Overview: FDA Regulation of Medical Devices

July 16, 2008

Medical Device Definition

Medical Device Recalls are either corrections or removals, depending on where the action is applied. The FDA posts consumer information about the most serious medical device recalls. These products are on the list because there is a reasonable chance that they could cause serious health problems or death.

Despite the great care taken during the development of medical devices, errors can still occur. The important thing, therefore, is to establish proactive practices to determine ‘recall readiness’ after launching of a medical device product. To explore the impact of managing the decision-making process of a recall (if you ever have to face one), Read More>>

Medical devices distributed in the United Sates are subject to General Controls, pre-marketing and post marketing regulatory controls.

General Controls include:

  1. Establishment Registration by manufacturers, distributors, repackages and re-labelers,
  2. Medical Device Listing with FDA of devices to be marketed,
  3. Manufacturing the devices in accordance with Good Manufacturing Practices,
  4. Labeling medical devices in accordance with the labeling regulations, 21 CFR 801 or 21 CFR 809,
  5. Medical Device Reporting of adverse events as identified by the user, manufacturer and/or distributor of the medial device.

Pre-marketing controls are device and device classification specific. Pre-marketing controls for a medical device may include:

1. Clearance to market by 510(k),

2. Approval to market by Pre-Market Approval (PMA)

3. Post marketing controls include Device Listing

4. Medical Device Reporting (MDR)

5. Establishment Registration and Quality System Compliance Inspection

Device Classification

There are 3 FDA regulatory classifications of medical devices: Class I, Class II and Class III. The classifications are assigned by the risk the medical device presents to the patient and the level of regulatory control the FDA determines is needed to legally market the device. As the classification level increases, the risk to the patient and FDA regulatory control increases. Accessories to medical devices, devices used with a medical device to support use of the device, are considered the same classification as the medical device.

The FDA classification of medical devices is based upon classifications for devices currently legally marketed in the United States. The FDA determines the device classification by the device intended use and risk the device presents to the patient. New medical devices are compared to legally marketed medical device classifications with the same intended use and technological characteristics to determine the device classification.

Class I medical devices have the least amount of regulatory control. Class I devices present minimal potential harm to the user. Class I devices are typically simple in design, manufacture and have a history of safe use. Examples of Class I devices include tongue depressors, arm slings, and hand-held surgical instruments. Most Class I devices are exempt from the premarket notification and may be exempt from compliance with the good manufacturing practices regulation.

Class II medical devices are devices where General Controls are not sufficient to assure safety and effectiveness and existing methods/standards/guidance documents are available to provide assurances of safety and effectiveness. In addition to compliance with General Controls, Class II devices are required to comply with Special Controls. Special Controls include:

  • Special labeling requirements,
  • Mandatory performance standards, both International and United States
  • Postmarket surveillance
  • FDA medical device specific guidance

Class II devices typically require pre-market notification by submission and FDA review of a 510(k) clearance to market submission. A few Class II devices are exempt from the premarket notification. Information on Class II exempt devices is located within the device regulation, 21 CFR 862 through 892. Examples of Class II devices include physiologic monitors, x-ray systems, gas analyzers, pumps, and surgical drapes.

Class III medical devices have the most stringent regulatory controls. For Class III medical devices, sufficient information is not available to assure safety and effectiveness through the application of General Controls and Special Controls. Class III devices usually support or sustain human life, are of substantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury to the patient. Typically a Pre-Market Approval (PMA) submission to the FDA is required to allow marketing of a Class III medical device. A few Class III medical devices are required to only have a 510(k) cleared by the FDA to be marketed. Examples of Class III devices that require a PMA are: replacement heart valves, silicone gel-filled breast implants, and implanted cerebella stimulators.

510(k) Clearance to Market

The majority of Class II medical devices are cleared to market by submission and FDA review of a 510(k) Pre-Market Notification submission. The 510(k) submission identifies characteristics of the new or modified medical device as compared to a medical device with similar intended use, currently legally marketed in the United States. The currently legally marketed device is referred to as the “predicate” device.

The information required in a 510(k) submission is defined 21 CFR 807.87. A 510(k) submission includes:

  • Device trade or proprietary name, common or usual name or classification, Class of the device (Class I, II, III)
  • Submitter’s name and address, Contact person, telephone number and fax number, Representative/Consultant if applicable
  • Name and address of manufacturing/packaging/sterilization facilities, Registration number of each manufacturing facility
  • Action taken to comply with the requirements of the Special Controls.
  • Proposed labels, labeling, and advertisements to describe the device, its intended use, and the directions for its use.
  • 510(k) summary or a 510(k) statement.
  • For Class III medical device, a Class III certification and a Class III summary.
  • Photographs of the device, Engineering drawings of the device.
  • Identification of the marketed device(s) to which equivalence is claimed including labeling and description of the medical device.
  • Statement of similarities and/or differences with marketed device(s)
  • Data to show consequences and effects of a modified device, performance Data (bench, animal, clinical)
  • Sterilization information (as applicable)
  • Software development, verification and validation information
  • Hardware design and development information
  • Information requested in specific guidance documents (as applicable)
  • Kit Certification Statement (for a 510(k) submission with kit components only)
  • Truthful and Accurate Statement

Depending on the complexity of the new or modified medical device, the FDA Review of a 510(k) submission takes between 20 and 90+ days. The more complex the changes or comparison required to support the safety and effectiveness of the new or modified medical device, the longer the FDA review process.

PMA (Pre-Market Approval)

A PMA is required for FDA Approval of medical devices that present significant risk to the patient and/or require significant scientific review of the safety and effectiveness of the medical device prior to commercial introduction. Most Class III medical devices require a PMA. Section 515(c)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) specifies the required contents of a PMA. PMA application content includes:

  • full reports of all information, published or known to or which should reasonably be known to the applicant, concerning investigations which have been made to show whether or not such device is safe and effective;
  • a full statement of the components, ingredients, and properties and of the principle or principles of operation, of such device;
  • a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and, when relevant, packing and installation of such device;
  • an identifying reference to any performance standard under Section 514 which would be applicable to any aspect of such device if it were a Class II device, and either adequate information to show that such aspect of such device fully meets such performance standard or adequate information to justify any deviation from such standards;
  • such samples of such device and of components thereof as the Secretary may reasonably require, except that where the submission of such samples is impracticable or unduly burdensome, the requirement of this subparagraph may be met by the submission of complete information concerning the location of one or more such devices readily available for examination and testing;
  • specimens of the labeling proposed to be used for such device; and
  • such other information relevant to the subject matter of the application as the Secretary, with the concurrence of the appropriate panel under Section 513, may require.

The FDA has a statutory 180-day review cycle for PMA applications. Often PMA applications require medical advisory board review prior to the FDA granting approval to market the medical device. A facility inspection verifying the manufacturing systems present to manufacture the medical device is usually performed prior to FDA PMA approval. FDA approval of a PMA often requires significantly more than 180 days. Risk evaluation and development of mitigation strategies
Read More>>

Good Manufacturing Compliance (GMP)Compliance

The Good Manufacturing Practice (GMP) requirements are defined in 21 CFR 820. The GMP is also referred to as the Quality System (QS) Regulation. A quality system is required for the design, manufacture, packaging, labeling, storage, installation, and servicing of finished medical devices intended for commercial distribution in the United States. The QS Regulation is similar to ISO 9001:1994, with FDA particular requirements. The QS Regulation covers:

  • quality management and organization,
  • device design,
  • buildings,
  • equipment,
  • purchase and handling of components,
  • production and process controls,
  • packaging and labeling control,
  • device evaluation,
  • distribution,
  • installation,
  • complaint handling,
  • servicing,
  • records.

The FDA may audit the manufacturing facility for GMP compliance every 2 years. FDA compliance inspections are based upon results of prior audits, device risks, recall of devices and FDA initiatives in regard to particular classifications of devices.

Establishment Registration

Establishments involved in the production and distribution of medical devices intended for marketing in the United States are required to register with the FDA. Establishment Registration requirements are defined in 21 CFR 807. Establishment Registrations are verified and updated annually.

Foreign establishments engaged in the manufacture, preparation, propagation, compounding, or processing of a device that is imported, or offered for import, into the United States must register their establishments and provide the FDA with the name of the United States agent representing their establishment. Foreign establishments must provide FDA with a list of the devices that they are exporting to the United States.

Device Listing

Most medical device establishments required to register with FDA must list the devices they have in commercial distribution. Medical device listing is completed by the classification name the FDA has assigned to the medical device, see 21 CFR Part 862 to 892.

Device listing should be completed within 30 days of entering a device into commercial distribution in the United States. Device listing is updated when a new classification of device is entered into commercial distribution, the marketing of a device classification is discontinued, or marketing of a discontinued device is started again.

Medical Device Reporting(MDR)

The Medical Device Reporting (MDR) regulation requires firms who have received complaints of device malfunctions, serious injuries or deaths associated with medical devices to notify FDA of the incident. The requirements for medical device reporting are defined in 21 CFR 803. The regulation requires:

  • A written MDR procedure,
  • MDR event files,
  • Individual adverse event reports,
  • 5 day MDR reports of remedial action taken to prevent unreasonable risk of substantial harm to public health,
  • 30-day MDR reports of deaths, serious injuries and malfunction attributed to the medical device,
  • Baseline reports for the medical device.

Risk evaluation and development of mitigation strategies

Read More>>

Ranbaxy probe includes AIDS relief meds

July 16, 2008

Ranbaxy can’t be happy. The Indian company’s stock is way down for the second day in a row, on news that the U.S. investigation into its operations includes allegations that it made weak or adulterated HIV drugs given to thousands of AIDS patients in Africa. The Indian company has U.S. government contracts to supply low-cost antiretrovirals for AIDS relief, but Justice Department and FDA investigators allege that some of those drugs were poorly made, unstable, or too weak to be effective.

Meanwhile, the company acceded to the government’s requests for documents, saying it would turn over the papers. The disputed documents are audit reports from Parexel, a consulting firm that examined Ranbaxy’s plants. You’ll recall that investigators claim at least some of these documents were fabricated to cover up the fact that Ranbaxy had made substandard products. The company had claimed that the audits were “privileged” and were thus confidential.

Ranbaxy also reiterated its conviction that its sale to Daiichi Sankyo remains on track and that its licensing deals–including a recent pact with Pfizer to produce an authorized generic version of Lipitor–aren’t affected by the probe, either. And the company says it “knows of no evidence to support” the U.S. allegations, which it acknowledged as “serious.”

Source: Wall Street Journal story

PhRMA Code’s revised guidelines take effect January 2009

July 16, 2008

The Pharmaceutical Research and Manufacturers of America (PhRMA) released updates to its voluntary Code on Interactions with Healthcare Professionals on July 10. The new guidelines take effect January 2009.

In addition to prohibiting small gifts and reminder items, the revised Code:Prohibits company sales representatives from providing restaurant meals to healthcare professionals, but allows them to provide occasional meals in healthcare professionals’ offices in conjunction with informational presentations
  1. Prohibits company sales representatives from providing restaurant meals to healthcare professionals, but allows them to provide occasional meals in healthcare professionals’ offices in conjunction with informational presentations
  2. Includes new provisions requiring companies to ensure their representatives are sufficiently trained about applicable laws, regulations, and industry codes of practice
  3. Provides that each company will state its intentions to abide by the Code and that company CEOs and compliance officers will certify each year that they have processes in place to comply
  4. Includes more detailed standards regarding the independence of continuing medical education
  5. Provides additional guidance for speaking and consulting arrangements with healthcare professionals
  1. Tracking aggregate spending is one of the biggest challenges for pharmaceutical companies
  2. Some companies do not have a system that will accurately record aggregate spending across the organization.
  3. Training employees is another. It’s going to be a challenge getting everyone on the same page.
  1. The new guidelines could help the industry regain public trust after “just getting shelled” and constantly being accused of wrongdoing. In addition, some
  2. Companies will be relieved they can reduce their spending on traditional marketing activities.

The IAEA safeguards agreement explained

July 16, 2008

Ever since India sent the text of its agreement with the IAEA to the agency’s board of governors, a lot of questions have been raised.

Even with the text being made public, the questions and accusations of what India can do and what it can’t have failed to subside.

Last Saturday, National Security Advisor M K Narayanan, Foreign Secretary Shiv Shankar Menon, Department of Atomic Energy secretary Dr Anil Kakodkar, and India’s chief negotiator with the IAEA Dr R B Grover met journalists and answered the persistent questions about the India-IAEA draft agreement.

Some of the pertinent technical questions were:

1. Can India test?
2. Will Indi
a’s reactors be under perpetual safeguards, even if fuel supply stops due to some reason or the other?
3. What about the Hyde Act, which seeks to put a lot of restrictions on India?
4. What will happen to India’s Intellectual Property Rights (its nuclear know-how)?
And the one political question:
5. Did the government hoodwink the Left and go to the IAEA behind its back?

The experts gave lucid explanations to all these questions (India can test, perpetuity of safeguards is tied with perpetuity of fuel supply, India’s technical know-how is safe and no, the UPA did not cheat the Left) and more.

Just what does the text of the agreement between India and the International Atomic Energy Agency say?

The text essentially consists of these parts: The preamble, the general considerations, safeguards procedure and miscellaneous considerations.

In the preamble India has embedded important concepts like sovereignty, nuclear activities and expanding international cooperation on a reliable, stable and predictable basis.

The general considerations are specific to India. The IAEA usually has an agreement for individual reactors, like for example India has for the Koodankulam reactor.

There is a departure from convention in the safeguards procedure. India and the IAEA will have an agreement that specifies 66 types of safeguards for all civilian reactors in the country. This is an umbrella agreement and applies to all civilian reactors and there won’t be any reactor-specific agreement.

The miscellaneous considerations consist of clauses for agency inspectors and settlement of disputes should they arise in the future.

What is the legal sanctity of the text?

The text is in keeping with the guidelines of the Vienna Convention. So there won’t be any legal trouble. “The entire text rose from the Vienna guidelines and stands on that one single pillar,” Narayanan said.

Kakodkar further explained that the 66 safeguards specified are applied to all non-NPT nations. “What we have done is instead of have an agreement for individual reactors, we told the IAEA to draw a single umbrella agreement that will cover all those reactors that India declares as civilian,”

Both Grover and Kakodkar clearly specified that the agreement would not apply to India’s strategic programme, which will continue.

In terms of any disagreement in the future, will it stop India from getting nuclear fuel?

The first thing that should be understood, the experts said, is that the agency does not supply fuel. It is the 45-member Nuclear Suppliers Group that will provide the fuel. “Through this particular safeguards agreement, we have to create conditions that help us in importing fuel and using it in our reactors.

Any supply agreement has to be between the supplier and us so we will have to build in, as we have been doing always, a strong commitment on the part of suppliers to continue, whether it is fuel or spares or whatever,” Dr Kakodkar said.

Another key asset in the text is that it provided a strategic fuel reserve to be used for the lifetime operation of those reactors.

“It means we can create a bank, and can fill it with fuel as and when we get fuel from other countries,” Foreign Secretary Shyam Saran said. He said this will allow for India’s programme to go ahead without any disruption even if a dispute arises in the future.

Kakodkar also said that with foreign supplies, it has always been India’s policy to “put whatever comes from outside under IAEA safeguards”.

He said, “In the India-specific safeguards agreement, India has very strongly connected such cooperation agreements with other countries and supply agreements with supplier countries with our going in for safeguards with IAEA. So there is this linking which says we are going in for IAEA safeguards because we are also talking about the supply agreements where continuity is built and then we can develop legally from that point onwards.”

Corrective measures:

India has always had agreements with various countries and has honoured it, the experts said, adding that with respect to the current agreement the fact that it allows for India to stockpile is the key.

“We have created a total framework, which will help us realise lifetime operation of fuel. The whole process will move in a way that will ensure that India always honours the agreement with a particular supplier country,” Kakodkar said.

“There will not be any requirement where there is a fuel supply disruption. But if such a situation arises, Article 52c provides for us to first raise this as a material violation of the agreement and that this itself might act as a deterrent.

If still a danger of disruption arises, we have here the combination of Articles 29, 30f, 10, 4 and the preamble, this will help us with whatever steps we want to take further.”

What about the perpetuity of the safeguards? Will they remain even if there is a disruption and India walks out of the deal?

There is no problem here, the experts said. “The permanence of safeguards is coupled with the perpetuity of supply of fuel. So in case there is a disruption in the supply of fuel, the safeguards agreement will cease to hold,” Kakodkar explained.

What about future reactors that India may build?

“Any reactor that India declares as civilian, will be put under IAEA safeguards. This applies for current as well as future reactors”.

Does India keep the right to test nuclear weapons?

“We are a nuclear weapons state. Now, the NPT may not include India as a nuclear weapons state. But, since we are not a NPT signatory, we do not need to care about what the NPT says. The world knows we are a nuclear weapons state.

We are talking civilian nuclear co-operation here. So, this text in no way says anything about our ability and right to test nuclear weapons. It is a purely civilian agreement and what more is necessary to be said?” Kakodkar said.

On the Hyde Act placing some roadblocks:

“The 123 agreement is what should matter. The Hyde Act does not find any mention in the 123 Agreement. The 123 Agreement is an India-US document, whereas the Hyde Act is a US legislation document. So we do not need to bother about what it says,” M K Narayanan said.

What happens when India transfers tech to other countries?

“The export of nuclear fuel from other countries is governed by the NSG guidelines. So when we are exporting it to other countries, there is no problem in harmonising our guidelines with the NSG guidelines.

Coming specifically to question of whether we can export, within the framework of the current agreement, we are free to export to whoever may want to buy.

When we export, we will notify the IAEA and insist on country X signing an agreement with IAEA so that the agency can put its safeguards in that country,” Kakodkar said.

Will the IAEA inspectors have access to Indian nuclear know-how? How will we safeguard our interests here?

“First up, the decision of what we declare civilian is up to us. It is well-embedded in the agreement. Even so, in the draft agreement, the role of the inspectors is restricted to ensuring that there is no diversion of fuel. There is no obligation for India to share tech. Also, we have a long experience of implementing IAEA safeguards and we know how things work and we can assure that no tech will be shared,” Menon said.

What was the sequence of events? When was the text initialed? When was it sent to the IAEA board of governors?

“The text was initialed by Dr Kakodkar on July 7. This does not mean that we went ahead with the agreement without letting the Left parties know. Initialing the text merely means that the two negotiators have agreed to the text in its present form and to made it be known that this is what we have agreed.

On July 8, the Left parties said they are not coming for the final co-ordination meeting on July 10. That is when we sent it to the IAEA,” Menon said.

When some journalists said that was before the Left parties withdrew support, Menon said withdrawal of support was never the criteria to send the text to the IAEA. “The co-ordination committee meeting was the deadline, not withdrawal of support. So when the Left decided against coming to the meeting, we sent the text. There is nothing wrong here,” he said.

What next?

The text will now go to the IAEA board of governors, which will meet sometime soon. “Once they clear it, it will be placed before the NSG. After the NSG gives us a clean exemption, the text will go to the US Congress where it will be put on an Up-Down vote. These are the tentative sequence of events for the next few steps,” Narayanan said.

Source: Rediff