Part VII: Clinical Trial Design

INTRODUCTION

Historical Review

Age-related macular degeneration (AMD) is an important public health problem. Of the estimated 34.8 million people in the United States who were 65 years of age or older in 2002, approximately 1.6 million had some form of visual impairment. Approximately 600,000 of these will have experienced a rapid, devastating loss of vision due to choroidal neovascularization (CNV), “wet AMD,” whereas the remaining 1.0 million may experience a slow, progressive retinal atrophy and possibly a severe visual handicap “dry AMD” (1). Most may have difficulty performing routine visual tasks, such as driving, reading printed material, or recognizing the faces of their friends.

As the U.S. population continues to age, more and more persons will become visually impaired from AMD; more, in fact, than from any other eye disease. In AMD with CNV, some of the worst losses of vision can occur.

Because a large number of individuals have AMD complicated by CNV, effective treatment of even a fraction of all cases (2) can lead to significant savings to society and can decrease the number of people requiring social security and other disability payments (not to mention the effects on patients’ dignity and independence), with savings far outweighing the costs of clinical research, management, and treatment.

Treatments studied have included photodynamic therapy, submacular surgery, external beam radiation, medications such as interferon, thalidomide, corticosteroids, and anti-vascular endothelial growth factor drugs as well as various oral supplements that are believed to be preventative. At the present time a number of randomized clinical research trials are looking at these various therapies for macular degeneration. Basic scientists are working hand in hand with clinicians to find a cure for this blinding disease.

Clinical Relevance

Prior to the Macular Photocoagulation Study (MPS), there was no proven treatment for AMD with CNV. The use of low vision aids and mobility training were recommended but little could be done other than observe the natural history of AMD with CNV. The MPS, a randomized, multicenter trial, showed that laser photocoagulation of AMD with CNV prevented the most severe types of vision loss, compared to no treatment. The study was also important as a natural history study of macular degeneration (2). Since the 1980s this randomized controlled clinical trial has served as a benchmark for AMD research, with other treatments evaluated in the same way.

CLINICAL RESEARCH METHODOLOGY

The path a new idea takes from the patient’s problem to the basic research laboratory to the clinical research center and ultimately back to the treatment of the patient in the clinical setting is extensive and expensive. The final research question can be answered and practice guidelines established, but the cost in time, commitment, and dollars is great.

The pathway from the patient and back again to the patient starts when the ophthalmologist sees a patient with a disease that either has no cure or would benefit from an improved treatment. Caseseries studies, in which an investigator has noted some interesting or intriguing observation, frequently lead to the generation of a hypothesis that will subsequently be investigated. The ophthalmologist then teams up with the basic scientist to address the hypothesis. Together, they design appropriate laboratory experiments to address the hypothesis. Results from these basic science studies lead to preliminary clinical investigations of a possible new diagnostic technique, a treatment, a drug or even a drug delivery device. A small group of carefully selected patients participate in a pilot study to study the safety of these

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new treatments. In addition, for drug therapies, the dose levels that may be most effective are also studied. If successful, such a pilot study generates a single center clinical trial to further evaluate the tolerability, safety, and efficacy of the treatments.

Subsequently a full-scale, multicenter, randomized clinical research trial is initiated to recruit enough patients to test the safety and the efficacy of the new procedure, operation, test or drug or device. These new approaches are also tested for their effects on the quality of life of patients with the initial disease. The order of the research steps are outlined in Table 1.

The randomized clinical research trial is the gold standard, or reference, in medicine, as it provides the greatest justification for concluding causality and is subject to the least number of problems or biases. Clinical trials are the best type of study to use when the objective is to establish efficacy of a treatment or a procedure. Clinical trials in which patients are randomly assigned to different treatment arms are the strongest design of all.

These innovative approaches to clinical practice are then presented and taught to other ophthalmologists through continuing medical education courses, publications in peer review journals, and presentations at national and international scientific meetings. Finally, the new techniques, medications, or test materials are available to all patients under standard practice guidelines for diagnosis and treatment for disease.

Design of a Clinical Research Trial

The initial step in determining whether a research proposal would fulfill all the ethical and investigational guidelines necessary to protect human subjects involved in a clinical research trial, is to go through a formal decision making process. After all the data from previous observational, basic laboratory

Table 1 Development Phases of a Clinical Trial

Phase I Actions of drugs etc. in humans: looking at side effects of dose levels/safety issues: early evidence of efficacy: may include normal subjects as well as patients: all subjects get study product: 5–15 patients (pilot study): can be multi or single center

Phase II Evaluate efficacy/tolerability of drug etc. for a particular indication in patients with the disease under consideration looking at side effects and short-term risks: all study subjects get study product: can be multi or single center

Phase III Expanded trials after preliminary evidence suggests efficacy: additional evidence of overall risk/benefit: may be randomized against standard of care for this disease, observation or a placebo: results submitted for approval pre-marketing

Phase VI Post-marketing to delineate additional information about the risks and benefits and the optimal use of the product

(in vitro and animal studies) case report studies, Phase I, and Phase II studies have been analyzed, and a protocol is established under which the trial will be conducted. This protocol is developed outlining every detail of the research study so that all personnel—investigator, coordinator, photographer, vision specialist—every participant in the study, is aware of the protocol detail and is able to follow this protocol for the length of the trial, maintaining standardization of evaluation, testing, surgery, and all other procedures. The steps that are involved in the development of a protocol are as follows.

The Rationale

The ophthalmologist will team up with a basic science researcher or will work in his/her own laboratory to design a series of experiments that may address a specific disease entity for which there may be no adequate treatment. The results of these experiments, done again and again and replicated in other laboratories, may suggest an intervention or therapy that would be tested on some laboratory animal under the strict guidelines of a research laboratory. The results serve as the basis for a limited trial on a small group of carefully selected patients. If these patients react well to the therapy or tolerated the therapy with minimal side effects, clinical research proceeds to the next phase: a single or two to three center clinical study of the therapy in patients with a specific disease.

This is the initial stage of the clinical research trial. All the data from prior studies are then analyzed along with any new information, and the rationale for conducting this particular study is outlined. The objectives of the study, the safety and efficacy of the treatment, the design of the experimental plan, the number of enrolled subject required to prove the hypothesis and most importantly, whether the research study will benefit the population at large.

The Protocol

The protocol for the study will include:

Background

&The background of the disease to be studied and the results of all previous related research, both basic science and clinical.

&All information to support the justification of this research project and the impact it will have on the population in general and the population with this specific disease entity.

& The expected benefits to be obtained from the study.

&All the information about the study product, be it drug, device, surgery, delivery system, with all the

risks and adverse events noted during the prior uses of the product.

Objectives

&The primary objectives of the study could be: halt the progression of the disease.

&The secondary objectives could be: improve visual acuity by O than three lines.

Study Design

&Description of the study which will include:

&Type of study: randomized/open label/multidose

&Rationale answers why: Why that treatment? Why that dose? Why that duration?

&Outcome measures: primary measures; safety and tolerability, secondary measures; for example: the change in visual acuity/leakage

&Safety plan: unmasking/laboratory values/ detailed adverse event evaluations

&Compliance: good clinical practice/Food and Drug Administration (FDA) guidelines/ IRB guidelines.

Material and Methods

&Subject selection criteria with the inclusion and exclusion criteria with justification for both

&Justification for or against inclusion/exclusion of vulnerable subjects

&Treatment assignment: randomized/stratified

&Study treatment details: formulation/dose/storage

&Excluded therapies

&Study assessments: visual acuity/photography/ quality of life instruments/early exit criteria

&Discontinuation: subject/study

&Statistical methods: sample size/safety analysis/efficacy analysis

&Data quality assurance: DSMC/monitoring

Safety Assessment

&Adverse event reporting. Serious adverse events that require hospital/surgical intervention or result in death are immediately reported to the IRB and the sponsor

&All adverse events are followed until resolution or stability

&All subjects are contacted after study completion if adverse events have occurred

&Medical condition confounders

&Laboratory assessments

The Informed Consent

Before any research trial that includes human subjects can be instituted, an Institutional Review Board (IRB)

must approve all the components of the trial. The responsibility of an IRB is to establish the requirements and procedures for requests for the performance of human research, development, demonstration, or other activities involving patients or patient products, in addition to the usual scope of established and accepted methods. The IRB monitors approved research in accordance with the requirements the Office of Protection from Research Risks, the regulations of the FDA, National Institutes of Health and the Department of Health and Human Services. The IRB uses a group process to review research protocols and related material, e.g., informed consent documents and investigator brochures, to ensure the following:

&Risks to human subjects are minimized by using procedures that are consistent with sound research design and that do not unnecessarily expose subjects to risk. Whenever appropriate, such procedures already will have been performed on subjects for diagnostic or therapeutic purposes.

&Risks to subjects are reasonable in relation to the anticipated benefits (if any) to the subjects and the importance of the knowledge that may be expected from the result.

&The selection of the subjects is equitable, i.e., the study subjects are of both genders and from different racial/ethnic groups, and no age limitations exist other than those associated with a disease entity. This will decrease the risk of bias in patient selection.

&Informed consent will be sought from each prospective subject or the subject’s legally authorized representative and will be documented in accordance with and to the extent required by informed consent regulations. Provisions to prevent the suggestion of coercion are documented.

&Where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects either by using a Data Safety Monitoring Board that looks at the data to note any untoward adverse events or even unexpected improvement that may determine the study should end.

&Adequate provisions are in place to protect the privacy of the subjects and to maintain confidentiality of the data.

&Appropriate additional safeguards have been included in the study to protect the rights and the welfare of subjects who are members of a vulnerable group (e.g., children etc.).

The IRB has the authority to disapprove, modify, or approve studies based on consideration of human

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subject protection aspects. It also has the authority to suspend or terminate a study, to place restrictions on a study, and to require progress reports and oversee the conduct of the study and the study investigators.

The informed consent should be signed by the patient before entering into a clinical research trial. The informed consent will include the length of patient’s participation, the alternatives to this treatment modality, the risks involved in this trial, and a statement allowing the patients to withdraw from the trial at any time without consequence.

Data Collection

It is imperative that the collection of the research data, based on the design of the study, is accurate and complete. All research trials have case report forms on which data is recorded. These forms do not contain any patient identifying information other than a unique identifying code number and/or a combination of the patient’s initials. These forms are sent to the sponsor and, therefore, can only contain this unique identifying information. The types of data collected include:

&Results of laboratory testing

&Quality of life questionnaires

&Clinical evaluations

&Eligibility criteria

&Medications, medical history, surgical history

&Detailed ophthalmic history including prior treatment details of the disease entity

&Adverse events both serious and non-serious

&The study product

&Investigator signatures

All data have to be checked and corrected before they are sent to the sponsor and this is done by representatives of the sponsor. These monitors’ responsibilities include: to make sure the data are correct and legible; that the patients have met the enrollment criteria and received the correct treatment to which they were assigned. The clinical chart where the investigator notes the clinical examinations is known as the source document. The data on the case report forms are matched to the source documents. This cross check of data verifies accuracy.

All data and investigational study products are stored in a secured area with access to the area only by the study staff, investigator, and coordinator.

The principal investigator of the clinical research study is responsible for the conduct of the study, the accuracy of the data collection and the conduct of the study staff and the safety of the study subjects at all times.

Settings for Research Trials

Advancing medical knowledge—through screening, treatment, surgical, and pharmaceutical interven- tion—has prolonged the life of many people with disabling chronic disease conditions and increased the number of survivors of traumatic injury. At the present time, 13% of the population is over the age of 65; by the year 2040, this number will have grown to 23% of the population (3). By 2040, 70 million people will have some form of activity limitation, whether mental, physical, or visual, that will require intervention from the healthcare systems in some form. Research into the most effective care for persons with chronic disease, including eye disorders in particular, and efforts in prevention will be at the forefront of future clinical research. The projected cost of healthcare in the year 2040 is $906 billion, a huge percentage of the gross national product of the United States and the highest of the entire world’s developed countries (4).

With such huge expenditures anticipated for health care, and in response to continued pressure by government regulatory agencies to drive down costs, evaluation of cost in conducting research is suggested. Researchers must include cost research objectives, such as costs associated with screening programs, alternative treatments and procedures, use of new technology and implementation of new regulatory measures associated with programs and trials. The results obtained from including cost analysis in research help health care decision makers weigh the costs and consequences of competing treatment alternatives. Cost information provides additional data that can supplement clinical judgment when making therapeutic choices. Therefore, clinicians and researchers at major academic institutions need to focus on advancing the care and prevention of eye disease. Efforts should be based on rigorous clinical methods, i.e., randomized controlled clinical trials and analysis of economic and humanistic outcomes. With research of this nature, the results can be applied directly to the patient, where they will accomplish the greatest good. This is especially true when these outcomes may mean the difference between sight and blindness, and when they impact on the outcome measures of quality of life and ultimately, life expectancy.

Limitations of Randomized Clinical Trials

The cost of developing the necessary infrastructure to support the scientific and clinical activities involved in conducting major national and international clinical research makes it prohibitive except for large academic ophthalmology centers unless under the sponsorship of industry. There are obvious downsides to this type of sponsorship that is somewhat obviated by the

inclusion in the project of an independent clinical research organization.

Most major academic ophthalmology centers involved in clinical and basic science research are referral centers for patients with complicated disease who have not responded to standard therapy or who have a disease with no known cure. However, because of the nature of this population, i.e., those with severe disease as well as those with rare and complicated disease, the numbers of patients who would be eligible to enter a clinical research trial would be limited, making recruitment difficult. This places a potential for selection bias on these clinical research studies, such that when the studies are completed, they may not translate to the population in general.

On the other hand, a more common disease entity, such as macular degeneration, with its potential for marked vision loss if untreated, offers access to more subjects for inclusion in a clinical trial. These patients are seen routinely in the private practice ophthalmologist’s office that is now involved in clinical research. The disadvantage to academic institutions that have invested in the development of an infrastructure to rigorously support all basic and clinical research is that they no longer have access to this large patient population. The disadvantage to the patient may be that the strict protocol that is the hallmark of academic institutional research may not be adhered to so rigorously in a community where that infrastructure is not present.

Another limitation is access to the underserved— those people who have no access to health care providers, either because of lack of insurance or distance from those same providers. These patients are likely to postpone needed care until their conditions have escalated in severity. This group would have no representation in the clinical research arena, the subsequent lack of diversity in the research population may result in possible bias.

The tremendous increases in new technology have not been accompanied by changes in the clinical evaluation of new approaches. As a result, new approaches become established that may harm many patients, and researchers may have difficulty obtaining approval to perform properly designed clinical trials from the human subjects committees that oversee the ethics of research because of the presumed standard of practice that is present in the field.

RESEARCH STAFF AND DOCUMENTATION

The goal of all clinical research is to provide information that will help the practitioner treat his or her

patients more effectively. The clinical trial provides the best means to objectively quantify and compare the benefits and risks of new or alternative treatments to establish treatments for disease, especially when the difference between a new or old treatment is not clear or when a large number of factors may influence the course of the disease or the outcomes of the treatment

(3). To ensure that the treatment groups are compared objectively, standardized methods of gathering data, training and certifying the personnel who collect the data, and treating patients either surgically or pharmaceutically, are imperative. Continuous monitoring of adherence to the protocol, uniform data accumulation and routine re-certification of personnel will eliminate any concerns of bias or ambiguity when the data is presented. All data accumulated on a case report form, the form that is submitted to a central data collection agency, must be documented in the patient file and these two documents must be reconciled at all times. All clinical research studies are monitored at regular intervals to ensure that all information is recorded on all the legal documents and that no data are missing or unsubstantiated. The success of all clinical research is totally dependent on this accurate and standardized collection of data, and strict adherence to the protocols.

SUMMARY POINTS

&MPS was the first clinical study to look at macular degeneration

&The aging population is 34.8 million with 1.2 million having some form of visual impairment.

&Clinical research is the best means to quantify and objectively compare the benefits and risks of new or alternative treatments for disease or injury especially when:

&the difference between a new or old treatment is not clear;

&the disease naturally follows a chronic, variable and erratic course;

&a large number of factors, known or unknown, may influence both the course of the disease and the outcome of the treatment.

&A well-designed and conducted randomized clinical trial incorporates the following:

&High ethical standards—of paramount importance are patient welfare, informed consent, adherence to protocol, and careful data monitoring.

&Control groups that are matched to the treatment groups for the baseline characteristics.

&Random assignment of patients to both study and control groups when comparability of results among groups is essential.

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&Masking to minimize bias of both the examiner and the patient, if possible.

&Enrollment of an adequate number of patients enrolled in the trial for the results to be statistically significant.

&Completeness of patient follow-up.

&Use of statistical methods for study design and data analysis.

&Continuous monitoring of adherence to protocol and accumulation of data by the Data Safety Monitoring Committee (DSMC), the study Advisory Committee, the Executive Committee and the Steering Committee to ensure the safety of the subjects involved in the trial (5).

REFERENCES

1.Administration on Aging (AoA). A Profile of Older Americans. U.S. Department of Health and Human Services, 2000.

2.Macular Photocoagulation Study Group. Argon laser photocoagulation for senile macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol 1982; 100:912–8.

3.Walonker AF, Sturrock D. The Ryan Leopold Beckman Center for Clinical Research. Masters Thesis School of Public Health, UCLA, 1999.

4.Chronic Care in America. A 21st Century Challenge. Princeton, NJ: Prepared by the Institute for Health and Aging University of California, San Francisco for the Robert Wood Johnson Foundation, August 1996.

5.Clinical Trials Supported by The National Eye Institute. U.S. Department of Health and Human Services, 1987.