Contact Lens and Solution Regulation
BY RICHARD LIPPMAN, O.D., WILLIAM GLEASON, O.D., &
PAUL WHITE, O.D.
FEB. 1997
Regulation of medical devices has become a complex balancing act. Insufficient premarket evaluation could jeopardize public health, while excessive regulation could stifle new product development. Here, we review FDA classifications of contact lenses and solutions.
Until the early 1970s, the Food and Drug Administration (FDA) did not regulate contact lenses and solutions, although polymethyl methacrylate (PMMA) contact lenses and accessory solutions had been in general use for about four decades. With the advent of soft hydrogel contact lenses, however, the FDA decided to regulate contact lenses and solutions in the public's interest. Because the FDA had no regulatory mechanism specifically for medical devices, contact lenses and solutions were first regulated by the the Bureau of Drugs as new drugs, which required approval of a New Drug Application (NDA) before commercial distribution was allowed.
In 1976, the U.S. Congress enacted Medical Device Amendments to regulate medical devices differently from drugs, and the Bureau of Medical Devices (now the Center for Devices and Radiological Health) was established within the FDA. Some medical devices, including contact lenses and solutions, that had been regulated as new drugs by the Bureau of Drugs were considered "transitional." This put them in the strictest device regulatory group, Class III, where they remained until down-classification to Class II began for some of them in 1993.
CLASSIFICATIONS
The FDA's principal objective is to provide a reasonable assurance of safety and efficacy of drugs or devices both before and after they are allowed to be marketed to the public. Based upon its general history and potential risk/benefit relationship, a product is placed in one of three classes: Class I general controls; Class II special controls; and Class III premarket approval.
Devices in all three classes must meet Good Manufacturing Practice (GMP) regulations. This ensures that methods and facilities used in manufacturing, packaging, storing and installation of devices are safe, effective and in compliance with the Food, Drug and Cosmetic Act.
Class I general controls are not sufficient to ensure that contact lenses and solutions are safe and effective. Paradoxically, PMMA contact lenses were "grandfathered," that is, they were not required to conform to the newer regulations. Thus, regulation of PMMA lenses consists only of a device notification process within Class II despite the fact that they have greater potential safety consequences than soft or RGP contact lenses. Class II and Class III devices are more rigorously tested and they require a higher level of FDA review prior to U.S. marketing.
Nonclinical/Preclinical Testing
Before the FDA permits clinical testing, a device's manufacturing, physical and chemical characteristics, toxicology and microbiology must be evaluated in an accepted manner. These nonclinical/preclinical procedures must demonstrate that a device should be sufficiently safe to be used by human subjects in a clinical trial.
Microbiological testing is necessary because contact lenses and solutions require sterility, stability and shelf-life dating. Sterilization is the total elimination of a population of microorganisms. Disinfection implies a certain level of microorganism kill, and the standard is a reduction of selected microorganism groups by a factor of 10[6] (one million) on a lens or in a specified volume of solution. Regulations for contact lenses and solutions require that they be delivered sterile from the manufacturer and remain sterile until opened. Shelf-life dating indicates the duration that the chemical integrity and sterility are maintained until the package is opened. Once containers are opened, contact lenses and solutions are readily subject to external contamination.
Data from studies demonstrate significant contamination levels in many contact lens solutions and lens cases and on contact lenses. True routine sterilization by patients involves a high potential for damaging lenses. Ongoing maintenance of lenses is accomplished by disinfection to reduce the microorganism load to an acceptable level without lens damage. Disinfection systems must be sufficiently bactericidal to accomplish this, and proper cleaning and rinsing before lens storage reduces the microbial burden by about 10[3]. Chemicals in preservative-containing rinsing or lubricating solutions should be sufficiently bacteriostatic so that no new contaminants can grow in unopened containers. It is assumed that in opened containers the bacteriostatic effectiveness of the solutions will maintain contamination at safe levels for the reasonable expected period of solution use under normal conditions. However, it has been found that approximately 45 percent of opened and used solution bottles and accessories are contaminated, and this increases with time.
The chemical composition of contact lens materials and solutions makes toxicological analysis critical. Chemicals may be carcinogenic, mutagenic, irritating or sensitizing to ocular tissues. Unpolymerized monomers of lens materials and color additives may produce toxic, leachable by-products. Before contact lens polymers, additives and solutions can be tested on human subjects, their potential toxic response must be evaluated by animal model, bench and laboratory testing. Only after these exhaustive and expensive tests substantiate sufficient safety can in vivo human studies begin. Non-human tests include ocular irritation in rabbits evaluated by the Draize test (slit lamp biomicroscopy and histology), the Agar Diffusion test for cytotoxocity, and a systemic toxicity test. Most tests involve complex protocols accepted by the scientific community and modified for ophthalmic application.
The physical and chemical properties of contact lenses and solutions differentiate and define various groups. The FDA has developed a matrix to categorize soft lens materials into four major lens groupings. Criteria are water content (less than 50% water is low water and more than 50% is high water) and ionic surface reactivity (less reactivity is termed nonionic and more reactivity is ionic). Group 1 is low water, nonionic; Group 2 is low water, ionic; Group 3 is high water, nonionic; Group 4 is high water, ionic. These groupings clarify lens polymer characteristics, simplify solution testing and identify potential compatibility issues (Table 1).
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The groupings for RGP lens materials include silicone acrylate, fluorosilicone acrylate, tertiary butylstyrene and polyperfluorether. Most RGP lenses are silicone acrylate or fluorosilicone acrylate and many solutions are tested with only these materials. Solutions may be incompatible with other nontested materials. Identification of soft or RGP lens material groupings is very important in Class II regulation.
Class II
Special controls help establish substantial equivalency of potential new contact lenses or solutions in relation to already approved and marketed comparable products. Class II also requires measures of quality assurance that demonstrate accurate and consistent device reproduction and ensures that devices perform their labeled indications.
Performance characteristics in the nonclinical/preclinical areas of microbiology, toxicology, chemistry and manufacturing are ascertained according to established procedures adapted from previously approved applications. Class II clinical trials are limited to demonstration of performance characteristics in relation to comparable devices and not to direct safety and efficacy. Randomization techniques, controls of a known comparison population, or a one-eye-to-one-eye control provide the necessary information. The overall determination of substantial equivalency is whether or not the contact lens or solution performs as it should in relation to comparable, previously approved and marketed products.
Class III
How do the extensive controls in Class III compare to the special controls in Class II? In both classes, appropriate nonclinical/ preclinical testing must be done. However, the number of human eyes tested and the duration of clinical testing differs in each class.
Initially, with Class III, the FDA required that 400 patients (800 eyes) be followed for six months in daily wear and for 24 months in extended wear. In 1989, the FDA reduced this to a 100-eye clinical study followed for three months for daily wear lenses or contact lens solutions, and a 400-eye study followed for one year for extended wear lenses.
Under Class III requirements, the results of the nonclinical/preclinical and the clinical testings must demonstrate that the lenses or solutions provide an acceptable level of safety and efficacy. Unlike Class II products, these lenses or solutions are not directly compared with similar, approved products to prove substantial equivalency. Data from Class III device testing is reviewed by FDA personnel and periodically by the Ophthalmic Device Panel, a group of nongovernmental optometric and ophthalmologic experts who function as an objective, independent advisory group to the FDA and make recommendations on specific device applications. Class III devices must then receive premarket approval (PMA). Testing data for Class II devices is evaluated without input from the Ophthalmic Advisory Panel. The device is cleared under a 510(k) notification.
Also, FDA regulations state that a submission for a Class III device should be evaluated and responded to within six months, but this often takes much longer. Submissions for Class II devices must be responded to within three months and this can often be accomplished. In essence, the 510(k) procedure for Class II devices often reduces the amount of time for a company to market a product by a year or more as compared with the Class III PMA procedure. Therefore, when Class II special controls are sufficient to assure reasonable equivalence to those which have been determined to be safe and efficacious, it is in the interest of the public, practitioners and industry to use this quicker, less expensive procedure (Table 2).
RECLASSIFICATION
In 1977, the Classification Panel for Ophthalmic Products, a panel of nongovernmental experts, decided that contact lenses and solutions should remain in Class III. In the early 1980s, the FDA considered placing these devices in Class II, but decided that change was inappropriate. Some contact lens and solution manufacturers challenged the FDA's decision in the U.S. Court of Appeals for the District of Columbia. On July 9, 1985, the court ruled in favor of the FDA and these devices remained in Class III.
Within the context of existing laws, however, the FDA streamlined its internal review process to simplify and expedite evaluations and approvals. As a result, the Division of Ophthalmic Devices issued new guidance to contact lens and solution manufacturers in April 1989. The new guidance standardized regulations to aid in new product development and existing product modification. Changes were made in the nonclinical areas of manufacturing, toxicology, microbiology and chemistry. Clinical trials for daily wear lenses were reduced from six months to three months, while clinical trials for extended wear lenses remained at 12 months. The number of eyes remained at 400 for extended wear, but was reduced to 100 for daily wear.
Congress rewrote the Medical Device Amendments and passed a new law, which was signed by President George Bush on Nov. 28, 1990. This Safe Medical Devices Act contains provisions specific to contact lenses and their subsequent regulatory status. The intent was to have all transitional devices that had been regulated by the Bureau of Drugs prior to 1976 reclassified to Class II, assuming that no additional concerns of their safety or efficacy arose in a two- to three-year period, and that there were no challenges to this reclassification.
In 1993, in accord with the Safe Medical Devices Act of 1990, daily wear soft and RGP contact lenses were placed in Class II. In May 1994, the FDA provided new guidance to reflect this change. The FDA reduced the amount of clinical data needed for daily wear lenses but increased the amount of attention paid to clinical study design and outcomes, placing more emphasis on study controls and randomization to reduce or eliminate bias. Overall, these changes should still provide the necessary reasonable assurances of safety and efficacy while expediting new daily wear product approval and marketing.
Product-specific guidelines to reclassify contact lens solutions and accessory products from Class III to Class II are currently pending within the FDA. Reclassification is anticipated in early 1997. Substantial equivalence to presently approved products must be demonstrated, and there are specific requirements for each category of salines, cleaners, chemical disinfection solutions, multipurpose solutions, in-eye contact lens lubricating/rewetting drops, thermal disinfection units and contact lens cases. In general, a new product requires a three-month clinical trial period and tests in 60 eyes, with about two-thirds of patients using the new potential product and the remainder using a similar, approved product as the control for establishing substantial equivalency. A small modification of an already approved product requires a one-month clinical trial period and 30 tested eyes. The 510(k) procedure is used for both the new and modified products.
Present soft and RGP lenses are made of conventional plastics. However, in the future, some contact lenses may be made from animal or human-derived biological materials synthesized into plastic polymers. Because this would be a new developmental area, requirements for testing and approval will likely be more stringent. The biopolymers probably will be placed in Class III until their safety and efficacy is sufficiently proved to place them in Class II.
The materials for disposable, frequent replacement or programmed replacement soft contact lenses are the same as those for conventional soft contact lenses. According to FDA regulations, any product labeled 'disposable' is a one-time-use product. Therefore, a disposable contact lens must be discarded upon removal, whether this is after one day or one week of wear. The contact lens industry and the professions have often ignored this FDA policy and have developed their own operational definitions. Programmed or frequent replacement lens modalities are generally considered as lens replacement of anywhere from one-month to six-month intervals; disposable lenses are those that are replaced every seven days or less. Classification in terms of approval relates to the intended daily or extended (flexible) wear of the lenses. The former would be classified as Class II, the latter as Class III.
CLINICAL INVESTIGATION
To obtain valid evidence of safety and efficacy for Class III devices and substantial equivalency for Class II devices, clinical trials are necessary. The Investigational Device Exemption (IDE) is the mechanism that allows this in a controlled manner. An IDE's purpose is to protect patients in clinical studies. The primary tenets of an IDE are that patients should not be subjected to undue risk during clinical trials and that they should be fully informed about the study and its potential risks before they consent to participate. This is communicated to them in a written informed consent form and amplified verbally by the investigator (Table 3).
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Nonsignificant risk and significant risk are the two IDE categories. As of this writing, only extended wear studies are considered significant risk. Nonsignificant risk studies are performed under an abbreviated IDE, which must be approved by an Institutional Review Board (IRB) prior to study implementation. The IRB is typically composed of five to seven members. One member is a layperson and the others are qualified professionals. IRBs exist at hospitals, academic institutions or other places as defined by IDE regulations.
An IRB and the FDA must review and approve significant risk studies before the inception of clinical trials. IDE progress reports and continued monitoring by the study's sponsor and the FDA are required to ensure safe progress throughout the study. If there are safety concerns, the study protocol may be modified to address them and the study suspended pending corrections, or it may be terminated.
The two major components of a proposed study submitted to an IRB or the FDA are the prior studies and the investigational plan. Prior studies include nonclinical/preclinical testing and may also include previous clinical testing done on similar products and small feasibility studies done on the investigational product. The investigational plan includes the study's objective, design and conduct (Table 4).
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An IRB or the FDA first determines if prior studies substantiate sufficient safety for clinical trials. If they do, the investigational plan is evaluated to ensure that all essential elements are included and properly described so that investigators understand what to do and how to do it, so that subjects receive the proper information and instructions, and so that the study's data is properly gathered and transmitted. A scientifically valid investigational procedure must safeguard patients' well-being.
Significant components related to patient protection are the informed consent, the written and verbal instructions, and the management of any significant tissue complications or adverse reactions. An adverse effect can be described as, but is not limited to, any unanticipated condition that might be sight-threatening, e.g., corneal ulcer. Significant tissue complications are less serious than this but are still greater than acceptable. Slit lamp quantification of findings are graded as 0 (none), 1 (trace), 2 (mild), 3 (moderate), and 4 (severe) for epithelial edema, epithelial microcysts, corneal staining, limbal injection, bulbar injection, corneal neovascularization and tarsal conjunctival abnormalities. The grades of each of these are specifically defined in an approved manner. While grades 0-2 are often acceptable, usually grade 3 is suspicious and grade 4 is unacceptable. Corneal striae, corneal infiltrates, corneal ulcers and iritis are not graded, but their occurrence is unacceptable. A very small incidence of adverse reactions or sufficient incidence of significant grade 3 or 4 tissue reactions requires that a study be modified, suspended or terminated to protect the subjects.
INTERNATIONAL REGULATION
For more than two decades, there has been detailed FDA regulation of contact lens and solution products marketed in the United States. With the notable exception of a few countries, such as Japan, there has been much less regulation worldwide.
Recently, Canada increased its regulatory requirements (formerly a simple notification procedure) so that they simulate FDA standards, but to a lesser degree. There is little regulation in Central and South America, but most of the contact lenses and solutions used there come from U.S. companies.
Japan's Ministry of Health and Welfare has very strict regulation, reflecting Japan's general attention to product safety and efficacy, as well as concerns raised by infections in some contact lens wearers. Australia and New Zealand regulate soft contact lenses and solutions, but not rigid lenses. China has almost no contact lens regulation.
Western Europe's regulation has varied greatly among countries. Some countries, such as Italy and France, have had no regulation for contact lenses, but they regulated contact lens solutions with the same stringent requirements used for pharmaceutical drugs. With the establishment of the European Common Union (EU), uniform standards for member countries are being developed for many products.
The EU will use the quality standard established by the global International Standards Organization (ISO) to regulate products, to allow marketing within a country, and to market across the borders of EU member countries. Products that meet the quality standards will use a certification (CE) mark. After June 1998, all medical devices will be required to carry the CE mark.
Nongovernmental independent quality assurance companies will confirm that a product has met the ISO quality standards. The manufacturers contract with and pay the quality assurance companies for their initial review and for required subsequent semiannual reviews. In essence, product manufacturers will self-certify based upon the reviews of the quality assurance companies. This is somewhat comparable to U.S. nonclinical/preclinical testing, which is often performed and certified by specialized companies independent from the product development company. There are also various subgroupings of the ISO standards. CLS
Dr. Lippman is past director, FDA Ophthalmic Device Division. He is senior consultant for C.L. McIntosh and Associates, a medical and regulatory affairs service group.
Dr. Gleason is past vice president of regulatory affairs for Polymer Technology. He has his own consulting firm.
Dr. White is a professor at the New England College of Optometry.
References are available from: Paul White, O.D., New England College of Optometry, 424 Beacon St., Boston, MA 02115.
QUESTIONS
1. The FDA's initial regulation of contact lenses and solutions was via:
a. an NDA
b. an IDE
c. a PMA
d. a GMP
2. Congress enacted Medical Device Amendments in:
a. 1966
b. 1976
c. 1986
d. 1996
3. Good Manufacturing Practice (GMP) of medical devices includes:
a. manufacturing
b. packaging
c. storing
d. all of the above
4. The standard used for microorganism kill with disinfection is:
a. 10(12)
b. 10(9)
c. 10(6)
d. 10(3)
5. Nonclinical/preclinical toxicological test includes:
a. Draize test
b. Agar diffusion
c. systemic toxicity
d. all of the above
6. Group 3 soft lenses are:
a. high water
b. nonionic
c. both 'a' and 'b'
d. neither 'a' nor 'b'
7. Class II devices require:
a. establishment of substantial equivalency
b. review of Ophthalmic Device Panel
c. PMA
d. both 'b' and 'c'
8. Class III devices require:
a. establishment of substantial equivalency
b. review by Ophthalmic Device Panel
c. PMA
d. both 'b' and 'c'
9. Class II device procedure is called:
a. 510(k)
b. PMA
c. NDA
d. none of the above
10. When did the Classification Panel for Ophthalmic Products decide to keep contact lenses and solutions in Class III?
a. 1957
b. 1967
c. 1977
d. 1987
11. The Safe Medical Devices Act was signed into law in:
a. 1990
b. 1980
c. 1970
d. 1960
12. Daily wear soft and RGP contact lenses were placed in Class II in:
a. 1996
b. 1993
c. 1990
d. 1987
13. Future biopolymer contact lens materials will probably be placed at first in Class:
a. I
b. II
c. III
d. IV
14. The mechanism that allows for controlled clinical trials is:
a. a 510(k)
b. a PMA
c. an IDE
d. a GMP
15. Significant risk studies must be reviewed and approved by:
a. FDA
b. IRB
c. both 'a' and 'b'
d. only 'b'
16. The investigational plan for clinical trials includes the study's:
a. objective
b. design
c. conduct
d. all of the above
17. Significant components related to patient protection in clinical trials include:
a. informed consent
b. written and verbal instructions
c. management of tissue complications
d. all of the above
18. Which of the following grades of slit lamp findings is usually considered unacceptable?
a. 2
b. 3
c. 4
d. all of the above
19. Which of the following countries has historically had the strictest contact lens and solution regulations?
a. Canada
b. Japan
c. China
d. Brazil
20. Medical devices will not be allowed to be sold in the EU without CE marks beginning in:
a. 1997
b. 1998
c. 1999
d. 2000
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