Cover Story

Global coordination sought for approval of ophthalmic devices

Requirements for approval of ophthalmic devices differ widely around the world, and the U.S. Food and Drug Administration’s ophthalmic device approval process is considered one of the gold standards. The agency is now taking part in an effort to create global standardization of the approval process.

Stephen S. Lane, MD
Stephen S. Lane, MD, a medical monitor for Alcon, acknowledged that the rigorous, lengthy FDA approval process can be frustrating for physicians.
Image: O'Brien T

“The FDA is very interested in global harmonization,” Malvina B. Eydelman, MD, director for the FDA’s Division of Ophthalmic, Neurological and Ear, Nose and Throat Devices, said. “To that end, there are several processes that the FDA is actively involved in.”

Two examples are the Global Harmonization Task Force (GHTF) and the International Organization for Standardization (ISO), two organizations that work to introduce more streamlined requirements around the world. Dr. Eydelman said the subject of ophthalmic approval processes continues to gain attention and is now being more widely discussed, as numerous groups rally for unified approval requirements.

Countries have been sharing data and standards in the ophthalmic device approval process for some time. For example, European studies provide clinical data that the FDA may use in its approval process. In addition, officials worldwide may consider the FDA approval of an ophthalmic device to be the best standard for approving devices in their own countries, according to Stephen S. Lane, MD.

“A lot of foreign countries see the FDA as their aptitude test,” Dr. Lane, a medical monitor for Alcon, said. “Once it’s approved by the FDA, a lot of times it’s a very easy step for the other countries to approve a product because they have the reassurance that this has already been scrutinized significantly by the FDA.”

Global coordination of processes

Approval processes in countries such as Japan can be as complex and regulated as in the United States. In Europe and, to some extent, Canada and Australia, the process is also involved, but typically not as lengthy and with different protocols.

In the United States, the approval process is conducted by the FDA, a government regulatory body, whereas in Europe, the process is largely conducted by manufacturers and third-party assessors and is based on European regulatory directives overseen by national agencies.

The U.S. process is unique in several ways, Dr. Eydelman said.

“[The] FDA has a very distinct classification process, with each class having its own associated regulatory requirements, which is different than many countries,” she said. “The other big distinction, I think, is that the FDA has many guidance documents and many recognized standards to actually help the industry to understand the FDA’s expectations for each type of ophthalmic device.”

The FDA has been involved with the GHTF in an effort to assist with achieving international harmonization of regulatory procedures. According to information from the GHTF, the voluntary group of device regulatory and industry authorities was formed in 1992 to “encourage convergence in regulatory practices related to ensuring the safety, effectiveness/performance and quality of medical devices, promoting technological innovation and facilitating international trade.”

The FDA has also been active with the ISO. The nongovernmental world-standard organization has technical committees and working groups with representatives from numerous countries that develop and publish standards for ophthalmic devices, which are then often formally adopted or recognized by nations around the world, according to Dr. Eydelman, who is the ISO U.S. representative.

ISO has published many standards for various ophthalmic devices. Some examples include monofocal, phakic and multifocal IOLs, ophthalmic viscosurgical devices, and ocular endotamponades.

“Even though our processes are so vastly different, once different countries recognize the respective standard, that implies that the requirements for that particular device are going to be the same, as far as preclinical and clinical expectations of performance. We have many ophthalmic ISO standards recognized by the FDA,” Dr. Eydelman said.

Malvina B. Eydelman, MD
Malvina B. Eydelman

Although ISO standards are frequently adopted by regulatory agencies worldwide, individual country’s rules and regulations govern the actual processes for getting devices to the market, she said.

FDA approval process

In the United States, the FDA’s Center for Devices and Radiological Health oversees the approval of medical devices, including ophthalmic devices. A medical device, as defined by the FDA, “diagnoses, cures, mitigates, treats or prevents a disease or condition; affects the function or structure of the body; does not achieve intended use through chemical action; is not metabolized.”

Medical devices are then divided into one of three classifications: class 1, 2 or 3.

Class 1 has the least regulatory control and includes ophthalmic devices such as perimeters and topographers, Dr. Eydelman said.

Class 2 devices have increased regulation that requires 510(k) premarket notification. Examples of class 2 ophthalmic devices include daily wear contact lenses and phacoemulsification instruments.

Class 3 devices require a premarket application. For these devices, the “application needs to contain sufficient valid scientific evidence to provide reasonable assurance that the device is safe and effective for its intended use,” according to information provided by Dr. Eydelman. Examples of class 3 ophthalmic devices include IOLs and excimer lasers.

Kerry D. Solomon, MD, the American Society of Cataract and Refractive Surgery FDA committee chair and an OSN Refractive Surgery Board Member, called the process “fairly complex” but effective at what it was designed to do.

“The main goal of the FDA is to approve technology [and] in terms of the ophthalmic devices, to approve devices in a timely manner so that people in the United States can have access to some of the latest advances possible. While at the same time, their role is to try to protect the American public from harm,” Dr. Solomon said. “It’s a delicate balance that they walk, so they want to make sure due diligence is done.”

Dr. Lane has been involved in the ophthalmic medical device approval process in all its stages. He recently presented data from the Implantable Miniature Telescope (VisionCare Ophthalmic Technologies) clinical studies before the FDA’s Advisory Ophthalmic Panel.

He said that the current FDA process differs from the past process, in which physicians or companies, known as “sponsors,” would develop a protocol for the new product or device and then conduct a study. Afterward, sponsors would present results to the FDA. However, that process could be stymied if FDA panelists discovered an issue with the application, he said.

“I think there’s been really significant improvement in the relationship between the FDA and the sponsors, in that the FDA is making a very good attempt to work with industry to assist them in developing clinical protocols and guidelines that give the product the best chance to be approved and eventually come to market, if the rigors of the protocol are followed and safety and efficacy are proven based on those rigors,” Dr. Lane said.

CE mark in Europe

In Europe, a CE mark is needed for a device to reach the market. The CE (“Conformité Européenne,” French for “European conformity”) mark ensures that a product has been manufactured in a consistent way through specific standards and protocols, Richard B. Packard, MD, FRCS, FRCOphth, said.

“It’s sort of process-based, in a way,” Mr. Packard said. “Depending on what sort of products you’re producing, whether it’s considered a sensitive product or not, you can only self-register. And all you have to do is to show that the product is being produced in a consistent manner. It’s a much, much lower bar than FDA approval. So you can have products CE marked really quite easily.”

Richard B. Packard, MD, FRCS, FRCOphth
Richard B. Packard

How easily and quickly the CE mark can be obtained is based on the complexity of the device. There are several classifications, based on degree of risk, to obtain a CE mark: class 1, class 2a and 2b, and class 3. Devices must meet the “Essential Requirements of the Medical Devices Directive,” which provides that devices are safe and effective and have a fair risk-to-benefit ratio, according to the Medicines and Healthcare products Regulatory Agency (MHRA), the United Kingdom’s authority that enforces the European directives.

For manufacturers of class 1 devices that meet the essential requirements, conformity can be done as a “self-certify,” meaning that the CE mark can be obtained by the manufacturer in as little as a day.

However, for devices that are more complex and at a higher classification level, clinical data is required and a “Notified Body” must rule on assessment of conformity, according to the MHRA. In some cases, a clinical trial also must be conducted.

After obtaining the CE mark, devices can be sold throughout the European Union.

Mr. Packard said U.S. companies often seek CE marks so they can launch their products more quickly in Europe. European countries can sometimes be testing grounds for ophthalmic devices.

“A lot of products we get in Europe before the U.S. because we don’t have to get FDA approval. And getting a CE mark is relatively straightforward,” he said. “For example, I designed a new knife for a smaller incision, microincision phaco, and in order to get that on the market, we had to get CE marking, which was relatively inexpensive, very easy to do. You just had to show that you have the suitable ability to manufacture it in a consistent manner.”

Comparing processes

Differences between the U.S. and European approval processes have resulted in discussions about the merits of both systems. Dialogue about the variations in approval processes and secondary requirements for ophthalmic devices at meetings such as the International Symposium on Ocular Pharmacology and Therapeutics (ISOPT) symposium could assist in establishing global harmonization, Dr. Eydelman said.

The FDA has prevented devices that had major complications from entering the U.S. market, Dr. Eydelman said. Because of FDA regulations that prohibit her from discussing confidential matters, she could not give specific examples, but said that she had seen numerous occurrences of devices being pulled from the European market while still in the FDA approval process.

“I truly believe our process ensures rigorous assessment of the safety and efficacy of the device prior to its release to the market,” Dr. Eydelman said.

For example, before reaching the U.S. market, in 2007 the Vivarte and NewLife phakic IOLs (IOLTech/Carl Zeiss Meditec) and Icare lens (Cornéal) were withdrawn from the French market following evidence of significant endothelial cell loss in patients 2 to 3 years after implantation. Those lenses were still being investigated through the FDA’s approval process.

Dr. Lane called the rigorous, lengthy phases of the FDA approval process a double-edged sword that can sometimes frustrate U.S. physicians.

Fast Facts

It can take 5 years to 7 years for a class 3 device to be approved for the U.S. market, he said.

However, vigilance in the approval process is also important. Dr. Lane said the classic example is the use of thalidomide in the late 1950s and early 1960s. Thousands of European infants were born with birth defects after their mothers had taken the drug while pregnant. At that point, thalidomide had not reached the U.S. market because of research by FDA scientists. Thalidomide use was eventually approved by the FDA in the late 1990s.

“I think that [the FDA process] certainly protects us,” Dr. Lane said. “The question is, during the time you are safeguarding the public by going through the rigors and expense of a clinical trial, how much are you preventing improved treatments or even potential harm by not making the technology available to physicians and their patients?”

Dr. Solomon said some delays in the approval process can be caused by sponsors if they do not meet preset guidelines or provide necessary information.

However, he thinks that the approval process accomplishes its mission of providing safe and effective devices in a timely manner.

“There are a lot of perceptions that the FDA is slowing things down, and the FDA is at fault for a number of things,” he said. “The FDA is in a difficult position because on the one hand, it’s seen as something that slows down the new advances of technologies, and then on another, it’s seen as, ‘How could they approve a device or a pharmaceutical agent when clearly there are problems associated with it?’ So they’re in a difficult position.

“I’ve had a chance to meet and speak with these people, and they’re good people; they’re well-intentioned. They’re doing a good job. They’re interested in getting better. They’re gaining input from the public, from societies and industry, and in general, they’re motivated and properly orientated so that their goals are aligned with what the public needs them to be,” Dr. Solomon said.

Future of globalized harmonization

Information about the coordination of various processes will be disseminated at several meetings this year. In September, the Asia-Pacific Economic Cooperation (APEC) will host the APEC-Funded Asian Medical Devices Regulatory Harmonization Delegation Visit to Australia. The meeting will serve to inform officials on “global harmonization of medical device regulation” issues, according to APEC.

In addition, for the first time, a symposium on the topic will be held at the ISOPT meeting in Italy in December. The symposium, called “Regulatory issues in ophthalmology across the world,” will bring together experts from three continents to discuss approval processes in those regions.

Dr. Eydelman will attend the ISOPT meeting as the U.S. representative. She said the symposium will highlight various aspects of approval processes and how global cooperation could benefit approval of ophthalmic devices around the world. – by Erin L. Boyle

POINT/COUNTER
Are there advantages to the FDA’s stringent approval process for ophthalmic devices for physicians and patients?

  • Malvina B. Eydelman, MD, can be reached at malvina.eydelman@fda.hhs.gov.
  • Stephen S. Lane, MD, can be reached at 2950 Curve Crest Blvd., Stillwater, MN 55082; 651-275-3000; fax: 651-275-3099; e-mail: sslane@associatedeyecare.com.
  • Richard B. Packard, MD, FRCS, FRCOphth, can be reached at Arnott Eye Associates, 22a Harley St., London W1G 9BP, England; 44-20-7580-1074; e-mail: eyequack@vossnet.co.uk.
  • Kerry D. Solomon, MD, can be reached at Medical University of South Carolina, Storm Eye Institute, 167 Ashley Ave., Room 221, PO Box 250676, Charleston, SC 29425; 843-792-8854; 843-792-6347; e-mail: solomonk@musc.edu.

Requirements for approval of ophthalmic devices differ widely around the world, and the U.S. Food and Drug Administration’s ophthalmic device approval process is considered one of the gold standards. The agency is now taking part in an effort to create global standardization of the approval process.

Stephen S. Lane, MD
Stephen S. Lane, MD, a medical monitor for Alcon, acknowledged that the rigorous, lengthy FDA approval process can be frustrating for physicians.
Image: O'Brien T

“The FDA is very interested in global harmonization,” Malvina B. Eydelman, MD, director for the FDA’s Division of Ophthalmic, Neurological and Ear, Nose and Throat Devices, said. “To that end, there are several processes that the FDA is actively involved in.”

Two examples are the Global Harmonization Task Force (GHTF) and the International Organization for Standardization (ISO), two organizations that work to introduce more streamlined requirements around the world. Dr. Eydelman said the subject of ophthalmic approval processes continues to gain attention and is now being more widely discussed, as numerous groups rally for unified approval requirements.

Countries have been sharing data and standards in the ophthalmic device approval process for some time. For example, European studies provide clinical data that the FDA may use in its approval process. In addition, officials worldwide may consider the FDA approval of an ophthalmic device to be the best standard for approving devices in their own countries, according to Stephen S. Lane, MD.

“A lot of foreign countries see the FDA as their aptitude test,” Dr. Lane, a medical monitor for Alcon, said. “Once it’s approved by the FDA, a lot of times it’s a very easy step for the other countries to approve a product because they have the reassurance that this has already been scrutinized significantly by the FDA.”

Global coordination of processes

Approval processes in countries such as Japan can be as complex and regulated as in the United States. In Europe and, to some extent, Canada and Australia, the process is also involved, but typically not as lengthy and with different protocols.

In the United States, the approval process is conducted by the FDA, a government regulatory body, whereas in Europe, the process is largely conducted by manufacturers and third-party assessors and is based on European regulatory directives overseen by national agencies.

The U.S. process is unique in several ways, Dr. Eydelman said.

“[The] FDA has a very distinct classification process, with each class having its own associated regulatory requirements, which is different than many countries,” she said. “The other big distinction, I think, is that the FDA has many guidance documents and many recognized standards to actually help the industry to understand the FDA’s expectations for each type of ophthalmic device.”

The FDA has been involved with the GHTF in an effort to assist with achieving international harmonization of regulatory procedures. According to information from the GHTF, the voluntary group of device regulatory and industry authorities was formed in 1992 to “encourage convergence in regulatory practices related to ensuring the safety, effectiveness/performance and quality of medical devices, promoting technological innovation and facilitating international trade.”

The FDA has also been active with the ISO. The nongovernmental world-standard organization has technical committees and working groups with representatives from numerous countries that develop and publish standards for ophthalmic devices, which are then often formally adopted or recognized by nations around the world, according to Dr. Eydelman, who is the ISO U.S. representative.

ISO has published many standards for various ophthalmic devices. Some examples include monofocal, phakic and multifocal IOLs, ophthalmic viscosurgical devices, and ocular endotamponades.

“Even though our processes are so vastly different, once different countries recognize the respective standard, that implies that the requirements for that particular device are going to be the same, as far as preclinical and clinical expectations of performance. We have many ophthalmic ISO standards recognized by the FDA,” Dr. Eydelman said.

Malvina B. Eydelman, MD
Malvina B. Eydelman

Although ISO standards are frequently adopted by regulatory agencies worldwide, individual country’s rules and regulations govern the actual processes for getting devices to the market, she said.

FDA approval process

In the United States, the FDA’s Center for Devices and Radiological Health oversees the approval of medical devices, including ophthalmic devices. A medical device, as defined by the FDA, “diagnoses, cures, mitigates, treats or prevents a disease or condition; affects the function or structure of the body; does not achieve intended use through chemical action; is not metabolized.”

Medical devices are then divided into one of three classifications: class 1, 2 or 3.

Class 1 has the least regulatory control and includes ophthalmic devices such as perimeters and topographers, Dr. Eydelman said.

Class 2 devices have increased regulation that requires 510(k) premarket notification. Examples of class 2 ophthalmic devices include daily wear contact lenses and phacoemulsification instruments.

Class 3 devices require a premarket application. For these devices, the “application needs to contain sufficient valid scientific evidence to provide reasonable assurance that the device is safe and effective for its intended use,” according to information provided by Dr. Eydelman. Examples of class 3 ophthalmic devices include IOLs and excimer lasers.

Kerry D. Solomon, MD, the American Society of Cataract and Refractive Surgery FDA committee chair and an OSN Refractive Surgery Board Member, called the process “fairly complex” but effective at what it was designed to do.

“The main goal of the FDA is to approve technology [and] in terms of the ophthalmic devices, to approve devices in a timely manner so that people in the United States can have access to some of the latest advances possible. While at the same time, their role is to try to protect the American public from harm,” Dr. Solomon said. “It’s a delicate balance that they walk, so they want to make sure due diligence is done.”

Dr. Lane has been involved in the ophthalmic medical device approval process in all its stages. He recently presented data from the Implantable Miniature Telescope (VisionCare Ophthalmic Technologies) clinical studies before the FDA’s Advisory Ophthalmic Panel.

He said that the current FDA process differs from the past process, in which physicians or companies, known as “sponsors,” would develop a protocol for the new product or device and then conduct a study. Afterward, sponsors would present results to the FDA. However, that process could be stymied if FDA panelists discovered an issue with the application, he said.

“I think there’s been really significant improvement in the relationship between the FDA and the sponsors, in that the FDA is making a very good attempt to work with industry to assist them in developing clinical protocols and guidelines that give the product the best chance to be approved and eventually come to market, if the rigors of the protocol are followed and safety and efficacy are proven based on those rigors,” Dr. Lane said.

CE mark in Europe

In Europe, a CE mark is needed for a device to reach the market. The CE (“Conformité Européenne,” French for “European conformity”) mark ensures that a product has been manufactured in a consistent way through specific standards and protocols, Richard B. Packard, MD, FRCS, FRCOphth, said.

“It’s sort of process-based, in a way,” Mr. Packard said. “Depending on what sort of products you’re producing, whether it’s considered a sensitive product or not, you can only self-register. And all you have to do is to show that the product is being produced in a consistent manner. It’s a much, much lower bar than FDA approval. So you can have products CE marked really quite easily.”

Richard B. Packard, MD, FRCS, FRCOphth
Richard B. Packard

How easily and quickly the CE mark can be obtained is based on the complexity of the device. There are several classifications, based on degree of risk, to obtain a CE mark: class 1, class 2a and 2b, and class 3. Devices must meet the “Essential Requirements of the Medical Devices Directive,” which provides that devices are safe and effective and have a fair risk-to-benefit ratio, according to the Medicines and Healthcare products Regulatory Agency (MHRA), the United Kingdom’s authority that enforces the European directives.

For manufacturers of class 1 devices that meet the essential requirements, conformity can be done as a “self-certify,” meaning that the CE mark can be obtained by the manufacturer in as little as a day.

However, for devices that are more complex and at a higher classification level, clinical data is required and a “Notified Body” must rule on assessment of conformity, according to the MHRA. In some cases, a clinical trial also must be conducted.

After obtaining the CE mark, devices can be sold throughout the European Union.

Mr. Packard said U.S. companies often seek CE marks so they can launch their products more quickly in Europe. European countries can sometimes be testing grounds for ophthalmic devices.

“A lot of products we get in Europe before the U.S. because we don’t have to get FDA approval. And getting a CE mark is relatively straightforward,” he said. “For example, I designed a new knife for a smaller incision, microincision phaco, and in order to get that on the market, we had to get CE marking, which was relatively inexpensive, very easy to do. You just had to show that you have the suitable ability to manufacture it in a consistent manner.”

Comparing processes

Differences between the U.S. and European approval processes have resulted in discussions about the merits of both systems. Dialogue about the variations in approval processes and secondary requirements for ophthalmic devices at meetings such as the International Symposium on Ocular Pharmacology and Therapeutics (ISOPT) symposium could assist in establishing global harmonization, Dr. Eydelman said.

The FDA has prevented devices that had major complications from entering the U.S. market, Dr. Eydelman said. Because of FDA regulations that prohibit her from discussing confidential matters, she could not give specific examples, but said that she had seen numerous occurrences of devices being pulled from the European market while still in the FDA approval process.

“I truly believe our process ensures rigorous assessment of the safety and efficacy of the device prior to its release to the market,” Dr. Eydelman said.

For example, before reaching the U.S. market, in 2007 the Vivarte and NewLife phakic IOLs (IOLTech/Carl Zeiss Meditec) and Icare lens (Cornéal) were withdrawn from the French market following evidence of significant endothelial cell loss in patients 2 to 3 years after implantation. Those lenses were still being investigated through the FDA’s approval process.

Dr. Lane called the rigorous, lengthy phases of the FDA approval process a double-edged sword that can sometimes frustrate U.S. physicians.

Fast Facts

It can take 5 years to 7 years for a class 3 device to be approved for the U.S. market, he said.

However, vigilance in the approval process is also important. Dr. Lane said the classic example is the use of thalidomide in the late 1950s and early 1960s. Thousands of European infants were born with birth defects after their mothers had taken the drug while pregnant. At that point, thalidomide had not reached the U.S. market because of research by FDA scientists. Thalidomide use was eventually approved by the FDA in the late 1990s.

“I think that [the FDA process] certainly protects us,” Dr. Lane said. “The question is, during the time you are safeguarding the public by going through the rigors and expense of a clinical trial, how much are you preventing improved treatments or even potential harm by not making the technology available to physicians and their patients?”

Dr. Solomon said some delays in the approval process can be caused by sponsors if they do not meet preset guidelines or provide necessary information.

However, he thinks that the approval process accomplishes its mission of providing safe and effective devices in a timely manner.

“There are a lot of perceptions that the FDA is slowing things down, and the FDA is at fault for a number of things,” he said. “The FDA is in a difficult position because on the one hand, it’s seen as something that slows down the new advances of technologies, and then on another, it’s seen as, ‘How could they approve a device or a pharmaceutical agent when clearly there are problems associated with it?’ So they’re in a difficult position.

“I’ve had a chance to meet and speak with these people, and they’re good people; they’re well-intentioned. They’re doing a good job. They’re interested in getting better. They’re gaining input from the public, from societies and industry, and in general, they’re motivated and properly orientated so that their goals are aligned with what the public needs them to be,” Dr. Solomon said.

Future of globalized harmonization

Information about the coordination of various processes will be disseminated at several meetings this year. In September, the Asia-Pacific Economic Cooperation (APEC) will host the APEC-Funded Asian Medical Devices Regulatory Harmonization Delegation Visit to Australia. The meeting will serve to inform officials on “global harmonization of medical device regulation” issues, according to APEC.

In addition, for the first time, a symposium on the topic will be held at the ISOPT meeting in Italy in December. The symposium, called “Regulatory issues in ophthalmology across the world,” will bring together experts from three continents to discuss approval processes in those regions.

Dr. Eydelman will attend the ISOPT meeting as the U.S. representative. She said the symposium will highlight various aspects of approval processes and how global cooperation could benefit approval of ophthalmic devices around the world. – by Erin L. Boyle

POINT/COUNTER
Are there advantages to the FDA’s stringent approval process for ophthalmic devices for physicians and patients?

  • Malvina B. Eydelman, MD, can be reached at malvina.eydelman@fda.hhs.gov.
  • Stephen S. Lane, MD, can be reached at 2950 Curve Crest Blvd., Stillwater, MN 55082; 651-275-3000; fax: 651-275-3099; e-mail: sslane@associatedeyecare.com.
  • Richard B. Packard, MD, FRCS, FRCOphth, can be reached at Arnott Eye Associates, 22a Harley St., London W1G 9BP, England; 44-20-7580-1074; e-mail: eyequack@vossnet.co.uk.
  • Kerry D. Solomon, MD, can be reached at Medical University of South Carolina, Storm Eye Institute, 167 Ashley Ave., Room 221, PO Box 250676, Charleston, SC 29425; 843-792-8854; 843-792-6347; e-mail: solomonk@musc.edu.