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Remarks by Tony Coelho Past National Board Chair, Epilepsy Foundation

FDA ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE AND CLINICAL PHARMACOLOGY
regarding the
Proposed Bioequivalence Method for Oral Vancomycin Capsules
July 21, 2009

Good Afternoon.  I am Tony Coelho, Past Chair of the Board of the Epilepsy Foundation and former Member of Congress.  I am here today not because I want to say anything about vancomycin but because it gives me an opportunity to speak about bioequivalence issues regarding a different class of drug products—anti-epileptic medications. The Epilepsy Foundation has had longstanding concerns about FDA’s bioequivalence standards for anti-epileptic drugs. In particular, there are numerous reports of breakthrough seizures and other side effects following switches among different manufacturers’ versions of the same therapeutic agent—irrespective of whether the switching takes place among generic or brand products. As I will describe below, I recently had my own problem with switching among supposedly bioequivalent anti-epileptic drugs, so I come to you today both on behalf of the Epilepsy Foundation and as a consumer of anti-epileptic drugs.

Unfortunately, the Epilepsy Foundation has not had an opportunity to have our concerns reviewed and discussed by an advisory committee as you are doing here today for vancomycin, despite repeated requests from the Foundation and experts in epilepsy that such a review take place. I therefore want to formally register our request that anti-epileptic drugs be afforded the same type of focused and public analysis taking place today for vancomycin.

Antiepileptic drugs successfully prevent seizures in the majority of people who take them regularly and as prescribed. It has been estimated that between fifty to sixty percent of all patients with epilepsy will gain complete control of their seizures over time.  Let me just stress, that for people with epilepsy who are fortunate to have their epilepsy controlled by medication, this freedom is critical to every aspect of their daily lives.  

Control of seizures can mean a return to flexibility and control over one’s life that can be dramatically undermined upon diagnosis of epilepsy.  Up until the time I was a teenager, life was pretty good to me. I was a happy kid living and working on the family farm.  Everything changed suddenly when the pickup truck I was in flipped and overturned in an irrigation ditch.  I got a nasty crack on the head and for a couple of days had a terrible headache. It went away by itself and I felt fine, none the worse for the accident.  I was in the barn milking cows when I had my first convulsion.  It took years for my epilepsy to be accurately diagnosed, but that is another story. Like most of us, I had no idea as a youngster of what the future held in store. Being elected to Congress never entered my mind.Up until the time of my accident I had no indication that my life would be anything but completely normal and that I would fulfill my ambition to go to law school and become a trial lawyer.  When the “spells”  continued, my parents sent me to witch doctors. As sons and daughters of deeply religious Portuguese immigrants, they had been taught to seek supernatural explanations for things that couldn’t otherwise be explained. Or, as I later learned, that they couldn’t accept.  After finishing high school, I entered Loyola University in Los Angeles as an undergraduate, where I got good grades and was elected president of the student body.  In my senior year, I decided I had a calling to be a priest and upon graduation I applied for admission to a Jesuit seminary. I didn’t know then that the cross I was destined to carry would be the stigma of disability, not the crucifix of a priest.  The Jesuits were overjoyed to accept me.  I was just what they were looking for: a young man with leadership qualities and a deep commitment to serve God.

It was during a routine physical examination in preparation for the seminary, six years after the accident, that I learned I had epilepsy.  I almost jumped for joy when the doctor told me. Like many people with unexplained physical or mental problems, I experienced an exhilarating sense of freedom and relief after a firm medical diagnosis was finally made.  Uncertainty is the worst part.  Knowing something is wrong, but not knowing what, is like being sentenced to life imprisonment, without knowing what you did to deserve punishment. Once it was understood that the convulsions were related to my brain injury and could be treated with proper medication, I thought everything would return to normal. 

My elation was short-lived. I soon discovered that my epilepsy was an insurmountable obstacle to ordination and would prevent me from driving and would make it difficult to become employed. I turned to drinking and became suicidal. Fortunately, I began to regain my footing after Bob Hope took me under his wing and encouraged me to find a different ministry in life. Although I could not be a priest, I could minister through politics.

Like others who have faced adversity, the stigma and discrimination I faced opened up new opportunities and meaning in life. What I first thought to be a curse later taught me to confront deeper meanings of life in ways that might never have been possible, to discover who I really am, and to know what I stand for. Epilepsy shaped me, strengthened me and gave me a strong sense of identity and, indeed, dignity. Epilepsy gave me direction. Above all, it gave me a mission in life. Following Bob Hope’s encouragement, I worked for a Member of Congress, worked my way up through the office, and then, won my very first election to the U.S. House of Representatives in 1978 when I ran for my former boss’s open seat. I had the distinct honor of serving as Chairman of the Democratic Congressional Campaign Committee from 1981 to 1986, and then as the first-ever elected Majority Whip from 1987 to 1989. While in the Congress, I was proud to author the Americans with Disabilities Act.

I tell you this background to illustrate the breadth of experience with epilepsy. It can be a completely debilitating condition, as witnessed by my journey toward suicide. However, anti-epileptic medications, along with lifestyle management, can enable people like me to manage epilepsy successfully without interrupting one’s personal and professional life. I could not have served in Congress the way I did without effective medication and lifestyle management. However, precisely because medication plays such a critical role for people with epilepsy, problems with a medication regimen caused by a change in drug product can completely undermine one’s post-diagnosis stability.

Concern about switching has been a longstanding concern for the Epilepsy Foundation. Regrettably, I know how importance this issue is because I recently had nightmarish switching experience of my own.

This past May, my pharmacy automatically switched me from the brand drug Topamax to a generic version of topiramate, without me taking note of the switch. I continued to take my medication as usual and did not notice any major difference for about the first week, though I now recall feeling a little slower and somewhat detached. After the first week, my condition worsened markedly. I began feeling lethargic to the point of being incapable of engaging in normal daily activities and withdrawing from all social interactions. I soon developed what a level of depression I had not had for decades since I was suicidal in 1964.

I searched desperately to try to figure out what might be causing such a severe and abrupt depressive episode. It finally dawned on me that I had been switched to a generic drug, and I wondered whether that could have made an impact. I stopped taking generic topiramate on my own and, within less than two days, I began to feel more like myself—more alert and more energetic. After just one more day, I felt completely normal. I subsequently called my doctor. Although he said he could not know for sure, he confirmed that it was possible that depression is sometimes a side effect of this medication, and might have been  triggered by the switch.  Since I had been doing well – no depression or other side effects while on the innovator product – he wrote me a new prescription for the brand-name medication.

I understand that pharmacies are authorized to make automatic substitutions with drugs that FDA says are therapeutically equivalent. But I’m nonetheless furious with the pharmacy for making the switch without checking with me or my doctor! And I am profoundly concerned that FDA has not considered seriously enough the cries for help and attention to this matter from other people like me who epilepsy and from organizations advocating on behalf of people with epilepsy.

Indeed, my experience is not an isolated anecdote.

The Epilepsy Foundation announced a new report of survey data obtained from more than 1000 consumers who report an increased risk of seizures and side effects when they have switched from one manufacturer’s formulation of an antiepileptic drug (AED) to another. Based on evidence in the clinical literature as well as reports from physicians and patients, the Epilepsy Foundation has developed serious concerns about policies that permit or require AED substitutions without the consent of the doctor and patient. In fact, the results of the Epilepsy Foundation’s recent survey, ‘In Their Own Words: Epilepsy Patients’ Experiences Changing the Formulation of the Drugs They Use to Prevent Seizures,’ demonstrate that for some patients with epilepsy, AED substitutions have been neither effective nor safe.

While most patients can safely switch their medications among different formulations of the same antiepileptic medication, the Epilepsy Foundation recommends that consent must be obtained from the individual with epilepsy and their physician before any such substitutions are made – to avoid potentially life-threatening seizures. Too many people have been harmed; some have even died as a result of an unsupervised switch.  

I want to emphasize that this is not a brand versus generic issue. It is, rather, a switching issue. The switch can be between different manufacturers’ versions of the same generic drug, from a generic to the brand-name drug, or from the brand-name drug to a generic. It can also be caused by a switch from one manufacturer’s formulation of its antiepileptic drug to a new formulation of the same drug. The Foundation’s just-released survey tells the stories that too many individuals have experienced, and supports other newly published studies documenting that switching can cause breakthrough seizures and severe, unexpected side effects.  In addition, the scientific literature now contains:

  • clinical confirmation that switching between “equivalent formulations of the same anti-epileptic drug, whose differing effects in the body are not considered "significant" by the FDA, caused serious adverse consequences in patients
  • case studies affirmatively establishing that switching between “equivalent” AEDs can lead to breakthrough seizures
  • statistical analysis showing that persons with epilepsy who recently switched between “equivalent” AEDs sought more in-patient and emergency care than those who did not,
  • case studies documenting that epilepsy patients on the brand name and generic versions of “equivalent” AED medications had different levels of therapeutic medication in their blood, and
  • population data revealing that epilepsy patients have “switch[ed] back” to brand-name medication at significantly higher rates than patients who have switched to generic drugs to treat other long-term conditions.

Two distinguishing features of epilepsy further suggest that AED-switching should be approached with special caution.  First, seizure control can be an all-or-nothing proposition. Slight changes in the amount of medication received by a person with epilepsy can mean the difference between a fully controlled condition and breakthrough seizures.  Critically, the patient with epilepsy exists in either of only two states: the patient is either seizure-free, or is not.  In some patients, there may be correspondingly little room for error when changing the patient’s dosage or prescription.
           
Second, the consequences of a breakdown in a well-functioning seizure-control regimen can be catastrophic.  The consequences of a breakthrough seizure can be extreme: seizures increase the likelihood of serious bodily injury and death, and, even when no physical injury occurs, seizures often result in significant social, legal and developmental consequences, including loss of the patient’s driver’s license, loss of employment, and loss of self-esteem.

The Foundation believes that short-sighted cost considerations should never be allowed to trump efficacy or take precedence over patient welfare.  Indeed, if a patient is switched off of a well-functioning drug to avoid costs, the direct economic consequences borne by society if the cheaper drug fails—whether incurred in the form of increased ambulance rides and emergency-room admissions, greater numbers of in-patient doctor visits, or lost worker-productivity—will quickly eliminate any short-term savings occasioned by the switch. Meanwhile, the concurrent human costs borne by patients and their families can be immeasurable. 

I wish I could tell you precisely why switching poses such significant problems for some people, or describe to you precisely what, if anything, should be done to the basic bioequivalence standard used for approving various formulations of anti-epileptic drug products. What I can tell you is that there is a substantial and real concern that can no longer offered to be dismissed by FDA as mere anecdotal evidence, which has been the typical response we get. We therefore urge FDA to research the impact of variations in switching between anti-epileptic drugs to determine if bioequivalence standards should be changed, guidance is needed, and/or if patient safety warnings are necessary. And we urge FDA to bring the results of its inquiry before an advisory committee such as the one gathered here today so that FDA can fulfill its mission of protection our nation’s public health.

I want to call the agency’s attention to the numerous studies that have been put forward for the FDA’s consideration regarding patient problems when switching anti-epileptic drugs.  All of these have been dismissed by the FDA.  We are concerned that the FDA is dismissing as frivolous the chronic consumer and physicians’ anecdotal reports and complaints of problems with switching.  The consumer is requested to “show us the data”, when all the individual can do is report the experience they have had and ask for an investigation.  The consumer is told that they have to prevent blood level documentation of a problem; the fact that they had a seizure following a switch, when previously seizure free, we are told is an artifact of epilepsy not the treatment. We are told to file Medwatch reports with all details.  However, FDA representatives have also told us that they ignore Medwatch reports on this topic because the spike in complaints that occurs when generic versions of an innovator product come to market is a result  of consumer misinformation and misunderstanding.  We have been told that the reason for increased complaints following a switch is because the Epilepsy Foundation drums up the public.  We are told that big pharma is responsible for the increase in complaints. This is all a problem.  It is not just insulting to consumers and to people with epilepsy, it violates the FDA’s responsibility to ensure safety and efficacy of all medications, knowing how they are used and prescribed today.  If the agency is not monitoring the consumer and physician complaints to find out why there are increases in complaints following a switch to generic version, or why these complaints taper off over time; if it is forcing consumers to provide the documentation of the problem; if it claims it has no money to address the problem, it is basically making consumers responsible for the safety and efficacy of their medications rather than itself taking on its role.

The FDA recently released a “Facts and Myths about Generic Drugs” web statement, which includes its opinions about epilepsy medication switching complaints.  The FDA unfortunately demonstrates that it does not have medically current understanding of epilepsy.  For example, it inaccurately claims that “Many people who are on a seizure medications will re-experience a seizure despite continued treatment on a single drug. The likelihood of re-experiencing a seizure, despite staying with the same drug product, goes up with time.”  In fact, long established medical knowledge of the epilepsies and its treatment is that the longer a person with epilepsy remains seizure free on whatever drug product has controlled their seizures, the less likely that person is to experience a seizure in the future.  See:  Epilepsy Frequency, Causes and Consequences, Hauser, W. Allen M.D. and Hesdorffer, Dale C. M.P.H., (1990) and Epilepsy A Comprehensive Textbook, Volume One, Engel, Jerome Jr. and Pedley, Timothy A. (1998).  Indeed, all public policy decisions involving epilepsy and the risk of future seizures rely upon and confirm the common public understanding that once seizures are controlled, most people with epilepsy will remain seizure free absent changes in medications or other external factors.  Every state in the country licenses people with epilepsy to drive based upon this understanding.

It is also extremely disconcerting that the FDA includes a citation as support for its bizarre medical assertion above a study that does not support the claim and is not even relevant to the statement on remission of seizures. See Brodie et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology. 2007;68(6):402-8. 

In this FDA statement that presents the problems with generics and switching as a myth, the FDA actually acknowledges that there is a valid concern, when it states that some subset of people “may experience an undesired effect when switching from brand name drug to a generic formulation or from one generic drug to another generic drug.” However, the FDA says that it neither has the money nor the responsibility to study this problem.  This is the first time the FDA has publicly admitted there may be a problem.   The agency also claims it has requested that the generic industry investigate these issues.  Over the many years that we have been bringing this concern to the agency attention, the Epilepsy Foundation has never received information from the FDA confirming this claim.  Neither have we received reassurances from the FDA that they are investigating these reports as they claim in this recent statement, nor that the agency is concerned about its regulatory authority to take action in this area.  Quite the contrary, the FDA has made clear to the Foundation that is not investigating this problem, and has no intention to issue public or professional recommendations regarding these problems, until we produce data they respect to support our concerns.

I do not believe it is my individual responsibility or the Epilepsy Foundation’s duty to produce data and studies on problems with prescription drug approvals or consumer safety warnings.  However, the Foundation has gone above and beyond to not only bring this material to the agency, but to ask for the FDA to take a leadership role in examining this problem.  We believe that this problem has risen to the level that the FDA must consider undertaking research, guidance and patient communications regarding anti-epileptic drugs, switching of AEDs, and determining how or if the small therapeutic differences in bioequivalence or the variations in inactive ingredients in AEDs might be significant enough to warrant close monitoring or warnings. 

STUDIES ON THE ISSUE