Grassley comment on FDA announcement about review of ReGen’s Menaflex device

M E M O R A N D U M

TO: Reporters and Editors
FR: Jill Kozeny, 202-224-1308 for U.S. Senator Chuck Grassley, Ranking Member of the Committee on Finance
RE: FDA announcement re. ReGen’s Menaflex device

Senator Chuck Grassley issued the comment below about the announcement made todayby the Food and Drug Administration about the agency’s concerns with its own review of theReGen Menaflex device. (Information about the report is posted with this statement athttp://finance.senate.gov and http://grassley.senate.gov.) Senator Grassley has been askingquestions about the FDA’s review of this product. He wrote to FDA and ReGen in March 2006,regarding allegations that ReGen influenced FDA’s actions on the device.

“The report issued today is more good news about the FDA recognizing shortcomings inits review process for the majority of medical devices. The specific findings about the review ofthe Menaflex device track what I’ve found in my own review. The agency failed to followprocedures, excluded the review team from speaking before an advisory panel, and was too quickto accommodate demands made by the device manufacturer. More broadly, the report admitsthat the agency needs to take a closer look at the 501(k) review process to make sure itadequately protects the American people. The kind of reflection and the commitment to actionmade in this report is key to the FDA building public confidence in its commitment to publicsafety through scientifically rigorous and independent review.”

Below is a news release issued yesterday by Senator Grassley.

For Immediate Release
Wednesday, September 23, 2009

Grassley works to improve medical device safety

WASHINGTON --- Senator Chuck Grassley said it was good news that the Food andDrug Administration has commissioned the Institute of Medicine to examine the agency’s 510(k)system for clearing medical devices.

The 501(k) system is used for reviewing most devices approved by the agency. It is lessstringent than FDA’s premarket approval process used in reviewing high risk devices, such asimplantable defibrillators and pacemakers.

A provision requiring the FDA to commission a study was included in legislationintroduced last April by Grassley and the late Senator Ted Kennedy. Their bill, the Drug andDevice Accountability Act (S.882), would give the FDA more resources to inspect domestic andforeign manufacturers of prescription drugs and devices.

“A study by the well regarded Institute of Medicine will provide valuable information toimprove the FDA’s review of medical devices. Questions have been raised about the agency’swork in this area,” Grassley said.

A January 2009 report of the Government Accountability Office detailing concerns aboutthe FDA’s review process for medical devices is attached.

Grassley has conducted active oversight of the FDA during the last five years. He’sadvocated greater independence in post-market surveillance and sought greater transparency andaccountability in the drug and device approval process.

Here is the section of S.882 that called for the study:

SEC. 143. STUDY BY THE INSTITUTE OF MEDICINE REGARDING THE REVIEW OFMEDICAL DEVICES.

(a) In General- The Secretary of Health and Human Services shall enter into a contractwith the Institute of Medicine to conduct a study to--

(1) evaluate the organizational structure and operations of the Food and DrugAdministration with respect to the review of medical devices for clearance undersection 510(k) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k))and for premarket approval under section 515 of such Act (21 U.S.C. 360e);

(2) evaluate the analytical and methodological tools used by such Administrationto conduct such reviews; and

(3) identify strengths, weaknesses, and limitations of the system used by suchAdministration to conduct such reviews.

(b) Report- Not later than September 31, 2010, the Institute of Medicine shall completethe study described under subsection (a) and submit to the Secretary of Health andHuman Services, the Committee on Health, Education, Labor, and Pensions and theCommittee on Finance of the Senate, and the Committee on Energy and Commerce of theHouse of Representatives a report that--

(1) describes the findings of such study; and

(2) makes recommendations regarding the organization structure and operationsof the Food and Drug Administration, legislation, and regulation to improve orenhance the review of medical devices by such Administration.

Here is a copy of the FDA’s announcement about the study being commissioned:

FDA NEWS RELEASE
For Immediate Release: Sept. 23, 2009
Media Inquiries: Karen Riley, 301-796-4674, karen.riley@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA: Institute of Medicine to Study Premarket Clearance Process for Medical DevicesThe U.S. Food and Drug Administration today announced that it has commissioned the Instituteof Medicine (IOM) to study the premarket notification program used to review and clear certainmedical devices marketed in the United States.

The IOM study will examine the premarket notification program, also called the 510(k) process,for medical devices. While the IOM study is underway, the FDA’s Center for Devices andRadiological Health (CDRH) will convene its own internal working group to evaluate andimprove the consistency of FDA decision making in the 510(k) process.

“Good government conducts periodic reviews and evaluations of its programs,” said JeffreyShuren, M.D., acting director of CDRH. “Our working group and the IOM’s independentevaluation will help us determine how the 510(k) process can be improved to better supportFDA’s mission to protect and promote the public health.”

The 510(k) process was established under the Medical Device Amendments of 1976 with twogoals:

• Make safe and effective devices available to consumers

• Promote innovation in the medical device industry.

During the past three decades, technology and the medical device industry have changeddramatically, making it an appropriate time for CDRH to review the adequacy of the premarketnotification program in meeting these two goals.

Established by the National Academy of Sciences, the IOM provides independent, objective,evidence-based advice to policymakers, health professionals, the private sector, and the public.As part of the study, the IOM will convene a committee to answer two principal questions:• Does the current 510(k) process optimally protect patients and promote innovation insupport of public health?

• If not, what legislative, regulatory, or administrative changes are recommended toachieve the goals of the 510(k) process?

The $1.3 million IOM review is slated for completion in 2011, and is one of six priorities Dr.Shuren has outlined for CDRH. Others include:

• Creating an internal task force on the use of science in regulatory decision-making

• Developing an effective compliance strategy

• Optimally integrating premarket and postmarket information

• Increasing transparency in decision-making

• Establishing clear procedures to resolve differences of opinion.

The IOM will hold two public workshops during the next nine months as part of its review, andwill publish a final report in March 2011 containing its conclusions and recommendations.

The FDA classifies medical devices into three categories according to their level of risk. Class IIIdevices represent the highest level of risk and generally require premarket approval to supporttheir safety and effectiveness before they may be marketed. Class III devices include heart valvesand intraocular lenses.

Class I and Class II devices pose lower risks and include devices such as adhesive bandages andwheelchairs. Most Class II devices and some Class I devices can be marketed after submission ofpremarket notifications—also called 510(k) applications—that support their substantialequivalence to legally marketed devices that do not require premarket approval.

Devices that present a new intended use or include new technology that presents new questionsof safety or effectiveness may not be found substantially equivalent and require premarketapproval.

For more information Premarket Notification 510(k)
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/default.htm.

For Immediate Release
Friday, March 6, 2009

Grassley asks for an accounting of contacts between FDA and device maker

WASHINGTON – Senator Chuck Grassley has asked the Food and Drug Administrationand a medical device maker for information about their communication during the approvalprocess of a new device for knee injuries.

Grassley said his inquiry is based on information provided to him, including emails that“make it look like the device maker was calling the shots and the FDA was going out of its wayto accommodate the company.”

The text of Grassley’s letters is below. He has conducted oversight of the FDA for nearlyfive years and documented what he calls a “too cozy relationship” between the FDA andindustry.

“I hope this new example helps compel the new administration to name an FDACommissioner committed to independent, scientific assessment on behalf of consumers.Congress needs to do its part, too, but the culture of the agency is set from the top down, and thenext commissioner needs to be a reformer.”

March 6, 2009

Frank M. Torti, MD, MPH
Acting Commissioner
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

Dear Dr. Torti:

As Ranking Member of the United States Senate Committee on Finance (Committee), Ihave a responsibility to the more than 80 million Americans who receive health care coverageunder the Medicare and Medicaid programs to oversee the proper administration of theseprograms and ensure that taxpayer dollars are appropriately spent on safe and effective drugs anddevices.

Recently, I wrote to the Food and Drug Administration (FDA or Agency) regarding theCenter for Device and Radiological Health’s (CDRH) handling of device reviews. In particular,I asked the FDA to respond to questions and provide information related to allegations ofmisconduct and retaliation within the Center’s Radiology Devices Branch.

In the course of my inquiries into those allegations, I have obtained documents thatsuggest FDA’s actions related to a particular device may have been influenced by themanufacturer, ReGen Biologics, Inc. (ReGen). In particular, emails provided to the Committeeshow that ReGen was involved in the convening of an FDA advisory panel for the review of thecompany’s Collagen Scaffold used in knee surgery. A consultant to the company made thefollowing points in an email to FDA’s Assistant Commissioner for Accountability and Integrityin October 2008:

The company has serious concerns about any involvement by CDRH and Dr.Schultz in the panel – given that you had to involve OCC to prevent Dr. Schultzfrom issuing a 3rd illegal NSE letter.

* * *

We feel very strongly that you should run the panel meeting or somebody in theCommissioner’s office and think that Dr. Torti should be involved in thisprocess. I am concerned that things are moving very quickly and the companywill not have the opportunity to have ANY input in the make up [sic] of thepanel, who will run it, and what questions will be asked.

* * *

Finally, if Dr. Schultz is allowed to run this panel and make the final decision –that is not fair or acceptable to us.

The Assistant Commissioner summarized the consultant’s message in an internal email toDr. Daniel Schultz, FDA attorneys and others, stating that the consultant “suggests severalquestions for the panel that ReGen thinks are legally acceptable, but he has voiced strongconcern about having CDRH run the panel (because he thinks they are biased against ReGen)and asserts the company should have input into [sic] sits on the panel.” See attached.

It appears, based upon the materials in my possession, that in response to ReGen’sconcerns, former Commissioner Andrew von Eschenbach became personally and activelyinvolved in the matter. In a draft of his letter to the ReGen Chief Executive Officer (CEO), hestated that the “FDA has welcomed your [ReGen’s] input into the structure and composition ofthis advisory committee in an effort to assure you of its effective and impartial deliberations.”See attached. In addition, he stated that the FDA had “invited six temporary voting members toparticipate in the advisory committee, five of whom, per your [ReGen’s] request, have sportsmedicine backgrounds. In selecting these temporary voting members, we have been mindful ofthe criteria you sent us regarding the types of experts that you believe are best qualified toevaluate the CS Scaffold.” The draft letter also included the following statement regardingquestions to be addressed by the advisory panel: “FDA will be the final arbiter of the meetingquestions to the committee. However,...I am assured that your company has made amplecontribution to their development.”

After reviewing the draft letter, an FDA deputy chief counsel asked whether all sponsorsare given the opportunity to provide such input regarding the composition of an advisory panel.The response he received was, “No, we do not give everyone that oppoprtunity [sic]. I think thatstatement would cause significant problemas [sic] for the agency.” I understand the statementwas ultimately removed from the final letter but its genesis is of great interest.

In addition, according to FDA’s slide presentation to the Orthopaedic and RehabilitationDevices Advisory Committee on the Collagen Scaffold on November 14, 2008, the FDA focusedits clinical data presentation “on the approved IDE [investigational device exemption] protocol,JBJS [Journal of Bone and Joint Surgery] article, and clinical data provided in the 510(k)submission.” An internal FDA email dated November 11, 2008, noted that the first author of theJBJS article is ReGen’s Vice President of Scientific Affairs. Another listed author is a memberof the ReGen Board of Directors. However, it was brought to my attention that FDA’s slides didnot mention that these two authors were affiliated with ReGen.

Furthermore, it appears that a potential panel member for the Orthopaedic andRehabilitation Devices Advisory Committee may have been excluded from participation in theNovember 14, 2008 meeting to discuss the Collagen Scaffold as a result of ReGen’s concerns.According to an internal FDA email dated May 6, 2008, the Assistant Commissioner stated, “Iexpect ReGen will want to make the case why [redacted] is biased against them. I explained toMichael [ReGen’s consultant] last week that ReGen needs to do more than allege a bias based on[redacted] surgical specialty in meniscus replacements.”

As I have stated in the past, I am concerned about the cozy relationship that sometimesexists between the FDA and manufacturers of the products regulated by the Agency. Thus I amvery troubled that the documents that I presently have in my possession seem to suggest that theFDA allowed ReGen to play an active role in the make-up of the advisory panel, among otherthings. Furthermore, since the FDA Commissioner is not typically involved in regulatorydecisions regarding an individual product, I am interested in the events that led to the formerFDA Commissioner’s personal involvement in the Agency’s review of ReGen’s device.

Accordingly, I would appreciate FDA’s response to the following questions and requests forinformation. Please repeat the enumerated question and follow with the appropriate responseand documentation.

1. Are sponsors of pre-market approval applications and/or 510(k) submissions typicallyinvited to contribute to the development of advisory panel questions and/or the structureand composition of an advisory panel that is reviewing their products? If it is notcommon for the FDA to obtain such input, please explain why it was appropriate to do sofor the Collagen Scaffold.

2. According to an email dated October 31, 2008, former Commissioner von Eschenbachplanned to “review the CVs of the SGEs [special government employees] over theweekend to be sure we have the right people” for the advisory panel reviewing ReGen’sCollagen Scaffold.

a. Please describe in detail the circumstances under which the FDA Commissionerand/or staff from the Commissioner’s office would become personally involved inthe convening of an FDA advisory panel and/or other activities related to thereview of a product application. Please include in your response a detaileddescription of the other types of review activities.

b. Identify the number of times from January 2004 through the date of this letter thatthe FDA Commissioner and/or staff from the Commissioner’s office have beenpersonally involved in the convening of an FDA advisory panel to evaluate aspecific product. Please identify the product(s) of interest and the center(s)overseeing the product(s).

c. Please identify the number of times from January 2004 through the date of thisletter that the FDA Commissioner and/or staff from the Commissioner’s officehave been personally involved in other activities related to a center’s review of aspecific product. Please identify the product(s) of interest, the center(s)overseeing the product(s), and the activity(ies).

3. If the FDA did disclose to the Orthopaedic and Rehabilitation Devices Advisory Panelthe authors’ affiliations with ReGen, please explain how and when that disclosure wasmade and how it was documented.

4. When did ReGen first raise concerns about a particular physician’s bias against thecompany? Please describe in detail and provide supporting documentation for why theFDA excluded that physician from participation on the Orthopaedic and RehabilitationDevices Advisory Committee for the review of the Collagen Scaffold on November 14,2008.

5. Please provide a copy of all internal and external communications and other materials,including emails, memoranda, personal notes, and telephone notes, relating either directlyor indirectly to ReGen and the FDA, the make-up of the Orthopaedic and RehabilitationDevices Advisory Committee, and the development of the panel questions for the periodof September 2007 through the date of this letter.

Thank you for your attention to this important matter. Please respond to the questionsand requests set forth in this letter by no later than March 20, 2009.

Sincerely,

Charles E. Grassley
Ranking Member

March 6, 2009

Gerald E. Bisbee, Jr., PhD
Chairman, President and Chief Executive Officer
ReGen Biologics, Inc.
411 Hackensack Avenue
Hackensack, NJ 07601

Dear Dr. Bisbee:

As Ranking Member of the United States Senate Committee on Finance (Committee), Ihave a responsibility to the more than 80 million Americans who receive health care coverageunder the Medicare and Medicaid programs to oversee the proper administration of theseprograms and ensure that taxpayer dollars are appropriately spent on safe and effective drugs anddevices.

In the course of my inquiries into allegations of misconduct within the Food and DrugAdministration’s (FDA or Agency) Center for Device and Radiological Health (CDRH), I haveobtained documents that suggest FDA’s action related to a particular device may have beeninfluenced by ReGen Biologics, Inc. (ReGen or Company). In particular, I am very troubled bythe attached emails suggesting that the FDA allowed ReGen to play an active role in the make-upof an FDA advisory panel for the review of the company’s Collagen Scaffold used in kneesurgery and the development of panel questions, among other things.

In October 2008, a month before FDA’s Orthopaedic and Rehabilitation DevicesAdvisory Committee was scheduled to convene, a consultant to the Company made thefollowing points in an email to the FDA assistant commissioner for integrity and accountability(Assistant Commissioner):

The company has serious concerns about any involvement by CDRH and Dr.Schultz in the panel – given that you had to involve OCC to prevent Dr. Schultzfrom issuing a 3rd illegal NSE letter.

* * *

We feel very strongly that you should run the panel meeting or somebody in theCommissioner’s office and think that Dr. Torti should be involved in thisprocess. I am concerned that things are moving very quickly and the companywill not have the opportunity to have ANY input in the make up [sic] of thepanel, who will run it, and what questions will be asked.

* * *

Finally, if Dr. Schultz is allowed to run this panel and make the final decision –that is not fair or acceptable to us.

The Assistant Commissioner summarized the consultant’s message in an internal email to Dr.Daniel Schultz, FDA attorneys, and others, stating that the consultant “suggests several questionsfor the panel that ReGen thinks are legally acceptable, but he has voiced strong concern abouthaving CDRH run the panel (because he thinks they are biased against ReGen) and asserts thecompany should have input into [sic] sits on the panel.” See attached.

It appears, based upon the materials in my possession, that in response to ReGen’sconcerns, former Commissioner Andrew von Eschenbach became directly and personallyinvolved in the matter. In a draft of his letter to you, he stated that the “FDA has welcomed your[ReGen’s] input into the structure and composition of this advisory committee in an effort toassure you of its effective and impartial deliberations.” In addition, he stated that the FDA had“invited six temporary voting members to participate in the advisory committee, five of whom,per your [ReGen’s] request, have sports medicine backgrounds. In selecting these temporaryvoting members, we have been mindful of the criteria you sent us regarding the types of expertsthat you believe are best qualified to evaluate the CS Scaffold.” The draft letter also included thefollowing statement regarding questions to be addressed by the advisory panel: “FDA will be thefinal arbiter of the meeting questions to the committee. However,...I am assured that yourcompany has made ample contribution to their development.”

After reviewing that draft letter, an FDA deputy chief counsel asked whether all sponsorsare given the opportunity to provide such input regarding the composition of an advisory panel.The response he received was, “No, we do not give everyone that oppoprtunity [sic]. I think thatstatement would cause significant problemas [sic] for the agency.” I understand the statementwas ultimately removed from the final letter but its genesis is of great interest.

In addition, it was brought to my attention that a potential panel member for theOrthopaedic and Rehabilitation Devices Advisory Committee may have been excluded fromparticipation in the November 14, 2008 meeting to discuss the Collagen Scaffold as a result ofReGen’s concerns. According to an internal FDA email dated May 6, 2008, the AssistantCommissioner stated, “I expect ReGen will want to make the case why [redacted] is biasedagainst them. I explained to Michael [ReGen’s consultant] last week that ReGen needs to domore than allege a bias based on [redacted] surgical specialty in meniscus replacements.”

I have been and continue to be concerned with the cozy relationship that sometimes existsbetween the FDA and manufacturers of the products regulated by the Agency. Accordingly, Iwould appreciate ReGen’s response to the following questions and requests for information.Please repeat the enumerated question and follow with the appropriate response anddocumentation in accordance with the terms and conditions set forth in the attachment:6. Please provide a list of all meetings and/or telephone calls between representatives ofReGen, including any third party contractors, and any FDA official/employee relateddirectly or indirectly to the November 14, 2008 advisory panel meeting on ReGen’sCollagen Scaffold. Please sort the list by date and provide the names of all participants ateach event and a description of the subject matter discussed. This request covers theperiod of January 1, 2008 through December 31, 2008.

7. Please provide a copy of all documentation of communications, including but not limitedto emails, memoranda, meeting notes, and telephone notes, related directly or indirectlyto the Collagen Scaffold, between representatives of ReGen, including any third partycontractors, the former Commissioner von Eschenbach and the following FDA officials:Dr. Frank Torti, Mr. William McConagha, Mr. Les Weinstein, Dr. Daniel Schultz, andDr. Donna Bea Tillman. This request covers the period of September 2007 through thedate of this letter.

8. Please provide a copy of all internal communications related to the November 14, 2008FDA advisory panel meeting on the Collagen Scaffold, including but not limited to thestructure, composition, and substance of the meeting and the development of the panelquestions. This request covers the period of January 1, 2008 through December 31, 2008.9. Please explain in detail why ReGen thought that Dr. Schultz was biased against ReGen.10. State the date on which ReGen first raised concerns to the FDA regarding theparticipation of a specific physician on the Orthopaedic and Rehabilitation DevicesAdvisory Committee for the review of the Collagen Scaffold on November 14, 2008. Inaddition, please describe in detail the basis for which ReGen believed that the physicianshould be excluded from participation on that advisory panel.

In cooperating with the Committee’s review, no documents, records, data or informationrelated to these matters shall be destroyed, modified, removed or otherwise made inaccessible tothe Committee.

Sincerely,

Charles E. Grassley
Ranking Member

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