Ординатура / Офтальмология / Английские материалы / Ocular Neuroprotection_Levin, Polo _2003

3.Winblad B, Poritis HN. Memantine in severe demintia: results of the 9M-Best Study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999; 14:135–146.

4.The Ischemic Optic Neuropathy Decompression Trial Research Group. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA 1995; 273:625–632.

5.Sergott RC, Cohen MS, Bosley TM, Savino PJ. Optic nerve decompression may improve the progressive form of nonarteritic ischemic optic neuropathy. Arch Ophthalmol 1989; 107:1743–1754.

6.Kelman SE, Elman MJ. Optic nerve sheath decompression for non-arteritic ischemic optic neuropathy improves multiple visual function parameters. Arch Ophthalmol 1991; 109:667–671.

7.Spoor TC, Wilkinson MJ, Ramocki JM. Optic nerve sheath decompression for the treatment of progressive nonarteritic ischemic optic neuropathy. Am J Ophthalmol 1991; 111:724–728.

8.Spoor TC, McHenry JG, Lau-Sickon L. Progressive and static nonarteritic ischemic optic neuropathy treated by optic nerve sheath decompression. Ophthalmology 1993; 100:306–311.

9.Boghen DR, Glaser JS. Ischemic optic neuropathy: a clinical profile and natural history. Brain 1975; 98:689–708.

10.Repka MX, Savino PJ, Schatz NJ, Sergott RC. Clinical profile and long-term implications of anterior ischemic optic neuropathy. Am J Ophthalmol 1983; 96:478– 483.

11.The AGIS Investigators. The advanced glaucoma intervention study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000; 130:429–440.

12.Holopigian K, Greenstein V, Seiple W, Carr RE. Rates of change differ among measures of visual function in patients with retinitis pigmentosa. Ophthalmology 1996; 103:398–405.

13.Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol 1993; 111: 761–772.

14.Sunness JS, Schuchard RA, Shen N, Rubin GS, Dagnelie G, Haselwood DM. Land- mark-driven fundus perimetry using the scanning laser ophthalmoscope. Invest Ophthalmol Vis Sci 1995; 36:1863–1874.

15.Hood DC, Seiple W, Hologigian K, Greenstein V. A comparison of the components of the multifocal and full-field ERGs. Vis Neurosci 1997; 14:533–544.

16.Miglior S, Casula M, Guareschi M, Marchetti I, Iester M, Orzalesi N. Clinical ability of Heidelberg retinal tomograph examination to detect glaucomatous visual field changes. Ophthalmology 2001; 108:1621–1627.

17.Zangwill LM, Bowd C, Berry CC, Williams J, Blumenthal EZ, Sanchez-Galena CA, Vasile C, Weinreb RN. Discriminating between normal and glaucomatous eyes using the Heidelberg retina tomograph, GDx Nerve Fiber Analyzer, and Optical Coherence Tomograph. Arch Ophthalmol 2001; 119:985–993.

18.Wollstein G, Garway-Heath DF, Fontana L, Hitchings RA. Identifying early glaucomatous changes. Comparison between expert clinical assessment of optic disc pho-

tographs and confocal scanning ophthalmoscopy. Ophthalmology 2000; 107:2272– 2277.

19.Bowd C, Zangwill LM, Berry CC, Blumenthal EZ, Vasile C, Sanchez-Galeana C, Bosworth CF, Sample PA, Weinreb RN. Detecting early glaucoma by assessment of retinal nerve fiber layer thickness and visual function. Invest Ophthalmol Vis Sci 2001; 42:1993–2003.

20.Hutchings N, Hosking SL, Wild JM, Flanagan JG. Long-term fluctuation in shortwavelength automated perimetry in glaucoma suspects and glaucoma patients. Invest Ophthalmol Vis Sci 2001; 42:2332–2337.

21.Klistorner A, Graham SL. Objective perimetry in glaucoma. Ophthalmology 2000; 107:2283–2299.

22.Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol 2001; 119:1050–1058.

23.WoldeMussie E, Ruiz G, Wijono M, Wheeler L. Brimonidine is neuroprotective to ganglion cells in rats with laser-induced chronic ocular hypertension. Invest Ophthalmol Vis Sci 2001; 42:2849–2855.

valuable assets in the development and implementation of an organized plan for dissemination of information. Referral sources should be encouraged to utilize their patient databases to identify subjects at risk or with the disease, but privacy issues regarding contact with such patients (see below) must be addressed.

2.Motivation of referral sources and subjects. The disease being investigated may be currently untreatable, and referral to a trial may provide a possible new hope for the subject as well as prestige for the referring physician by association with the center. However, both subjects and referring physicians must be invested in answering the question of effectiveness rather than simply obtaining a possible therapy, because a placebo or a standard therapy will be a possible result of entry; receipt of the study medication is not guaranteed. Subjects may be paid a reasonable amount for participation, but coercion by too high a sum must be avoided. Similarly, referral sources may receive some perquisites for their participation, including reimbursement for time in examination, but specific referral fees or “kickbacks” for referral of subjects are not acceptable. Referral sources must be comfortable that patients will be returned to their care following the trial.

3.Availability of clinical center personnel. A critical factor in subject recruitment is the ease with which subjects may be referred to the nearest Clinical Center. A single telephone call to the center should allow the referring physician to establish the subject’s probable eligibility and obtain instructions for timely evaluation of that subject without further demands on the referring physician’s time. This requires Center staff that is adequately trained, motivated to facilitate entry of subjects, skilled at interpersonal relations, and available to devote the necessary time to the trial. Additionally, ethical considerations in recruitment become important for clinical trials.

1. Overzealous recruitment. There is, of course, ample motivation for an investigator to recruit as many subjects for the trial as possible, for reasons related to rapid completion of the trial, prestige of high recruitment, and financial gain. The risks of overzealous recruitment include

a.Coercion of subjects by counseling that slants information to encourage entry into the trial;

b.Bias of data obtained (entry of subjects with incorrect diagnosis, poor followup for subjects who lack true motivation due to inaccurate counseling, and entering subjects after a time window for treatment in acute disease, thus biasing results of therapy negatively).

c.Exposure of subjects to undue risk in cases of incorrect diagnosis or missed time window, when there may be no scientific basis for therapy.

Advertisements or flyers must not be misleading. Examples of such improprieties include claims of safety and efficacy, referring to “new treatment” or “free medical treatment,” when in actuality the subject simply will not be charged for participating.

2. Treatment outside the trial. If a study drug is available outside the study but is not FDA-approved for the studied disease or at the dosage being

studied, its use for the disorder may not be supported by the FDA except under special conditions. However, when the study drug is available and approved, for example when the study is comparing it to another therapy, subjects must be advised that it is available outside the trial. While such advice may impede recruitment, it is ethically required; the IRB will generally address this issue in the informed consent process.

III. INSTITUTIONAL REVIEW BOARD ISSUES

Human medical research in the United States is guided by ethical principles developed and outlined in the World Medical Association Declaration of Helsinki (1964) and in the Belmont Report, a 1979 document created by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. All research involving human subjects in the United States is subject to Institutional Review Board (IRB) approval. The basis for IRB review of research is contained in the Code of Federal Regulations, Title 45, Part 46 (45 CFR 46). The IRB approval process is often complex and time-consuming, but is deemed essential for the adequate protection of human subjects, particularly where scientific and financial stakes are high. The investigator must become familiar with IRB requirements of the institution sponsoring or supporting the research; these may vary widely depending on the IRB constituency (private vs. public). Regarding the conduct of clinical trials, the following aspects are highlighted:

A. Informed Consent

Informed consent is considered to be a process, not an isolated, one-time counseling session between investigator and subject. This ongoing dialogue should provide continuing disclosure of risks and benefits as new information becomes available. It begins with the initial description of research activity in the recruitment phase and continues through the subject’s final participation in the research activity, with updates as necessary regarding new findings, risks, and benefits detected as the trial progresses. Such updates may include complications occurring during the trial, new treatment options that become available, or decisions by sponsor to provide study drug to subjects without charge following the study. The updates may require pre-approval by the IRB.

The informed consent form (ICF) is the documentation of this process. In today’s clinical research environment, many elements of the ICF are required, and both IRBs and pharmaceutical sponsors develop templates for investigators’ use in clinical research. A great deal of time and effort may be saved by reconciling differences in required wording that may exist between the two versions prior to IRB submission.

B.Recruitment

In addition to the recruitment issues discussed above, certain points are of significant concern to the IRB, particularly with regard to privacy issues and the possibility of coercion. Areas of focus in reviewing studies include:

Selection. Unless there is a specific medical justification that may be provided, subjects for a trial should not be preselected on the basis of age, race, gender, or other potentially biasing feature.

Method of identification. The use of medical records or any information that is not in the public domain to identify potential subjects on the basis of existing medical conditions violates individual privacy rights. Similarly, the investigator should request that referring physicians approach their own potential subject patients to inform them of possible research, allowing them to make their own decision as to whether to contact the investigator, rather than asking the referring physician to identify specific potential subjects without their knowledge and prior approval. In some cases, the use of a flyer or information sheet, requiring the potential subject to initiate contact with the investigator, may be required. Such recruitment tools must not mislead potential subjects into believing that a study treatment is superior to current therapy. These flyers must have IRB approval.

Avoiding coercion. This is especially critical in the common situation in which potential subjects are under the care of the investigator and may be concerned that their medical care may be jeopardized if they do not participate in research. A statement is generally placed into the ICF to explain the potential conflict which may exist between an investigator’s interest in a study versus an individual patient’s care.

Additionally, coercion in the form of excessively high payment to subjects must be avoided. Amount and method of payment should be detailed in the ICF.

C.Definition of “Minimal Risk”

“Minimal risk,” as defined by federal regulations, is a specifically described situation, “where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” It is important to note, in the preparation of IRB and FDA documents, that this may not necessarily correspond to the investigator’s intuitive concept of minimal risk. For example, even though a proposed research procedure may entail little physical or psychological risk to the subject, if that

risk is more than encountered in “routine activities” for that subject, it may involve more than “minimal risk” and may require additional approval procedures.

D.Statement of Emergency Care and Compensation

All research that presents more than the strict definition of “minimal risk” as noted above requires a statement regarding “Emergency Care and Compensation for Injury.” This statement generally outlines the responsibility of the institution, such as a university, supporting the clinical center for a trial, in case of injury to a subject during a trial. Specific wording is generally required by the institution, and it may vary depending on whether the sponsor is a public (governmental— e.g., NIH) entity or a private (industry—e.g., pharmaceutical company). The sponsoring agency may also require specific wording, and the two may conflict. In clinical trials conducted by a pharmaceutical company in a university-based clinical center, agreement must be reached between the two organizations regarding financial responsibility for emergency care resulting from injury during the conduct of a trial. It may either be outlined in the ICF or in the clinical trial agreement (CTA) contract detailing the financial reimbursement from the pharmaceutical company to the university for the conduct of the trial. It is not acceptable to require that such emergency care be provided by third-party payers.

E.Reporting Adverse Events

An adverse event (AE) is defined as “an undesirable and unintended, although not necessarily unexpected, result of therapy or other intervention.” It may or may not be drug-related. Most IRBs require the reporting of such events, in writing, within a specified period of time, usually within 2–5 days, depending on the severity of the event. Typical adverse events involve injury, problems in the consent process, and other violations of protocol. The investigator is responsible for determining whether the event requires a change in the research protocol and/ or ICF, and recommending such changes when indicated. Subjects should be instructed to report any unusual medical occurrence to the PI as soon as possible.

Determinations as to whether an incident is considered an adverse event, whether an AE is considered serious, and whether it is causally related to study drug are critical issues.

Incidents considered non-AE include those that occur before or later than 4 weeks after dosing and worsening of disease that is considered within the normal variation of clinical course for the disease.

Serious AEs are specifically defined by the FDA as those that result in or prolong current hospitalization, produce persistent or significant incapac-

ity or disability, result in congenital anomaly, are life-threatening, or result in death. The severity of an AE is a separate issue. Other medical events not specifically meeting these criteria may be considered serious if they jeopardize the subject. If life-threatening, these must be reported to FDA by the pharmaceutical company within 7 days, and any SAE must be reported within 15 days.

Causality for AEs is generally an issue for the FDA to decide, the guideline being a “reasonable possibility” that the event was caused by the drug.

F.Investigator Training and Certification in Human Research

As of October 1, 2000, the NIH instituted a policy requiring all proposals for contracts and grants for research involving human subjects to certify that all key personnel have received education on the protection of human subjects. In many university research environments, this same requirement is applied by the IRB to all human research, including that sponsored by sources other than NIH. Both live teaching sessions at research institutions and web-based training programs are available to fulfill this requirement. Certification is time-limited, with duration for the current programs 2 years.

IV. FOOD AND DRUG ADMINISTRATION ISSUES

A.Investigational New Drug Exemption

Federal law prohibits the distribution of new drugs, biologics, and medical devices until the Food and Drug Administration (FDA) has reviewed clinical data and determined that a product is safe and effective for a specific use in human patients. Testing of a new drug requires an exemption from that law, and the sponsoring agent must apply to the FDA for an Investigational New Drug (IND) exemption before tests with human subjects may begin. If the investigator, rather than a pharmaceutical company, is the developer of the drug, that person or the sponsoring institution may be responsible for submitting an IND application to the FDA and providing the response to the IRB. In certain cases in which an approved drug is being tested for a slightly modified use, the FDA may issue a response indicating that an IND is not required. In general, however, approved drugs tested for new indications or at new doses require an IND exemption. Any study of such a drug must strictly adhere to the submitted protocol; changes must be submitted in writing and approved by the FDA and IRB.

B. Classification of Trials

The FDA classifies clinical trials according to the following schema:

Phase 1. Initial introduction of an investigational new drug into humans. Designed to determine pharmacologic and metabolic actions, side effects with increasing doses (establish safe dosage), and gain early evidence for effectiveness. Study is very closely monitored, often involves healthy volunteers and a few patients with disease, usually 20–80 subjects. The goal is to gain sufficient data to design a valid Phase 2 study.

Phase 2. Controlled study to evaluate effectiveness for a specific indication and to determine short-term risks and side effects. Closely monitored, usually several hundred subjects.

Phase 3. Large-scale controlled study of the drug administered as it would be when marketed, often involving several hundred to thousand subjects. Performed after preliminary evidence of effectiveness has been obtained, it is designed to evaluate effectiveness, safety, and appropriate dosage, to provide a basis for labeling. Following this study, a sponsor typically applies for FDA approval to market the drug. Most large-scale clinical trials fall in this category.

Phase 4. Concurrent with approval, the FDA may seek agreement from the sponsor to conduct post-marketing (Phase 4) studies to evaluate other doses, indications, or duration for drug use.

C. Controlled Studies

The FDA describes five categories of controls which may be used in drug trials:

1.Placebo concurrent

2.Dose-comparison concurrent

3.No-treatment concurrent

4.Active-treatment concurrent

5.Historical

The FDA requires that the study design be adequate to obtain valid results, but it does not indicate a preference for type of control. There is misunderstanding regarding this issue. The use of placebo in a clinical trial may be unethical if there is proven effective therapy for the disease and it is withheld in favor of placebo. Many believe the FDA prefers placebo for comparison of effect, requiring it as a feature of randomized clinical trials. Placebo would be expected to have an advantage over the use of an active-treatment control, as the difference between effects of study drug and placebo may be greater than that between study drug and active-treatment control, thus allowing smaller sample size to