CDG Whitepapers

Literature Evaluations for Biological Safety

A Whitepaper by Dr. Nancy J Stark

During the course of product development there are three times when you should do a literature evaluation: 1) to justify animal use, 2) to justify a clinical trial design, and 3) to apply for certification and CE Mark or Medicare reimbursement. I've written previous whitepapers about doing literature evaluations as a part of clinical evaluations. In this whitepaper I'll do a brief overview and then look at literature evaluations to justify animal use.

Three literature evaluations
Selective Clinical Evaluations
ISO 14155 requires a clinical evaluation to justify the design of a clinical trial. 0. ISO 14155. A European colleague showed me several literature evaluations that were done for this purpose. The most important point I noted was that they focused only on the selected indication being investigated, and resulted in a relatively short, compact literature review utilizing only 5-10 publications.

 

Comprehensive clinical evaluations
The literature evaluations intended for certification and CE Mark are supposed to be comprehensive, "The clinical evaluation is based on a comprehensive analysis of available pre- and post-market clinical data relevant to the intended use of the device in question…." 1. MEDDEV Clause 5.5.1. However, CDG has been successful with Notified Bodies by averaging ~40 articles per review for Class IIa and IIb devices. The number of articles reviewed depends on the number available, the quality of the articles, the age of the technology, the volume of competition, and other similar factors. I observed one European Class III device that got certification and CE Mark based on a review of only 9 case series and 7 publications.

Literature reviews for Medicare reimbursement application should be larger and will be more persuasive if they follow the examples found at www.ahrq.gov. The Agency for Healthcare Research and Quality (AHRQ) has been publishing technology assessment literature reviews for years. If you look at the technology assessment for negative pressure wound therapy (NPWT) devices, you'll see that 1078 citations were identified, 288 full-text articles retrieved, and 137 articles reviewed. There were also more than 1400 items submitted for review by independent "interested parties". The authors point out that none of the studies compared an NPWT system head-to-head to another system. 2. Negative Pressure.

Similarly, AHRQ recently released for comment a comparative effectiveness review of devices used in diagnosing cardiac disease in women, including stress electrocardiography, echocardiography, single proton emission computed tomography, cardiac magnetic resonance, and computed tomography angiography. A total of 7163 citations were identified, 1452 full-text articles retrieved, and 101 articles (98 studies) reviewed. The authors note that none of the studies were randomized controlled trials. 3. Diagnosing CAD. This review is currently open for public comment and device manufacturers should absolutely submit publications and data based on research they have done.

In 2010 AHRQ received $500,000,000 from the federal government to prepare comparative effectiveness reviews on a wide variety of products. These reviews will surely affect the availability of new and old technologies to the American patient as Medicare revisits its reimbursement decisions based on these reviews. The message to device manufacturers is that we will have to rethink how we design clinical trials and be prepared to submit our own clinical evaluations if we are to obtain reimbursement in the American marketplace.

Literature evaluations for biological safety
I haven't yet written about literature evaluations to justify the use of animals for biological safety testing or preclinical animal testing. The beauty is that the way you un-justify the use of animals is by demonstrating the work has already been done and does not bear repeating—saving you costly resourses and the unnecessary use of animals. Let's look more closely at literature evaluations to justify (or un-justify) animal tests.

How to Write A Clinical Evaluation—CD Workshop

A new CD workshop is now available on "How to Write a Clinical Evaluation". This well-researched presentation takes you step-by-step through the complicated process of writing a clinical evaluation by making it organized and understandable. The 100+ content slides and supporting handouts explain the logistics of clinical evaluations, how to define objectives and key questions, identify and retrieve abstracts, filter and screen abstracts to identify articles, filter again to zone in on the articles that are applicable, assess and weight the literature, and write the evaluation to address the key questions originally posed. The presentation discusses the three major purposes for evaluations, discusses their regulatory foundation, and proposes a strategy to allow each evaluation to build upon the previous ones. Finally, some average metrics are disclosed.

If you want a learning guide to help you write a clinical or literature evaluation, this workshop is the place to turn. A procedure, protocol, and template—meeting the requirements of MEDDEV 2.7.1 r3—are available for a small, additional cost. Click here to purchase or more information.

Authority—who says so
Take out your current copy of ISO 10993-1 "Biological evaluation of medical devices—Part 1: Evaluation and testing within a risk management process" (2009) and turn to Annex C, "Suggested procedure for literature review." 4. ISO 10993-1.

The introduction tells us, "A review and evaluation of the literature is essential for justification and planning of any biological evaluation of a material or a medical device. The aim of such a review is to determine scientific background for the biological evaluation. It also provides essential information for assessing risks/benefits and achieving the ethical conduct of the planned evaluation as required by ISO 10993-2.

NOTE Such a literature review can be helpful to assess whether the relevant data available in the literature are sufficient to demonstrate biological safety of the device in question without the need to generate further data from actual testing or to conclude that the available data are not sufficient.

Performing a literature review is a scientific activity that should be done with rigor and objectivity, and
should allow verification by third parties."

Methodology
[1] Establish a plan
The methodology, taken from Annex C, sounds a lot like the methodology described by GHTF Study Group 5 and MEDDEV 2.7.1 r3. The first step is to establish a plan or protocol for the identification, selection, collation and review of all available studies and data. The plan should be documented in writing and based on recognized practices for the systematic review of the scientific literature.

[2] Define objectives or key questions
The objectives of the literature evaluation should be clearly defined up-front. Sometimes it is easier to phrase the objectives in the form of key questions, for example, which, if any, animal safety tests from the G95-1 Matrix should be performed? 5. FDA BlueBook G95-1. Does the chemical characterization of the materials justify not doing animal safety tests? Do literature data satisfactorily explain the negative outcomes of certain animal tests? Do literature data justify the design of preclinical animal tests, selection of species, route of exposure, duration of exposure or follow-up, or other design parameters?

[3] Document sources and selection criteria
The next step is to identify the sources of literature and other databases that will be searched. The selection will depend on what information you need. For example, you might need evidence regarding the safety of chemicals such as additives or adulterants, information about chemical properties such as glass transition points or vaporization, data about adverse effects related to the device or technology, published studies about in vivo animal use, or information about 'active water' concentration. The type of data you need will influence where you look for it.

You will probably need to contact suppliers directly (called manual searching) to ask for specific information. For example you might need, say, formulation or processing information that isn't published.

In addition, you'll need to specify criteria for the data. For example, you might accept data from rodents but not from fish, you might require data from certain bacterial strains, large mammals, or ex vivo studies. You might need data with a certain sensitivity, such as parts per billion rather than parts per million. I find it easier to specify what I need than what I don't need until I have a feeling for what kind of information is out there.

[4] Assessment of documents
The documents are then valued in such a way as to group them by low, moderate, and high quality, depending on pre-determined assessment criteria; and then the values for each criteria are summed to give the document a weight. It may be that some high quality documents are unfavorable to the objectives, but these documents must be included in the evaluation nonetheless.

A 'document' may be anything from a MAUDE report of an adverse event to a full-text published article to information provided directly by a supplier. Documents might be assigned a value on: 1) the similarity of the device in the document to the device under consideration, based on technology, critical performance, design, and principles of operation; 2) the relevance of the particular experimental animals used in the selected studies for the biological evaluation of the device under consideration; and 3) conditions of use of the material or device in the selected documents and the intended use of the device in question.

Documents might also be valued on, 4) whether the author's conclusions are substantiated by the data, 5) whether the document reflects the current medical practice and state of the art technology, 6) whether documents are taken from recognized scientific publications and whether or not they have been reported in peer reviewed journals, and 7) the extent to which the data were acquired through established scientific literature.

[5] Critical evaluation of the literature
Note that valuation means the act of setting the value of something, while evaluation means a diagnosis or diagnostic study based on those values. 6. Dictionary.com.

Applying these definitions to literature reviews, we can say that we assess a document through the process of assigning it a separate value for each of several criteria, we weight the document by adding up the values, and we evaluate the body of documents (the literature) by determining if they address the key questions, placing the most emphasis on the document with the highest weights. The idea is to evaluate high quality data whether or not it is favorable to our technology.

The hoped-for outcome is to conclude than no new animal testing is justified, but it may be that we identify that new animal testing is indeed needed.

[6] Format and content
The literature evaluation itself may follow the standard format and content of other literature reviews.

[a] A short description of the material and device, including its intended use. I like to include the European and US classification, if known.
[b] Discussion of whether or not the literature supports the objectives or key questions.
[c] Evaluation of the hazards, risks, and appropriate safety measures that should be taken by the manufacturer.
[d] Description of the method of document selection, reasons for omitting documents, and methods of weighting documents.
[e] List of documents (full citations) used in the evaluation and appropriate cross-references.
[f] Conclusion with a justification for whether additional animal testing should be performed or is not necessary. The conclusion should include a discussion of probable risks and benefits, considering the 'state of the art' of the technology. And the conclusion should identify any gaps in evidence regarding safety or performance that should be addressed by future testing.
[g] The printed names, signatures, and responsibilities of the reviewers, and the dates of signature. I recommend attaching a biosketch or curriculum vitae of the reviewers as evidence of their experience.

Conclusion
Literature evaluations for biocompatibility are used to determine the need for animal biological safety testing or preclinical testing. Documents both favorable and unfavorable to the technology should be reviewed, but only those documents of the greatest assessed value need be evaluated. Naturally, the hoped-for outcome is that no further testing is needed.

The more common situation, however, is for the manufacturer to do a bunch of tests and then turn to the literature to defend an unfavorable outcome. While I'm not a proponent of this strategy, it is wiser to turn to the literature to explain an unwanted test result than to do even more animal testing. If you have unfavorable animal test results, find a knowledgable medical device toxicologist to assess what is currently known about your material, technology, or device, and then do whatever testing is still needed.

References
0. ISO 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2011).
1. MEDDEV 2.7.1 r3 "Clinical Evaluation: A guide for manufacturers and Notified Bodies," (2009); clause 5.5.1.
2. AHRQ "Negative Pressure Wound Therapy Devices", 2009, http://www.ahrq.gov/Clinic/ta/negpresswtd/references.htm#ref65.
3. AHRQ "Comparative Effectiveness of Noninvasive Technologies for the Diagnosis of Coronary Artery Disease in Women", 2011, http://effectivehealthcare.ahrq.gov/index.cfm/research-available-for-comment/comment-draft-reports/?pageaction=displaydraftcommentform&topicid=202&productid=770&documenttype=draftReport.
4. ISO 10993-1 "Biological evaluation of medical devices—Part 1: Evaluation and testing within a risk management process" (2009).
5. FDA BlueBook Memo G95-1, "Use of International Standard ISO-10993, 'Biological Evaluation of Medical Devices Part 1: Evaluation and Testing'" (1995).
6. Dictionary.com, http://dictionary.reference.com/browse/evaluation.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

Clinical Trial Agreements

A Whitepaper by Nancy J Stark

Clinical trial agreements (CTAs) are the legally binding agreements between a sponsor and an institution (site) as to how certain business and property rights will be dealt with between the parties. These agreements are separate from Investigator Agreements and Confidentiality Agreements and are not regulated by FDA or disclosable to FDA. CTAs are important because they allocate risk, responsibility, financial support, and obligations of the parties; and they protect the rights of the parties.

Usually the sponsor presents an initial draft of the agreement to the institution, and then each of the terms and conditions are negotiated by the party's attorneys. Agreements follow a typical format of: preamble, acknowledgements and responsibilities, term and termination, payment and reimbursement of costs, HIPAA and patient privacy, publication, data ownership and use, intellectual property, indemnification and insurance, subject injury, best efforts, waiver of consequential damages, miscellaneous (export controls, governing law, and dispute resolution/arbitration/mediatio, exhibits), and signatories. (1. Perry-Northwestern University)

 

The most common problem areas are publication, data ownership and use, intellectual property, indemnification and insurance, subject injury, best efforts, and signatories. In the text below I explore these problems and solutions suggested through various model CTA templates. (2. Weill Medical College of Cornell.) (3. UIDP) (4. MAGI) (5. Arizona template) (6. IOM template)

Conflicting missions
Universities, teaching hospitals, and other not-for-profit institutions are grounded in the principles of academic freedom and the discovery and sharing of information. Furthermore, in order to maintain a tax-exempt status, they must fulfill certain duties such as education of students, creating generalizable knowledge, or dissemination of knowledge. (7. Guiding Principles)

Sponsors, manufacturers, and other for-profit firms have commitments grounded in creating value for their shareholders, providing useful goods and services, and expanding the state of the art. They contribute to society by developing and providing new technologies to ease the medical conditions of mankind, but they must be profitable to survive.

Since neither party can live without the other, the challenge is to find contractual language that supports the mission of each within the constraints that limit them.

[F] Publication
The publication clause outlines who can publish what, and when. The clause is important to industry because they need to hold early developmental information confidential until the design of the device has matured into a functional, manufacturable, and marketable configuration. Revealing information too early, or revealing the wrong information, may allow your competitors to learn from your mistakes. Sponsors are also concerned about the accuracy of reporting, both of data and of product descriptions. And for multi-center studies, solutions are needed that allow for a complete manuscript incorporating results from all sites, and which pre-determines the order of authors.

Conversely, a non-profit institution needs to publish new knowledge. Publication creates recognition of the investigator's efforts, allows results to be used in future trials, enhances the site's prominence, contributes to public knowledge, and allows graduate students to use the data for their theses.

A typical industry draft clause might say, in essence, "Institution shall submit to Sponsor a copy of any proposed publication at least 90 days prior to submission for review and approval."

Compromise language suggested by the University of Arizona is, "Sponsor has no objection to publication by Institution of the results of the Study based on information collected or generated by Institution, whether or not the results are favorable to Sponsor. However, to ensure against inadvertent disclosure of Confidential Information or unprotected Inventions, Institution will provide Sponsor the opportunity to review any proposed publication or other type of disclosure at least thirty (30) days before it is submitted for publication or otherwise disclosed. If any patent action is required to protect Inventions, Institution agrees to delay the disclosure for a period not to exceed ninety (90) days from the date Institution initially submitted the proposed publication, or other type of disclosure, to Sponsor for review. Institution will, on request, remove any Confidential Information before disclosure.

If Study is part of a multi-center study, Institution agrees that the first publication is to be a joint publication covering all centers. However, if a joint manuscript has not been submitted for publication within twelve (12) months of completion or termination of Study at all participating sites, Institution is free to publish its results separately…." (5. Arizona template)

[G] Data ownership and use
Data ownership and use is another common sticking point. Sponsors may argue that they "own" the data because they have paid for it, but Institutions counter that they cannot retain their non-profit status if they engage in contract research or "work-for-hire". Institutions want to protect the right to use study data for non-commercial, research, development, and educational, purposes.

A typical industry draft clause might read, "All study data shall be the sole and exclusive property of Sponsor."

MAGI offers this compromise clause, "Site owns all Source Documents. Sponsor owns all Sponsor Data. Site owns all Specimens and Genetic Data, and grants Sponsor access to such property only for purposes of the Study. Sponsor and Site may freely use their own data subject to Subject consent and IRB approval. In addition, Site may freely use Sponsor Data after first multicenter Publication is published or Sponsor waives right to a multicenter Publication. Sponsor has no right to Site’s pre-existing biological samples, genomic database, or other proprietary database." Sponsor Data is defined as, "Study lab test results, CRFs and other reports completed by Site or Investigator per the Protocol, Agreement or other written instruction by Sponsor, excluding Source Documents and Genetic Data. Specifically excludes results derived from analysis of data." (4. MAGI)

ISO 14155 "Clinical investigation of medical devices in human subjects—
good clinical practice" (2011)

What makes this ISO 14155 training so special? The author served on the Editing Committee of Working Group 4, the inner circle of individuals who put finger-to-keyboard and wrote the standard. In this three-hour recorded training Dr. Stark discusses the standard in a topic-by-topic format; identifying what is new, what were the controversies, and what was the Working Group's thinking in adopting the language it did. It is this background information that helps you apply the standard appropriately to your study.

You can buy this newly released training on CD on our website cdginc@clinicaldevice.com or by phoning 773-489-5706. Private training from Dr. Stark is also available.

[H] Intellectual property
Intellectual property is a little different than data ownership, in that it covers who has the right to obtain a patent, or own an invention, development, or discovery.

A typical industry draft clause may read, "Any inventions made as a result of Institution's performance of this Agreement will be disclosed promptly to Sponsor and shall be deemed the property of Sponsor." But again, the sale of information is at cross-purposes with the non-profit mission of the institution.

The University of Arizona offers this compromise clause, "Inventorship of any inventions, developments, or discoveries, whether patentable or not (collectively referred to as "Intellectual Property"), resulting from the performance of the Study, shall be allocated according to U.S. Patent law (Title 35 U.S. Code) in effect at the time the Intellectual Property was created…." (5. Arizona template)

[I] Indemnification and insurance
Indemnification is language whereby one party agrees to protect another against an anticipated loss or damage; insurance is a policy through a third-party which guarantees payment to cover the costs of loss or damage. Although FDA does not require sponsors to carry insurance to cover the possibility of loss or damage to the Institution resulting from the study, most Institutions will have insurance requirements for sponsor-initiated clinical trials. In the event a sponsor in unable to meet the insurance requirement, the study will probably undergo a clinical risk assessment via which the institution attempts to assess the likelihood of loss or damage.

A typical industry draft clause might read, "Sponsor shall indemnify and hold harmless Institution from any damages and liability that are caused by Sponsor's negligence."

A compromise clause might read, "Sponsor shall indemnify, defend, and hold harmless Institution from any damages and liability that arise out of the proper administration of the Study device, Study-required procedures, Sponsor's use of the results, or Sponsor's negligence or breach of the Agreement."

[J] Subject injury
While indemnification and insurance have to do with loss and damage to the Institution, the issue of subject injury has to do with loss and damage to the subject. Sponsors readily agree to provide subject injury coverage if it is determined the injury is related to the investigational device, but who gets to make the determination? Good clinical practice tells us the principal investigator makes this determination.

Some sponsors like to add a clause that they will not pay for injuries until insurance is billed and denied. But billing third-party payors, whether Medicare or private insurance, should be at the Institution's discretion. If the injury is related to the medical device there should be no billing.

Some sponsors are concerned with injuries that are, in fact, attributable to the underlying illness. A solution is to qualify underlying illness by saying, "to the natural progression of the underlying illness."

Some sponsors try to limit their liability if the injury is attributable to the negligence of the study subject or the failure of the study subject to follow the instructions of the Principal Investigator. But such thinking is contrary to current ethical standards. Subjects are donating the use and study of their bodies for other people's gain; there may be little or no benefit to them beyond the satisfaction of contributing to the world's knowledge. Either the institution, sponsor, or third-party payors should bear the cost of their injury regardless of it origins.

IOM's suggested language is, "The Sponsor shall reimburse actual and reasonable medical expenses incurred in treating any injury or illness to a Study Subject that is directly related to the administration of the Investigational device or the proper performance of any other procedure, each in accordance with the Protocol and the Sponsor’s written instructions to the Institution (or to the extent that the Sponsor’s written instructions conflict with the Protocol, the Sponsor’s written instructions to the Institution only). The Sponsor is not required under this Section to provide compensation for (a) other injury- or illness-related costs (such as lost wages), (b) medical expenses that are paid for by a third party (provided that neither the Institution nor the Study Subject shall be obligated to seek reimbursement from a third party insurer), (c) medical expenses that are incurred as the result of a violation of the Protocol or other misconduct or negligence, in each case by any agent or employee of the Institution (including the Study Staff), or (d) medical expenses for injury or illness unrelated to the Investigational Device and unrelated to the proper performance of any other procedure required by the Protocol or Sponsor’s written instructions to the Institution." (6. IOM template)

Arizona offers a simpler suggestion, "Should a subject suffer any adverse effect caused by the Study drug/device/biologic, the Study procedures, or laboratory work required by the Protocol, Sponsor will pay for all medical and hospital costs required for the diagnosis and treatment of such adverse effect." (5. Arizona template)

[K] Best efforts
Consultants (such as Clinical Device Group) know that research projects are dynamic. No wise Institution, consultant, or research contractor should agree to work under time, cost, and performance constraints. Deadlines and results cannot be guaranteed. Furthermore, work product is constrained by the laws and standards of the United States.

One might think the Sponsor is left defenseless, but this is not the case. Institutions will agree to a "best efforts" clause, a contractual provision which requires the institution to use its highest efforts to perform its obligations and to maximize the benefits to be received by the sponsor. Sponsor's are obligated to terminate a site's participation in a study if non-compliances to protocol or regulations are discovered. And sponsors always have the right to terminate a study for business or ethical reasons. Cost overruns, project delays, or non-performance (of investigator or device) are all legitimate business or ethical reasons for terminating a study or an institution's participation in a study.

[N] Signatories
Industry sponsors sometimes don't realize the employee-employer relationship between investigators and investigative sites and they propose to have the investigator sign the CTA. They're also concerned about the performance of the investigator because of their financial investment in the trial.

A typical industry suggestion for the signatory clause is, "This Agreement is entered into by and among Sponsor, Investigative Site, and Principal Investigator." But if you think about it, an investigator—as an employee of the institution—has no legal authorization to sign the CTA.

A compromise clause is, "This Agreement is entered into by and between Sponsor and Investigative Site. The Principal Investigator shall conduct the trial as an employee of the institution and not as a party to this Agreement." Then the Principal Investigator is asked to sign the Agreement to indicate their understanding and intention to comply.

Conclusion
Sponsors and Institutions both have a vested interest in performing clinical research, and each party has much to gain from the process. By thinking through the issues and appreciating the needs of the other party, it is possible to come to an Agreement that is fair, balanced, and meets everyone's needs.

References
1. My thanks to Sean Perry, JD, Sr. Contract and Grant Officer, Office for Sponsored Research, Northwestern University, Chicago for his insights into this topic.
2. The format is taken from Clinical Trial Agreements, Weill Medical College of Cornell University, Office of Clinical Trials Administration. Contact CDG for link.
3. University-Industry Demonstration Partnership (UIDP), National Academy of Sciences, http://sites.nationalacademies.org/PGA/uidp/PGA_060368.
4. MAGI Model Clinical Trial Agreement, https://www.magiworld.org/standards/.
5. Template for Clinical Trial Agreement, University of Arizona Board of Regents, http://www.orca.arizona.edu/ctas.html.
6. Template for Clinical Trial Agreements, Developed by Jim Snipes, Covington & Burling LLP for the Institute of Medicine, April 2009. Contact CDG for pdf copy.
7. Guiding Principles for University-Industry Endeavors, National Academy of Science and the National Council of University Research Administrators and the Industrial Research Institute, April 2006.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

 

Registry Studies: Why and How

There is only one difference between registry studies and clinical studies: registry studies are observational and clinical studies are investigational. (When clinical studies are randomized they are called randomized clinical studies or RCTs.) To put it another way, in a registry study we tell the physician to treat the condition however they want—as sponsors, we are passive observers; in a clinical study we instruct the investigator to treat the condition in a certain manner—we are active researchers.

There is another, inevitable, feature of registry studies that I want to point out. The words "effectiveness" and "efficacy" are often misused, even by FDA. Effectiveness refers to how well a device performs as intended in the general population of patients and the general chaos of clinical practice. Effectiveness is measured in registry studies. Efficacy refers to how well a device performs in a setting of carefully selected patients and a carefully controlled protocol. Efficacy is measured in clinical studies.

 

Why do a registry study?
[1] Reimbursement data
One common reason for doing a registry study is to obtain data for reimbursement purposes. While CMS prefers comparative effectiveness data obtained from randomized clinical trials, such studies aren't always possible. 1. Definition of Comparative Effectiveness. There may not be a direct comparator for your new technology: the comparators might be an office procedure versus a surgical procedure or a device versus a drug. Imagine the complexities of comparing a device that emits a magnetic field intended to lower the viral load of patients with AIDS or hepatitis C to a multi-drug regimen. Or co-pay policies may be different for the comparators. Martin et. al. described an issue where a new (possibly more effective) drug costing $2000 per month was to be compared to an older drug being used off-label and costing $50 per month. There was concern that patients assigned to receive the expensive drug would drop out of the study. 2. Martin, et. al. In such a case, the sponsor would pick up the copay for every subject, no matter what their third-party coverage might be, in order to level the playing field.

[2] Post-approval effectiveness publications
Before adopting your technology most clinicians will ask about its effectiveness in the real world. Registry studies are ideal for obtaining effectiveness data. By allowing wide patient selection criteria you will include patients with multiple confounding complications, wide age ranges, various socioeconomic backgrounds, and differing healthcare attitudes. Learning how your technology behaves in these complex scenarios can provide valuable information to clinicians and important data for publications.

[3] Section 522
In certain circumstances FDA may require a post-approval study under Section 522 of the Food, Drug, and Cosmetic Act. The so-called Section 522 Postmarket Surveillance authority is limited to Class II or Class III devices the failure of which might lead to serious adverse health consequences, devices implanted for more than one year, life-sustaining or life-supporting devices used outside a device user facility, or devices used in pediatric populations. 3. Section 522. Registry studies are an ideal way to collect the broad surveillance data required.

[4] Off-label uses
Devices aren't always used the way we think they will be or in the populations we anticipate. In registry studies we—as sponsors—are not dictating how our device will be used, so there is always the possibility it will be used off label. Off-label use in a registry study is not a protocol violation since we don't specify in the protocol how to use the device in the first place. A review of how our device is actually used in real-world practice can provide valuable marketing information, hypothesis development for future studies, and indications for use development for future regulatory submissions.

 

How to do a registry study
Implementing a registry study is not much different than implementing a clinical study. All the basic elements of design, planning, and project management are present. There is a lack of consensus standards for registry studies so it is difficult to find guidance on how to do them. Your primary resource for information will be "Registries for Evaluating Patient Outcomes: A User's Guide, Second Edition" from the Agency for Healthcare Research and Quality. 4. Registries.

[1] Planning
In the planning phase, identify your stakeholders, the scope of data required, define the core data set (what do you need to know?), identify the patient outcomes or endpoints, define the target population (i.e. inclusion and exclusion criteria), and most importantly, get your funding. Funding may come from top management, venture capital firms, government grants, private grants, or other resources, but in the end we are all accountable to someone. Next you'll set up the registry team, determine if safety monitoring boards, IRBs, or other committees are necessary, and finally plan an exit strategy so you'll know when the study is completed.

[2] Registry design
In the design phase, the details of the registry study are worked out and a protocol is written. There are only a few options for study design:

a) Cohort designs follow over time a group of people who possess a characteristic to see if they develop a particular endpoint or outcome. 5. Registries, p38.

b) In case-control designs you gather 'cases' of patients who have a particular outcome or who have had a particular adverse event and 'controls' who have not, and then you look backwards to see what proportion had an exposure or characteristic of interest. For example, in the evaluation of re-stenosis after coronary angioplasty in patients with end-stage renal disease, investigators found both cases and controls from an existing PTCA registry. Alternatively, cases could come from the PTCA registry and controls from outside the registry (say, Medicare data). 5. Registries, p38 and p46.

For example, in 2004 Cordis began a registry designed to assess stenting outcomes in relation to the outcomes of their SAPPHIRE trial, which was used as the historic comparison group. The research question was to see if non-academic physicians would achieve the same level of success as the academic investigators used in the clinical study. The registry was conducted because of concerns by FDA and the Centers for Medicare and Medicaid Services (CMS), and involved 74 sites and 1493 patients. The large number of sites and subjects are characteristic of registry studies. 5. Registries, p38.

c) A case-cohort design is a statistical variant of a case-control study. Controls are sampled from a list of people, with each person having an equal probability of being sampled. 5. Registries, p38.

Help with Registry Studies

CDG is pleased to offer a five-hour workshop on designing and implementing registry studies for medical devices. Designed and recorded by Dr. Nancy J Stark, the workshop is a focused presentation of the AHRQ User Guide, adapted to medical device registries. You can find more information on our website. Scroll down to Registry Studies for Medical Devices.

If you're short on human resources and need to outsource the planning and implementation of a device registry study, please phone or email us at 773-489-5721 or cdginc@clinicaldevice.com. Dr. Stark will be happy to discuss a proposal.

[3] Selecting subjects and comparison groups
The target population is all the patients with a common disease or condition or a common exposure. For example, the target population might be all people with cataracts, all women with urinary incontinence, or all people who have been exposed to radiation for cancer treatment. Then broad inclusion/exclusion criteria are used to select a representative population of patients. One common feature of registries is that they have few inclusion and exclusion criteria, thus enhancing their applicability to broader populations.

Selecting comparison groups is more critical in observational studies than in clinical studies, because subjects have a choice as to which intervention they receive. The sickest patients may choose your technology, while less-ill patients may choose the comparator. The result will be an unfair imbalance in adverse events for the new technology. Key demographic factors—such as age, lifestyle, and disease advancement—are collected and statistically applied to help achieve equipoise.

Comparison groups may be "internal" (data collected simultaneously), "external" (data were collected outside of the registry, such as Medicare data), or "historical" (data collected under the registry protocol but not simultaneously). Comparison groups are essential when you want to distinguish between alternative procedures, assess the magnitude of differences, or determine the strength of associations between groups.

Registries do not need comparison groups when the purpose is to characterize the "natural history" of an intervention.

[4] What data should be collected?
Registry enthusiasts have their own language for many of the concepts we are already familiar with from RCTs. For example, they talk about "domains" of data, and by that they mean data should be collected from the personal domain (patient demographics, medical history, health status, and patient identifiers), the exposure domain (patient's experience with the technology or device), and the outcomes domain (primary endpoints, secondary endpoints, adverse events, and technology deficiencies.) In addition, you should collect information about potential confounders (say a drug being taken to treat the same condition as the study device). The collected data should relate directly to the purpose of the registry.

"Data elements" refers to the exact data that will be collected. Currently there are few, if any, broadly accepted sets of standard data elements for most disease areas, making it difficult to use external data as a source of comparison data. Look to the specialty societies to see if they have created clinical data standards that you can use as a guide for selecting data for collection. For example, the American College of Cardiology has created clinical data standards for acute coronary syndromes, heart failure, and atrial fibrillation. 5. Registries, p53. Whenever possible, tie your data elements to established terminology, such as Current Procedural Terminology (CPT) codes, International Classification of Disease (ICD-10), or events related to device deficiencies. 6. ISO 19218-1.

[5] Data Sources for Registries
Depending on the data sources required, registries may utilize certain personal identifiers for patients to locate the specific patients and link the data. For example, Social Security numbers (SSN), as well as a combination of other personal identifiers, can be utilized to identify individuals in the National Death Index (NDI). What peaks my interest is that data may come from many different sources: outpatient clinic records, inpatient hospital records, laboratory records, billing records, and even payer claims data! Data may come from medical chart abstraction, electronic medical records, institutional or organizational databases, administrative databases, death and birth records, census databases, or existing registry databases. For example, if you are developing a thermoebolization technology for treating liver cancer, you may want to access data from the Registry of Liver Diseases.

[6] Ethics, Data Ownership, and Privacy
The principles of ethics, data ownership and privacy are the same for registry studies as they are for clinical studies. You need IRB approval to conduct the study, HIPAA waiver to access patient medical records, a financial agreement with the institution regarding payments, data ownership and publication rights, and assurances of patient privacy.

Consider the case study of the National Oncologic PET Registry, a registry developed to collect data about PET scans in cancer management with the goal of obtaining expanded CMS coverage for PET scans. The registry was to be conducted at hundreds of hospitals and free-standing PET facilities. The sponsor's believed the registry was not subject to IRB approval because it was being "conducted by or subject to the approval of Department or Agency heads" for the purpose of evaluating a "public benefits or services program." CMS agreed. One week before starting operation the Office of Human Research Protections (OHRP) issued a letter of disagreement. The study was put on hold while the sponsors contemplated the difficulty of obtaining approval from hundreds of IRBs. Ultimately OHRP conceded that only the registry was engaged in research and study needed to be approved by only a single IRB. 5. Registries, p84.

[7] Recruitment
Recruitment of sites becomes a major issue in studies the breadth of registries. Sites must be paid fair-market value for their time and must see a benefit to their operations if they are to join and actively participate in a registry. This is especially true if the registry study is to include community physicians or high-volume specialty centers, as well as academic centers. Community physicians are more likely to participate if the registry is viewed as a scientific endeavor, is endorsed by leading organizations, led by a respected opinion-leader, provides useful self-assessment data to the physician, or helps meet other physician needs such as maintenance of certification, credentialing, or pay-for-performance programs.

Patient recruitment presents the same challenges as clinical studies. The best success comes from recruitment by the patient's own physician. It also helps to communicate that registry participation may help improve care for future patients, to provide written materials in language easily understood by the lay public, keep survey forms short and simple, and provide incentives such as newsletters, reports, and modest monetary compensation.

[8] Data collection and quality assurance
Three sets of documents, together, form the system for data collection. The first is the case report forms, be they paper or electronic. These are the forms whereby data is gathered in the field, entered into coded fields, and transmitted to a data management center. The second is a data dictionary which contains a detailed description of each variable used in the registry. For example, the question may be: "Do you smoke?" And smoking may be defined has having smoked tobacco within the last year. The third is the set of data validation rules. These are logical checks on data entered to look for inconsistencies such as males taking birth control pills.

A data management manual should be developed to define how missing data will be handled, how invalid entries will be handled, how data will be cleaned, and what level of error will be accepted. The manual should describe how data will be tracked and coded, how query reports will be generated and resolved, and how it will be stored and secured. Finally, the data management manual should describe a quality assurance system for data entry and registry procedures.

[9] Adverse event reporting
For device and device procedure registries, adverse event detection, collection, and reporting is the same as adverse event reporting for any other post-approval setting. It begins with the "becoming aware" principle; i.e. the clock for reporting adverse events starts at the moment the investigator becomes aware of symptoms or events reported by the patient or signs such as out-of-range laboratory results reported by a lab, or from the moment the manufacturer learns of an event from an investigator.

Investigators are responsible to report serious injuries to manufacturers within 10 days and to FDA within 10 days if the manufacturer is not known. Investigators are responsible to report deaths to both the manufacturer and FDA within 10 days. 7. 21 CFR 803. Interestingly, if an adverse event occurs with a comparator device the investigator must report the event to the comparator's manufacturer. Manufacturers have 30 days to report deaths, serious injuries and malfunctions to FDA, and 5 days to report events that require remedial action to prevent an unreasonable risk of substantial harm to the public health. Events are logged into the Manufacturer and User Facility Device Experience Database (MAUDE).

[10] Analysis and Interpretation
Statistical analysis of registry data is no different than statistical analysis of clinical data. There are a couple of points that deserve mentioning, though. First, you'll need to determine how closely the actual study population represents the target population. Second, there should exist a statistical analysis plan for how the data are to be analyzed and interpreted. And third, there should exist a plan for how to handle missing data.

Conclusion
Don't be misled, registry studies are not cheap, second-rate clinical studies. They are easily as complex and costly than the exalted RCT. What they are is different. They are observational studies that asses a technology's ability to achieve its intended use in the real world. They are used when alternative technologies don't exist, are outdated, or perhaps unethical.

References
1. Draft definition, prioritization Criteria, and Strategic Framework for Public Comment.
2. Identifying and Eliminating the Roadblocks to Comparative-Effectiveness Research, Martin et.al., New England Journal of Medicine, June 2, 2010.
3. Food, Drug, and Cosmetic Act, Section 522 Postmarket Surveillance.
4. Registries for Evaluating Patient Outcomes: A User's Guide, Second Edition. Agency for Healthcare Research and Quality, 2010.
5. Registries for Evaluating Patient Outcomes: A User's Guide, Draft. Agency for Healthcare Research and Quality, 2006.
6. ISO/DTS 19218-1 Medical devices—Hierarchical coding for adverse events—Event type codes (2010).
7. 21 CFR 803 Medical Device Reporting.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Medical Device Biocompatibility

A Whitepaper by Dr. Nancy J Stark and Dr. Dan McLain

There are commonly three scenarios in which manufacturers call on CDG for biocompatibility help: a) FDA has raised questions about the safety tests you performed, b) you disagree that you need sensitization, genotoxicity, or carcinogenicity tests, or c) you have a new device and don't have a clue as to what tests to do. Can an expert opinion help?

Materials and the manufacturing process
We usually think about biological safety when selecting the materials for a new device. Many materials may be under consideration for a particular component. The mechanical properties, manufacturability, availability, aesthetics cost, as well as biological safety issues, are all considerations in the material selection process.

Often manufacturers believe they are using "common" material in their medical devices, but when challenged by FDA to give reasonable assurance of the material's safety they cannot offer specifics. You must establish the material is comparable after your manufacturing process. This is why biological safety tests are performed on final manufactured product. Some companies use final manufactured devices, others run a coupon of the material through the manufacturing process to get a material that is representative of the final process.

Back in the day—when one of us started working in the device industry—there were no recognized standards for device biological safety testing. Manufacturers floundered around looking for tests that seemed applicable. I once used US Pharmacopoeia (USP) tests for drug containers when developing a new syringe. Even today, suppliers and manufacturers sometimes assume that materials which meet USP Class V or VI requirements are sufficiently safe for device applications. (1 USP)

 

 

Step Two: "The Matrix"
Because of its long history, most manufacturers base their biological safety testing on "The Matrix". In 1986, regulators from FDA, the UK, and Canada published the Tripartite Biocompatibility Guidance. The guidance built upon standards that had previously been published by AAMI, ANSI, ASTM, and others. It looked at materials based on the type of tissue the material contacted and the duration of that contact. Then a testing category was recommended for each combination of contact and duration. The problem with the Tripartite Guidance was that nearly every category of biocompatibility test was recommended for nearly every combination of material contact and duration (198 out of a possible 240 categories were recommended.) (2 Tripartite) There were other problems too: it didn't tell you how to handle whole devices, and it didn't apply to metals or ceramics.

In 1992, the International Standards Organization (ISO) published ISO 10993 Part 1 "Guidance on selection of tests". The standard was part of a series of biological safety standards, but Part 1 included a matrix similar to the contact and duration matrix of the Tripartite Guidance. The major difference was that far fewer categories of tests were recommended (117 out of 240). (3 ISO 19003-1 Selection of Tests) This matrix was not accepted by FDA.

  

1995 brought us The Matrix as American manufacturers know it today. It is found in FDA's General Program Memorandum G95-1. (4 G95-1) With clairvoyance and foresight FDA modified the matrix presented in a version of the ISO 10993-1 standard that would not be published for another two years. (5 ISO 10993-1 Testing and Evaluation) The goal was to harmonize the agency's biological safety policy with the expectations of the international community. In the modified matrix, an additional 36 categories of tests are "suggested" for manufacturers to consider (for a total of 153 out of 240).

Step One: ISO 10993 Part 18 'Chemical characterization of materials' (2005)
A more ethical and efficient practice is to chemically characterize materials and compare them to materials in existing clinical use before performing animal tests. This is done in conformance to ISO 10993-18 'Chemical characterization of materials' (2005) and it should be done before the matrix is even consulted. (6 ISO 10993-18)

To put it in context, the chemical characterization of materials justify the performance or omission of animal biocompatibility tests, just as clinical evaluations justify the performance or omission of human clinical investigations.

  

Chemical characterization is the accepted method for comparing one finished, manufactured material to another in order to make the argument that they are clinically equal or that one material is no worse than a currently used material. The methodology has been developing over the years and was described in detail in a book by Dr. Stark in 2003. (7 Stark) The characterization is done in the following manner.

[1] Qualitative information
Describe the material and its intended purpose within the device. The description includes qualitative information such as supplier name, common name, chemical name, batch or lot number, visual and physical characteristics such as color, hardness, flexibility, and chemical family, and other specifications. The intended use of the material (type of tissue contact, duration of contact, and function) are also described.

[2] Material equivalence
The new material is compared to an existing material that is used in a device with the same clinical exposure; the device can be a commercial device from your own firm or it can be from your competitor. You can readily visualize a spreadsheet or database listing each material in the device and comparing it to another known material. If you have sufficient information for an expert to make a toxicological risk assessment you can stop here.

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Expert Opinions and Consultation for Biological Safety

Dr. Dan McLain, is an internationally renowned medical device toxicologist. His position as convener of ISO 10993-11 is evidence of his global stature. Dan is available to assist with pre-clinical strategies and chemical risk assessments for your materials and devices. Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

 

[3] Quantitative data
Quantitative data will be needed if a sound risk assessment cannot be made purely on qualitative information. This means a thorough knowledge of the chemical composition, additives, manufacturing residues, and leachables must be obtained through analytical and physical chemistry. The goal is to determine the amount of identified chemicals (such as monomers, anions, radioactive elements, and the like) that are present in the final, manufactured material.

[4] Quantitative risk assessment
In the quantitative risk assessment the amount (in µg, Gy for radiation, or other unit of exposure) of identified chemicals are compared to existing toxicological information, rather than to another material. The objective is to determine which, if any, of the chemicals in the material might be harmful at the calculated exposure.

[5] Estimate clinical exposure
Finally the amount of potentially harmful chemicals, the 'dose', is compared to the clinical dose a patient might receive in a lifetime, a procedure, or other unit of time. Such a comparison seeks to show that the maximum dose of a chemical one might receive is acceptable in light of the lowest dose that could case medical problems. Detailed methods for risk assessments are discussed in ISO 14155-17 'Methods for the establishment of allowable limits for leachable substances' (2008). (8 ISO 10993-17)

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"The Matrix" Is Available as a Mousepad/Notepad

CDG's talented graphic artists have reconfigured The Matrix and printed it on a high-quality mouse-grade paper pad. Now you can always have The Matrix at your workstation, in plain sight where you can find it. You can quickly look up the test categories needed while the boss is quizzing you on the phone. And at ten sheets to the pad, you can take notes on the conversation (or doodle), tear off the sheet, and keep it safe in the technical file.

Find it here, or contact Peggy at 773-489-5706 or cdginc@clinicaldevice.com.

Consider these examples, they are intended to illustrate the kind of issue you'll be addressing: a) Let's say you have a metallic implant that you clean by washing with perchloroethylene. Known to be highly volatile, but also highly toxic, you must ask if enough perchloroethylene remains on the metal implant to preclude its use as a cleaning agent; b) Let's say you make a wound dressing that contains a potassium salt. You know that potassium affects cardiac function and in sufficiently high concentrations could put a patient into cardiac arrest. You must ask if sufficient potassium can leach out of the dressing and into the wound to affect cardiac function.

References
(1 USP) United States Pharmacopeia.
(2 Tripartite) Tripartite Biocompatibility Guidance G87-1, (1987).
(3 ISO 10993-1 Selection of tests) ISO 10993-1 Biological evaluation of medical devices: Selection of tests (1992).
(4 G95-1) "Use of International Standard ISO-10993-1 Biological Evaluation of Medical Devices: Evaluation and Testing", G95-1 (1995).
(5 ISO 10993-1 Evaluation and Testing) ISO 10993-1 Biological evaluation of medical devices: Evaluation and testing (1997).
(6 ISO 10993-18) ISO 10993-18 Biological evaluation of medical devices: Chemical characterization of materials (2005).
(7 Stark) "Biocompatibility Testing & Management" Fourth Edition, Nancy J Stark, Clinical Device Group Inc, 2003.
(8 ISO 10993-17) ISO 10993-17 Biological evaluation of medical devices: Methods for the establishment of allowable limits for leachable substances (2008).

Questions or Comments?
Do you have questions, comments, or additional information? Please post them below.

 

Reimbursement Strategies for New Technologies

A Whitepaper by Dr. Nancy J Stark and Dr. Vincent Jaeger

Reimbursement strategies
A reimbursement strategy is a plan for: 1) working in clinical research to design studies that show "medical benefit" and "added value" to secure coverage; 2) identifying codes for new technologies (i.e., drugs, medical devices, medical and surgical procedures and services); 3) working with the FDA to phrase the intended use and indications for use to fit coverage and coding; and 4) presenting the clinical trial data to the Centers for Medicare and Medicaid Services (CMS) for reimbursement approval. Ideally, reimbursement strategies must be part of the early-on process of development for every new technology. Unfortunately, most manufacturers wait until they launch their product or are faced with resistance from Medicare before they begin to formulate a pathway toward reimbursement.

Reimbursement is the primary driver to profitability of a new technology in that it assures the all-important revenue stream that keeps a company viable. Medicare, by far the largest third-party payer, is limited by the Social Security Act to only cover technologies that are "reasonable and necessary" for diagnosis or treatment of diseases, conditions or injuries. (1 Social Security Act) In this whitepaper, Dr. Vincent Jaeger and I will review only the Medicare reimbursement process with the understanding that, because of its size and influence, private payers will usually adopt the same or similar coverage, coding and payment policies.

The challenge of new 510(k)'d technologies
Isn't it interesting that one of FDA's missions is to foster medical device innovation, (2 FDA & Innovation) but CMS has no parallel mission to reimburse it? Approximately 5000 510(k)s are cleared by the FDA each year, and most of these represent incremental improvements to medical devices and other technologies already on the market. Medicare’s bundled payment systems, i.e., diagnosis-related groups (DRGs) for inpatient care and ambulatory payment categories (APCs) for outpatient services, allow payment for incremental improvements without additional clinical evidence. Most 'new' technologies fall into the bundled payment system and do not face a full reimbursement challenge.

 

Although it is often possible to make a substantially equivalent argument to the FDA and gain 510(k) clearance to market a new technology, the technology may not meet Medicare's bundled-payment requirements or qualify for reimbursement. Some start-up manufacturers don't realize that it can take 3-4 times as long or more to gain CMS coverage as it took to get 510(k) clearance and that approaching the necessary activities to gain reimbursement in a sequential manner will unquestionably add to the overall timeline. The most serious obstacle facing manufacturers is not gaining FDA approval, but securing a positive reimbursement decision by Medicare.

Reimbursement decision process
The term reimbursement is used to describe activities related to the mechanisms by which patients have access to medical technologies through their health insurance payer. The elements necessary for reimbursement are: [1] coverage; [2] coding; and [3] payment. (3 Innovators' Guide) It is most important that a strategic plan is begun early in product development to ensure a positive coverage and reimbursement outcome. It is imperative to develop parallel regulatory, clinical and reimbursement paths that address the needs of both the FDA and the payers who ultimately control the technology’s marketing destiny through their policy-making decisions. Hospitals and physicians may use the device, but public and private payers reimburse and they set the rules.

 

Coverage
Coverage refers to the terms and conditions under which Medicare and private payers will (or will not) provide payment for drugs, services, procedures and medical devices. Coverage is the first, and unquestionably the most important, component of the reimbursement process. The decision for or against coverage of a new technology is directly related to the presence of valid scientific evidence from well-designed comparative clinical trials published in the peer-reviewed medical literature. The evidence must support the medical device’s effectiveness in substantially improving health outcomes over existing technologies. Over the last twenty years a system for ranking the quality of evidence has been developed and is known as evidence-based medicine. (4 Jaeger) Randomized, blinded, controlled clinical trials designed to overcome the many possible sources of bias rank as the highest quality of evidence. Testimonials rank as the lowest quality of evidence. (5 Evidence)

In May 2000 Medicare published a Notice of Intent (NOI) proposing a set of criteria to be used for determining which items and services are reasonable and necessary and therefore eligible for coverage. (6 NOI) The NOI proposed that technologies must demonstrate "medical benefit" as well as "added value." But just how medical benefit and added value should be measured remains controversial.

.....Registry studies
Randomized controlled trials (RTCs) for new technologies are sometimes difficult to conduct because physicians, surgeons, interventionists and patients are often reluctant to compare the new technology to an existing standard of care. And blinding device studies is usually an impossibility.

In these circumstances, registry studies, conducted according to the Agency for Healthcare Quality and Research (AHRQ) "Registries for Evaluating Patient Outcomes: A User's Guide", lend themselves well to comparative studies for commercial medical technologies. (7 Registry User's Guide) (8 Stark) Registry studies have been successfully used by manufacturers to gain CMS coverage. (9 CMRI) A registry study is research carried out in a prospective, observational manner in which subjects with certain shared characteristics are studied, and ongoing and supporting data over time is collected on well-defined outcomes of interest for analysis and reporting. Investigators are instructed to select and use 510(k) cleared devices as they would in their normal practice. The protocol refrains from dictating treatment or follow-up care. The value is that objective, observational data comparing new technologies to other technologies already being used can be gathered. These effectiveness data address benefits, outcomes, complication rates, adverse events, and deficiencies in real practice settings.

Don't be misled, a well-controlled registry study costs about the same as a well-controlled clinical trial. It requires a protocol, case report forms, informed consent, IRB review, monitoring, data collection, data analysis and a final report. The regulatory advantage is that the study is exempt from the Code of Federal Regulations (CFR), Title 21, Part 812 - Investigational Device Exemptions.

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CDG's Network Staff Associates have the expertise and understanding to implement observational, comparative studies on commercial devices; whether in the States or in Europe. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

Codes, codes, codes
There is no lack of codes. There are current procedural terminology (CPT) codes used primarily to identify medical and surgical procedures and services performed by physicians and other health care professionals. ICD-9 (International Classification of Diseases, 9th Revision) codes, used in both the inpatient and outpatient settings, convey a patient’s diagnosis(es), and provide the medical justification for the episode of care for which the provider is filing a claim. There are ICD-9 procedure codes primarily used by hospitals to identify and define procedures performed during an inpatient stay. Codes for diagnosis related groups (DRGs) are a classification system developed by Medicare as part of the prospective payment system for inpatient care. There are T-codes for emerging technologies, as well as nondescript codes (-99 codes) to identify new medical technologies until a specific code is assigned. Healthcare Common Procedure Coding System (HCPCS) codes are intended to report supplies, medical equipment and services that are regularly billed by suppliers, not physicians. (10-Clark) ICD-10 will add a new complexity to the mix in 2013.

In other words, code sets have been created to accurately describe and convey information between the various providers of healthcare and payers about medical diagnoses, procedures, products and services rendered to patients. These codes, when placed on a claim form, operationally link coverage to payment. When seeking reimbursement, it is better for the manufacturer to have an existing CPT code that adequately describes the procedure which is recognized by payers as valid for payment levels acceptable to physicians.

  

No Codes?
If there is no existing code which adequately describes the new medical technology, application for creation of a new code must be made to the appropriate committees within CMS and the American Medical Association (AMA): ICD-9 diagnosis codes to CMS, CPT procedural codes to the AMA, and HCPCS codes to CMS. New code applications are received on strict deadlines and take a long time for approval, which certainly is a major factor in the long delay for reimbursement approval by Medicare.

....Step 1—CPT
The first step in obtaining codes is to apply to the American Medical Association (AMA) for a CPT code. The AMA first developed and published CPT in 1966. The first edition helped encourage the use of standard terms and descriptors to document procedures in the medical record, helped communicate accurate information on procedures and services to agencies concerned with insurance claims, provided the basis for a computer oriented system to evaluate operative procedures, and contributed basic information for actuarial and statistical purposes. (11 AMA & CPT codes)

 

To ensure that physician services across all specialties are well-represented, the AMA established the Relative Value Scale Update Committee (RUC). Annually, the RUC makes recommendations regarding new and revised physician services which are then accepted, rejected or modified by CMS. As such, the RUC significantly influences the relative value units (RVUs) of CPT codes and, as a result, how much physicians are paid. The impact of the RUC becomes even more important when one considers that Medicaid and private payers tie their fee schedules to Medicare's.

The first step in obtaining a new CPT code is to make application to the AMA, specifically, to the Department of CPT Editorial Research and Development. The AMA staff reviews all applications to evaluate their coding suggestions. If they determine that the request is a new issue, or significantly new information is received on an item that the CPT Editorial Panel reviewed previously, the request is referred to appropriate members of the CPT Advisory Committee. If the advisors concur that a new CPT code should be added or a change should be made to an existing CPT code, the application is approved. If two or more advisors disagree, the issue is referred back to the CPT Editorial Panel for resolution. The Panel meets three times each year, evaluates approximately 350 new technologies and deletes those procedures that are outmoded.

....Step 2—ICD-9-CM
The second step is to apply to the Coordination & Maintenance Committee at CMS for an ICD-9 code. (12 ICD-9) This Committee provides a public forum where thoughts and comments are given; however, no decisions are made. All final decisions are made by the Director of the CDC’s National Center for Health Statistics (NCHS) and the CMS Administrator. Tentative agendas for the scheduled meetings are usually posted one month in advance.

Applicants can make presentations at these meetings, describing the clinical issues of their products. The participants at the meeting are encouraged to ask questions concerning the clinical and coding issues and to offer recommendations to those applicants requesting a change. Recommendations concerning proposed code revisions can be made either at the meeting or in writing before the end of the comment period. Final decisions on code revisions are made through a clearance process within the Department of Health and Human Services.

....Step 3—HCPCS
HCPCS is a standardized coding system that is used primarily to identify services (such as ambulance services) and durable medical equipment (DME), prosthetics, orthotics, and supplies (DMEPOS). These codes are primarily used by medical suppliers, so they are typically not costs that get passed through a physician's office. HCPCS coding is intended to be used to identify DMEPOS and formulate fee schedules in a consistent manner for billing purposes. "Level III" HCPCS codes refer to Medicaid and other state and local codes.

The preliminary step in the process for recommending a modification to the HCPCS coding system for DMEPOS is to contact the Statistical Analysis Durable Medical Equipment Regional Contractor (SADMERC). (13 Level II) CMS contracts with SADMERC to provide assistance to the public in determining whether or not a HCPCS code exists which describes the new product. If none is found, an application form for a new code, a cover letter outlining the new code request and a brief summary of why the code is needed should be submitted to CMS, together with the FDA letter confirming 510(k) approval, data supporting clinical effectiveness, and product brochures and/or booklets. Samples of the device can be included with the application. Once the application is received, the product is placed on an agenda and reviewed by a panel whose membership includes representatives of Medicare, Medicaid, and private insurers. These informal, public meetings permit interested parties to make oral presentations or to comment in writing regarding the coding issues.

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Vincent Jaeger, MD, a proven expert in reimbursement strategy, has 15 years experience in evaluating new medical technologies for Aetna, Health Net, and Connecticut Health Network. Dr. Jaeger’s considerable experience on the payer side now qualifies him to offer his advanced skills and knowledge to the medical technology industry to ensure a positive coverage and reimbursement outcome. No matter where you are in the developmental cycle of your new technology, Dr. Jaeger can help you create a reimbursement strategy which will ensure commercial success of your product and generation of the all-important revenues you need to keep your company viable. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

Council on Technology and Innovation
The Council on Technology and Innovation (CTI) at the Centers for Medicare & Medicaid Services (CMS) oversees the agency's cross-cutting priority on coordinating coverage, coding and payment processes to enable CMS to more efficiently identify high value technologies and services that will improve healthcare quality and the lives of Medicare beneficiaries. (14 CTI) CTI is developing the capacity to better prepare for new kinds of medical innovations. The agency recently issued a revised guidance on Coverage with Evidence Development (CED). (15 CED)

Payment
Payment refers to the amount of monetary compensation provided to the physician and other healthcare professionals who use the new technology. It is important to realize that Medicare pays for the procedure associated with a medical device, not for the device itself. Medicare’s inpatient and outpatient prospective payment systems include provisions designed to provide an extra payment amount for certain new technologies. To merit such additional payment, the new technology generally must represent a substantial clinical improvement relative to existing technologies and meet specific cost thresholds. (16 Innovator's Guide)

Conclusion
FDA approval, clinical trial outcomes data, the presence of appropriate coding and payment levels are vital for reimbursement of new technologies. The quantity and quality of the outcomes data arrived at by randomized controlled trials (RCT) or an observational, well-controlled registry study will dictate the decision for or against reimbursement. Products with explicit reimbursement pathways to increase revenue are more likely to be used by providers than products with limited or no coverage. As improper coding is often the cause of Medicare’s delayed or denied payments to providers, manufacturers must make certain that an identifying code is clearly available for placement on the insurance claim form. The somewhat long and drawn out timeframe for coverage can be reduced if a thoughtful reimbursement strategy is implemented at the earliest stages in product development.

References
(1 Social Security Act) Title XVIII, The Social Security Act of 1965, sec. 1862(a)(1)(A).
(2 FDA & Innovation) http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM192268.pdf.
(3 Innovators' Guide) https://www.cms.gov/CouncilonTechInnov/Downloads/InnovatorsGuide5_10_10.pdf.
(4 Jaeger) Cost Effective Analysis and Medical Device Utilization (Nov 2009).
(5 Evidence) http://en.wikipedia.org/wiki/Evidence-based_medicine.
(6 NOI) Federal Register 65, no. 95 (16 May 2000): Proposed Rules, 31124–31129.
(7 Registry User's Guide) http://www.effectivehealthcare.ahrq.gov/repFiles/PatOutcomes.pdf.
(8 Stark) Registry Studies for Medical Devices - Workshop (Mar 2010)
(9 CMRI) https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=228&ver=16&NcaName=Magnetic+Resonance+Imaging+(MRI)&bc=gQAAAAAAIAAA&.
(10 Clark) Device Case Studies for Reimbursement Codes (Nov 2008).
(11 AMA & CPT Codes) http://www.ama-assn.org/ama/pub/physician-resources/solutions-managing-your-practice/coding-billing-insurance/cpt/cpt-process-faq/code-becomes-cpt.page.
(12 ICD-9) https://www.cms.gov/ICD9ProviderDiagnosticCodes/03_meetings.asp
(13 Level II) https://www.cms.gov/MedHCPCSGenInfo/Downloads/2012HCPCSApplication.pdf
(14 CTI) https://www.cms.gov/CouncilonTechInnov/01_overview.asp
(15 CED) http://www.cms.gov/coverage/download/guidanceced.pdf
(16 Innovator's Guide) https://www.cms.gov/CouncilonTechInnov/Downloads/InnovatorsGuide5_10_10.pdf

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Getting to First-in-Man Studies

Last month I had the opportunity to attend the CRT2011 meetings in Washington, DC. My purpose was to report on the March 1 "Workshop with the FDA" on device development in the US. My whitepaper today is to combine the cardiovascular message from "Workshop with the FDA" with significant findings published by AdvaMed in a November 2010 publication titled "FDA Impact on US Medical Technology Innovation." I hope to take a deeper look into the why behind the what, and then hopefully propose a way forward.

The Device Development 'Ecosystem'
When I talk about innovation, I am referring to either the conception and invention of new devices or to incremental improvements to existing devices. When I talk about development, I am referring to the bench, animal safety, pre-clinical and clinical studies that occurs before FDA clearance or approval or EU certification. When I use the adjective "clinical" in this paper, I am referring to human studies. By the way, the 'ecosystem' is the new buzzword for global device development, including regulatory, economic, and resource availability effects.

  
While the US is still the leader in medical device innovation, development has largely fled to other continents. Most first-in-man studies are done in Europe, Asia, Latin or South America. The reasons are a ready patient population, modern hospital facilities, and English-speaking physicians trained in Western medicine and good clinical practices.

But all of this begs the question, how is it that it is easier to get first-in-man trials approved in countries outside the US?

First-in-Man Approval in the US
In the States, first-in-man trials require the same review process as any other clinical trial, which means you must get an IDE from FDA if the device is significant risk. While FDA reports an average of 27 days to get IDE approval from time of IDE submission, and six months if you count from first communication, Advanced reports an average of 14 months to get an IDE approval from the time of first communication with FDA. The long lead-time results in costs and delayed revenue stream that venture capital firms are becoming unwilling to fund.

  
First-in-Man Approval in the EU
In many European countries the Ethics Committees (ECs) have the real control over approval for clinical trials; the National Authority is only notified of the trial's initiation but doesn't take an active review role. The Notified Body serves as the inspection arm and reviews certification sometime after the device is commercialized. This means the level of review for first-in-man studies rests in the hands of the Ethics Committees, which are usually local and most certainly not funded or trained to the level of FDA.

I can't find any figures for the time required from first EC submission to initiating the first-in-man study, but AdvaMed reports that a 510k-level device requires an average of only seven months to certification. When you compare the benefits of earlier revenue stream with the inconvenience of implementing studies on the other side of the ocean, it is small wonder that American manufacturers have moved their development process to Europe.

 

The Global Harmonization Task Force
As an aside, the Global Harmonization Task Force (GHTF) has attempted to close the gap between continents but it lacks regulatory teeth. Its documents are written with more hope than how-to, (Medical devices should be designed and manufactured in such a way that...they will not compromise the clinical condition or safety of the patients....), and an Australian report says GHTF is closing shop and will reopen as "regulators only."

The Flight of Device Development
Both the speakers at CRT2011's Workshop and the report from AdvaMed draw a disturbing picture of the flight of medical device development to Europe. Sean M Salmon of Medtronic (VP and General Manager, Coronary and Peripheral) said he does 95% of his clinical trials outside the US, "why bother with FDA?" He acknowledged that US investigators feel left out and that he, too, is frustrated with the US system. But exceptional competencies exist around the world and there is no reason to restrict clinical studies to the US.

As device development moved to Europe and to other countries, US investigators fall increasingly behind the curve. One trend is the development of international relationships between US and outside-US hospitals (example) whereby American physicians can participate in international clinical trials by practicing outside the country.

So if manufacturers have found a way to go to Europe and elsewhere, and investigators are finding a way to go to Europe and elsewhere, where does that leave the American patient? According to the Medical Tourism Association, medical tourism is one of the fastest growing industries within healthcare. Traveling to another country to receive healthcare is the pathway of choice for many Americans seeking leading-edge care. Many insurance companies, such as Aetna, the Blues, WellPoint, and others, have implemented medical tourism pilot programs to support such care.

The workshop with the FDA can be summarized in a few simple statements:
[1] Device development has moved to Europe.
[2] US investigators are following.
[3] Device availability is delayed two-to-five years in the US.
[4] Medicare reimbursement doesn't necessarily follow FDA clearance/approval.
[5] Patients are following the new technologies through medical tourism.
[6] As development leaves the US, innovation and jobs will follow.
[7] The device industry is struggling under Healthcare Reform's federal excise tax on sales.

FDA's Response
Next at the workshop it was FDA's turn to speak. Dr. Ashley Boam (Branch Chief, Interventional Cardiology Devices, CDRH, FDA) summed FDA's position up simply: "Bring us better pre-clinical data."

Pre-clinical Strategies
In addition to ISO 10993 biocompatibility testing, preclinical animal testing to investigate potential harms to humans before doing first-in-man studies may be necessary. Such testing is often done in large animals in order to mimic clinical use of the device. You need to select a species whose anatomy can receive the device or provide reasonable feedback regarding human use.

There is no single, prescribed protocol for preclinical studies. Instead the intended use of the device is reproduced as best as possible. The potential harms from the device are identified from the literature or prior experience, including biological harms, mechanical harms, electromagnetic harms, software harms, harms from human error, or harms from any other source. Finally a protocol is developed to investigate the device's safety and performance. The species of animal, sample size, endpoints and pathology must all be justified. The protocol should be approved by an Animal Care and Use Committee and implemented in conformance with ISO 10993-11 "Systemic toxicity" Section 6. FDA favors the involvement of an experienced toxicologist in the development of the protocol and the final report.

For example, an embolization system was evaluated in a rabbit model, a thrombectomy device was evaluated in porcine whose arteries had been injected with fribrin-laden thrombi, a robotic spinal surgical system was evaluated in a porcine model, but I could find no accepted animal model for evaluating joint surface repair or osteonecrosis.

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CDG Can Help with Pre-Clinical Strategies

Dr. Dan McLain, convener of ISO 10993-11, is available to assist with pre-clinical strategies for your device. Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

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Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

ISO 14155 (2011) Good Clinical Practices for Medical Devices Is Here

It's time to update your procedures!
Coming into force very, very soon.

The International Standards Organization (ISO) has finally done it. Earlier this week they published the good clinical practices for medical device clinical investigations: ISO 14155 "Clinical investigations of medical devices in human subjects—good clinical practices" (2011). You can buy your very own copy at www.iso.org for 158 Swiss francs, search for 14155.

 

Once the standard is harmonized via publication in the Official Journal of the European Union it comes into force immediately; it will be tough, so you should start updating your procedures for European studies now. What's the "proof" that enforcement is immediate? And what will it mean for your study? Read on.

No phase-in period—the tedious proof
You can take my word for it, or you can follow the tedious proof presented in the next paragraphs to convince yourself about the enforcement date. We will look only at the Medical Device Directive (MDD); you can follow the same logic for the Active Implantable Medical Device (AIMD) directive on your own.

Annex ZA of the standard
Annes ZA of the standard states: "Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the normative clauses of this standard confers, within the limits of the scope of this standard, a presumption of conformity with the relevant Essential Requirements 6a of that Directive and associated EFTA regulations."

Which means—in American English—once the standard is cited in the Official Journal, you will meet the Essential Requirements of the MDD for clinical investigations if you conform to the standard.

Essential Requirements of the MDD
Turning our attention to the MDD, in Article 3 we read:

"Article 3
Essential requirements
The devices must meet the essential requirements set out in Annex I which apply to them, taking account of the intended purpose of the devices concerned.”

And in Article 4 of the MDD paragraph 2, we read:

“Article 4
2. Member States shall not create any obstacle to:
— devices intended for clinical investigation being made available to medical practitioners or authorized persons for that purpose if they meet the conditions laid down in Article 15 and in Annex VIII,”

And in Article 5 of the MDD, paragraph 1, we read:

“Article 5
Reference to standards
1. Member States shall presume compliance with the essential requirements referred to in Article 3 in respect of devices which are in conformity with the relevant national standards adopted pursuant to the harmonized standards the references of which have been publishes [sic, published] in the Official Journal of the European Communities; Member States shall publish the references of such national standards.”

Harmonized standards
You can check the MDD at ec.Europa.eu to see if the standard has been harmonized to the directive. Scroll down on the page to see the long list of harmonized standards. As of today, the 2003 versions of the clinical investigation standards are still in force. I'm told it takes 5-6 months before the a new ISO standard is cited in the Official Journal and harmonized to the directive.

 
 

Frequently asked questions—my guess at the answers
Your Notified Body is your final arbiter for enforcement of the new ISO standard for ongoing studies. A good rule of thumb is that the standard applies to your investigation from the time it is harmonized and going forward, but does not apply retrospectively to activities that are already completed.

[1] When the standard comes into force, what happens to clinical investigations that are currently enrolling?

The new rules will apply to the remainder of the investigation. This means investigators and study staff must to be trained to the new standard and their heavier responsibilities, new data forms for collecting device deficiencies should be created, and the like. It may be useful to develop an educational pack for the Ethics Committees.

[2] When the standard comes into force, what happens to clinical investigations that are completed (last subject is out) and I am analyzing the data?

The final report, i.e. clinical investigation report, should follow the format and content of the standard.

[3] When the standard comes into force, what happens to clinical investigations I am setting up? Let's say I have investigators and sites, and I have EC approval, but I have not yet enrolled the first subject?

Your clinical investigation procedures and quality management system should be updated now to meet the intense requirements of the new standard. Because you haven't enrolled subjects yet, you can expect to redo most of your administrative set-up if it wasn't done in conformance to the new standard.

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CDG Can Update Your Procedures

CDG was actively involved in writing ISO 14155 (2011). We understand the intention behind the words and can help explain standards-speak in a way you can understand. We can review your procedures, provide recommendations to bring them into conformance, or write additional procedures if needed.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

 

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

CDRH's 510(k) Working Group Preliminary Report—Findings 6 & 7

 Valuable, not-commonly-known information

In August 2010, CDRH's 510(k) Working Group published a preliminary report consisting of more than 60 recommendations grouped under seven findings aimed at improving the Center's effectiveness in implementing its missions. In our cycle of whitepapers, Kathleen and I have been reviewing the findings and recommendations, offering our observations of how they will affect the industry, and making alternative recommendations when we think we have a better idea.

Last week FDA issued its plans for Next Steps, but before we look at them I'd like to make some comments on Findings 6 and 7 because we uncovered some valuable, yet not-commonly-known information.

To recap, the first five findings were:
[1] There is insufficient clarity with respect to the definition of "substantial equivalence".
[2] CDRH's current practice allows for the use of some types of predicates that may not be appropriate.
[3] The de novo pathway is important and has not been optimally used across the Center.
[4] It is challenging for reviewers to obtain the information they need to make well-supported clearance decisions.
[5] CDRH's knowledge management infrastructure is limited.

In this final whitepaper we will look at Findings 6 and 7.

Finding 6: Variations in the expertise, experience, and training of reviewers and managers, including third-party reviewers, may contribute to inconsistency or uncertainty in 510(k) decision making.

More than 30% of reviewers, 31.5% to be exact, have less than two years experience; which means that one-third of the 510(k)s submitted to FDA will be reviewed by people with little agency history in their heads. One former high-level manager from CDRH advised me to study the preambles to every regulation. Preambles have legal standing, but most reviewers have never read them. I once asked a mid-level manager from CDRH BiMo how they could give a warning letter to a sponsor over a consent form that had been approved by an IDE reviewer; she scoffed and said: "Reviewers don't have time to read all that stuff."

 

[1] Reviewer Memoranda
Reviewers prepare an internal "review memo" for every 510(k) reviewed. The review memo documents the rationale of their decision. The Working Group Report states that less experienced reviewers write lengthier review memos, which are presumably more efficient. Something unexplained seems to happen with reviewers with more than ten years' experience; their highest percentage falls into an "unknown page count" column. (See Table 5.9 of the Report.)

 

Working Group Recommendations
The Working Group did not make recommendatations specific to review memos.

CDG recommends the very existence of review memos be more widely publicized. A careful search of the FDA website, Device Advice, and Google turned up very litle information about review memos. In fact, the only information I found concerned the 510(k) Quality Review Program, which states that a random selection of 510(k)s will be selected for review each quarter. A phone call to CDRH's Office of Device Evaluation gleaned the information that an internal review memo is written by the reviewer for every 510(k) reviewed, the memos are not generally offered to the submitter, and are available under the Freedom of Information Act. A call to FOI Services Inc (301-975-9400) confirmed this information, and copies of review memos for specific 510(k)s can be obtained through their office.

The review memo is of vital importance in gaining insight into the reviewer's thinking. Because the memos are available under Freedom of Information, why not make them available in the 510(k) database so that everyone can see them without making an independent FOI request? It would contribute to better submissions and more consistent reviews.

In addition, if your 510(k) submission was not cleared or received an NSE decision, the review memo should automatically be included in the FDA letter to the submitter.

[2] Third-Party Review
Class I and Class II 510(k) that do not require clinical data may go through a pre-review by an accredited third-party. While data show that submissions that have gone through pre-review tend to go through the final FDA review faster, there are no data to show if the total review process (pre-review plus FDA review) is longer or shorter. Concerns have been raised about the quality and consistency of third-party reviews.

Working Group Recommendations
The Working Group recommends regular evaluation of what devices are eligible for third-party review and that the agency enhance its third-party training programs.

CDG agrees. The third-party review program should be promptly expanded as planned in the Next Steps. Kathleen's personal experience with third-party reviewers has been extremely positive. She recommends shopping for companies who have reviewer's experienced in your type of product, checking their schedule for reviewing, and assessing the cost of the review. Typically the reviewer willl require less than a month to give tentative approval (or discuss deficiencies) for the submission. In Kathleen's experience FDA has always concurred.

[3] Enhance reviewer training
The Working Group recommends that reviewer training, professional development, and knowledge-sharing be enhanced.

CDG agrees. A lack of reviewer experience has serious consequences for manufacturers. Submissions are not reviewed consistently, reviewers may not have the scientific training to adequately review the submission, decisions may be delayed, review decisions may be inadequately documented, unnecessary or even outdated or inappropriate testing may be requested. In one situation, the reviewer of an IVD submission utilizing de-identified data asked the submitter to obtain additional information from the clinical subjects—an illegality because it would violate privacy rules, as well as impossible because the subject's identity was not known. In the case of the IDE approved informed consent form, BiMo nevertheless issued a warning letter for alleged deficiences.

Finding 7: CDRH does not currently have an adequate mechanism to regularly assess the quality, consistency, and effectiveness of the 510(k) program.

CDRH's primary tool for assessing the quality of 510(k) reviews is its 510(k) Quality Review Program. Through this program, managers in ODE and OIVD assess a sample of review memoranda on a quarterly basis. A standardized checklist is used to evaluate the completeness of each review memorandum, but not the adequacy or appropriateness of the reviewer’s decision making rationale and explanation.

Further, although CDRH collects information on device performance in the postmarket setting, important limitations, including the inability to consistently link postmarket events to specific 510(k)s, make this information, in isolation, an unreliable measure of program effectiveness.

Working Group Recommendatons
The Working Group recommended that CDRH develop metrics to continuously assess the quality, consistency, and effectiveness of the 510(k) program, to periodically audit 510(k) review decisions, and to measure the effect of any actions taken to improve the program.

CDG agrees and is hopeful that such information will be made publicly available in ODE's annual reports. Submitters can only increase the quality of their submissions if they have examples to work from.

CDG Can Write Your 510(k)

CDG's extensive Network Staff has expertise in writing 510(k)s in a wide variety of therapeutic, management, or diagnostic areas. My co-author, Kathleen Johnson is a regulatory consultant with more than 10 years experience in medical devices. CDG has capabilities in regulatory submissions, clinical research, toxicology, biostatistics, information research, medical writing, design control—we focus exclusively on medical device pre-approval issues.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

European Medical Device Update

A Few Items of Note about Device Regulation in the European Union

Life keeps moving along in Europe in spite of the snow and closed airports. Here are three important medical device regulatory issues you'll want to address in the new year.

[1] No phase in period for ISO 14155 "Clinical investigation of medical devices in human subjects—good clinical practices"
If the stars align, Jupiter stays in the heavens, and my cat stops catching birds, ISO 14155 may be published in the first quarter of 2011. But don't wait around for the big event. Implementation will be immediate and there is no phase in period!

The convener recommends all sponsors start updating their clinical investigation procedures now. However, updating your procedures is a little bit difficult because the final draft of the standard is not available for purchase on the www.iso.org website. ISO.org lists the standard as being under publication (stage 60.00) but provides no means to add it to your shopping cart.

 

The same is true for the Association for the Advancement of Medical Instrumentation at www.aami.org, which has inexplicably truncated the title to "Clinical investigation of medical devices for human subjects" and left off the declaration of "good clinical practices". AAMI claims identical equivalency to ISO 14155/Ed.3 (edition 3?), and states the draft is not available 'outside of committee'.

CDG can update your clinical procedures to ISO/FDIS 14155

Clinical Device Group is a corporate member of AAMI, a member of ISO TC 194, and has access to the final draft versions of ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practices". While we can't provide you with a copy of the unreleased document, we can review your existing procedures and make recommendations to bring them into conformance. Our style is to work collaboratively with point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5706 or cdginc@clinicaldevice.com.

 If you don't work for one of the thirty or so firms who pay corporate dues to AAMI, are members of TC 194, and have access to the final draft standard, you will have to figure out another game plan. You might consider hiring a CRO with access to the final draft to update your procedures for you.

2] MEDDEV 2.7/3 Serious adverse event reporting under the amended Directives
The European Commission published MEDDEV 2.7/3 "Serious Adverse Event Reporting under 90/385/EEC and 93/42/EEC" in December 2010. Although the guidance is voluntary, you are strongly urged to follow it. The guidance uses the ISO/FDIS 14155 definitions of adverse events and effects, and recommends that all serious adverse events (SAEs), device deficiencies that might lead to SAEs, and any new findings regarding existing SAEs, be reported to every National Competent Authority (NCA) in which the investigation is being conducted.

Two categories of SAEs
The guidance takes the odd approach of dividing SAEs into two categories: a) those that require prompt remedial action, and b) those that do not.

SAEs that require prompt remedial action to mitigate an imminent risk of death, serious injury, or serious illness should be reported immediately but no more than 2 (two) calendar days to the NCAs using the Reporting Form provided in the guidance Appendix. SAEs that do not require prompt remedial action should be reported no more than 7 (seven) calendar days. The MEDDEV 2.7/3 guidance and an Excel spreadsheet of the Reporting Form are provided on CDG's website.

Observations
A serious adverse event that occurs at a US site should be reported to every European NCA in which the investigation is also being conducted. CDG recommends that investigations in the US and EU be administered and managed as separate studies because: 1) it is difficult to meet the reporting requirements of two different regulatory entities in the same investigation, and 2) it is difficult to justify pooling data given the differences in medical practice. Patients in countries with socialized medicine tend to be farther along in the disease process before receiving medical care than patients from countries with for-profit medical care.

The guidance makes no mention of reporting serious adverse events to Ethical Committees. It doesn't discuss sharing of data between National Competent Authorities. It doesn't address setting up a European database of serious adverse events. And it doesn't address making the SAE reports available to the public. As much as we have complained about a lack of transparency and organization at FDA in recent whitepapers, Europe has a long way to go before it catches up.

[3] MEDDEV 2.7/4 Clinical investigations: A guide for manufacturers and Notified Bodies
The European Commission also published MEDDEV 2.7/4 "Guidelines on Clinical Investigation: A Guide for Manufacturers and Notified Bodies" in December 2010. Again the guideline is not legally binding, but it reflects the thinking of the European Commission and what manufacturers can reasonably expect from their Notified Bodies.

Distinctions
The guideline tries to clarify the European distinctions between clinical data, clinical evaluation [reports], and clinical evidence. The logic is not obvious, so I've designed a graphic to help sort it out.

 

Clinical data are numbers, values, measurements, and the like, taken from the literature, sponsored clinical investigations, and other reports such as complaint history files and risk management systems.

Clinical data are assessed, analyzed, and written up in clinical evaluation reports.

Clinical evidence is both the original clinical data (numbers and values) and the clinical evaluation report.

If the clinical evidence is sufficient to establish the safety and performance of a device for its intended use, then the manufacturer may declare conformity to the essential requirements and proceed to market the device. If the clinical evidence is insufficient to establish safety and performance, the manufacturer may withdraw the claim or proceed to a new clinical trial in an effort to generate data to substantiate the claim.

Differences between US and EU
The fundamentals of good clinical practices haven't changed and are not much different between the US and EU. The new ISO 14155 standard was written to harmonize as close as possible with the existing ICH-GCPs; so if you are an experienced clinical research professional there will be no surprises. But there are some differences in implementation.

The first difference is the heavy level of adverse event reporting in Europe. Even for European Class I and IIa devices, all adverse events are reportable to sponsors, Ethics Committees, and NCAs; and all serious adverse events—device related or not—are reportable to NCAs within 2-7 days. In the States, for significant risk devices, only adverse device effects are reportable to sponsors, IRBs, and FDA (unless FDA requires more for a particular investigation); and for non-significant risk devices, adverse device effects are only reportable to sponsors and IRBs.

The second difference will be the increased emphasis on risk management in the clinical investigation process and figuring out how to apply ISO 14971 "Application of risk management to medical devices" to clinical investigations.

Got feedback?
If you have comments, disagreements, or additional information, please post them below. I look forward to hearing from you.

Happy New Year,

Nancy J Stark, PhD
President, Clinical Device Group Inc
cdginc@clinicaldevice.com

 

 

CDRH's 510k Working Group Preliminary Report: Finding 5

A GLIMPSE AT THE FUTURE?
A Cycle of 510(k) Whitepapers by Nancy J Stark and Kathleen Johnson

In August 2010, CDRH's 510(k) Working Group published a preliminary report consisting of more than 60 recommendations grouped under seven findings aimed at improving the Center's effectiveness in implementing its missions. Will the recommendations work? Do they comprise a forward-thinking strategic plan for the device industry? Herein you'll find CDG's summation of Finding 3 and part of Finding 4, along with our opinions of their worth.

Finding 5: CDRH's knowledge management infrastructure is limited

Neither Center staff nor 510(k) submitters have access to meaningful information
The only comprehensive electronic source of non-public information on prior 510(k) reviews available to Center staff is a database of archived image files. The database is searchable only by 510(k) number. To find information within each file, staff must conduct a labor-intensive, file-by-file text search. Without looking through each file individually, it is impossible to determine what predicate(s) the reviewer used as the basis for a substantial equivalence determination, and what the rationale for the decision was. Moreover, archived files contain varied levels of detail. Older 510(k) submissions and review memoranda are inconsistent in format and content, and many of them are handwritten.

[1] Enhanced 510k database needed
The Working Group recommends that both internal and public information systems be enhanced.

CDG agrees and further suggests the databases be made available through PubMed, Embase, or even Google where the ability to limit date ranges, use 'not' operators, turn on keyword explosion, use fuzzy logic, and use sophisticated text-search tools are available. Furthermore, the database in its entirety should be downloadable to Excel. The Summaries of Safety and Effectiveness or 510(k)s themselves should be keyworded by K number, product code, predicates, generic and brand names to allow for 'family trees' or 510k pedigrees to be constructed. The information should be available all the way back to 1976, and not stop at 2002.

CDG can write your 510(k)
CDG's extensive Network Staff has expertise in writing 510(k)s in a wide variety of therapeutic, management, or diagnostic areas. My co-author, Kathleen Johnson is a regulatory consultant with more than 10 years experience in medical devices. CDG has capabilities in regulatory submissions, clinical research, toxicology, biostatistics, information research, medical writing, design control—we focus exclusively on medical device pre-approval issues.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

[2] Product Codes, also known as classification numbers
Product codes are the underpinning for CDRH’s information management systems. They are the primary tool for organizing medical device information in CDRH’s databases, and staff across the Center rely on product codes in their day-to-day work. Product codes are used for tracking and analysis of medical device data across a device’s total product life cycle, including information from premarket submissions, adverse event reports, device recalls, inspections, and compliance actions. Review staff and 510(k) submitters use product code searches to identify and obtain information about potential predicate devices. Product codes were intended to provide more granular distinctions than the general descriptive language provided in the classification regulations. However, inconsistencies in the way product codes are assigned make it difficult to access meaningful device information.

The origin of "product codes" is so old even the Working Group could not give it an accurate reference; a day of research revealed the term "classification number" on FDA Form 2892, which was introduced in 1977 in 21 CFR 807.26, somehow transformed itself into the term "product code" (for a three letter, non-numeric code) at some point in time.

Working Group Recommendations
The Working Group recommends that the agency develop procedures for assigning product codes consistently and that special attention be given to IVD multiplex devices.

CDG agrees and suggests the search engine for product codes be improved. At this time, in order to find a predicate device you can: 1) search keywords in the classification database (simple search) to get a list of product codes and regulation numbers that match your keywords, 2) then search on the product code in the 510(k) database to find possible predicates for your new device. But this method is laborious, time-consuming, and the list that results may not contain good matches for your device. Furthermore, if your device is made of multiple components you will have to do a separate search for each component. And the list does not go back to 1976, so a comprehensive search is not possible. We also suggest that the device listing Form FDA 2892 ask for a product code rather than a classification number to dispel confusion, and that a history of the relationship between the two terms be clarified.

[3] 510(k) Databases
The 510(k) database is not easily searchable for either reviewers or submitters. Lacking a reliable source of accurate information, 510(k) submitters may be forced to look at how the predicate is advertised, which does not necessarily reflect the intended use for which it was cleared. Once cleared, device 510(k) are not accompanied by a revewer-prepared Decision Summary or a reviewer-prepared Summary Basis of Approval, as are IVD 510(k)s or pharmaceuticals. These Summaries are written by the FDA reviewer and capture the thought process and rationale for clearance.

 The data are from page 39 of the Working Group Preliminary Report

 
Working Group Recommendations
The Working Group recommends that CDRH develop a publicly available, easily searchable database that includes, for each cleared device, a verified 510(k) summary, photographs and schematics of the device (to the extent that they do not contain proprietary information), and information showing how cleared 510(k)s relate to each other and identifying the premarket submission that provided the original data or validation for a particular product type.

CDG believes that if a decently searchable 510(k) database were made available to submitters, the quality of submissions and appropriateness of predicates would improve automatically and the time to clearance would decrease. The database should go as far back as 1976 to facilate comprehensive searches. No further changes or requirements should be made until a functional seach engine is developed.

CDG further recommends that a reviewer-prepared Decision Summary be prepared for every cleared 510(k) as an enhancement to the 510(k) Quality Review Program (I96-1). It should be made available to the public, along with the company-prepared 510(k) Statement or Summary. This would enhance quality in 510(k) submissions and consistency in 510(k) clearances.

[4] Final Device Labeling
One frustration for FDA is that final device labeling and updates to labeling are not routinely reviewed; hence labeling may be inconsistent with, or over-interpret, cleared indications.

Working Group Recommendatons
The Working Group recommended the agency explore the requiring manufacturers to submit final device labeling to FDA by the time of clearance or within a reasonable period of time after clearance, and also to provide regular, periodic updates to device labeling.

CDG's concern is that requiring final labeling before a 510(k) is cleared would merely add to the timeframe for clearance. Annually updating device labeling—when taken together with the previous recommendations for annual updates for device modifications and the recommendation that all scientific information be included in the original submission, regardless of whether or not it supports an argument of substantial equivalence—is tantamount to requiring an annual 510(k) supplement similar to that required for PMAs. It is unduly burdensome for manufacturers of 510(k) devices and an already overburdened FDA staff could not handle the additional data.

We suggest that FDA update the 1997 guidance document "Deciding When to Submit a 510(k) for a Change to an Existing Device" and make available an online webcast to educate manufacturers about its contents.

[5] 510(k) Ownership
CDRH’s databases rarely reflect changes in 510(k) ownership that occur after clearance, largely because the Center is not typically notified of transfers of ownership.

Working Group Recommendations
The Working Group recommends the agency develop guidance and regulations regarding appropriate documentation of transfers of 510(k) ownership. The Center should update its 510(k) database in a timely manner when a transfer of ownership occurs. CDG, as well as a majority of public comments, support the recommendation.

CDRH Missions
The Center for Devices and Regulatory Health has two important missions: 1) to protect the public health, and 2) to foster medical device innovation. Their difficult job is to keep these missions in balance, never compromising one in favor of the other. Do you have the original citation for fostering medical innovation?

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc