must remain vigilant in shaping public policy and read writing produce a three story f t s core mission of ensuring america's drug supply is safe for all americans with that in next turn to the ranking member of this subcommittee the gentleman series of hearings on this important issue the safety of our nation's drug supply and how it affects the health and well being of our fellow citizens questions have been raised for many years about the f d a as management of safety issues with respect to the approval and post market surveillance of drugs including questions questions raised by this committee with respect to the use of anti depressant drugs among children and studies showing that their use was linked to increased risk of suicide while f t s management of drug safety has received increased scrutiny this is certainly as i said not a new issue in fact in a two thousand and six report requested by then chairman joe barton and senator chuck grassley the government accountability office stated that problems have been raised about the f d a s management of drug approval and post market surveillance for the last thirty years these are certainly complex issues and often involve complicated scientific debate and judgment issues raised by the f d a approval of the drug key tactic which we will learn more about from today's witnesses certainly demonstrate this the debate within f d a about the key tech drug application was not simply a matter of approving or disapproving the drug and said the key tech application raises larger public health questions that were debated it by doctors and scientists within the f d a with respect to the approval of antibiotics and about what types of studies should be performed to demonstrate a drug safety and efficacy at what point should data collected during drug trials be included are disqualified from the society how should that regarding resistance to antibiotics be interpreted and how should this affect the availability of antibiotics these are questions about which scientist physicians and experts continue to debate while it is critical that we examine drug safety and whether f d a decision making processes are suited to ensure the safety of our drug supply it is also critical that we do so and i careful and deliberate way today we will hear from two witnesses dr david ross and dr john powers who are employed by the f d a when key tax application was pending and who were involved actually in reviewing the application we will also hear from a third witness anna maria says narrows who was employed by contractor for a key tech sponsor santa fe and then to us it is my understanding that these witnesses disagree with the actions of the f d a santa fe adventists are both with respect to how that application was handled today's witnesses have expertise and firsthand knowledge of the events that took place but is also important to note whom we are not hearing from today key tech sponsor santa fe eventis is not present today to offer in the story nor are other f d a officials who talk part and approving key ta but who do not share the view views of today's witnesses about the approval decision or agency processes here to defend their decisions but they will be asked to testify at a later hearing so we are at the beginning of our inquiry we just sent a document request to f d a and after obtaining additional records of hearing from all sides we will be able to determine whether mistakes were made during the f d a examination of  what those mistakes were and whether those mistakes were simply an aberration or a sign of a systemic problem in the way f d a manages drug safety the g a o report the institute of medicine report f response to these reports and recent actions today's testimony evidence collected by the subcommittee during previous investigations and senator chuck grassley in his committee's investigation of key tech all confirm that there is certainly room for improvement in f d a management of drug safety so the subcommittee will be keeping an open mind looking at the evidence and i look forward to the hearing and certainly i would be remiss about it did not senator grassley for joining us this morning he and his staff on the senate committee on finance has spent considerable time investigating the f d a oversight of drug safety and we look forward to his testimony i think the gentleman gentleman is right we will have the f d a and the manufacturer of this drug at a later hearing exactly when that will be will probably depend upon the cooperation we get from the f d a to open their files so that could be some time but we expect them to testify next recognize gentleman from pittsburgh mr doyle for the opening statement thank you mr chairman i want to thank you for convening this important hearing and i'm going to waive my opening statement gentlewoman from denver thank you very much mr chairman i want to thank you for calling this hearing and and thank you also for committing to make you miss the first of many hearings that will have about drug safety and asked d s handling of new drug applications and also post market review of adverse side effects as the public's public's watchdog on prescription drugs the f d a plays a critical role in protecting us from drugs whose risks outweigh their benefits i also want to thank you for asking dr steven nissen to testify today i met dr nissen last fall when i was in cleveland and his work in two thousand and four on the f d a advisory panel about the safety of vioxx led us to a much better understanding about the dangers of the drug mr chairman i remember hearing this committee say convene in two thousand and four to examine anti depressant use in pediatric populations and at that time we talked about the need for the f d a to fulfill its mission to conduct objective studies with rigorous scientific inquiries when risks are identified it's essential that they be communicated to the public and at that hearing we talked about why there had been delays in present haitian of data on the link between suicides and antidepressants the system clearly had broken down i also remember when vioxx was found to dramatically increase the risk of heart attacks for those of taking this medication we discovered that the f d a process was lacking as a valid concerns of f d a scientists were overruled by high ranking officials again the system had broken down i h mr chairman as we address concerns about f d a apparent mishandling of yet another drug review that we can begin to move towards systemic change and not more lip service i'm confident that our witnesses today will provide us with a comprehensive description of the inherent problems with the f d a system but but beyond that i think mr chairman we need to move far beyond talking about the problem and begin to develop a real solution once you've been all of us here have been on this committee for a long time and these issues keep coming up again and again the f d a issues the los alamos issues that we had hearings on just a week or two ago i think it's really time for congress to identify these issues but then move beyond that and start to work and collaboration of course with the f d a and others to begin to solve the problem and i look forward to doing that you know back my time thank the gen gentleman from new jersey and mr ferguson for an opening statement thank you mr chairman i appreciate you convening this hearing today i thank mr whitfield and our panelists and our guests for being here this morning i strongly believe that one of the most vital functions played by any of our government agencies that of the food and drug administration's responsibility to ensure the safety and efficacy of pharmaceuticals for our citizens i'd venture to say that at some point in almost every americans life when they're sick they'll turn to an f d a approved drug to make them better therefore almost every american will put their trust in the testing and the scientific review done by the f d a they must also trust that the drug was approved with their best interests in mind when the relative risks and the benefits that that drug might bring i've long been interested in the issue of responsibility for drug safety carried out by the f d a this issue has been brought to my attention both by constituents in my district but also my but in my own very strong interest to ensure that our nation's drug supply is not only on the cutting edge of medicine but also is the safest in the world i believe information is vital for patients to make informed decisions and i've urged through letters and conversations with a officials that they make available to patients necessary items like medication guides when they're necessary over the past few years news reports some generated by some of the panelists that we have here today have chipped away at the public's confidence in the ability of the f d a to protect them we need the f d a to be the worldwide gold standard coupled with our leadership role in research and development the f d a must have the full and complete confidence of the public to protect them cutting edge medicines can only have it live up to their full potential when it kompany had by public confidence in the f d a therefore i believe this conversation that we're having today is a necessary one and i'm very pleased that we're looking into these issues but as they look at the list of panelists today i note a stark absence of other stakeholders that i view to be very necessary to this conversation for instance we don't have anybody today here who's speaking officially on behalf of the f we don't have anybody here who is speaking on behalf of the patient community or the patient advocacy community we don't have anybody here today talking representing the institute of medicine who've made some important examinations and recommendations i doubt that the opportunity will have today that will have the necessary given take to constructively talk about what's wrong and what's going right and what we need to do to fix the problems that we see and i'm hopeful that in the future as mr chairman as you mentioned that we'll have those opportunities our conversation is particularly timely because we're quickly approaching the end of the authorization of the prescription drug user fee act or paducah and looking through the testimony offered today some assail paducah but let's not forget why produce it was created in the first place before produce existed there was a commonly held belief that life saving therapies were taking way too long to be approved by the f d a advocates for patients with cancer hiv aids and many other diseases cried out for a way to get drugs to market faster while safely weighing the relative risks and benefits that those drugs might bring let's not go back to the days when access to drugs was the most important problem that we faced last year the institute  of the f d a completed a thorough review of the state of drug safety at the agency they issued a number of recommendations and there are many ideas that we ought to consider when we go through the reauthorization of to do for this year but again the absence of a proper give and take today will really preclude us from having the conversation today anyway to help us that to do the job that we need to do properly mr chairman once again this is a good conversation to be having although today it's incomplete and i look forward to hopefully in the future that will have an opportunity to have a more complete and more thorough more comprehensive examination of these issues so we'll be able to move forward and do the right thing for our constituents and for the american people because at the end of the day their confidence in the safety of our drug supply is perhaps one of the most important things we can be doing i appreciate mr chairman i yield back thank you gentlemen first comments next we turn to the chairman of the focally mr dingell again should also be noted before mr dingell begins members of the moving back and forth as we have  climate change hearing also going on under mr dingell's leadership where we have five urines this week so we're busy committee this week with that mr dingell this german thank you and thank you for holding this oversight investigation and for holding the first hearing this many people do good work for the american people unfortunately from time to time this committee has had to address problems before that agency it seems every so often f d a loses its way sometimes because of the of scott rules and sometimes because of poor management or other unfortunate events but sometimes it's because of a more serious breakdown in the policies and procedures that are critical to assure the safety of food drugs blood and medical devices so essential to the health of the american people today's hearings will deal with just such a fundamental breakdown in the policies and procedures for evaluating the safety of drugs it is clear from the work th stupak has already for form which will be the subject of today's hearings that f d a is badly broken i expected before this investigation is finished and it is now just getting underway that we will discover whether the problems we have found are due to the work of scott rules irrational pending pitching's or because the doors to the f d a henhouse have been thrown open to fox's it is possible that it will be a combination of all three what we do know from our dear friend senator grassley who is going to be here this morning to testify and for whom we have the greatest respect and extend a very warm welcome isn't this administration appears to be engaged in hiding wrongdoing obfuscation and delay and that this committee will face a similar problem with an agency that seems to try to hide its poor decision making behind the specious veil of executive privilege a matter with which this fill fill its constitutional obligations they will find if that is an error there are those who may be counseling the secretary in the commission or the congress may not interview or call to testify department of health and human services and f d a employees under any sir chances there may even be those who are to just think that it is possible to deliberately mislead us i warned them these are dangerous thoughts i promise those in charge of  the other departments that chooses to drive this committee information access to proper and needed oversight as is our responsibility that they will not succeed i promise them however for treatment but they will cooperate and i hope clean but at least they will cooperate there is an easy way to be investigated there's a hard way and i can assure all and sundry that the hard way is not the better way mr chairman i thank you for your reco this particular investigation we must have an objective and balanced f d a the agency serves the american people and makes life and death decisions every day that affect our public health any credible concern that f d a subjectivity is in question must be examined at the very beginning of this particular investigation document requests have been made and are about to be my witnesses are being interviewed where you should have additional hearings including witnesses from the f today we're at a very preliminary stage subcommittees going to be hearing serious allegations and concerns about an antibiotic called key tech which is produced by us and off the event as individuals including some other former f t officials who took part in this particular review have charged that the safety data presented by the company in support of key techs approval was compromised or unreliable they contend that the company knew it that the f d a knew it and that although concerns were raised about the disputes some of the points that are going to be made today we've been assured by the majority that additional witnesses from the f d a and the company will be heard given the life and death consequences that flow from the f d a decisions on drugs like this from public information about prescription drugs the subcommittee needs to pursue these issues very carefully not attack the delicate and complicated matters with sledgehammer having said that it's important that we keep an open minded days we wait for an investigation unfold till we assemble the most complete and thorough record possible we should not draw premature conclusions about people's judgments motivations and integrity complicating our work is the fact that the banks over drug safety in the f d a decision making process involve complex and sometimes it's abstract issues for science and scientific judgment the f d a decision with respect to key takes new drug application took place against the backdrop of an ongoing debate about antibiotic resistance whether it's possible for certain types of studies such as not inferiority trials to demonstrate a drugs effect in this before we can determine where the key take should serve as a case study of how the management of drug safety is ineffective or worse two packs for holding this hearing is your efforts to improve drug safety the oversight and investigation subcommittee has been a leader in investigating problems and pushing for solutions at the f d a and within the pharmaceutical industry  uring the safety and efficacy of prescription drugs and is a top priority and i'm glad that we're continuing our investigations on a bipartisan basis i also want to thank senator graham grassley and the staff for their efforts on the issue it's clear we share a desire dri turn to evidence based decision making and to ensure that f d a advisory groups congress and the public receive accurate and science based information about prescription drugs it's also clear that we have office enormous difficulty  getting the information that we need from the bush administration i hope that we'll be able to work together to solve all these problems and protect the lives of our constituency evidence that we're going to hear today about the key tack approval process and the failure to report potentially fatal of facts is extremely serious what is more troubling is that as several witnesses will testify if you tag is not an anomaly the same problems the culture of secrecy and the hiding of significant health threats are mirrored in other drive drug application experiences and they appear to be ongoing despite past investigations the testimony we will hear from dr ross indicates that last summer f d a scientists were still being told to be quote team players unquote and  safety problems to those outside of the f d a this occurred after our subcommittee's hearings and childhood antidepressants raised serious problems about the lack of disclosure by drug companies and the f d a last year the union of concern scientists and public employees for environmental responsibility surveyed f d a scientists according to their survey nearly one in five scientists had been asked for nonscientific reasons to inappropriately exclude or alter technical information in an f d a scientific document sixty percent knew of cases where assay a political appointee is in commercial interest as in appropriately influenced f d a actions only forty nine percent agreed that the f d a leadership was is committed to product safety as to bringing products to the market and only forty seven percent believed f d a would routinely provide complete completely a complete and accurate information to the public what frightens me is that a survey taken today could show the same results one of my constituents whose mother committed suicide after participating in an adult anti depressant trial wrote me that quote there is a gaping hole between the data the f d a is collecting and the information reaching the general public unquote today's hearing shows that the public is not alone f d a is only advisory committees have been kept in the dark the data has been falsified a manipulated and serious safety concerns have been kept hidden from congress as well as physicians and patients mr chairman it is time for full accountability and for serious change i look forward to hearing the recommendations of our witnesses  that so many have come out of the research in this nation however we need to do so in a way that is scientifically reliable and valid and when errors are made in that reliability and validity  reporting problems with research so much comes into question of the organizations that perform those studies and those that manufacture the medications today's hearing is an essential part of the ongoing congress role of oversight of the f d a well there is a continuing demand from the public however and our doctors for new drugs and we understand the prescription drugs by their nature all have some risk associated with them we must ensure that the risks do not outweigh the benefits thus accurate research for new drugs is absolutely vital to continue our efforts to discover the next generation of life saving treatments or treatments for mental illness or treatments for cancer or diabetes on the one hand however there was a constant pressure on the f d a by many patients and families eager to realize the hope these drugs may provide to review these medications quickly and it is important that we do not succumb to that pressure just for the sake of bringing out a medication if we do not yet have the scientific data to tell us what those risk and benefits are this must be balanced and this hearing is important we view that balance because we must have accurate reliable research and medications so we can determine those risks and benefits now there are some concerns of perhaps this committee is not receiving information yet from the ministration to my knowledge i don't think we've yet requested information from the administration of the f d a and when we do so my assumption is we will get accurate in cooperation from ation if we do not then we should act accordingly however in the meantime i believe the what the american people expect of us is to keep the pressure on for scientific integrity here  all of us must review the studies ourselves to bring out the truth whatever that may tell us about these medications because at the very least physicians and patients and families want to know that that prescriptions filled by their pharmacist and taken by themselves a family member maintains a gold standard of quality that we can trust in our food and drug administration and all involved in that process we are not here to stop research  not here to rush drugs to market that are not ready we are not here to stop medications that is needed we are here however to make sure that that integrity is what we return to the f d a from the all the patients  indications changes for a second specific to the f d a remove two of the three previously approved indications from the drugs label leaving community acquired pneumonia as the only getting indication for which  problems lie in the approval process for new drugs and what actions need be taken to restore the public's confidence certainly a question arises not in for the studies are appropriate to begin with as opposed to traditional clinical trials where drugs three zero one four to be presented the f d a badgering committee specially in criminal investigations ring initiated on one physician investigator and serious question to raise about data from other sites with significant enrollment levels the key tech investigation us thank the gentleman from texas for the other member from texas mr burgess from texas opening statement rick nice refinement thank you mr chairman and i thank the chairman and ranking member for opening this hearing this committee has a vital role in providing meaningful oversight and investigations over important public health issues as a physician i take this role extremely seriously and i thank the leadership of this committee for their vigilant pursuit of truth in regards to our nation's health care issues today we're here to discuss the f d a is process for the approval and of new and important lifesaving drugs while i appreciate the whistleblowers being here to discuss their observations of the approval process of key tax i do find  curious that the f d a is unable to present their side of the story today the whistleblowers are making serious allegations and allegations that need to be heard and deserve to be heard but i'm disappointed that neither the f d a nor the manufacturers of key tech said if the adventists were invited to answer the serious allegations and tell their side of the story now i do understand that there is another hearing scheduled for later in march but unfortunately we all know with the shortened press cycle in this film that the damage will be done long before the weekend comes we've heard some discussion of fairness this morning we really can't talk about fairness the it's not reasonable to talk about it in ministrations don't wallow in a document request that frankly has not yet been made the question always comes down in the hearings what did they know when when did they know it that's important in this witi should dedicate itself toward answering that questions but an independent review of internal documents is going to be necessary before those questions could be answered i would also like to remind members of this committee that we must be cautious not to come to conclusions today it is merely the opening side of a preliminary investigation today we will only hear one side of the story an important side to be sure but it is still only one side we must be cognizant of the fact  power of oversight is in effect the power to destroy therefore it is crucial this issue be fully vetted and that all sides are heard before conclusions are drawn mr chairman as a physician i've long had a love hate relationship with the f d a i was concerned that they wouldn't bring medications quickly enough to the benefit my patients it seems that other countries in the world could get newer medications on a must much faster timeline and yet at the same time we look to the f d a to protect and ensure the the the certainty of safety of drugs in this country most of us don't question what a prescription is written torn off the patent put in our hands we don't question the validity or the safety of that medication and that's a good thing and we want that certainty that surrounds the f d a to be assured the f d a has no small task this is a physician's desk reference i don't even know how many medications are listed in this reference the print is very small the pages are very thin and there's a lot of information and here we charge the f d a with staying up to date on all of those medicines and assuring their safety it's a big past that we fund it properly that's surely a question that i going to have to be answered before these hearings are drawn to a close a conclusion well mr chairman as long as we're mindful of these issues and truly diligent in the work to obtain real answers and real conclusions i'm supportive of this investigation and i'll yield back the balance of my  morning center here will turn to our first witness the honorable charles grassley united states senator from the state of iowa senator it's a great pleasure to welcome you today here today as our lead witness in the first of all i predict will be many hearings that this subcommittee will hold this congress that will look into improving the way the f d a protect the american people before starting your prepared testimony i'd like to note that it's been a long tradition of the oversight investigation subcommittee to swear all witnesses whether they be private citizens cabinet members or senators i believe if my memory serves me correct the last senator to appear before us was your colleague senator hatch in one thousand nine hundred one who was sworn in and testified under oath before us on drug safety issues so accordingly senator please rise record as well as a shorter statement to present this morning before starting let me advise my colleagues the senator has a limit time and we will take questions ten minutes on each side for a question of the center this morning and center again thank you for being here and thank you for your work on drug safety issues throughout your career well it's very much your privilege for me to be invited here and i appreciate that in potations and i had a chance to hear many members of this committee give opening statements and i particularly want to thank chairman dingo chairman's two pack ranking members martin and whitfield for their statements and and most importantly to all of you that are involved in the oversight because it's such an important constitutional responsibility one that i don't think we talk on enough about or do enough about but it's so important that you do the work you're doing doing on this hearing and particularly hearing on drug safety and particularly the role of the food and drug administration and during the last three years i conducted extensive oversight of the food and drug administration while i was chairman of the senate finance committee and as you probably know we have jurisdiction over bo medicare and medicaid i view my role as working to ensure the safety and well being of more than eighty million americans who are beneficiaries of these programs the medicare and medicaid program spend billions on prescription drugs and medical devices and that money should be spent on drugs and devices that are safe and effective in the course of my oversight of the federal bureaucracy i develop many good relationships with whistle blowers and it was f d a whistleblowers and concerned f d a scientists who first drew my attention to the problems that the food and drug administration has started early two thousand and four with an f psychiatry's named dr andrew my shoulder who realized through his work that there was a serious suicide risk for teenagers taken certain antidepressants he wanted to make a presentation about his findings to an f advisory committee but for some reason f d a supervisors didn't want this information out they canceled dr my shoulders presentation and instructed him to write a script approved by his supervisors that he would use if anybody asked him why he was no longer presenting this fall i held a hearing or that fall which was two thousand and four i held a hearing on drug safety in the aftermath of vioxx the blockbuster pain medication being pulled off the market by its manufacturers rather than by the food and drug administration the testimony at my hearing turned a bright spotlight on problems with the f d a as post market surveillance effort the food and drug administration works tirelessly as it should to approve new life saving and life enhancing drugs but it could do a lot better job of keeping track of developments with these drugs after they get out onto the market reviewing what happened inside the f d a with vioxx and also working with a number of whistleblowers who bravely stuck their necks out and came to me after that landmark hearing i have identified problems at the f b i that consistently fit into a few which seems first scientific the sand is just worries about smoothing things over with the industry much more than it should with its regulatory responsibilities third inside the f d a there is widespread fear of retaliation for speaking up about problems and forcing the public safety would be better served if the agency was more transparent and more forthcoming with drug safety and drug grizz these problems involve then the culture at the food and drug administration those problems are not isolated but are systemic and they can be partly attributed to the organizational structure at the f my concerns are not isolated either during the last year they've been validated by highly regarded institute of medicine as well as the independent government accountability office and more importantly or as importantly respected medical journals what's at stake is public safety and public confidence in our nation's world renowned food and drug administration my admin or my investigations that f issues have also revealed a deeply troubling disregard for congress's responsibility to conduct oversight of the executive branch of government getting right to the heart of whether or not the checks and balances of the two hundred twenty five year history of our government are functioning properly to see that the laws we've passed are faithfully executed and to see that the money that we appropriate is spent in accordance with congress in tampa the f d a and the department of health and human services have put up so much resistance to my efforts to find out what happened inside the food and drug administration with a relatively new antibiotic called key tag that i can only wonder what there is to cover of every excuse under the sun has been used to create roadblocks even in the face of congressional subpoenas to determine who will be interviewed or testify before jurisdictional committees that strikes right at the heart of the work you're going here mr chairman today yet during my years in the senate my investigators have obtained access to every single one of these categories of so called confidential information even from h h s as well as other executive branch agenc so why now further i asked the congressional research service to look into the department's policies regarding this matter and c r s told me that there is in their words no legal basis for th subpoenas compel a privilege log but the department the f d a will not provide one the department in the f d a say that they have been responsive to the finance committee's key tec investigation because they made available millions of pages of documents but what they provided is quantity not quality they delivered hundreds of pages simply mark for example  quote fifty eight fifty seven pages removed on quote or forty three pages removed on quote and that's in attachments one through five that you'll have other documents have whole pages paragraphs and sentences redirected with no explanation for what has been held or redacted or why in fact listen to this the f d a redirected some of the same documents differently and they even redacted one of my own letters to them honey a different matter and that's attachment six when i point out the absurdities in the department's response to my requests for documents and interviews related to key tech the department argues it could not provide access to information and individuals related to criminal investigations just like that's what i was trying to do but i didn't ask for access to open criminal investigations i don't want to jeopardize a criminal matter you folks don't either that he part met in the f d a know that yet they keep using that excuse in a way even sol what i've learned about what happened with key to crumbles me i've learned that f d a gave its advisory committee questionable data on key dick and did not tell them about problems with that data i sent a letter to the f d a andy samberg regarding my findings on this matter and i'm still awaiting a response the f d a approved key tech without much safety data from the u s the agency relied almost exclusively on for post marketing safety data and lastly key tax sponsor in all likelihood was aware of the fact that it submitted some questionable data to the f d a regarding its large safety study the sponsor was informed of problems with one of the studies sites prior to the data submission to the however according to the f d a reviewers the sponsor never raised these problems with the f d a f d a learned about them after his own investigators inspected the site during the last three years i've also tried to work in a productive way with the commissioners acting commissioners at the f d a it will take leadership to get on top of the f d a these problems and to turn the agency around so far lip service has been fine the reality is meant a lot less last month senator chris dodd and i introduced to reform bills that we first proposed in two thousand and five to get the safety to fixes safety shortcomings that f d a our first bill would elevate and empower the office with the f d a that is responsible for monitoring f d a approved drugs after they're on the market it would make the post market safety function with within the f d a independent but within the f instead of under the thumb of the office and the center that puts the drugs on the market in the first place and that's the way it is today want to point your attention to the wall street journal who are supposed to monitor the safety of a drug on the market serve only as consultants to the f d a officials who approve the drug in the first place the officials who approve the drug would obviously be conflicted in making a judgment that approval is no longer appropriate or was a mistake in the first place kind of like having a gun your face a separate senator for drug safety within the f d a is a vital in japan when it comes to meaningful reform and improvement of the agency establishing greater transparency regarding clinical trials the good ones and the bad ones and the whole drug makers and drug regulators accountable and to give doctors all the information they can to their patients both of these legislative initiatives would make drug information used by doctors and patients more complete more accessible american consumers should not have to second guess the safety of pales in their cabinet i appreciate the attention that all of you are giving to this important n hearing you will hear from some of the heroic whistleblowers who have helped my work without whom my work would not have been possible two of the whistleblowers have  outstanding scientists outstanding investigators people that want to get to the bottom of something something that an agency like f d a can't afford to lose people like that it's a tremendous loss for our country when an agency like the f d a gets so dysfunctional that specialists like these whistleblowers are forced to leave the agency to avoid retaliation you know whistleblowers are like a skunk at a picnic they ought to be considered all by us as patriotic americans just wanting to do what the law requires them to do and spend money according the way congress wants to spend i want to work closely with you mr chairman to make sure that f d a whistleblowers can communicate with congress without fear we got laws that protect them but it doesn't protect them enough in addition they exist the agreement between the inspector general of h h s and f d a gives too much power to the f d a when it comes to how allegations of criminal misconduct by f d a employers are being investigated and that's we have an attachment a half on that that agreement should be revisited i look forward to reform opportunities in the year ahead there's no doubt that the f d a needs additional tools and resources in this work the f d r also needs an overhaul to make the agency more transparent more forthcoming and more independent minded i look forward to working with this committee and particularly with the leaders of this committee both republican and democrat subcommittees was a full committee and i thank you and as you indicated i'll be glad to say and answer questions well thank you senator we appreciate your time and effort and appearing here today we're going to take ten minutes on each side i'll begin the questioning i'm going to ask questions i'll turn organist or dingell and we'll reckoner you mentioned once again about in your testimony about the agreement between the office of inspector general for the department of health and human services and the food and drug administration in that agreement certain responsibilities were given to the f d a when it comes to how allegations of criminal misconduct by f d a employees are investigated and you mentioned in your testimony and with the whistleblowers that we tell you we still have some scientists within the f d a who come forward and assist us in our work and they're still there and i'm concerned about the retaliation could you explain that little bit more what you think should be done in this area this agreement how it should be restructured well obviously gets back to what's very basic about inspector generals great deal of independence over anything within the agency only very remotely connected with the administration of the and and and when the office of inspector general was was trying to do its work it was reported to me that they're concerned about  a as an institution onto itself thank you and your testimony you catalog your personal experience with f d a is suppression of independent researchers opinions harassment of whistleblowers persistent refusal to produce documents in response to your request in your chairman in your capacity as chairman of the senate finance committee so with respect to key tech you say that you learned that the f d a gave its advisory committee questionable data on key tech and did not tell them about the problems with the data the f d a approved much safety data from the u s a key tech sponsor in all likelihood was aware of the fact that it had submitted some questionable data to the f d a regarding its large safety study senator your still refusing to give you information that you requested on the key tech just occasion without a doubt and what's really miraculous about that approach on their part we asked for the log that i've already referred to in my statement so in a sense we don't even really know what's being held with held from us why it's being really held with held and and we happen to be aware of through information we get from inside some documents that are are we could be responsive and don't appear to be privileged but still being withheld from us but see there's no reason why we can't at least have that log so we can separate where maybe there's a legitimacy to their point of view something you know maybe it deals with her for tire proprietary information as an example although if that doesn't get out to the public that should warning any comments on that i think is quite evident since it just come out yesterday you're having this hearing today that the finding in the kitchen got a little bit too hot and they decided to move out of the kitchen but also it's perfect evidence that that you know eventually when you push the envelope enough they do have they do show some respect for the scientific process but in all of this whether it's key t earn a lot of others it's it's a lack of respect for the scientific process that i think is basic to what's wrong with some of these drugs getting on the market not getting there and when there's dissidents dissonant point of view let's say an alternative point of view or not it isn't a point of view alternative point of view among scientists you know all you have to do is let science operate if it's if scientists grassley has a view and it's got to be really reviewed by scientists to pack and you don't quite agree with me then it's out there for peers to take action everything in science might not be perfect but it's sure a heck of a lot perfect for then the subjective judgment of a few administrators stepping in for some reason or other short circuit the scientific process so if we get the f d a back to proper respect for the scientific process i don't know if you and i'd have to be here today last month the f d a proposed an increase in an user fees paid to the agency by pharmaceutical companies to improve drug safety oversight the post marking surveillance we speak of to speed time for a new drugs and monitor to consumer advertising you think user fees give companies too much influence already well you know from that standpoint it's kind of since money is fungible i suppose it shouldn't but when you when you've got an agency getting their money directly from the industry that they are regulating it's hard for the public and maybe for us and it causes us to be a little more suspicious here in the congress but for the public that's on sophisticated about how government works if you're going to appear to them of undue influence but more importantly than just the user fees i can make reference to a lot of e mails that we've  access to from within the f d a that would say things along this line i don't have a specific reference i could have my staff give you a specific reference but things that said well if there's any question about this or that pharmaceutical companies feel like they have a seat at the table and maybe this fee business makes them feel that way i don't know for sure but the point is there should only be one person across the table from the f d a and that's john q public not members of the pharmaceutical industry center you and all the way to the apartment of health and human services to talk to an agent regarding key tech as h h s finally giving you access to that agent absolutely not and there's no reason to but their excuse is that there's a criminal investigation or there's an investigation generally say an investigation generally and i'll tell you how absurd this gets and how they virtue of the fact that the department of justice is  advising them accordingly so i'm sitting in judiciary committee in the united states senate on an entirely different issue and senator kennedy with more seniority goes ahead of me and he says something to somebody from the department of justice i wan ask these line agents some questions where you're going to have access to these line ages well light bulb goes off that chuck grassley can have access to a line agent because somebody in the justice department told h h s that i couldn't talk to agent west so i talked to the justice department about the situation right after kennedy gets done and they said i could have access the same way kennedy had access to other agents in some other department i still don't have access to agent wes so if the justice department is advising a change as that you can have access to two agent west but justice department in a similar case in the line agent says senator kennedy has well what is the policy of this administration on having access to line agents is it one policy for kennedy a democrat and another policy for grassley a republican you brought attention to one of the basic tenants of our government and that is the responsibility of oversight by the legislative branch and i would just ask you question because i think you've touched on this significant issue just the difficulty that you had and attaining information from a branch of the government on the executive side did you consider using the same pain at any time to not only a subpoena but holding the contempt you know in the senate you get to this place we considered that yes but you know you have to have a majority vote of the committee you have to have a majority vote of the senate for that to happen and so we did not decide to go that route because we thought there were other routes we could go obviously the other routes have not been successful either well we appreciate very much your bringing attention issue and we look forward to working with the as we try to address said well let me suggest to you chairman or ranking member whitfield that you can be very helpful this double standard in this administration that a democrat supposedly not as friendly with the administration as i am i maybe they don't consider me friendly or but but the point is if senator kennedy can get access to line agents why can't senator grassley get access to a and i know when i've already had access to line agents over the years so this was some sort of no policy you know i understand i get frustrated i find appropriate or sometimes have access to things i don't have access to and it thank you mr whitfield senator thank you very much for being here today i can fully identify with your frustration and not always getting information that you're looking for i know you were commenting before and whether the administration considers you a friend or not we all certainly here consider you a friend that we very much appreciate your book sometimes i wonder why spent two days in the car would present a voice right around the cola vial to help him get nominated in the year two thousand as an example i  wish i could shed more light on that for you but maybe i ought to stick to my topic sooner you mentioned before the mosque holder investigation on s s r i s with children that was a very very important topic for this subcommittee something that i was very involved with personally and really highlights the importance of this post this topic this issue of post market analysis and i know in your bill  comment on the differences between your approach and the approach that was suggested by the recommendations of the institute of medicine i don't want to bring up senator kennedy's name because that seems to raise your your ire but i know in the bil that senator kennedy has been or introduced his approaches seems to be in a way more consistent with the recommendation that the institute of medicine had suggested would you just comment on those conferences place you know in a very general way i think that the main differences that i want within the f d a because some people think we're setting up something outside the f d a so on to emphasize we're doing it with an f d a report directly to the director so that there's no old doubt that even though on a on a chart of organization the office of new drugs has suffered from the all post marketing the office of drug safety but as i indicated you know it's not really solved so i want to get this to so we're here wherever this box is located i want to not to be under this the thumb of this agency even though the chart doesn't show it that way reporting directly to it and i think that that that's senator kennedy's approach and it's probably a bipartisan bill so it's not a it's not a political partisan issue is that  we're going to still have a cloudy relationship and not the black and white separation that i called for under the bill that came out of committee last year now i don't know whether senator kennedy and his new bill is going the same direction this year or not but last year that's the way it was and we just want guaranteed independence and reporting directly so that we don't who are patriotic americans want to make sure the scientific process works being blackballed and and ruined professionally because of that it doesn't need to be compromises too much and there's too much found out in post marketing surveillance that needs to have an independent judgment of it and i don't think that in the in the veil that senator kennedy has that it goes far whitfield senator thank you for for being here but perhaps just a side note yesterday in the wall street journal there was an op ed the clinical trials of patients who have reached the end of their therapeutic ropes if you will who are denied access to fake drugs are in phase two trials it raises a separate issue with the f d a but physicians and clinical staff who apply for exceptions to get their patients into these clinical trials find the statistical issues raised by the f d a staff think that the plight of the applying physician can sometimes rival receipt of an audit from the i r s clearly that's an interference in getting new cutting edge medications to patients again who have exhausted all therapeutic activities so i hope mr chairman we can we can perhaps spend some time looking at that as well i guess i'm most interested senator and i do agree we see that proper respect for the scientific process needs to be paramount in our minds agent west line agent west whom you referenced were you ever able to to establish contact with this individual and if not mr chairman are we planning  on on asking for similar access the line agent left center well i have not personally had access to him in the way that makes any difference i think maybe i better not speak beyond that because i don't want to get anybody in trouble but but we have some information but we want we need to get the information in an open transparent way and i and i don't want  we've got information that we just want to be more transparent we don't have all the information we can get if we can talk to it but i judge from your tone and demeanor you felt that this individual has a pretty important information or absolutely absolutely that i don't want to interfere with the things that you were bringing up that were in the wall street journal in the sense of special special opportunities for people who are willing to be guinea pigs because it's the end of the life it might save their life it might not say in their life where where an individual is totally aware of every gamble he's taken and he's educated that and he's willing to take it and everything's transparent you know i don't want to stand in the way of that as wada thank you thank you mr chairman senator welcome we appreciate your work on this issue i want to touch on one topic and that's that memorandum of understanding that i understand exists between in the f d a to allow the f d a to investigate itself basically on employee misconduct issues and i'm just curious i know that's an issue you've been concerned about senator and i wondered if if you or your staff has learned anything new regarding the status of that  well it's i i think a better look at my staff but i don't think we have anything more than we're just recommending that it should be reviewed and rewritten we i don't know that we're in the process of thinking it is being no ok all right it's just a concern i think we share well yeah send be nice if this is an extremely powerful committee you have here and the extent to which you can push that would be much appreciated by me but more importantly the people safety is at stake here and independence from from industry being regulated would be enhanced by it as well i think i think we concur with that opinion drugs that are being approved it appears from the s s r i vioxx and others when when a scientist within the f d a or whistleblowers willing to speak out they suddenly find themselves under some kind of criminal investigation from the f d a underneath this memorandum of understanding it seems like it's a form of retaliation and a rassmann time scientists who are willing to speak up and speak out and let me tell you stated it better than i could and as a matter of emphasis and more important because you're chairman of the subcommittee i hope people listen from that point of view and you pursue that because you're absolutely right thank you mr dingell anything from sen that's german only this i want to thank our our friends coming over here thank you very much for being here i would ask that perhaps if i send you a little letter requesting some information on your statement today forward to a return to the days of your aggressive oversight work where almost every agency knew that you were going to get to the bottom of things and that they ought to cooperate thank you well you've set me a good example and i i will certainly try to follow it but we have an outstanding chairman of the subcommittee senator and person of mr buck and he will do a super job of helping folks understand that we all work for the taxpayers and people as do you sir and they and they do very much for being that last statement he made if i can comment on it we all work for the taxpayers and we've got institutions not just f d a maybe the example i always use is the f b i more than the f d a and this ins in this manner but we've got too many agencies around here that talk about it as our agency or our institution in that case the f b i it was our institution and i got tired of the director saying that all the time at a meeting we were in our institution and i said you know that's what's wrong with the f b i and maybe that's what's wrong with the a although i haven't heard that from them but the point is that i said we all work for the american people it's not your agency it's not my agency it's the people's agency and we're all working for the american people and the sooner we understand we're working for the american people and not for our institution the better we're going to do our job well so you know and the other comments remember senator thank you once again thank you for your time and thank you for your work and we look forward to working with you thank you powers scientific applications international corporation if they would come forward please the policy of this subcommittee to take all testimony under oath please be advised that witnesses have the right under the rules of the house to be advised by counsel during testimony to any of the witnesses before us this panel be have counsel at this time ok records to reflect witnesses have been sworn in dr ross would begin with your opening statement please good morning mr chairman mr ranking member and members of the committee thank you for the opportunity to speak before this committee i am here today to speak about the drug he tech my name is david ross for purposes of identification only i am national director of clinical public health programs for the u s department of veterans affairs i am here today as a private citizen i was trained as a medical doctor at new york university and yale in a board certified in internal medicine and infectious diseases i take care of my patients my local v a hospital and teach medical students  safety team leader for key tech f d a approved key tech despite knowing that it could kill people from liver damage in the tens of millions of people would be exposed to it despite f d a knowing that the drugs make submitted fabricated data and despite knowing that key tech is no better than other antibiotics and may not even work why does key tech matter because f d a broke its own rules on a lot of key tech on the market because dozens of patients have died or suffered needlessly because f d a allowed key techs maker to experiment with it on children over reviewers protests because f d a ignored warnings about fraud because f could mean hundreds or thousands of deaths every year in april two thousand and one a federal advisory committee was so concerned about key techs potential to kill patients that it required a large safety study before the drug could be approved in october two thousand two f d a reviewers examining the safety study found serious pervasive misconduct pointing at fraud in december two thousand and two key text manufacturer admitted that it had known about issues at its largest enroll haven't told the f d a the company claims that there were no other issues with the study even though every study site inspected by f d a turned out to have major problems an unprecedented situation in my experience in january two thousand and three over reviewers protests asked a managers had the evidence of fraud in this conduct from the advisory committee which was fooled into voting for approval starting the same month f d a managers also pushed to uncontrolled unreliable side effect reports from overseas supplied by the drug manufacturer without independent checking by f d a as proof of key tech safety something that had never been done before in april two thousand and three in response to a fraud investigation the company turned over records to the f d a with most of the tax blacked out f d a managers did nothing in july two thousand and three f d a managers were warned by criminal investigators about possible fraud by the drug company with the tech they did nothing in october two thousand and three f d a received records from the company that raised further concerns about fraud f d a managers didn't even review in march two thousand and four f d a his own division of scientific investigations concluded that none of the safety study data were reliable one week later f d a managers approved key talk although f d a managers publicly deny it crystal correspondence shows that they used the safety study and repeatedly cited it as evidence of key tech safety in february two thousand and five seven months after key techs launch f d a managers received the first reports the managers did nothing in march two thousand and six f d a managers received new warnings from criminal investigators they did nothing in may two thousand and six f d a managers received warnings from safety reviewers the key tech was much more dangerous than comparable antibiotics they did nothing only after congressional subpoenas which f d a resisted in stories in the news media about key tech and fraud that f d a managers fin anything they rewarded the label in late june of two thousand and six f d a reviewers including myself were summoned to a meeting with commissioner von eschenbach in which he compared the f d a to a football team and told reviewers that if they told anyone outside the f d a about the problems with key talk they'd be traded from the team rather than be silenced i chose to move on to my current position how did this happen the f d a reviewers did their job this is not their fault kee tech can be laid directly at the door a senior f d a managers who knew better because they were told repeatedly by reviewers and criminal investigators but chose to look the other way their behavior was worse than being in a state of denial f d a managers were so bent on approving ke tak that they suppress evidence of fraud and pressured reviewers including myself to change their reviews what's the bottom line an unsafe drug got past the system despite warning after warning about fraud liver damage and death because f d a managers at the highest levels refused to listen will this happen again yes without significant changes in our drug safety system and members of the committee i'm honored that you're giving me the opportunity to tell my story my name is anne marie cisneros i'm currently an independent clinical research associate i was trained in the united states air force as a medical technologist have a bachelor's a science degree and occupational education from walen baptist university of the masters of business administration degree from five or university i have worked as a clinical research associate for approximately eight years my first three years in this industry i spent fifty p d i a contract research organization where i month prison sentence for fraud associated with a study thirty fourteen in addition she was ordered by the court to pay restitution to the drug sponsor of ventas which had paid her four hundred dollars per patient enrolled mr chairman based upon what i observed and learned in monitoring the visit a number of grad flags were apparent i knew that dr campbell had rolled over four hundred patients or one percent of the adult population of gaston alabama by comparison another site and gatson have enrolled twelve patients in a recent quality assurance audit by  several informed consent issues were noted as well significant under reporting of adverse events and no reports of serious adverse events no patients had withdrawn from the study and no pay since for last a follow up and unusual occurrence given the number of subjects she enrolled patients within minutes of each other and upward thirty patients per day she enrolled patients at times and on days when the office was closed once we started reviewing patient charts we discovered that every informed consent had a discrepancy most of the consensus like they had been diagnosed with more contests either had no history of the element or did not have a chronic definition she enrolled her entire staff and study frankly our common campbell thing truly interested in was getting more business from adventurous as an investigator at one point well at the site i was so concerned about patient safety i called copernicus independent review board to express my concerns and seek guidance and i or b which is under contract to the drug sponsor has its primary purpose as patient advocacy is allowed to contact patien actions of dentist took i never heard from the rb again and to my knowledge copernicus never did audit blacklist despite a report any irregularities to the f d a i emailed a summary of my site findings to robert mccormick head test personnel i also participated and a teleconference between p p d and event just at which i discussed issues identified in my visit at some point after that i understand the defense is to excite management responsibilities away from witnessed the pressing in my eight years in clinical research work this is the only incident instance i've come across such bad behavior by a drug sponsor i feel i can speak for those who agonized over this situation when i say we are hours a opening statement please thank you mr chairman members of the committee good morning my name is john powers i am a physician scientists who worked at the u s food and drug administration for eight years the five of which i was the lead medical officer for and microbial drug development and resistance initiatives i really do not consider myself as having blown a whistle but having done my job since i appropriately raised the issues i will discuss with you today to my supervisor s i chose to leave the agency to pursue other research opportunities after over half a decade of attempting to advance the science of clinical trials and infectious diseases feeling i could better serve the public outside the agency there are numerous individuals in both the f d a and the drug industry who work hard appropriately evaluating new drugs and i learned a tremendous amount while i was at f d a i would still be there today if i felt i could perform my job in the way it should be done many of the recent discussions regarding a new drugs have focused on their safety but the also important issues with the evaluation of drug effect of this especially with antibiotics in one thousand nine hundred eighty two congress amended the food drug and cosmetic act to state that there must be substantial evidence of effectiveness from adequate and well controlled trials in order to justify the adverse events that are inherent with all drugs in the absence of substantial evidence of effectiveness any adverse effect no matter how rare is not justifiable the approval of key tech is a symptom of a larger problem over the last twenty five years f d a has approved approximately sixty eight new drug applications for ear sinus and bronchial infection such are mostly self resolving all of these drugs were approved based on so called non inferiority trials the word itself non inferior means not worse  the purpose of these trials is to rule out an amount by which the new drugs effectiveness may in fact be worse compared to an older drug showing a new drug is potentially worse than an old drug whose effectiveness itself is unclear in the setting of a given trial is like the billy preston song nothing from nothing leaves nothing previous posts evoke controlled trials show twelve of seventeen studies in sinus infections and nine of fourteen studies and bronchial infections lack evidence of a benefit for antibiotics and the situation is similar for ear infections therefore showing that she think may be less effective than older drugs is not evidence that she take is effective at all and sinus and bronchial infections and this was clear at the time the drug was approved in two thousand and four while not inferiority trials are justifiable in serious infections where the benefits of antibiotics are clear even here the trial must be done properly in order to provide meaningful results the major problem is that many of the safeguards in trials to protect against false conclusions are less useful in the setting of non  instance trials in the monia man roll patients who don't have pneumonia but instead have the common cold this is nothing about the new drugs effect of this in the monia but the new drug may appear to be similar in effectiveness to the old drug this is like testing a new parachute against an older proven parachute when all the people are jumping out of a plane that is standing still and only two inches off the ground everyone will do well but it says nothing about how the new parachute will work in a real life situation lack of effectiveness is a more important problem than antibiotics than it is for other types of drugs if a non antibiotic doesn't work it only affects the person who takes it if an anabolic doesn't work it affects the person who takes it and other people by spreading resistance that drug and to other related drugs as well an resistance is a safety issue and lack of effectiveness of antibiotics to promote the problem of resistance we are actually trying to combat why would have to continue to allow approval of antibiotics without substantial evidence of effectiveness drug sponsors of expert in the field of an development over the last few decades and this was an attempt to provide an economic incentive for sponsors to develop drugs where we really need them in serious and like threatening diseases we do need new antibiotics but approval of ineffective and therefore inherently unsafe drugs is not a proper or effective incentive for drug development exposing children who might not even have a bacterial infection to key tech in the setting of a non inferiority trial is not the way to develop new drugs that children will be exposed to harm without the ability to determine the drugs effectiveness despite the approval over the last two decades of scores of antibiotics who's affected it's remains unclear there has been no boom in antibiotic development and developing an it in economic incentives to promote development is needed but it's the province of congress not the f d a in summary f needs to require sponsors to perform placebo controlled trials and self resolving diseases for serious diseases f d a needs to require appropriately design conducted and analyzed trials to give clinicians the information they need to make appropriate decisions for patients f d a needs to address the drugs that still carry approvals for self resolving these are without substantial evidence of effectiveness f d a need to promptly publish new guidances based on appropriate scientific and regulatory principles and remove the old guidances from its website now since they continue to miss lead drug sponsors this is chairman the bottom line is we must preserve the effectiveness of antibiotics which are among the marvels of modern medicine and that means they must be studied in trials that tell us where they truly help people not just have activity in test tubes thank you thank you before we begin questions in order to proceed proceed in a more orderly and efficient manner i would propose instead of five minutes for each member for questioning that each member will have ten minutes to use for questioning during this hearing if there is no objection i propose we do this this morning mr we have any comments or thoughts on that going the ten minutes no objections or two or three over viewers protest f d a managers had the evidence you want to talk about if the managers push to use uncontrolled unreliable side effect reports from overseas even if it's wrote your testimony that they did nothing fact of an optimal logic drug products dr janice or what rules did the f d a break in its approval of key tech you know you were there for ten years you were a senior analyst on these drugs i was the safety team leader for key tack and whatever you like the medical review officer assigned to key tech it would be like sir it different points to roles one was as the primary safety review or the person actually looking at the data and during the second review cycle i directed a team of safety reviewers ok and then later on in my career at f d a i was a member of what's called the senior leadership team for the office of new drugs so in terms of rules that keep that f d a broke with respect to key tac it approved key tack based on a study that its own investigator said was worthless which breaks the rule about needing adequate and well controlled trials and when i say a rule i mean that is a statutory requirement under the food drug and  it used uncontrolled foreign safety reports to answer a credible safety question that should have been answered by an adequate and well controlled trial it failed to assess the overall integrity of the key tech application despite warnings about potential systemically fraud warnings from whom warnings from reviewers and warnings from criminal investigators warnings from yourself yes and warnings as well from members of the office of criminal investigation it failed to verify the integrity of foreign data submitted to it before approving key tack it allowed managers to violate federal law by coercing reviewers into removing disagreements from the administrative r part title twenty one part ten point seven three of the code of federal regulations provides that disagreements on the provability of an application shall be entered in the administrative record finally the f d a failed to carry out its responsibilities to enforce parts fifty and fifty six of title twenty one of the code of federal regulations by failing to hold the institutional review  from studies thirty fourteen and its approval of key tech from what i can gather the f d a denies that it relied upon that study in its approval process of key tech can you shed any light on that yes let me just refer first off to yesterday's action by the f d a in changing the labeling for key talk and at the press conference for that dr john jenkins the director of the office knew of new drugs stated unequivocally that they did not rely on study thirty fourteen for the approval let me quote from an e mail that his own deputy sent on march twenty first two thousand and six to myself and another review or quote in speaking with the division about let me say the relevant clause again they did not completely ignore the data from the thirty fourteen study second f d a cited the safety study when it first issued a public health advisory by pete potential to cause liver damage it is still citing it on that same public health advisory as a large safety study if they didn't use it for approval why are they citing that on their own web site finally i've been told that in making the decision the approval process was moving forward on key tech well at the first advisory committee meeting i gave a presentation on the overall safety talk and at that point i did make my concerns very clear to the committee and is that when the committee voted then to do a larger study it is correct ok that the second advisory committee had been told by supervisors that the committee was not going to hear about the fraud issues if i had spoken about that i would have been fired immediately well before the second one you were told by f d a you were not allowed to bring up the fraud issue about it will be study thirty fourteen that's correct that we were told we're not going to discuss it with the committee and you felt that if you would have brought up that issue the fraud in the study obviously the f d a knew about it then you would've been fired there's no doubt in my mind and i think i likely would have been subject to investigation by o c i that would have been initiated ok and that's the approval of key tech then there was a third advisory meeting yes at that third committee meeting i appeared as a private citizen and spoke at the open public hearing where you don't know if no at that point i was not i took leave from my current position for that day so i was only appearing as for myself and i made facts known to the committee that they had not been told by f b i thank you on this and they're also in your testimony you state that  closely was the auditor you also indicate in your testimony that even before the visit to kirkland campbell site in number of red flags were parents you said what event this have known of these red flags absolutely i spoke with the in house c r a that managed dr campbell site and she had told me that she was communicating with her superiors on this the daily basis about the oddities that were occurring at her site were raised with regard to the kirkland campbell site for example one item says all subject four hundred percent compliant with the study medication have you ever seen a study in which a hundred percent of the subjects in this case some four hundred people this would have been february twenty seventh two thousand and two or thereabouts so that's some two years before he tech was over approved for general population in your last statement and i'd like to shed a light on it if you just had to prove a suspicion of fraud they didn't have to necessarily prove the fraud they just have to report a suspicion of fraud and the evidence that i brought back from my site visit the evidence that was discovered at the quality assurance  audit was pretty extraordinary so if i understand this correctly so then is knew there was suspicion of fraud right in any of the stuff even the suspicion if report that the f d a correct and that's required on your contract to do this service thank you mr to pack and thank the three witnesses for being with us this morning as well dr ross and your testimony you went through a number of pages  not review the f b i s own division of scientific investigation concluded that none of the safety study data was reliable and they have and then they went on one week later and improve  through a number of very strong statements and as a citizen and member of congress has oversight when these people are appointed in leadership positions that certainly f e m a they all are professionals that are physicians are scientists they have great responsibility as impact on all of our society and their decisions this is seems to be from your testimony that is an outstanding question and it's something i've been wrecked my brains about my best guess is that there is two things overall there is a culture of approval that if you can get a product on the market in this was particularly egregious in this particular office then you find some way of doing that the second thing that i have concluded and this is speculation on my part but i do want to bring it to the committee's attention it is inconceivable to me that after receiving a warning in july of two thousand and three from an experienced criminal investigator that the decision to seek to not have an investigation was made at this level i am also has been told the doctor quatre was also pray by o c i about the need for an multi drug directional taskforce it is my belief that the decision not to have an investigation was made at a higher level and that would most likely be the office of chief counsel and how long were you or that the f d a ten years yes or and you left simply because as a physician you felt like you could not work at an agency with that kind of culture anymore would that be safe to say let me one thing i have to say is f d a has wonderful physicians and scientists who are public health heroes they really are dedicated to doing the best job possible and the office i was in before i left the office of oncology drug products was one where i felt the managers were very committed to doing the right thing to getting lifesaving products out quickly to the american public but overall seeing how the senior managers the individuals who i mentioned were dealing with what was clearly a horrible situation and not dealing with it i felt they couldn't in good conscience continue to work at the agency and i gave them a chance to do this before i left i a year ago i met with dr jenkins and dr leader in the presence of a witness and follow this up with e mails and told them about what was going on and i said we've got a huge problem here but we can turn it around we can solve this problem i gave them stuff to follow a corrective action plan about key talking about the problems with scientific culture and i said please do this we don't we're going to get crucified they they really didn't do anything i  mean i told them survey the reviewers find out what the problem is they didn't do that i said get everybody together in a room so we're not following information about key tech and let's see what the fraud situation as they said will well look into thus i found out later at the doctor her concealed my briefing that i'd given to her from the office of compliance within caesar so you know at that point i felt i can't be in an agency that has a culture like this even if i like the people in the work that i'm doing and you name one two three four five six people that were so called senior management as dr jenkins and dr quatre yes were you at the agency i was there for eight years and years and you've certainly heard this housewives dr ross and and the same question i asked is i want to ask you why would they approve a drug like assuming that the facts that you've stated and that dr ross has stated are true what it would be your best guess now he said that there is a culture of approval let me answer specifically about this drug first  i think first of all that there were economic issues regarding antibiotic development that were pressuring f d a from the outside and what do you mean by that over the last twenty years several large pharmaceutical companies have decided that they were no longer going to participate in either discovering or developing new antibiotics and this was occurring at a time when we really do need new antibiotics because of rising resistance and when i say need well what i mean is in serious and life threatening diseases where people could die if they don't get appropriate therapy in two thousand and one of a member of the pharmaceutical industry and a prominent academician wrote a letter in the journal clinical infectious diseases and that letter was titled the u s food and drug administration and the end of an products and  it they outlined that if f d a made any moves to increase the rigor of scientific studies in the area of antibiotic that it would be perceived as a scientific disincentive and i remember having a meeting about this and this is clearly something we need to take take account of and we do need to make studies more efficient in fact placebo controlled trials can be done with fewer numbers of patients but that really seems to cause a lot of uproar within the agency as well i think there's a second reason though when i think that there is a bias about antibiotics in general and that is we tend to focus on microorganisms instead of people it's very clear that michael and a virus can kill microorganisms and they're very effective in preventing death and serious diseases like pneumonia the question is what do they do for is easy like a sinus infection where your own immune system gets you better even though they have a huge effect on bacteria what do they do for people and i think a lot of scientists in this area have this bias that if it affects the bug that's all we need to know and then there's a third issue and that is there were a number of antibiotics approved in this method and it's just human nature to sort of not want to go back and say whoa wait a minute maybe perhaps we need to re address all of this that's a huge undertaking actually so i think that there's just a human aspect to it as well in the article that was written about the f d a being responsible for the ending of antibiotic research and development what year was that article written it was published in early two thousand and two i believe two thousand and two and you say drug companies were letting it be known that they were going to stop developing and obama already had and this is an issue that's gone back to the one nine hundred eighty s actually were some companies that decided to stop antibiotic discovery and the reason for that was just the rigors of the approval process actually antibiotics have the highest approval rate of any therapeutic class of drugs and in some ways the studies are shorter and easier to do you don't have to study people for like rheumatoid arthritis for a year the issue is that antibodies usually given for a short period of time and there for the returns on actually investing in that of are not as great as they would be for a disease drug that you would take for your lifetime and there's also a lot of generic competition as well and key tech course is still on the market and was originally approved for a three conditions and now being used or approved for only one and that's pneumonia is that correct yes somewhere i read or someone told me that in some of the studies that said twenty only twenty three out of ten million would be expected to suffer any kind of liver damage and i just imagining this figure or is there any basis for that at all or let me go into that number in may of two thousand and six what was then the office of drug safety presented a analysis of the number of cases of acute liver failure that had been reported  and that in the context of the number of prescriptions that had been written let me just say in terms of the number of prescriptions that have been written i did a quick back of the envelope copulation last night i would say at this point a key tech was corruption is written in this country every twenty that's this is after all of the publicity last year it was every four or five seconds there were at the time twelve cases of acute liver failure that have been reported and without boring members of the committee q liver failure is an extremely serious condition that can lead to death or the need for a liver transplant patient thirty percent of the patients die so twelve cases probably doesn't sound like a lot but the problem is most serious liver events are never reported if you look at a study that was done in france and this is the only study of the type i'm aware of where researchers said how many seri liver once actually get reported compared to how many actually occur we found that physicians only reported one out of every twenty four thousand liver injuries and out of serious liver injuries things that were people were dying from liver failure it was still only one out of every sixteen so for each one of those twelve cases there are many patients who we don't know about so twenty three out of ten million says say well that may not sound like very much if you compare that to other antibiotics for example a comparable antibiotic for the same indications the rate was only to pretend million twenty three pretend million is a lot when you're talking about an antibiotic that does not save lives woman from colorado miss to get thank you very much mr chairman actually mr whitfield question about how did this happen and why does that happen was the first question i was going to ask so i'm just going to follow up on that very excellent line of questioning dr powers you gave three reasons why why you thought maybe this type of thing could happen that it's that that there had been disincentives to antibiotic development that there's not a focus on people and that and that people didn't want to have to go back in and revisit the whole thing that might be a good explanation except for the fact that over the years in this community we've seen similar problems that the f d a with respect to other types of drugs that are not antibiotics and so we begin to to wonder is the problem not just a drug specific problem but really a culture at the f d a that we have to figure out how to fix for patient safety wouldn't you agree with that i think so and i have to say there's my experience with this with quite confusing to me in terms of when this became an issue we had several public meetings before key tech was ever approved in two thousand and two in two thousand and three where we addressed these issues related to these kinds of studies and the general agreement was that really they didn't provide substantial evidence of effectiveness and yet we still got to the point where in two thousand and four we were approving drugs like the sec when i went to people my supervisors and and their supervisors i have to be honest and say there were people that were very rightfully concerned submitted fabricated data is that correct yes now how do you know that they knew that there was fabricated data first on the results of the initial inspections study thirty fourteen were available in the fall of two thousand and two and it was clear at that point it was clear as day that there were serious serious problems and why do you think that they went forward with  way i have never gotten a good explanation what's your opinion what do you think i mean why would they do this knowing that data was fabricated and knowing that the risks of the liver failure could be quite high i think that there was as i said there's a culture of approval and let me explain what i mean by that under the prescription drug user fee act there are obviously goals which everybody knows and f d a is fond of saying that that doesn't mean that we're going to approve it at the bottom line is the fastest way to deal with the drug application meet that deadline is not to raise too many questions and approve it that's number one number two after limited resources and dr jenkins is a very been very vocal about how we have to have to stop having multiple cycle reviews and i think the feeling was let's just get this thing out of the way well as i mean a structure power says maybe you don't need to have as large or many reviews but you certainly have to have thorough reviews that aren't fraudulent right and then you could restructure the way you do the review i agree one of the things that's missing right now from the review process is any measure of quality once a manager who's got sign off authority for a product writes a review nobody else looks at and says what were you thinking so there is no measure of the quality of decision making that goes on well later this year we're going to be and and i'm wondering and dr powers i'd also like to ask you this question is it do you think that tying the user fees to the drug review is causing a bias in the system and if so how what can we think about doing when we reauthorize the act to eliminate that bias let me first say i do not believe we can go back to the days in which we had three to four year reviews i mean we all know that everybody that's a nonstarter i just want to be but i just want to put that on the record but i'm mindful of a sinus on a repair shop once fast good she pick any too and i think right now what we've got i hate to say it is we are trying to do things on the cheap enough to say we need more resources and more reviewers and higher standards there and i think we are never going to get  things perfect but we can have fast and good it won't be cheap though dr powers i often think about when my medical license comes up for renewal i have to pay a fee to get the license renewed it seems clear to me that when drug sponsor asks an agency to review all this information it makes logical sense to pay a fee but i don't tell the medical licensing board what they can do with my money and i think the issue is this negotiating of what the money gets used for i think is an issue for the second thing i think is that it's not as much i don't know a single reviewer at f d a who says gee might my paycheck is coming from a drug company i have to do what they say that's not the way it works and reviewers are really doing an excellent job for the most part the question is could we have a doctor also pointing out some transparency about how s t s work is done and some accountability for when that work is not done properly and if that was built into the paducah system it would be and i want to ask you a couple questions about that do you think that she was that the fraud was that she said she was enrolling all of these people and she wasn't enrolling them or were she actually giving the drug to all of these people who maybe were sick what was the problem well it came out in the f d a audit that they never did find out what she did with a drug she never disclosed that and refused to do so and now i think they called all four hundred patients and she had actually enrolled maybe fifty and all of the other patients were fabricated so i guess the good news and she wasn't really telling people that the bad news  she wasn't doing the job well i mean the concern that i had when i was at the site is i didn't know what she was doing with the drug and she was giving a potentially harmful investigative medication to patients and not following them something else that piqued my first because i've been working for a long time on the issue of patient protection and and patient notification was when you called the parnassus i r b to talk to them and my question is and actually this is something both of the doctors could answer to is if we beefed up the i r b process in in these drug reviews would that help maybe ensure the efficacy of some of these independent studies well i'm not quite sure the who dropped the ball here with the ira the issue they did nothing they did not audit the site they did not blacklist the site even though they should have been should have received information about her data so i you know i b system in these cases yes i think there's two fundamental problems here one is the i r b system nationally is broken i replace don't know what their responsibilities are they don't know what they're supposed to do when there's a problem that's number one so we need to fix that number two is the enforcement side of things that f d a basically has caught it's in forstmann to the bone and beyond just one example for the committee we had a situation in texas when i was a deputy office director where an investigator and a physician injected women with breast cancer with a radioactive substance without getting proper informed consent when this came to our attention we jumped on it but it took f d a over a year to take any kind of action on this so you have a i r b system that's broken and then the enforcement office at f d a with good people who basically are being not supported by leadership dr i'm going to concentrate on the scientific end of the i r b process how does an i r b approve a non inferiority trial for key tech and little children with ear infections so when you think about that it says well what are the people at the arby's thinking about it and when i was at a we actually got a letter back from an i r b from a drug sponsor actually tried to do the right thing and try to do a placebo controlled trial saying we don't think you should be doing these kinds of trials and that's there's a lack of scientific understanding at the i r b level to mr  chairman and i do want to thank the witnesses for being here this morning and particularly thank you for the efforts you've done to ensure that we have safer reliable medications in this country  powers let me just pick up on some things that you were discussing with with mr jett on the in the producer system you mentioned that the barriers or what the requirement was we have full transparency an accountability what in your opinion are the barriers to prince parents and accountability in the produce a system i think it's interesting for me now is that as no longer working for the f d a what do i want to see as a as a physician out there in the community what i'd like to see is that when a drug gets approved that all of the documents which went into that approval all of the data including the decision making process the meeting minutes etc go up on the stas website within say seven working days when the drug gets approved then everybody could look at this information and be able to make those kinds of decisions but right now that kind of information gets up there and spotty at best and when you see an advisory committee you see a normal amounts of information that level of detail should be available for every kind of drug as well and then if there is scientific discussion within the review team and some people have differences of opinion those could also go into their doctors could read those in the able to make their own decisions about those things well certainly could be that a search database that would improve the information that's out there but i would also say having been a busy practice you don't always have time to to avail yourself of those things and unfortunately like many people do you rely on the other information that's available to you which which may come through post marketing advertising dr ross you talked about dr quitters who concealed the briefing that you all if you know why this would have happened i assume she didn't want them to know about it and look ultimately would have been the benefit to either the f d a or dr wieder about concealing that briefing i think in any bureaucracy the one thing you don't want our problems in the best way of making problems go away is by controlling information and concealing them and that's what i think was going on here just say my own experience i haven't been up here that long but my own experience it seems was a function of bureaucracy used to consume dollars from road value but that's from our hearings on katrina cha have are thirteen reported cases thirteen reports and that's what we know about of course as i said most cases are never reported yeah how does how does that happen how do you not report the case of acute liver failure requiring a transla everyone including f d a says we have with our current post marketing system and what we need as much better data the reason that we have trouble making the right decisions is that we don't have the right data systems in place and f d a just announced after years of urging that it is going to have partnerships with the veterans health administration as well as other agencies that have large databases that can be used for prospective collection of safety data but it's the sad fact that except for devices where there's mandatory reporting of problems most drug offenses even very serious ones never get reported with how many how many cases of acute liver failure requiring transplantation resulting in patient deaths occur with the acetaminophen see the medicine is certainly the most common cause of drug induced liver injury however it's important to remember that those events generally kerr in the setting of intentional overdose or in the setting of the consumption of alcohol and if you correct graham may be able to address this later i think there are certainly other tocs this is not the only toxin on the market but if i could use a medical example there's a biopic that we as physicians are all familiar with chloramphenicol for which i've only it's a life saving  does the f d a hold periodic meetings regulatory briefings that serve as an opportunity for different views or questions to be heard on drug safety you guys all get together in a room and talk about this stuff th but the problem is that it reminds me of a cartoon i saw where a bureaucrat is telling somebody on the phone i can assure you that your problem is being ignored at the very highest level the most recent example that i'm aware of occurred in april of two thousand sex where a product called gap to my son was discussed at a regulatory briefing and everybody unanimously with the exception of the division director said this product should not be approved for th indication everyone had their say and then the division director who happens to have been dr soares politely lessons and ignored them so it's not like these views again there's no accountability you can simply ignore good science and there will be no you won't be held to account for it let me ask you a question because you brought up the issue post marketing data that's not all bad because also being old enough  chloramphenicol i'm old enough to remember when so little it was held up in this country because of postmarking data but postmarking data from other countries obviously the experience in europe tempered the judgment of the f d a at that time as to whether or not to release that medicine in this country so it's not all bad that that post marketing data that comes from other countries now i would never say that it said but it's a question of the quality of the data and what do we want to be making our decisions if i can go to a building analogy which i'm fond of medication i think the problem is that while you can pick up a signal if you when you say well there's no signal here there's nothing going on that's where we got into trouble on the on the issue of post foreign post marketing surveillance of adverse events i mean you referenced the study of the of the adverse liver events and was that not a french study that's correct that used to prospective database to determine what was going on thank perry let me just ask you about the non inferiority issue with the antibiotics and you know like you i'm concerned about the emergence of multiple resistant strains of what previously were relatively easily disposed of bacteria this key take play any role in our armamentarium of challenging these more aggressive organisms i think the answer to that is we don't know we'd like to know we know that allergic to penicillin well that's the issue if you want to actually then but then you're saying that that key take as a safety benefit not effectiveness benefit that's changing the question what to on the question of of the institutional review boards i mean i was involved with clinical studies back when i was a resident was a long time ago and they were generally a pain in the neck because you had so much paperwork to fill out to use to show a review board was basically for me it was parkland hospital is it not the institution  is sponsoring the study that that is responsible for that is to show a review board or is that just a misconception on my part now i think that the name comes from an era in which most research was conducted at academic institutions so your example of the breast cancer injections was that just done in someone's clinic and not part of an institution now that was done at the institution here in texas yes or all right offline you can tell me which one  thank you mr chairman as this is narrows just before we leave you in march of two thousand and two you became aware that or when did you become aware that the of the fraud that was being perpetrated by the  working with at the time p p d now i left for a different ok thanks mr chairman thank you we have three or four members who would still like to question this panel but we have four votes on the floor pending right now in fact we are less than ten the vote on this first one so let's recess this hearing intel twelve thirty they want to stretch your legs grab something our witnesses if you come back at twelve thirty and we'll finish up with the members who have not yet asked questions and they will move to our recess until twelve thirty i would remind the witnesses they remain under oath i appreciate your patience they took care of one other matter on the floor made up a few minutes later and with that i'd like to recognize the gentleman from texas mr green for ten minutes for questions mr chairman and i have a number of questions chairman i don't know if we can get them all and i think we submit questions to the panel for later response is that possible yes there will be written questions will be appropriate time to thank you dr ross how unusual is it to see fraud in a clinical trial well it happens it's unprecedented in my experience to see it at the scope and scale why was the study considered unreliable wow first off out of ten sites that were inspected all had serious problems that made their data completely unreliable f t s investigators concluded that if these sites which were high and rolling sites were supposedly the company had been keeping close tabs on the doctors were unreliable the rest the cites couldn't be relied on either what do you mean that every side inspected by f d a had problems of the ten sites inspected every single one was found to have significant violations of what are called good clinical practices the rule book for conducting clinical trials four of the ten forty percent were referred for criminal investigation that's an astounding percentage me back up just a little bit then the advisory committee in two thousand and one first concern about liver damage from key to what was was that the only concern was the liver damage no there were also concerns over effects of key t and on vision as well as key text potential for interaction with many other drugs what exactly was the misconduct found in the safety study while the largest enroll or as we've heard was convicted of fraud and this was not sophisticated or subtle fraud it was absolutely blatant the second and third largest and rollers had significant violations of procedure they called into question the reliability of data from those sites and i think it's interesting to note that the third largest and roller was arrested shortly after the study on cocaine and weapons possession charges and this is not the type of investigator the study physician rather that f d a likes to see in clinical trials i can imagine coming from texas we don't mind a weapons but this narrows what came out of your teleconference with our evidence and regarding irregularities in the kirkland campbell site and did they seem concerned about it you know they really just glossed over all the nineteen had as an excuse for irregularity that we found you know i just i walked away from it being a stay sounded at the laissez faire attitude that they had about the issues that we found at the site  roller so there was not a for cause audit sure about the effectiveness of the old drug in the first place i think the second issue is that these are jesus that people commonly don't take antibiotics for i had a side infection myself us we couldn't take anything for it and got better anyway and thirdly people will find informed consent in the studies they know that they might be getting a placebo and fourthly there's actually some benefits to being on the placebo group you might get better anyway and yet not be exposed to adverse effects so the last thing is the real issue with doing a placebo controlled trial is is there a question to be answered a thing called echo poise and that question still remains unanswered as to in whom and when are and of objects effective for the self resolving disease were there be specific vendor this evaluating antibiotics controlled trials i think again it would be part of this is people would not be exposed to adverse events the other issue would finally be able to figure out how beneficial these drugs actually are and in a placebo controlled trial you can also weigh adverse effects of those drugs as well so say that we do find out that antibiotics do decrease symptoms of your infection to kids by two percent compared to placebo if they cause diarrhea and ten percent of kids then we'd be able to actually make that assessment and make an overall risk benefit don't clinicians and patients want to know how new drugs stack up against the old drugs in terms of safety and effectiveness i think that's an important question and the issue is do we really just want to know that a drug is better than placebo and that's why people do these kinds of trials with a comparison one drug to another but the problem with these trials is we missed the overall question of is it effective at all so if you did it if f d a had the authority to require three group trials that is comparing new drug to old drug we could actually answer both of those questions make sure the post drugs are better than placebo and how one drug stacks up against another one the f d a doesn't have the authority to do that right now right now the only the only thing f d a has the authority to say is the drug is effective compared to nothing and they're very fond of reminding us that there is no relative efficacy standard so all you have to do is be better than nothing and x actually the complaint some people have about placebo controlled trials is some people say well this just tells me it's better than nothing and that's not what i really want to know scientific investigations determine the doctor salerno the third highest enroll or been placed on probation by the state medical board and later during the study had his medical license been to well understand your experience this case is limited doctor hartmann campbell can you speak to the typical measures taken to ensure that the physicians participate in usual care settings are reputable and do contract research organizations check out the credentials of their rolling physicians it is my understanding that the ira is supposed to do that drug that's approved will be approved via adequate and well controlled investigations by investigators who are qualified by training and experience a physician who is on probation not a corporation which is a matter of common for company sellouts interested in role beyond the allowable limit is this use acceptable it is not it is something that should immediately trigger concerns and it's something that internally i send emails to people in management about pointing out the high end rollers were enrolling at rates that were far greater than would be expected in a normal trial there's the f d a have any inforced mechanisms for motor compliance by these drug sponsors yes if they choose to use them in your experience is there been a recent history of that using on the drug sponsors now for example dr kirkman campbell was the f d a did not even move to disqualify her from conducting clinical studies until after t tech at the news as of this point although she isn't present in a federal correctional facility disposition is still eligible to conduct clinical trials  additional light in the last thirty seconds i have there is there's definitely a fault in the system and there was a breakdown on the sierra level on the r v level and you know there are people that were interested in coming here today but  really shocking i think it's shocking to our constituents to see what's happening because we depended on the f d a when we deal with imported pharmaceuticals but it's just not there so i guess the committee again being back on the subcommittee after about three terms  you know i'm just shocked and and i hope we can deal with it during the authorising let's thank the gentleman mr weldon from oregon for comments thank you very much mr chairman and i want to thank our our witnesses all of them today for sharing your stories with us and most helpful as we do our oversight work dr ross you indicated in your testimony that you were pressured to change your view and i'm just curious was that pressure from the supervisor uniformly an approval letter to a ventus outlining requirements for key tech to be approved i have been the safety team leader for that review cycle i finished my safety review my c safety team leader memo in september of two thousand and three which was about eight months later and that was because i had another priority review to work on i gave that to my division director she called me into her office i think a couple weeks later and said could you soften us to give mark that is mark walberg or an ad that is at cox more wiggle room i knew from previous experience that if i refused to get very angry a number of colleagues advised me to comply lest she retaliate i decided that i would comply but i also sent an email to the office above hers outlining what had happened i put this in writing this was sent to mr david raider who is mar associate director i did not get any response in writing or otherwise from dr goldberg or when i didn't get any response i took my original review without the changes that dr stuart had requested put it in an electronic archive and added a note about what would happen in case there was any question down the line about the situation i did that  signed off on a march sixteenth two thousand and four that was almost three years before this committee hearing and it was almost two years before he talked hit the news  why would she say that because she'd get in trouble if she admitted to it and that would be a serious infraction to pressure reviewer to change their reviews i do not want to get distracted on this because i was you know personally it was angering to me i think the real question is why did f d a use this fraudulent data i will just say however that i documented at the time what was happening that was the only thing i knew what to do and i went to opera management as well and said here's what's going on and that seems like the responsible thing to do and it's most helpful as we look at i'm just trying to figure out how all this works inside this particular box within the understood understood my team leader memorandum for the second review cycle the key change was that initially i had said that it was doubtful that key tech could be approved for the lesser indications of acute that i'm sorry pneumonia i said i thought with additional safety data it could be approved for although i said i did not think it could be proof for a particular type of resistant bug mainly because of a lack of data all right why why do you believe it is as you put your testimony that the f d a managers were so bad i think it was the word you use to approve tech what was driving this i think there's a fear of being seen as holding up new products and frequently there is a perception that just because something's new it must work otherwise why would a company be submitting it and the sad fact is for example in cancer therapies ninety five percent of therapies that start trials never make it because they don't work and i think in this instance and others f d a managers were afraid of being perceived as holding up an important drug and so they felt really pressured to find some way to approve it and it is you talk to other reviewers i assume you all run in circles where you're talking i don't know that for now it's what i assume is this an isolated piece f d a the way this whole thing unfolded i mean is this what's happening in every division i mean that it isn't happening that way in on  now happening i urge this an isolated incident i let me answer that it's first off it does not happen in every division and i would certainly say an oncology when i told them  managers there about what had happened they were appalled i cannot imagine the sort of thing happening in the office of oncology having said that however there's a number of instances that i saw in the office of anti microbial products in which reviewers were pressured either directly or smore subtly to kind of get with the program and find some way of approving a product even if they had reservations now i have to say that if a reviewer says don't approve this and a manager just agrees the manager is fully free to write their own review and overrule that reviewer and put it on the record and everybody accepts that for example  that can go both ways right that can go both ways have you seen instances where it's gone the other way i have not ok i will say for example for gems are which was approved for treatment of not a static ovarian cancer in oncology the primary reviewer said i don't think that should be approved and the division director wrote a very carefully reasoned memorandum saying i disagree i'm going to approve it and it was on the record for everyone to look at so your issue is that approach versus one where the supervisor tells you to rewrite your get your report it is a way for the supervisor to avoid taking responsibility now i note that you cite senior f d a medical adviser dr robert temple in footnote six of your written testimony do you consider dr temple a reputable and credible witness on clinical trial matters and perhaps i think both dr powers and dr ross are you familiar with not condemn the agency's approach that's number one number two i can tell you that he has as disparaged the idea that reviewers are pressured he's openly said and this is an meetings of senior management do we ever know that this really happens and i would go up to  as a member of the senior leadership team and said bob i happen to me and what would you say just nothing i mean i think there's an air of disbelief you think he would be a good witness for this committe i think it would be helpful to the committee to get his perspective and raise these issues with him powers do you want to comment on arthur temple's i sort of i want to link the question about dr temple to a previous one you asked about how systemic is th right when i consider that the agency wouldn't even be as good a position as they are now in terms of the evaluation of drug products as if it wasn't for people like dr temple and in fact dr temple is one of the first people to write about the issues becomes what's the systematic issue when someone of of his stature who is the director of the office of medical products is still an able to alter or change the way things that were done in office below him in the office  microbial products and i think that's where you get to the systemic issue and i know for a fact that if he was capable of changing this he would have so i guess the question is he'd probably be a good person for us to ask under oath what's going on below him much appreciate it dr ross dr powers you have been extremely courageous in the actions which you have taken thus far and i just want to congratulate you for that i am going to go through some of the provisions in a piece of legislation which i'm introducing the swifts the pool approval full valuation drug act that i plan to re an interest and i plan to reintroduce this week with some changes and i want your opinions on whether these provisions will improve things at the a and if so how number one you have talked about the culture of scientific suppression and intimidation at f d a the safe drug addict will prohibit f d a employees from directing other f d a employees to censor oss oppressed scientific research analysis opinions or recommendations are directing employees to disseminate scientific information that is known to be false or misleading there will be penalties for any employee who engages in this conduct were no penalties for f d a managers who engaged suppression of reviewers and ordered reviewers to disseminate false information to an advisory committee this provision of the safe drug act would deter i believe f d a managers might be tempted to suppress reviewers either explicitly or by threatening retaliation to performance reviews or a doctor powers i think it's very hard to legislate culture but people do things for to read either to avoid pain or to gain closure and if in this case as dr also is pointing out someone would try to force someone to alter their review to refuse to take accountability for their own actions and this kind of a provision would help there be some transparency and accountability dr ross in your response to chairman stu pac you said that you believe that if you had told the second key tech advisory committee about the problems with study thirty fourteen and the f d a has questions about fraud in the study you would have been fired i am very concerned about the f d a its policy of censoring information going to the advisory committees we have not only heard about this happening in your case but we also have heard a employees working on a matter related to an issue before an advisory committee shall be allowed an opportunity to make a present patient to the committee this f d a employee presentation shall be separate from the time allotted to the public to comment on an issue before an advisory committee why is it important for all f d a employees working on a matter to have an opportunity to speak at advisory committee meetings would this provision help ensure that advisory committees get complete information from the f d a i think it's important that advisory committees hear the full range of scientific opinions held by reviewers not just those that are approved by management it's a sad fact and i'm not saying it happens often but i certainly seen it happen that an f d a manager can manipulate the information received an advisory committee to get the desired conclusion i think that the provision that you outline it would help lessen the risk of advisory  committees being manipulated by f d a managers talk to powers to have a view on that i think it's often said that f d a that they need to speak with one voice i think they need to make one decision obviously but the scientific process isn't about speaking with one voice it's about hearing lots of voices and then being able to make a cogent decision after that advisory committees usually occur before the drug is approved and that's the time to actually hear everybody's side of the story to be able to get and give the advisory committee the information that they need to give good advice thank you bill provides that unless publication of presentation of the data is subject to national security laws or regulations or is proprietary information f d a and f d a sponsored authors shall have the right to publish  i definitely witness this when you submit a manuscript this did not happen on college they're proud of their work there and they publish it but in the office of antimicrobial products for example you send a manuscript for clearance and then vanishes into a black hole i think that this provision is important because it would allow removal of arbitrary barriers from publication it would be important i will say to define proprietary information that term as nearly as possible so it can be used as a pretext to block publication power i can say that i myself was reprimanded for writing a book chapter in the premier infectious disease textbook two years after i wrote it actually and even though this was not part of my work at f d a done on my own time i clear it with the ethics department and i put a disclaimer at the bottom of it so i think it's very important that f d a reviewers should be allowed to participate in the scientific discussion not just with an f d a but with their peers outside the f well and i would actually say that the outside activity form that f d a requires you to fill out now should be for informational purposes only that you allow the managers to know you're going to publish something but that should not be that there needs to be a clearance process of what you're going to say ok thank you you talked about how it seems that some people within the act as if they were working for the pharmaceutical industry rather than regulating it part of this comes from the fact that the f d a must negotiate with the industry over what the drug labels should look like my bill will give the f d a the authority to mandate changes to drug labels instead of negotiating the label with the sponsor company many of the members of congress have also proposed similar legislation do you think the f d a needs greater authority to mandate label changes and require specific information on the label and do you think it will help empower the f d a to act more like a full fledged regulatory agency yes under the current system changes riposte by the air frequently watered down through extensive negotiations with sponsors in benefits that are accurate i'm sorry information i'm risks and benefits that's accurate is not communicated to providers or the public and i think that that authority  the powers i think it would be very helpful to spell this out one of the things i remember i found very confusing when i got to f d a was how people talked about it in terms of labeling negotiations and went back and forth and back and forth i think the drug sponsor needs to obviously be a part of that process and in fact they're the ones who write the first draft of the label but if it comes f d a go back one more time and then make a final decision i think if he already has that authority they don't use it and it would actually be very helpful to spell that out that that is the way things should work although i want i would like to believe that we can reply the f d a so that the f d a employees will no longer need to blow the whistle on the f d a we need to protect whistleblowers so that they can come forward to warn the public when necessary without fear of retaliation my bill will require increased protections for whistleblowers if they are retaliated against for reporting violations of laws or regulations are a significant threat to public health and safety to congress federal agencies all their bosses how would whistleblower protections improve the situation the f d a i think they'd allow greater freedom for reviewers to inform the public about trusts the public how they discourage suppression of review reviews and they'd help reform the culture at f d a with regard to scientific dissent the hope is that if you have whistleblower legislation that would mean you wouldn't need to use it actually but that would form some transparency and openness and that people would have that as an outlet valve if they needed to with that that would form a culture of f d a where you wouldn't have to have people going outside the agency to solve the problems thank you ross talk of powers this is nero's i thank all of you for your excellent testimony today it is a real tragedy that the f d a is losing good people with highly specialized expertise like dr powers and dr because they have grard to raise concerns about the safety of drugs according to the f d a mission statement the f d a is responsible for protecting the public health by assuring the safety the efficacy and security of human and unary drugs biological products medical devices if f d a is own medical reviewers are prevented from raising questions about the safety and effectiveness of drugs the f d a cannot possibly fulfill its stated mission instead of suppressing defense and preventing reviewers from asking questions about the safety of drugs the f d a should demand careful review of the drug risk of drugs that they are putting on the market you are latter day trying to warn the public about the dangers in the review process at the f d a you should be praised rather than punished we need to act now to reverse this dangerous trend trend of the f d a not only to protect public health but also to restore the public's confidence in the f d a a recent harris poll found that eighty percent of adults now say they are concerned about the f d a as ability to make independent decisions that will to turn and i'm sorry if you see ok so the private individuals who would who were had a desire to come forward but were fearful of repercussions yes and what was told to me is that these people were called by d attorneys and reminded of their confidentiality agreement and that a lawyer would have to be but he did where would have to be present with them in order to talk to the agency so they chose not to talk to the agency that this one person did with no i think the idea is that f d a traditionally approaches as you know if somebody takes a drug and they get a skin rash someone takes a drug and gets a liver failure that's the way they traditionally think about safety but with an antibiotic you're really not talking about just an adverse effect on one person you're talking about population effects which makes demonstrating effectiveness really even more important and i think we often talk about this is safety and effectiveness is if there are two different things there really are parts of a scale here and when people concentrate on the side of how many liver failures are there there's got to be something on the other side of the scale to balance that there's got to be effect in this otherwise even one case a liver failure is too many but the idea here is that most antibiotics are actually used for these less serious diseases so for instance there's about thirty four million kids who get an antibiotic a year for ear infections and there's about one hundred sixty thousand cases of hospital acquired ammonia which one is driving resistance it's the one where people use the antibiotics the most and some people have actually suggested that perhaps antibiotics should be regulated in a different way because of that so for instance in legislation that's coming up now the kennedy energy bill says perhaps we could look at drugs for three years well for antibiotics you're gonna have to look out longer than that because that's exactly where and thank you for your time and patience of being here thank you my name is stephen enough an m d i am chairman of the department of cardiovascular medicine at the cleveland clinic and the president of the american college of cardiology my testimony does not reflect the views of either the cleveland clinic or the a c c we face a crisis in public confidence in the f d a following an unprecedented series of revelations about drug and device safety the american people no longer trust the f d a to protect their health and fortunately patients are increasingly suspicious of new therapies and sometimes are reluctant to accept potentially lifesaving medications or devices decisive legislative action is now essential to improve the safety of drugs and medical devices and restart public confidence in this critically important agency i have served on many the advisory panels and this experience has undermined my confidence in the ability of the agency to adequately protect the public health in two thousand and one i participated as a guest member of the arthritis advisory panel that recommended a warning label for cardiovascular risk for  under current law the agency must negotiate with industry to make even simple changes in drug labels and act the officials frequently make inappropriate concessions to pharmaceutical companies following the two thousand and one advisor board meeting it took fourteen months before the f d a could secure agreement from the company to accept a weekly written warning during this period patients and physicians were not appropriately warned about the cardiovascular h hazards of vioxx when the label was eventually modified the wording was so weak that it did not did not adequately informed physicians and patients of the polk county will provide ochs to cause harm in two thousand and five another disturbing personal experience brought into sharp focus the inadequacies of the f d a in assessing a new drug application on september ninth two thousand and five officials from the under kind of metabolism  new diabetes drug known as a miracle it has are to an advisory panel for consideration of approval because of a previous lawsuit by the advocacy group public citizen the f d a is required to publicly disclose the briefing materials for advisory panel this because of my interest in this class of drugs i reviewed the briefing documents posted on the internet by the agency on september eighth the day before the public hearings i observed that this investigation all drug seemed to lower blood sugar but i also noted that there was a striking access of heart attacks strokes and deaths in patients treated with miracle a bizarre compared with placebo or other diabetes drugs based upon this observation i assumed that the advisory board would recommend that the agency not approve the right what is are yet astonishingly the following day and agency reviewers presented the drug in a favorable manner any concerns about cardiovascular risk this advisory panel they did not include any cardiologists voted eight to want to approve new york but as our anding the panel meeting at two p m in cleveland i watched the news reports complete with productions from financial analysts that the struggle to achieve annual sales exceeding one billion dollars i felt compelled to act my statistician and i rapidly downloaded the f d a material available from the internet and perform own independent analysis of the risk and benefit some of the struggle we concluded that miracle it is our doubled the risk of death heart attack stroke and congestive heart failure i phone the editors of the journal the american medical association who treated our findings as a public health emergency peer reviews were secured in a matter of days and jam opposed to the manuscript on their website october twentieth just seven weeks following the f d a advisory panel meeting shortly prior to our publication the f d a issued an approval letter to the sponsor following this publication the pharmaceutical company developing regulators are abruptly ceased all further development fortunately this drug will never threaten the public health but frankly it was a close call we are we were able to independently analyze the risk a miracle it is our because the drug was presented to an advisory panel for many new drugs the agency approved down without public disclosure of the key findings in pivotal clinical trials when drugs are presented to advisory panels the agency frequently provides an uncritical presentation that failed to adequately inform the advisory panel members of any internal f d a concerns this phenomenon was very evident during a meeting of the drug safety and risk management advisory board of the f d a which met february ninth two thousand and six to review drugs used to treat attention deficit hyperactivity disorder or a d h d i was asked to serve on this advisory panel to help with valuate the cardiovascular risks of these drugs most of which are unfounded means or in fact i mean like agents these drugs are closely related to methamphetamine or speed a major drug of abuse and nearly all advisory panel meetings the f d a provides a list of questions to panel members designed to assist in discussions and to guide the formulation of an action plan when the advisory board briefing materials arrives i was rather surprised by the questions that the agency intended to ask in this case the f d a did not request the committee to consider the arrests of the h d drugs nor did they ask us to comment on the need to change labeling instead they asked the committee to discuss how the agency might study the class of drugs during the hearings we learned that a d h d drugs substantially increased blood pressure and we heard reports indicating that approximately twenty five children had suffered sudden cardiac death after taking these drugs occasionally after the first dose surprisingly the motion passed by an eight to seven vote agency officials looked horrified and quickly called a news conference where they defended the safety of the drugs and sought to undermine the recommendations of the advisory committee some months later the f d a actually did write new warnings but it took a rogue advisory committee to motivate the agency to act it is important for the congress to recognize that there are many fine and dedicated public servants working within the f d a however their concerns often fail to reach advisory committees because of the actions of their supervisors who adopt a less courageous approach the congress must now fully evaluate the deficiencies within the f your engagement to investigate the problem and take decisive action can improve this agency that three hundred million americans who rely upon drugs to stay healthy are counting on you to take action these measures need not slow drug development if we improve drug safety oversight the increased vigilance will inspire confidence and allow us to bring new medications to patients more quickly because we will have a better safety net in my more extensive written testimony i outline ten critical initiatives needed to put the f d a back on course i hope you will consider these ideas as you move forward and greatly appreciate the opportunity to appear before you thank you very much director for science in medicine and stas office of surveillance and epidemiology or o s b for more than twenty years i have worked as an f d a physician epidemiologist concerned with post marketing drug safety the statements i make today are my own i do not represent the as official view as we've heard from the previous panels the key tech story is about f d r s betrayal of the public trust f d a ignored safety concerns raised by its own advisory committee and conceal from the committee the evidence that a crucial clinical trial was fraudulent subsequently f d a issued a public health advisory that referenced the same fraudulent study as proof of key tech safety f d a scientists were intimidated suppressed and ultimately compelled to leave the agency or use post marketing case reports from europe and latin america were reporting is far worse than it is in the united states to declare key tech safe rather than using clinical trials as it should have i cannot think of a single other example where f d a used such data as the primary basis for the approval of a drug safety o s c a sensibly responsible for post marketing safety issues was relegated to the role of back seat consultants with no power or authority unfortunately key tech is not an anomaly in november two thousand and four i testified before the senate finance committee that f d a is handling of vioxx with a co found regulatory failure and that f d a is currently configured was incapable of protecting america against another vioxx i am here to tell you that nothing has really changed our nation is still at risk vioxx was an enormous national catastrophe up to sixty thousand americans most over the age of fifty die from vioxx related heart attacks about as as the number of u s soldiers killed during the vietnam war another eighty thousand suffered non fatal but nonetheless life threatening heart attacks f d a had multiple opportunities to prevent this but did nothing to this day f denies that it made any mistakes and has yet to be held accountable a company my testimony if included a table that would show that every state in this country every congressional district in this country had patients i consider when we saw heart attacks and who died of heart attacks related to vioxx sadly vioxx was not an anomaly either think s s r i eyes and suicidality in children think accutane pregnancy exposure and the need for restricted distribution in my view there are four broad areas of critical f d a malfunction one organizational structure two organizational culture three the misuse and abuse of science and for suppression and intimidation of scientific staff the most important organizational structure seaters primary mission is to review and approve new drugs within ster the office of new drugs or o n g has this responsibility post approval oh indeed continues to have regulatory authority for all postmarking safety issues that arise this represents an inherent conflict of interest because the same people who stamp their approval on new drugs and certify that they are safe and effective also get to decide if a post marketing safety issue is important and if anything needs to be done about it there is no in control internal control there is no safety net this organizational weakness is amplified by a massive imbalance in staffing and resources within suter between pre and post market activities overall roughly ninety percent of sitters staff are focused on the review and approval of new drugs as the i o m report found and i quote the imbalance in formal role in authority between the review that's o n g and surveillance epidemiology that's o s d staff the notes the subservience of the safety function and along with that a management devaluation of the latter discipline and approach and of quote features culture regards industry as the agency's primary clients rather than as an entity in need of regulation is not a legislative hearing i'm compelled by conscience to make the following comments vioxx is the main reason why legislation three former f d a is being considered hence the litmus test by which potential legislation should be judged is whether it would have prevented the vioxx disaster in the first place if the ice response the i o m report recently released even if fully implemented would not have prevented a single vioxx death or heart attack vioxx was not a failure of surveillance or resources it was a failure of institutional decision making f t s response to i a whim would not have prevented ke tech or the s s r i anti depressant issues from the folding the way they did unless post marketing safety experts at f d a have regulatory authority over the post marketing portion of a drugs lifecycle that is separate independent from zero indian seed or all the money and data bases in the world won't change the end result similarly had the kennedy n z bill  not a single life would have been saved this bill also would have had no effect on the way ke tech or the s s r i antidepressant issues unfolded why the bill does not correct the root cause of f d a still year to protect the public health f vioxx and the other mentioned drugs was a failure of institutional decision making and the organizational structure giving rise to the spell your has been left unchanged kennedy as he leaves zero energy the office of new drugs in charge of post marketing drug for your consideration of this critical subject and the opportunity to address you today thank you dr graham dr nissen if i may i understand that to those they regulate you know how do we get the f d a to take or to make the best risk benefit decisions if those with the safety expertise are still subservient to the hierarchy that believe that the industry is your primary client well i first of all i think there are lots of potential solutions and i don't at least on the first pass of the grassley approach which is to separate the safety and efficacy assessment both benefits and there are risks and by the way i greatly respect the senator's passion and commitment and his testimony today was compelling for all of us that have been involved in in this area but here's the problem from my perspective safety and efficacy are inextricably linked if you have a drug a new drug for lung cancer that rapidly killed ten percent of the people that got it by curing the other ninety percent one can or it might be a very good drug you would save a lot of lives it would have a huge safety problem but it would be a drug that i might want to approve and so i like the idea that an agency that's well run can integrate safety and efficacy into a single decision i think the failure is a failure of leadership i think we've had a horrible leadership at the top in the f d a and at the next couple of levels down the leadership is actually quite good at the rank and file although frankly there is a streaming of talented people out of the agency now because of this culture that exists and so i think to fix the f d a we need new laws but we also need new people at the top and being very frank i think that goes all the way to the top could you discuss the negative publication bias issue that you raise in your written testimony this is one of the most profound problems in in medicine i think in general and here's the issue when companies do clinical trials if the trials do not show a favorable result that is either africa c or good safety they're simply never published only a small minority of clinical trials that are actually conducted are published and so as physicians scientists we only get to see a tiny fraction of the actual data one example i give in my written testimony is for a class of drugs called p pars where there have been more than fifty drugs that have filed i n d s where the drugs have been discontinued during development due to toxicity and  single publication has appeared of why any of those fifty more than fifty drugs were actually discontinued how can we make good decisions about successor drugs about the next generation how can we protect people in clinical trial if we never get to see the information and so negative publication bias the practice of allowing people to participate in clinical trials but we never see the results of those studies is not scientifically acceptable it's not acceptable in a public health sense for that for the citizens and here is the principle i would like you to consider if one of our citizens volunteers to participate in a clinical trial the results of that trial belong in the public  that there is an ethical and moral responsibility that that individual's noble commitment will translate into advancement of science if that study is buried in a pharmaceutical company then their commitment resolves in no ga for the public at all and it's just not an acceptable practice in your peepers example were those studies in phase one phase two some drugs were just continued and animal studies but many were in phase one many were in two few of them got to face three other toxicities that have been reported were extensive and bizarre tumors in various organ systems kidney failure you know a if you have any experiences like that please let this committee know we appreciate your willingness to come forward here still enough to employ them still but only because senator grassley prevented the retaliation from being completed that i was subject to after my senate finance testimony in two thousand and four and i must confess that i and extremely apprehensive that i will be the victim of retaliation for appearing here today  snow you stated in your testimony and this is your testimony if it wasn't clear to the f d a this was your testimony is correct and this is your personal belief based upon how many years in the f d a twenty three twenty three years you said in your testimony that the f d a doesn't believe it needs new regulatory authority to ensure drug safety why do you say that and what new regulatory authority or legal authority would you prescribe for you if you ok well if he has repeatedly said that it doesn't need new regulatory authority and in this in many other areas f d a really cannot be trusted during the hearings that were held by the i o m to investigate f d a and drug safety senior managers were asked by the i committee does the f d a need new resources more resources to do drug safety and categorically all the managers who present it said no we don't and the staff people complained to these managers after the meeting why are you guys lying to the i and what i was told was and what my colleagues were told was that the word come from higher up that they were to state in fact that no resources were needed now when it comes to labeling f d a has repeatedly also said we don't need new authority when all this was came out about f d a vioxx labeling delays and this f d a have the authority or or don't they f d a gave very invasive answers during the senate finance testimony and then subsequently where one official was quoted as saying no we don't have the authority the official f d a spokesperson came out and said we have the authority but we prefer to negotiate with companies what's really needed in my opinion is explicit authority the problem is going to be how does that authority get exercise we've heard in the last panel that you really have a management structure that is locked into use even the authority that it has giving it new authority will not mean that that authority gets used and this is i think has to do with it gets back to who's calling the shots pre approval making decision about whether drug comes on the market and post approval about what needs to happen safety wise you need to have those handled by different people and the regulatory authority needs to be separated out in the united kingdom which has i believe the world with probably would probably attest that they have a better pharmacovigilance system than we have in the united states they are the gold standard in their system the baton gets passed from the pre approval to the post approval the two sides talk to each other but they have separate authority and regulatory responsibility so that what happened with bias would happen with t tech let's say that i'm the f d a on the pre approval side and i want to approve cyanide well cyanide is a universal poison will kill everybody who takes it but i'm the f d a imo and a and i say i'm going to prove that drugs well right now cyanide would stay on the market because there's no authority if i want he doesn't want for the drug to be removed from the market you need to deal with that you see here's another thing that gets back to the culture is so many things this is like a carpet with so many different interwoven threads the people who go in the  house the focus on these clinical trials basically a handful of patients really we're talking a few thousand patients which really when you talk about a drug is going to used by millions of people it's a hand it's a handful think of it as an envelope and you got a little postage stamp up in the corner that's a postage stamp is the diversity of the types of patients that get studied in a clinical trial in terms of age gender you have underlying disease what medicines are you taking once a drug gets on the market in the real world that's the rest of the envelope and f d a doesn't pay any attention back if that's the world i live in that's the post marketing world you need to you need to you need to have people who know what they're doing and whose orientation is different i come from a public health background internal medicine and public health my orientation is towards treating the population treating the three hundred million people who are out there they're my patients and that population perspective can take an adverse reaction and put it into perspective and but that doesn't happen now sorry i went on some  your time in the f d a have you been on advisory panels i have presented to advisory committees but i'm not a member of any of the advisory panels have you in presenting to the advisory panels has your testimony been restricted or if you've been forbidden to make present taishan to advisory panels yes i had that experience with wrestling wrestling with and and with a diabetes drug from the same class of drugs actually as miracle it is our it was the original ok to adam and eve of all this class of drugs and it caused liver failure and profound lehi rate and i thought that the drug should come off the market there was critical data from clinical trials in which there were three different clinical trials they were small than each of the clinical trials a patient had died of acute liver failure and i wanted to present that in advisory committee meeting that was being held on that topic the company went ballistic when they learned that i was going to do this i was at the meeting and they went ballistic and they actually raised their voices at the office rector from o and d who was there who then subsequently after the meeting asked me not to present that and what i said to him was i said  have to present it if i don't present it's that scientific misconduct and it's a violation of my duty as a public health scientists i said if you don't want me to present and you tell me not to present and i won't present period but if i present i'm presenting this information well at the end they allowed me to present other people in drug safety i could give you apple after example i'll give you just a couple acetaminophen using tylenol the main ingredient tylenol liver failure came up earlier in the u k and other places and in the world they have done regulation of acetaminophen to reduce the possibility of unintentional or intentional overdose and liver failure from occurring when our people wanted to present that in advisory committee several years ago that was convened specifically to talk about this issue they were ordered not to talk about it before the committee the same thing happened with loach are next another drug that's happened with accutane i could go on and on but that is routine and it happens routinely and it's the office of new drugs telling the office surveillance and epidemiology that you can't talk about safety issues retaliation and filling in for the ranking member here i want you to understand that i want anybody at f d a to understand that this committee does not tolerate retaliation on witnesses who we asked to come before this committee or servants of the public who in some way are trying to make government better for the american people we don't want their supervisors those above them or anywhere else around them to retaliate we will not tolerate that and so we want you to have that assurance from this committee and this member that this is a bipartisan view that retaliation is not going to be tolerated i appreciate  opinion also oh yes definitely can you well dr ross is talking about key tech has some common features with the experiences that i bring and some that are more unique to the world that he lives on the pre approval side to deal with the actual clinical trials to give rise to the approval of the drug and there being irregularities there in addition to there being this post marketing safety issue where  people try to sweep it under the rug and it's on that post approval side that i have my most familiarity what i know on the pre approval side with clinical trials or fraudulent conducting of them or the way safety problems get dealt with is more by staff people who come and talk to me because i'm such an infamous individual when they run into difficulties in their workplace i've become sort of a central clearinghouse if you will for helping them navigate through it so the answer is yes ok i want to get back to the clearinghouse function just a moment but let me ask you about the post marketing aspect that before coming to congress i was a physician or still am a physician and i would periodically get communications from the a and it was for reporting for adverse drug events i can honestly tell you that i ever filled one out and sent it in but i would get them all the time and i would assume that they go somewhere within the structure of the f d a are those things in number well maybe not so large so that the forty individuals whose full time job it is to evaluate those case reports when they come in we call them spontaneous or voluntary case reports and sometimes referred to as med watch reports and they review those sort of a hands on review of all reports that are classified as serious and on labeled so things that if he doesn't know about and then there's a long list of i've lost count now of how many fifty or one hundred w professionals when they report actually end up telephoning the particular drug company if it's a name brand drug and that's how f d a ends up getting most of its reports through the company and then does f d a periodically disseminate that information to clinicians  think that the answer to that is probably not there's there's i think there are plans actually for them to do some kind of newsletter but i don't think that there is any formal mechanism in place up until this point well actually going on the f d a web site i found that in fact that's where communication does happen and it's been going on for some time i just never availed myself of the f d a website and and when it looked at it let's let's talk a little bit about your being a clearinghouse can you tell the committee what other key techs are out there what are what are some of the other red flags we should be watching for well i'll tell you a couple i would pay careful attention to and i psychotic medications effect profile the problem with these drugs they're enormously expensive the problem with these drugs are that we know that they're being used extensively off label in nursing homes to sedate elderly patients with dementia and other types of thought the sorters it's known that the drugs don't work in those settings and you say it's off label use we should do what they want but the fact is is that it almost it increases mortality perhaps by one hundred percent double doubles mortality so i did a back of the envelope calculation on this and you probably got fifteen thousand elderly people in nursing homes dying each year from the off label use of anti psychotic medications for an indication that  a knows the drug doesn't work this problem has been known for the f d a for years and years and years and let me just interrupt is that the f d a that you are that issue of the policing of the of medical practice no no no it's i believe that it's a public health issue and it's a public health issue because the companies are laughing all the way to the bank with every with every pill that gets dispensed in a nursing home the drug company is laughing all the way to the bank if f d a isn't there to step in where you know if there's in a group i'm not talking about this off label use in this off label use for this is off label use what we've got so many clinical trials to show you these drugs don't work that it's like it's no practice to be using it as well as that and that actually brings up another issue but you do you have another another one to put on our watch list well i think it's been in the newspapers in the new york times like cracks in diabetes die what is f d a been doing with this all these clinical trials that you know we only learn about in in the new york times of the weight gain zyprexa and the diabetes and diabetes is a life threatening disease don't kid yourself it's responsible for more lost years of life than than many many disorders and it's a it's a biggie and dr nissen could talk to you more about it it turns out the company knew for a long time apparently based on what i read a new york times that it was a big problem my question is if i know if they knew about it too and in talking to reviewers that f d a about if you use approach in dealing appears to dr graham both of these broad categories that have been mentioned which bill is going to do the better job of protecting the american public like it will be a structured missile that question first first of all i must tell you i don't think either of them go far enough and there are a lot of things that aren't in the bills and i tried to outline those in my reading my written testimony and i think we need to understand and be very clear about this that we should not renewed produce we should repeal producer producer is not the solution it's at least part of the problem we started down the wrong pathway when we said that there regulated industry was going to pay the f d a to regulate its itself and i think that ultimately given the amount of money that's involved we spend about two dollars per person in america for drug regulation that's the total expenditure in the federal budget is nine is a drop in the bucket it's nothing and yet we insist on industry paying that once you do that then they become the stakeholders for the f d a around the american people why not come up with the money find a way and fund the f d a independently without user fees well you'll see improvements and that may be something that we need to explore and produce it was done long before i got here but my understanding as a clinician at the time was if this was a way to get to open up the pipeline to try to get things through in a more timely fashion because as a practicing physician i used to review the f d a is kind of an obstruction to getting to getting new and timely treatments available to my patients so anything that would would move that process along more quickly if it could be done in a safe manner would be would be something that would would be beneficial but we don't need to do for to do that i mean i think what produce a dad was it's an arbitrary deadline that you have to buy a certain date make a decision and the problem the as is in conditions of uncertainty when you have an agency which at the top is basically going to lean towards approval what you end up doing is what happened with marilyn is our which was very nearly got a drug approved because it's producing date was coming up very shortly that would have been a catastrophe and i just don't think we and in fact we do and you know i think we need to move the f d a further away from the political arena and more into the public service arena and you know we've had some very disturbing events where you know  that you know political decision making was affecting what the f d a well aware of those and and i think we have to insulate the f d a from that kind of that kind of effect and i actually agree my time's expired but we always have to go to the senate conf confirmation process for our f d a commissioner amid a straight or is that something that's an anachronism we should no longer be doing now but i think we've got to find people that see their role as a public health official and not as a pet as a political official forgive me but if you go through the senate confirmation process it is in a hair politically you can't help but be political i've read you saw a rather impassioned senators there's a there's ninety nine other of those guys men and women over there on the other side of the capitol yeah i let me just say i think anyone can put a hold on the commissioner for any reason i understand but we can do that or we can have better leadership we need better release of the f d a it all comes from the top well and i agree but i wonder i mean just just me wondering if the process itself whereby that person has to go through senate confirmation rather than a scientific assessment leads us to the types of decisions that we've been seeing mr chairman you've been indulging value back an interesting idea  these individuals through the senate and i can't help but wonder if that doesn't harm the f d a to constantly have its head changed or or under the microscopic scrutiny of the senate but i'm not too sure the confirmation of commissioner results and what we're seeing in within the f d a we need strong leadership there's no doubt about it if we change every two years you won't have that leadership i would agree with that point but we see the same at los alamos with the changes fre change in leadership and we've gotten no no no improvement with multiple hearings on on that issue was well that's my second favorite subject and again i'm going to go solve global warming also you look at  that's not what you're talking about you're talking about the to do for the approval process and the way the fees are conducted creating conflicts of interest within the f d a drug approval process cracked absolutely correct and i just think it creates an inherent conflict them to do it is a mistake it was a predictable mistake it's had consequences i would claim they maintain their predictable consequences i'll give congress the benefit of doubt and say that there are unintended consequences but the consequences nonetheless know and in fact what i was just sitting up here thinking the reason we enacted to do this is so that we could get important drugs approved more quickly which is a good and a good goal but actually if you have problems later with those drugs then not only do you have a slower it ends up being slower because you have to go back and review them but you have a potential grave risk to human life michael it's even worse than that if you're on the pre approval side of the house your your your bonus your awards your promotions really have to do more with getting the n d s approved in anything else and you're basically in a factory and lots of it  reviewers medical officers talk about you're in an n d a factory new drug application factory and you've got to meet these timelines to get these things done ok i've got six months to review this application now some drugs that got approved three years ago has a safety problem and i have this other review that i got to do what were my priorities my priorities are here they're not on the safety issues but this is like the office and address is the same group that approved has to deal with the post marketing and they call the decision it's a back seat issue because it's not a priority right i understand is the idea of conditional approval and i actually think this could work you have a drug where you don't know enough about the drug but you think it may benefit patients maybe it's a cancer drug that looks like it's going to make a difference for people but you'd like to know more if you gave that drug a three year approval that would automatically expire at the end of a period of time unless sufficient studies were done and you outline what those are then you've got kind of a club over they had about a manufacturer one of the problems we have is that most of the post approval studies that are promised are never performed why are they never performed because once the drug is on the market the f d a rarely if ever you know puts the genie back in the bottle and i'm suggesting that you might want to consider the possibility of legislation allowing provisional approval that would expire and less certain information were brought to bear that could further describe the safety and fact they do that in europe as i understand there and there are countries that do that and so you know we don't have to to to turn the f d a over to the pharmaceutical industry for funding in order to get drugs more quickly approved we need better leadership we need people to understand when you should move quickly because something is a life saving drug and when it's an antibiotic used to treat trivial infections maybe you ought to slow down a little bit of good leadership can make these kinds of decisions if it's in place and dr craig yes well we just wanted to if i could follow along the way up innocent part of the problem with to do for is that we talk about i've heard multiple different members talk about bringing lifesaving drugs to the american people has it every drug was a breakthrough drug that was going to cure some cancer or something something else the truth is most of the drugs approved under paducah are not lifesaving drugs they're what are called me two drugs another drug to lower your blood pressure another drug to treat diabetes and other drugs to treat cholesterol so the innovation that you're looking for i guess what i'm saying is well what we did here for example with respect to antibiotics on the previous panel how there really has been some difficulty in getting the development of some of the well that's true and part of the problem is that the pharmaceutical industry is really risk averse because it's so expensive to develop to develop a drug right the most of the time they'll go after the sure thing which is and which is a need to maybe creating incentives for industry for example to use to invest in the higher risk of new drugs to treat new to treat diseases and new ways would be something to explore and make it more difficult to make raise the bar i understand and so what you're saying is give folks incentive to develop the drugs under stringent right through the guidelines and maybe conditional approval rather than rather than going down the other path of approving drugs that haven't been adequately tested or worse right and relating to paducah i think that it's basically a tax i know congress hates to hear the word tax but if the companies are passing take all the republicans left the companies are not the quite ok i guess your company companies pass that cost on to consumers if you were to charge a penny prescription a penny a prescription surcharge put it in the treasury and it's it's not like social security where can stress for what it's dedicated to safety you could have complete funding of the post marketing aspects of drug regulation with no attachment industries no ownership within just no control of industry over it because it's coming from the people now it's called a tax and that's a dangerous work but you've got to launder that money to go to cut the strings because right now it's a quid pro and and and one thing we have learned with this los alamos issue is that once you develop a culture i mean it was now almost the problem we have is they keep accidentally losing top top secret data and very last one we learned about because someone got searched for drugs in her home and lo she had this information at f d a i mean we have the same problem over and over again we feel like it's groundhog day up here because all of these key issues with senior level government officials we keep seeing these these pharmaceuticals that are really threatening lives over and over again and and and at los alamos pointed out we keep changing the leadership and still these problems keep happening same thing at the f d a and i guess i'm wondering we'll start with you dr nissen and then you dr graham what can we do aside from repealing  for to change that that culture at the senior levels of the f d a because i'm not convinced that it's just the the head of the f d a i think there's more of a culture throughout the agency well there's clearly a cultural problem and and you know i think that it goes far beyond going to fire gray and does go beyond the director but it does at the top and really if if we had really passionate leadership at the a that was strongly in favor of balancing safety and efficacy right rapidity of drug approval with protecting the public it would at least in part trickle down there are several cultural issues that i wished i understood completely but let me give you one of them there's the culture of secrecy that everything seems to happen in kind of a closed black box now why was i able to publish a manuscript about miracle it is our it's because they had an advisory panel meeting and because of a lawsuit a number of years ago the f d a was forced to put on the web the briefing materials that they gave to the panel members if a drug doesn't go before a panel you never get to see what actually happen you don't get to actually see that raw data and science can't work effectively when you have blinders on and so you can with legislation take the blinders off you can say that clinical studies belong in the public domain and then it's kind of doesn't matter because there's always somebody out there that will look at the data really reanalyzed it as i did for erik what is are and say wait a minute we've got a problem here so i think you can overcome some of that i wanted to say one more thing about this balance between the drug approval and drug safety and that's this if we knew we had a robust post marketing surveillance system that would pick up problems quickly then we could have wrapped more rapid drug approval this is an example where better safety monitoring actually speeds bringing new drugs to market because when i said an advisory panel now i have to be very cautious because i know that if i let the genie out of the bottle that the chances are if something bad happens it won't get seen for five years and then we've heard a lot of people but if we had a very i would say is that the comments of dr nissen is man are good but if you really want to change the outcome if you want vioxx not to happen again you want to see tech not to happen again you need to work on the structure you need to focus on how are decisions made the orientation in the pre approval people or towards getting the drugs out the door people in the post marketing who come from public health backgrounds population it's towards what's going on here is there a problem here is something we need to do to protect the public it's two different mindsets one is based on a population others focus on the small little studies the needs and and the the culture of those two organisations is remarkably different what happens now is the superior culture i don't need to fear is the dominant culture you know in the culture suppresses that post marketing safety culture and that's part of what we have but if you want to you want to solve the problem you separate the organizations in terms of authority how you do it maybe you meld kennedy n z together with dod grassley but you've got to separate out who's making decisions which part of the life cycle of the drug and what you'll see is this is going to be a feedback loop now because if we postmarking people had told key tech when we said it needed to be pulled or pulled vioxx when we said it needed to be pulled or pulled wrestling when we said it needed to be pulled the pre approval people now they're getting feedback oh we overlook something maybe if we make a mistake on this drug we're going to get embarrassed because those people are going to expose it right now there's no there are no internal controls there's no checks and balances thank you thank you very much thank the gentleman mr bush carol in point of personal privilege absolutely i have that said duty to notify you and the other members of the committee in our audience that moments ago we were notified that our friend and colleague who served on this committee since one nine hundred ninety five dr turning or what has passed away at his home in athens georgia our prayers are certainly with his wife gloria and his family and friends he able e and forcefully represented people in georgia in his district and mr chairman if we could have a moment's silence in honor and memory of our friend questions because i know charlie would want us to pursue this issue especially with his passion for health care and improving the lives of americans so dr dr graham let me  start with you in discussing you take your testimony states that the f d a scientists were threatened intimidated suppressed transferred and ultimately compelled to leave the agency who are that the f d a scientists that you're referring to you've heard them you've heard them speak in i'm sure they have colleagues i know that there is at least one other reviewer who was involved in the key tech review who was afraid of retaliation and who actually no is no longer with that particular group  transfer to another group to get out of that hellhole but in any event that's who we're talking about and you know i was asking dr ross or others about whether or not this is agency wide or is it sort of isolated a couple of places this type of person this hyper practice happens i can tell you now for post marketing the drugs been approved you know gets on the market now a safety issue comes up i can tell you and i could assemble a list later of the multiple examples where we impose marketing bring a safety issue to the new drugs people and they do nothing or worse i'll give you just one example because this is my introduction to d a and what the reality of what it is to have the people who approve the drugs decide what happens to them and how long ago that was and this is i came to the agency in nineteen eighty seven so this would have been eighty eight eighty nine ok things have only gotten worse since then but listen to this vallium is there's oil leak and it doesn't if it causes the veins to get in flame so this is an improvement for patient comfort soon after approval we got twenty three reports of patients who died of respiratory arrest they stopped breathing during their routine medical procedure we brought these twenty three case reports to the office of new drugs to the division director in the office director that office director is still there is no higher up in there in cedar and his name is already been mentioned once today at this meeting  very high up and and and they threw out all twenty three cases saying nothing here two examples are particularly they stuck in my mind these years one of them was a sixty three year old woman with breast cancer who they said she's got pressed cancer for you know she's gotta die sometime the other was did they actually say yes they actually said that the other was a ninety one or ninety two year old some guy in his ninety's ok he's ninety one years old he's got it i saw time and so he picked that very moment to stop breathing fine we go back to our offices this may water we going to do two years or so later some academics do some pharmaco kinetic experiments where they determine hundred eighty seven so right but that you see we're talking how we're talking culture attitude right happens when you're oh indeed you're the people who approved the drug and you're the lord and master and you control everything that happens afterwards now the thing in the modern day it's gotten even worse because what happens is is that all of our supervisors for example in my office most of them come from the office of new drugs we don't have any promotion from within into the upper ranges of drug safety it comes from a car i come from across now so are you are you saying by that that they sort of protect their old turf that is some of them do they're not our office directors very good he sees public health and that's really wonderful the problem is is that not everybody who's come over over the years going to have a lot of people coming from a windy over to iowa city they don't have that public health background they're used to looking at the clinical trials and saying is the p value less than point zero five and if it is it's truth and if it's not we're going to forget about it and that's not the way population medicine is and that's not the way post marketing is supposed to be done now the problem is i just have to get the full sound byte in physicians bury their mistakes one of the time the f d a buries its mistakes in unmarked mass graves and what i've just described this dynamic of who is responsible for decision making previous post marketing that is the crux of that issue do you think that these are the sort of internal structural cultural problems of the f d a do they saying pay attention to getting this drugs out the door and get them out fast and safety is an afterthought pre approval what happens now pre approval is in i mean it's dr golf and he said fifty percent of seizures resources are spent in safety i'd like to see a real accounting of that because the medical offices i've talked to say the safety review is the last thing that gets done and they don't spend nearly as much time on it and that's we're just talking pre approval i'm most concerned about the post approval as i said before  and it's helpful did you perform a failure mode analysis in the ok so i did but f d a has not and and this is this is one of the critical issues you know when an airliner goes down the national transportation safety board out there you know it's a switch colored the vioxx up as an example and say or is what we're recommending would actually have dealt with these problems so explain to me how a failure mode analysis works what is it what well it's used in engineering mostly in systems analysis where you you have boxes on a process chart or something like that you can kind of see if this breaks down what happens if this breaks down the failure mode that i did was sort of looking at what is the evidence we had on the drug and so what did you find on what i found the clinical trials were done showed a tendency an increase in cardiovascular events but it didn't reach the to stickle significance c f and the this is this is this is one of the problems at f d a for safety it assumes the drug doesn't work and then a company has to do a study and show statistically that it does work in order for it to get approval for safety f d a assumes before gets on the market that the drug is safe and now it's up to the company to prove that it's not well the company in their right mind is going to do that and the standard that f d a and places on safety is is unreasonably high so with the vioxx for example there's ample evidence the medical officer says it right there cardiovascular events are increased but i don't have complete certainty in quote in other words the p value wasn't less than point zero five so that was this in my analogy in the senate finance this is the knowledge i was trying to make about i have ninety bullets in one hundred bullets chamber and the guns not loaded well it's loaded it's just not loaded enough for you to to agree it's loaded and so that's on the pre approval on the post approval side having the suspicion that the marker information would occur in april of two thousand t a had the results of the vigor trial which was with a study that was started before the drug got approved finished after the drug got approved a large randomized clinical trial and it showed that firefox increased the risk of heart attack by a factor of five ok i five hundred percent increase as a postmark as a as a population medicine person what f d a should have done as soon as it had those results was yanked the high dose of vioxx there was no earthly reason for why this was high dose study earthly reason for the high dose a high dose was approved for the short term treatment of acute pain well you know four million women a year give childbirth and have acute pain and there are a lot of other safe pain relievers for short term use don't increase your risk of  did the benefit risk analysis f d a has never done a benefit risk analysis and entire history i've done several anytime i've done it i have been reprimanded for doing so in any event the public health perspective would have been pulled a high dose now this thing called dose response maybe the logo's does it as well we see in the clinical trials it is lower doses twelve and a half milligrams increase the risk but it wasn't statistically significant you would've been faced with a dilemma there do i pull that those or do i say to the company go out and do a really big study really to answer the question on the low dose and maybe we could debate what happens hindsight shows that the low dose did it as well and and so but you see this is a difference of who's who's calling the shots pre approval in post approval and that's that's the core issue the reviewers at the level the reviewer who said we don't have complete certainty i know her we're friends she's a very good reviewer the reviewers of the theatre very good but the rules they operate under they're training to think this way so basically in the pre approval world the trained to say if the p value is less than point zero five i can ignore it if i if i could jump in a second not only did they not do that but they let the company go ahead and put on television ads with skaters skating around you know being free and so so what we what we saw here is here was a time by two thousand by the time of the victory i knew there was a problem and it was clear i mean it was clear in the manuscript that was published it was clear and the f study report it was clear to us in february two thousand and one at the f d a panel and yet they allowed the company to continue to show us people skating as young woman skating around rain without already having yeah you know i didn't was going to mention her name because i'm sure she was well remunerated for time but the point is that that drove you know millions of people to use the drug now a prudent agency would have said ok maybe we can just agree about about the data but at the very least we ought to pull back here until we really learn more we certainly ought not let the company go we had and promote this in this extravagant way and the drug was promoted heavily in just point out something here kennedy enzi as i understand it would possibly have resulted in it was like almost a two year delay in f d a getting a label changed on kennedy and he would probably shorten that would deal with that you see that that's not the problem the problem was this drug should have been there in the first place to hide oh should have been gone immediately in the low dose been to the fire prove that it's not dangerous and kind of the n c c this is the mindset so just to give you insight into the way these things work i just have to probe one other issue that's somewhat related but we had a hearing on this issue as well and that is supplements dietary supplements we had a panel witnesses on a federal who i think the common denominator i don't think i'll get in trouble for saying this is they had some sort of conviction for fraud and maybe a high school education in the recipe was written on the back of an envelope and people are this stuff out there being marketed and people are dying from that what do many council farmers are way off our topic there's nothing you go for and in my in my written testimony i actually speak to this and i'm going to tell you that if we don't do anything there will be a major catastrophe involving the dietary supplement industry what we're doing is absolutely insane i could go out in my backyard and i could cut up grass clippings and put in a capsule and put it in a bottle and say promotes heart health and i could sell at the local pharmacy for three hundred dollars a bottle and people do is to do that very thing i recently saw a patient there's a drug we use called niacin niacin is a drug that's used to raise h d l the good cholesterol and it's an effective drug although it has a problem which is it causes a lot of continuous flushing people flush very badly when they get when they get when they take the drug and so health food stores i'm regulated by the f d a have begun selling something called no flush failure need a heart transplant and died while waiting for a transplant now anybody who tries to tell you that dietary supplements are harmless is out of their everloving mind taking gar leak rather cholesterol real cholesterol lowering medication is harmful and the greatest setback to drug safety in the last hundred years was a hat rehab richardson act which took away the f d a as authority to regulate he would provide a list to us of a couple drugs that he thought are approved in the marketplace we should take a closer look at or someone should take a closer look at for safety if you have any so use suggestions or like to provide a list of committee would be receptive to receiving the i will certainly think about that and i will inform you about some thoughts i have about that but i do think there are real issues in currently marketed drugs i don't think we've seen the end of the kind of drug safety revelations that have occurred something that's come up recently if you watch the news you know that that yesterday and then on journal of medicine there were five manuscripts about the drug dealing stance which is a very hot controversy right now about whether they are in fact are are are as safe and effective for the indication which they were developed you are going to hear a lot more about that in the next couple of years that we haven't talked at all about the device side and one of the things that's not in z kennedy that really is missing and i hope on the house side something can be done about is the device world we've had problems with the febrile eight years that failed we've had a law a lot of safety issues on devices heart valves and you know stance are a great example and so if you want to look at safety it's not just pharmaceuticals it's also devices and if anything the regulatory environment on the device side is more like the wild west than it is on the drug side it's actually if anything worse well it sounds like it's a great topic for this committee as we often say we deal with crime drugs and sex all times in this subcommittee and i'm sure we will in the future as i said this is the first of many hearings will be having on drug safety and the three panels the excellent panels we had today have suggested other areas that we will explore over the course of this congress but that concludes our questioning i want to thank all our members that our panel members i thank all the members for coming down a little bit of bookkeeping or housekeeping i should say these documents filed in the white pamphlet without objection will be for the record will be submitted for the record and if the members have additional questions for the record to be answered by our relevant witness this will give you ten days to submit them to the committee clerk within the next ten days please do so in electronic form that will conclude this hearing thank you again for over a witness this thank you for everyone for being here today