly used treatments, and collect
information that will allow safe use of the drug or treatment
- The Phase IV clinical trials are performed after the drug
or treatment has been authorised for medical prescription and has been
marketed. These studies continue testing the drug or treatment to collect
information on the effect in various populations and any side-effects
associated to long-term use. Patients are randomly assigned to the group
receiving the new treatment (treatment group) or to the standard group
(control group) to ensure the trial's impartiality. Post-approval studies
further characterise the drug. For HIV drugs, which are approved on
the basis of surrogate markers (for example, CD4 counts, changes in
viral load), these studies are intended to document the drug's clinical
benefit. If the drug shows no clinical benefit, the sponsor is required
to voluntarily withdraw the drug from the market. Phase IV trials also
enable sponsors to evaluate the drug in populations that may not have
been well represented in the Phase III trials
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Stringent protocols
Mary Francis
CEO
Ace Biomed |
Not everyone, who is willing to participate in the study can
be considered for the study. There are certain norms that researchers have to
follow and tests that are to be done before including volunteers for a study.
Patients who take part in clinical trials must fulfill all inclusion criteria
as per the trial protocol.
Every study has a protocol, which should be fulfilled by the
patients. Some of the inclusion criteria are age, sex, BMI, the type and stage
of the disease. In addition, pathological investigation should be done on the
patient like haematological tests, sterology, biochemistry, urine analysis and
tests for abuse of drugs. "They have to be deemed healthy, for which these
criteria are taken into consideration. We conduct complete pathological investigation,
ECGs and X-rays, by which we come to know that a person is healthy to undertake
a drug trial," says Mary Francis, CEO of Ace Biomed.
The recruited subjects are not allowed to participate in any
other clinical trial for a period of three months.
Authoritatively speaking…
The recruitment of a patient also varies on the therapeutic condition of the
drug that is tested. "Patient selection for a therapeutic segment depends
upon what answers we are seeking from a particular study. In other words, objectives
of the study will determine design of study and complexity of issues to be answered.
Usually, a demographic homogeneity is attempted to reduce variables," says
Dr I S Gandhi, Medical Director, Vimta Labs.
One has to try and ensure that the trial population is as
close as possible to each other. To ensure this, the study population is controlled
to keep it as close as possible. There are authorities which have a say in the
determination of the type of patients recruited. When evaluating a drug, competent
authorities (medicine regulatory agencies such as DCGI, USFDA) seek to determine
that the drug has been tested in patients, who are similar in demographics to
the group who will be using the drug. These authorities also ensure that efficacy
and safety have been assessed. In addition, the authorities assess:
- Drug-demographic interactions to identify demographic
features that could alter the metabolism or distribution of the drug or be
associated with altered efficacy or adverse events
- Drug-disease interactions to identify disease features
that could alter the metabolism or distribution of the drug, or be associated
with more frequent or more severe adverse events.
| Animal testing and human testing are two important
phases in the research that goes into drug testing. Though human testing
is on the higher end of the value chain, there are certain disadvantages
that are encountered in human testing unlike in animals where the quality
of subjects can be absolutely controlled. In animal testing, the pedigree,
the strain, living conditions and the diet can be controlled to the point
of precision. This kind of flawlessness cannot be ensured from human subjects
though, making the recruitment of the right kind of subjects a difficult
proposition. Though the researcher cannot control the quality of patients
constantly, they can ensure similarity by recruiting them right. In addition
to the all the considerations, the researchers should consider the 'humane'
element in clinical trials as there they cannot be bred and terminated unlike
animal models. |
Patient education
Yet another important part of the patient recruitment is
educating the patient about the intricacies of the study. "We are soliciting
participation from willing persons, whether patients or healthy human volunteers,
to answer scientifically valid, socially acceptable and ethically appropriate
questions, which can lead to better alternatives or newer approaches for diagnosing,
treating and preventing diseases. This requires awareness, education, questioning
assessment and willing participation," says Gandhi.
Patient education will help ensure compliance on part of the patient. "When
the volunteers come for the test, we give them complete details like—what
is the drug that they are taking, its strength, the use of the drug and the
adverse events," agrees Francis.
A patient taking part in a clinical trial is required to follow instructions
given by the trial physician, in terms of taking treatment, any dietary or other
advice given, as per the trial protocol. "They must report all medical
issues to the research physician before taking any medicines (prescription or
over-the-counter) outside the trial drugs (unless the same have been prescribed
for a medical emergency)," says Sharma. Clinical trials and investigational
treatment trials are conducted to protect people safety. They are rigorously
designed so that they do not pose any unnecessary risk to the user and are of
consistent quality and quantity.
| GCP specifies strict guidelines that protect people,
who choose to participate in clinical trials. All clinical trials must be
approved and monitored by the Institutional Review Board (IRB) and the Ethics
Committee (EC) to make sure that the risks are as low as possible and are
worth any potential benefits.
The IRB and EC reviews the trial protocol and ensures
the scientific content of a clinical trial, its scientific importance,
the cogency of the hypothesis, appropriateness of the experiment plan,
statistical analysis, adequacy of participants and feasibility with regard
to the completion of the trial within a reasonable time-frame.
EC is an independent committee composed of physicians,
pharmacists, nurses, experts in bioethics, legal affairs, patients' rights
and other experts. EC ensures the ethical content of the trial and safeguards
the rights and safety of all trial participants. According to GCP, patients
must be fully aware that they have rights both before they give consent
to participate in a clinical research study and during treatment:
- Participating in a trial is a choice. Patients
can discuss it with their physician or anyone else to arrive at that
choice
- Patients must be fully informed about the trial and explained all
reasonable risks and obligations, and given adequate time to consider
all information
- Patients must give their voluntary, written informed consent for
participation in a clinical trial
- Throughout the trial, physicians and nurses must closely follow the
patient's response to the treatment and monitor his or her safety
- If researchers realise that the treatment may have negative effects,
the patient is immediately excluded from the trial
- Patients can discuss with physicians whether it is possible to receive
a different treatment
- Patients are entitled to leave the trial at any time
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Monitoring safety
The patients are regularly monitored for emergence of new signs and symptoms,
physical findings, and any adverse effects experienced by the patient. Patients
may be asked to record certain symptoms or observations in patient diaries.
X-ray, ECG, blood and urine tests and other, more sophisticated investigations
are conducted at regular intervals to monitor safety. The effect of the new
drug on quality of life and other important parameters may be monitored with
the help of standard, validated questionnaires. "Subject safety is a major
issue. All adverse events, whether in form of signs, symptoms or abnormal laboratory
values, should be monitored and their relationship should be assessed. Any unsuspected
serious adverse event should be immediately shared with competent authorities
and other investigators if involved in a multicentric study and appropriate
actions should be immediately taken to minimise risk," says Gandhi.
editorial@expresspharmaonline.com
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