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Regulating in an Era of Increasingly Sophisticated Medicines – Striking the Balance Between Patient Benefits and Risks -- An Address by Dr. Margaret Hamburg to the National Rx Drug Abuse Summit

Remarks by Dr. Margaret A. Hamburg
Commissioner of Food and Drugs
2014 Rx Prescription Drug Abuse Summit
Atlanta, Georgia
April 22, 2014

Thank you so much Melissa (Fitzgerald) for that kind introduction and let me echo the words of thanks to Operation Unite and to all of you for participating in this important summit. And I also want to applaud Chairman Rogers for having the foresight some 11 years ago to found Operation Unite, which works to rid prescription drug abuse in Southern and Eastern Kentucky. The Congressman’s vision that a comprehensive strategy is needed to address the problem of prescription drug abuse, and that no one approach and no one group can do it alone, is certainly something that FDA agrees with and is committed to. 

His vision is reflected in the many remarkable people, programs and contributions that comprise the work of Operation Unite, and of course in this three-day summit which will share ideas and strategies for reversing the opioid scourge.

A year ago when we met in Orlando, much was said about how prescription drug abuse was, without a doubt, a public health crisis. I vividly recall meeting with Congressman Rogers to hear the powerful stories of the three high school students from his district that he just mentioned, who had lost family members to prescription drug abuse but they were now taking action to prevent this tragedy from happening to others.  And I'm so delightd to hear that they're also going on to build what will be successful, promising careers. But unfortunately, their poignant stories are not unique and they must serve as a call to action for us all.

Over the last year, there have been substantial efforts to confront the opioid abuse tragedy on many fronts, including much hard work at the FDA.

Yet, sadly, the need for even greater urgency and attention to this opioid issue is unrelenting. Few of us are untouched by this issue – it has affected our communities, our schools, our friends, our families, and our children.

Your stories and your voices – whether you are a patient, a family member, a first responder, a doctor, a caregiver, or someone else involved in addressing this crisis -- have helped to focus attention on this critical public health problem and its profound impacts.  It's also pointed the way to important solutions.

Let me say, in no uncertain terms, that the prevention of prescription opioid abuse is of the highest priorities for us at the FDA. Our mission as an organization is to protect and promote the health of the public.

Stemming the rise in opioid misuse, abuse, addiction and overdose is a huge challenge, but one that we are deeply committed to confronting along with our federal partners and so many other partners and stakeholders, and many of you are here in this room.

But we also must meet the very real medical needs of the estimated 100 million Americans living with chronic pain or coping with pain at the end of life, which is also a major public health problem in this country.

Debilitating pain affects more people than heart disease, cancer, and diabetes combined, according to an Institute of Medicine study. And it contributes to significant social and economic costs each year.

We have heard from many people who must cope with pain on a daily basis and are fully aware of their pressing need for a variety of therapies to have any hope for a quality life.

These are two complex and very important problems. And unfortunately, there are no simple solutions. Actions to advance one should not have to impede the other, and we must continue to balance our efforts and apply sound science as we move forward to achieve this balance.

And we must address these tough drug issues under our mandated framework. As regulators, we apply the best available data and science to make our decisions. In the end, what we decide can be controversial, but it is never made lightly, knowing that it could impact the lives of millions of Americans.

To explain this a bit further, I want to discuss the roles and responsibilities of the FDA. Our statutory role is to review the scientific data to assess questions of safety, efficacy and the balance of risks and benefits for patients. As part of that evaluation we must examine which patients a given product should be used for, how it should be used, and if there should be restrictions on how the drug should be marketed to assure appropriate use.

Correspondingly, we seek to assure that accurate drug prescribing information is provided and that there is the right level of monitoring for the safety and quality of drugs throughout their lifecycle, including, importantly, after their approval.

We will approve a new drug after reviewing the scientific evidence collected on the product’s safety and efficacy for a specific patient population that, in the case of opioids, would be a certain group of patients with pain.

We need to be able to conclude that the benefits of the drug outweigh the known risks of that drug. And part of that benefit-risk analysis does include consideration of information related to addiction potential and to the potential for abuse of the drug.

Drugs like opioids, which carry the risk of addiction and can be abused, have additional controls over their use, guided by the Controlled Substances Act, to protect against misuse, abuse, and diversion. 

One important tool we employ to improve how drugs are used is the information that's provided in the product’s labeling, what many call the package insert. FDA has made many changes to drug labels in an effort to improve their safe use. 

As I think many of you may know, we’ve recently added the requirement that the manufacturers of long-acting and extended-release opioids such as Opana and OxyContin, include strong new warnings about the risks of addiction, abuse, overdose and death in their labeling to alert both prescribers and patients. 

Today this labeling contains some of the most restrictive language that can be found in a drug label, including a Boxed Warning.

Labeling is also used to help prescribers identify who could benefit from the drug. In the case of opioids, we recently revised the labeling of extended-release, long-acting opioids to better inform decisions about whether or not a doctor should use them, specifying that they are indicated only for the management of pain severe enough to require daily, around-the clock long-term opioid treatment and for which alternative treatments are inadequate. 

It makes clear that these drugs should be reserved for those patients who find that non-opioid analgesics are ineffective, not tolerated, or would otherwise be inadequate to provide sufficient pain management.

This represents a significant step forward in helping providers decide whether an opioid is the best choice for their patient.

Broader prescriber and patient education is another essential tool for encouraging the safe use of powerful drugs like opioids. And you've already heard the other speakers before me underscore this important point. Beginning in March of last year we required manufacturers of this class of drugs to offer educational training to prescribers covering appropriate patient selection, prescribing, and monitoring, and include an updated Medication Guide for patients to receive with each prescription filled.

Again, we did this both to protect the public health and improve care for patients in need.

Indeed, we continue to support the notion of mandatory training as a requirement for obtaining a DEA license to prescribe this class of drugs to ensure an even more comprehensive and sustained approach.

Finally, once a medication is in the marketplace, FDA, the manufacturer, and health care professionals must monitor the product for safety concerns.

We can require post-market studies to better assess particular safety issues in actual use, as we are now doing for the Extended Release/Long Acting (ER/LA) opioids. In fact, we just announced a public meeting to obtain stakeholder input on the design and conduct of the post-marketing requirements for the class-wide ER/LA opioid analgesics. Such post-market studies will enable further assessment of the known serious risks of misuse, abuse, increased sensitivity to pain (or hyperalgesia), addiction, overdose, and death from these products and also patterns of drug abuse.

And this information will help us to continually weigh the benefits and the risks of these powerful medications . . . . and to take action as needed.

And so, working within the limits of our laws and regulations, we use our authorities to target key drivers of the problem at critical points along the lifecycle of an opioid product. 

I know that many of you here today are confused and disappointed about our decision to approve Zohydro Extended Release. And I want to address that, because it illustrates the tough decisions we often face.

Zohydro, which contains only hydrocodone, is in the same class of Extended Release and Long Acting opioids as OxyContin and Opana Extended Release -- sharing similar risks of abuse with others in its class.  It therefore has the same strict labeling and requirements for post market studies, training programs for prescribers, and a Medication Guide for patients.

In fact, Zohydro was the first extended release/long-acting opioid to include the new safety labeling changes now required for all of these products.

We expect these changes will help providers make more informed decisions about which patients should receive Zohydro and other Extended Release/Long Acting opioids.
And I want to correct some misinformation circulating about Zohydro’s safety and potency, but first let me outline the important reasons for why we approved it.

First, we believed that patients would benefit from a new and effective option to manage pain that is severe enough to require daily, around-the clock opioid treatment and for which alternative treatments are inadequate. This debilitating pain often prevents patients from living normal lives.

These patients need treatment options because each patient responds differently to a drug, and over time the drug can lose its effectiveness for a particular patient or the patient may no longer tolerate it.

Moreover, Zohydro offers an important safety benefit when compared to existing hydrocodone products: it is not associated with the very real risks of liver toxicity associated with the combination hydrocodone products such as Vicodin that include acetaminophen.

Some have said that Zohydro should not be marketed without an abuse-deterrent formulation. Frankly, that position puts too much faith in the current state of technology.  I wish we were there but we are not.  It remains a hope more than a reality. But there is promise, and Dr. Collins so eloquently outlined some of the new science and technology being brought to bear to improve the options for real abuse deterrent technology. And FDA places a high priority on abuse-deterrent technology. We strongly encourage the research community and companies to continue efforts to develop meaningful approaches. However, the science of abuse-deterrence is still in its infancy and has yet to be fully tested and proven in actual market or use conditions.  There are even limits to the abuse-deterrence of OxyContin, the only opioid with a claim on its label that the drug has abuse-deterrent properties.

People intent on abusing opioids will still be able to circumvent the abuse-deterrent features currently available. And importantly, abuse-deterrent formulations do not prevent someone from taking more pills orally -- which is the most common form of opioid analgesic abuse.

Much of the public debate about Zohydro has focused on its potency -- even though the top dose of Zohydro is in fact considerably less potent than the top doses of other extended-release opioids like OxyContin and extended-release morphine.

And while Zohydro does contain more hydrocodone per pill than products like Vicodin, this is not unique to it. In fact, all extended-release opioids contain more active ingredient per pill than their immediate-release counterparts. And with the exception of OxyContin, none of them have been shown to have abuse-deterrent properties.

Equally significant, the introduction of Zohydro is not likely to have a significant effect on the overall prescribing of opioid analgesics. Rather than increase the number of patients treated with opioids, it will generally be used as an alternative treatment by those who are already prescribed an opioid. Zohydro is a powerful drug that must be managed with caution and concern. But I worry that confusion about Zohydro’s potency and its potential impact on the growing opioid problem has caused diversion of attention from comprehensive policy solutions to a focus instead on a single drug. But certainly we do understand why these concerns have arisen and I assure you that we will continue to monitor the drug, working with health care providers, patients, the public health community, and law enforcement to help ensure its appropriate use, and with manufacturers and others to achieve the goal of a meaningful abuse deterrent formulation.

On a different but related issue, I also want to mention our recent decision to recommend a change in the scheduling for hydrocodone combination products, such as Vicodin, by moving them from Schedule III to Schedule II, which would increase the controls on these products. 

Like with other decisions we face, this is not a simple issue. It also generates strong opinions about the science, issues of patient access, and public health.  We thoroughly and carefully analyzed extensive scientific literature, reviewed hundreds of public comments, and held several public meetings with input from a wide range of stakeholders. We listened carefully, and our decision was based on the best available data and science.

FDA recognizes the importance of more effectively addressing other critical aspects of the opiate problem, including overdose and addiction treatment. To that end, as you've heard, we recently approved Evzio, a product that delivers a single dose of naloxone via a hand-held auto-injector in a matter of seconds. Naloxone reverses an opioid overdose, whether it is from a prescription opioid or an illicit one such as heroin. Previously, it was available in a vial for IV administration – for use by trained medical personnel in emergencies, and it has saved literally thousands of lives.

Now, this important product will be available with a doctor’s prescription, importantly enabling its use by family members or caregivers in an emergency situation.

FDA fostered the development of this life-saving tool, reaching out to product developers to encourage them forward.  We held a scientific workshop with a variety of stakeholders to discuss the potential value of making naloxone more widely available and describing the data requirements to support a new drug application for a naloxone product that would be suitable for use outside of supervised medical settings.

When such a product was developed, I’m proud to say that we reviewed the drug application in 15 weeks - a very quick turnaround to approve a drug. 

We’re looking at additional ways to make naloxone more accessible. And you heard about serveral approaches from Dr. Collins. In fact, at this meeting last year we at the FDA first connected with the Clinton Foundation and talked about expanding the availability of this life-saving drug. Just last week they held an exciting meeting on this topic and we participated in it. Just one more example of the difference this Summit can make.

We also encouraged the development of Vivitrol, a long-acting injectable form of naltrexone – a drug for opioid dependence. We met with the company to discuss their development program and advised on designing their clinical study protocol. We then granted them priority review status because the drug offered an important option for opioid dependence treatment and, based upon that review, ultimately approved the product.  

These are important steps, but we strongly believe that a meaningful and enduring response to reducing prescription opioid abuse must also focus on the broader context of the epidemiology and evolution of the problem, which is driven by a relatively small number of providers, a significant lack of provider oversight, and inadequate prescriber and patient education. Collectively, these can lead to excessive prescribing, improper storage and disposal of medications, and of course, diversion.

Quite simply, the potential for abuse begins in the doctor’s office with the choice of a particular drug. Therefore it is vital that the doctor be well informed about when to prescribe that drug, how to use it safely and have the tools and know-how to convey that information to the patient.

It is crucial that prescribers understand their responsibility for educating patients about the appropriate use of prescription drugs, potential risks, and proper disposal techniques.

Manufacturers must provide doctors and other health care professionals with the information they need to write prescriptions responsibly.  And prescribers need adequate training in opioid therapy, which includes knowledge of the content of the most current drug labels and broader information about the appropriate context for use.

Although the requirement that manufacturers of long-acting and extended-release opioids provide training programs offered by accredited continuing education providers cannot mandate prescribers to take it –we are looking at ways to encourage participation.

We’re also supporting work by New York University on a model prescriber patient agreement that can replace the variety of opioid treatment contracts or agreements currently in use in some healthcare settings.    

Finally, there are three other important FDA activities that I want to quickly mention.  

First, many have noted that opioids aren’t the best medication for chronic pain in all cases. We need better drugs for pain that are not opioids or have less addictive potential. To spur development in an area in which treatment options are limited, FDA has leveraged its expedited review programs to try to accelerate progress.  Using this approach, FDA has approved five new medications for certain types of neuropathic or chronic musculoskeletal pain conditions. 

Second, FDA is exploring the use of new packaging and storage technologies to foster the safe use of opioids. We recently published a notice in the Federal Register asking for public input about drug packaging, storage and disposal. I know you are interested in these technologies, and we do want your input on this important initiative.

Finally, FDA is working with Brandeis University on how to combine and analyze data from Prescription Drug Monitoring Programs (PDMPs) from several states to better identify problematic prescribing and use patterns. Building on the vision originally put forward by Congressman Rogers to create robust PDMPs, I think we all must ensure that they fulfill their promise to improve patient care and reduce abuse, overdose, and diversion.

I’ve tried to explain FDA’s role in taking on the challenges posed by these powerful pain medications throughout their life cycle, including mitigating the risks of addiction, abuse and misuse of prescription opioids.  But for effective solutions we must work closely with all of you. As Congressman Rogers so well has noted, a comprehensive, collaborative approach must be taken by federal, state and local governments, the public health community, opioid prescribers, addiction experts, researchers, industry, patient organizations and so many others.

I will conclude by saying that I recognize that nothing can erase the tragedy that so many people – including many here – have had to face as a result of abuse, addiction, or misuse of opioids. But we can make meaningful progress to reduce and prevent our nation’s prescription drug crisis. We're seeing promise already. FDA is committed to reducing abuse of opioids and its terrible consequencing while ensuring appropriate access to pain medicines for patients in need. So we are committed to working with you. This is a complex challenge that requires a comprehensive solution and sustained attention. We are in it together with you. 

Thank you.