Clinical Research Trials

In the past, the National Eye Institute has funded investigator-initiated grants that looked at such topics as the aging retina, cone photopigments, and the effect of light or chemical factors on the integrity of the photoreceptor/retinal pigment epithelial complex. The first randomized clinical research study that looked at the treatment of macular degeneration was the Macular Photocoagulation Study (MPS).

1.The Macular Photocoagulation Study (MPS)

The MPS Group published its first reports in 1982. The studies evaluated the usefulness of laser photocoagulation in the treatment of macular degeneration. These studies showed that laser treatment reduced the risk of severe visual loss in eyes with extrafoveal choroidal neovascular membranes secondary to macular degeneration [confluent laser treatment for well-defined, classic, choroidal neovascularization in which the posterior edge of the neovascularization was at least 1 mm from the foveal center (2)]. Subsequent studies evaluating photocoagulation for presumed ocular histoplasmosis (3) and idiopathic neovascularization (4) came to the same conclusion: the photocoagulation effectively treated extrafoveal membranes.

However, long-term follow-up revealed that extrafoveal choroidal neovascularization recurred in a high proportion of the patients. These findings were corroborated by investigators in other countries. It appeared that nearly 75% of these recurrences occurred within the first year. This led investigators to hope that if no recurrence occurred in the first year, the possibility of new neovascularization was low (5).

In the past 18 years, the search for a more long-lasting cure for macular degeneration with choroidal neovascularization has led to many different approaches. Treatments studied have included photodynamic therapy, submacular surgery, external-beam radiation, medications such as interferon and thalidomide, and various oral supplements that are believed to be preventive. At present, a number of randomized clinical research trials are looking at various therapies for macular degeneration. Basic scientists are working hand in hand with clinicians to find a cure for this blinding disease.

B.Clinical Relevance

Prior to the (MPS) Macular Photocoagulation Study, 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 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, against which other treatment trials can be measured.

II.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 im-

proved treatment. Case-series 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 this problem. Together, they design appropriate laboratory research to address the question. Results from these basic science studies lead to preliminary clinical investigations of a possible new diagnostic technique, a treatment, or a drug. A small group of carefully selected patients participate in a pilot study to study the safety of these new treatments. If successful, such a pilot study generates a single-center clinical trial to further evaluate the safety and efficacy of the treatments.

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

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 treatments are the strongest design of all.

These innovative approaches to clinical practice are then 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.

This path from clinical problem to clinical cure, from an idea in the clinic to the research laboratory, and finally back to the patient in the clinic is difficult, challenging, and expensive. Yet the future of maintaining healthy eyes and vision for all of us depends on the success of this vision research process.

A.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 (in vitro and animal studies), case report studies, Phase I, and Phase II studies have been analyzed, a protocol is established under which the trial will be conducted. A manual of procedures is developed outlining every detail of the research study so that every participant in the study is aware of the protocol detail and is able to follow this protocol without deviation, maintaining the standardization of testing and of any other procedure. These steps are as follows.

1.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 problem. 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 would be the basis for a limited trial on a small group of carefully selected patients. If these patients reacted well to the therapy, the next phase would be a single-clinical-center study, a pilot study, of patients with a specific disease.

This is the initial stage of the 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, and the experimental plan, including the design, are then detailed.

2.The Protocol

The protocol for the study will include:

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.

Subject selection criteria with the inclusion and exclusion criteria with justification for both. Justification for or against inclusion/exclusion of vulnerable subjects.

Discussion of the appropriateness of the research methods and statistical justification for the chosen sample size with the statistical method of analysis explained.

Provisions for managing any adverse reaction.

Detailed description of the procedures to be performed with the frequency of these procedures outlined and the time commitment of the patient explained.

3.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, outside the scope of established and accepted methods. The IRB monitors approved research in accordance with the requirements of the Office of Protection from Research Risks (OPRR) and the regulations of the Food and Drug Administration (FDA), National Institutes of Health (NIH) and Department of Health and Human Services (DHHS). 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.

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.

Where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

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 welfare of subjects who are members of a vulnerable group.

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

The informed consent the patient will sign before entering into a clinical research trial will also include the length of the 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.

4.The Manual of Procedures

The manual of procedures for the clinical research study is divided into several sections. Each section covers in detail a different component of the study.

The background of the research design.

Directory of personnel/committees

The research plan

1.Objectives

2.Treatment groups: control versus treatment

3.Outcome variables

4.Eligibility and exclusion criteria

5.Randomization

6.Statistical consideration

Examination descriptions and schedules

1.Screening evaluation

2.Baseline visits

3.Follow-up visits

4.Study visit windows

5.Missed visit and inactive patient considerations

Examination procedures

1.List of examination procedures

2.Equipment and facilities

3.Refraction protocol

4.Visual acuity protocol

5.Intraocular pressure protocol

6.Ophthalmic examination protocol

7.Other testing protocols as appropriate for a particular trial

Ancillary testing protocols

1.Performance

2.Labeling/processing

Surgical protocols

1.Description of the surgical procedures/laser procedures

2.Description of the postoperative medications to be used

Certification of personnel

1.Detailed description of the performance required for each role in the trial

2.Performance evaluation methods

3.Certification procedures

4.Importance of standardization

Data collection

1.Patient identification/name codes

2.Case report forms

3.Mailing instructions

4.Procedures for tracing patients

5.Reports on adverse events

6.Edit queries

7.Monitoring visits/data collection corroboration

Data safety and monitoring

1.Functions of the committee

2.Frequency of meeting

3.Endpoints

Statistics

1.Detail of the statistical methods used

2.Justification of the patient sample size chosen

3.Randomization process and justification

B. Settings for Research Trials

Advancing medical knowledge—through screening, surgery, 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, 13% of the population is over the age of 65; by the year 2040, this number will have grown to 23% of the population (7). By 2040, 70 million people will have some form of activity limitation, whether mental, physical, or visual, that will require intervention from the health care systems in some form. Research into the most effective care for persons with chronic disease, including eye disorders in particular, and efforts at prevention will be at the forefront of future clinical research. The projected cost of health care in the year 2040 is $906 billion, a huge percentage of the GNP of the United States and the highest of the entire world’s developed countries (7).

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.

C.Limitation 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.

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. This population would comprise the carefully selected patients who could be enrolled in a clinical research trial to address the safety and efficacy of a new treatment approach. 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 and may now be involved in limited 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, because of either 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 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.

III.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 quantify and compare objectively the benefits and risks of new or alternative 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

(6). 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 protocol, accumulating data in a uniform way, and recertifying personnel on a frequent basis will eliminate any concerns of bias or ambiguity when the data are 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 (8).

IV. SUMMARY

MPS was the first clinical study to look at macular degeneration The aging population numbers 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:

1.The difference between a new or old treatment is not clear.

2.The disease naturally follows a chronic, variable, and erratic course.

3.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 well-conducted randomized clinical trial incorporates the following:

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

2.Control groups that match treatment groups.

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

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

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

6.Completeness of patient follow-up.

7.Use of statistical methods for data analysis.

8.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 (8).

REFERENCES

1.A profile of older Americans. Administration on Aging (AoA), 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;100:912–918.

3.Macular Photocoagulation Study Group. Argon laser photocoagulation for ocular histoplasmosis. Results of a randomized clinical trial. Arch Ophthalmol 1983;101:1347–1357.

4.Macular Photocoagulation Study Group. Argon laser photocoagulation for idiopathic neovascularization. Results of a randomized clinical trial. Arch Ophthalmol 1983;101:1358–1361.

5.Macular Photocoagulation Study Group. Recurrent choroidal neovascularization after argon laser treatment for neovascular maculopathy: Arch Ophthalmol 1986;104:503–512.

6.Walonker A F, Sturrock D. The Ryan Leopold Beckman Center for Clinical Research, Masters thesis, School of Public Health, UCLA, 1999.

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

8.Clinical trials supported by the National Eye Institute, U.S. Department of Health and Human Services, 1987.