Health Committee on April 29th, 2008

[The Chair, Conservative, Joy Smith]

Good morning, ladies and gentlemen. I would like to welcome you all to the committee this morning.

This morning I want to welcome to our committee Gerald Dal Pan. We're going into a video conference. Can you hear me, Doctor Pan?

[Dr. Gerald Dal Pan, Director, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration]

Yes, I can hear you.

[The Chair, Conservative, Joy Smith]

Good. I want to welcome you to our video conference.

[Dr. Gerald Dal Pan]

Good morning. It's a pleasure to be with you this morning.

[The Chair, Conservative, Joy Smith]

We're having trouble hearing you. The sound people are working on it right now.

Gerald, tell us who you are and your role at the U.S. Food and Drug Administration.

[Dr. Gerald Dal Pan]

I'm Dr. Gerald Dal Pan. I'm a physician and an epidemiologist, and I'm the director of the Office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

[The Chair, Conservative, Joy Smith]

Great. Welcome to our committee today.

We have Mr. Dal Pan here because we want to hear, on a more international level, how post-market surveillance is being done.

Gerald, would you go ahead and give us your presentation? Thank you.

[Dr. Gerald Dal Pan]

Good morning, honourable members.

The Office of Surveillance and Epidemiology focuses on monitoring post-marketing safety of human drugs and therapeutic biologics, on the development and evaluation of risk management programs, and on the prevention of medication errors. The monitoring of post-approval safety of the blood supply, vaccines, tissues and other biologic products, medical devices, and dietary supplements is located in other FDA units.

I am pleased and honoured to appear before you today to describe our post-marketing drug safety surveillance system and to answer any questions you may have.

FDA's mission is to ensure that safe and effective new drugs are available as quickly as possible and that drugs already marketed remain safe and of the highest quality. The monitoring and understanding of the safety of drug and therapeutic biologic products is a process that proceeds throughout the product's life cycle, spanning the period prior to first administration to humans, through the entire marketing life of the product.

In each stage of drug development, important drug safety information is obtained. At the time a drug is approved, there is a substantial amount of data regarding its safety profile. In the pre-approval review process, FDA reviews these data, along with data on the product's efficacy, to determine if the potential benefits of the drug exceed the potential risks for its intended use. The risks of a product are presented in a product's approved labelling, a document that can be updated throughout the product's post-marketing life.

Although the pre-approval testing of a drug is very rigorous--and the review of the data is very thorough--there are still some uncertainties about the complete safety profile of a drug when it is brought to market. Even the most extensive pre-market testing cannot anticipate all the potential adverse reactions that might occur. This is because clinical trials include a limited number of patients, a relatively short duration of treatment, relatively narrow patient populations, and often do not include special groups such as the elderly, children, pregnant women, or different ethnicities.

The goal of the post-marketing safety program is to identify adverse events that were not identified prior to approval and to understand better the spectrum of adverse events associated with a drug, including adverse events recognized prior to approval.

A core aspect of the post-marketing drug safety system in the United States is the reporting of adverse events to FDA. In the U.S., suspected adverse events in individual patients are generally identified at the point of care. Patients, physicians, nurses, pharmacists, or anyone else at the point of care who suspects there may be an association between an adverse event and a drug or a therapeutic biologic product can, but is not generally required to, report the adverse event to either the manufacturer or to the FDA.

The public can send reports directly to FDA via the MedWatch program, which was established in 1993 to allow health care providers and consumers to send a report about serious problems that they suspect or associate with any medical product--be it a drug, biologic, or medical device--directly to FDA. Members of the public can also voluntarily report suspected adverse events to a product's manufacturer, which is then subject to regulations regarding the submission of these reports to FDA.

For certain serious adverse events, manufacturers must report them to FDA in an expedited fashion, within 15 days. These requirements vary according to the marketing authorization status of the drug. For other adverse events, manufacturers report on a periodic basis, either quarterly or annually, depending on how long the drug has been on the market.

The adverse event reports that FDA receives from the public and from manufacturers are entered into a database known as the Adverse Event Reporting System, or AERS for short. FDA receives more than 450,000 reports a year. About 94% of them are from manufacturers. The remaining 6% are directly from the public via the MedWatch program. This database currently contains over four million reports of adverse events.

FDA safety evaluators review these individual case safety reports to determine if new safety information needs to be added to the products label. The review of adverse event reports is a complex process and cannot be covered here in detail. The analysis of these reports has been a cornerstone of our post-marketing safety system for over four decades, and will continue to be an important part of our drug safety system. However, the science of drug safety has evolved over the past two decades. New sources of data and other methodological approaches are being developed and implemented to complement the information we obtain from the reports we receive from patients and practitioners.

Today there are available to us certain large databases containing administrative medical data as well as electronic medical records. With increasing staffing and access, we anticipate much greater availability of these resources in the future. These are rich sources of information on the potential side effects of medications. Observational epidemiological studies, which include case control studies and cohort studies, are approaches that can confirm an association between a drug and an adverse event and can also provide a quantitative measure of that association. Observational epidemiological studies are time-consuming and costly. FDA uses them to examine important drug safety questions that cannot be answered with data from spontaneous report systems.

Clinical trials also provide another approach to examining drug safety questions. Many clinical trials are designed primarily to examine a drug's efficacy; nonetheless, they collect important safety information. Clinical trials for new doses and new uses of drugs often continue after a drug is approved. In some cases, clinical trials are designed primarily to examine a specific safety question. I would like to emphasize that many recent important drug safety actions in the U.S. have been on the basis of observational studies or clinical trials, and not on the basis of individual case safety reports.

Active surveillance systems are also being explored to identify and examine drug safety issues. Active drug safety surveillance systems, which take advantage of large repositories of automated health data, are now being developed and tested by multiple organizations. The commonality of these systems is that they do not rely on individual health care providers or patients to recognize and report adverse events that may be related to medication use. Rather, these systems often use sophisticated statistical methods to actively search for patterns in databases that link prescription use, outpatient medical care, and in-patient medical care in a way that might suggest the occurrence of an adverse event related to drug therapy.

While there is much interest in developing these systems, there is also much work to be done in the validation of these systems. In any case, one system is unlikely to address all drug safety problems for all patient populations. Thus, while the spontaneous reporting system has been the cornerstone of post-approval drug safety in the United States for several decades, new approaches based on large population-based databases are being used and are being explored, and will likely play an increasingly important role in this system.

In addition to our activities related to the monitoring of drug safety, we are interested in the safe use of drugs. Toward that end, we have implemented risk management plans for certain drugs whose benefits exceed their risks only when there is careful adherence to certain conditions of use. Many of our current efforts are directed at assessing the public health benefits of these plans, which involve all sectors of the health care system.

New legislation passed in the United States in September of 2007, the Food and Drug Administration Amendments Act, recognizes the importance of post-marketing drug safety by explicitly granting FDA the authority to require companies, under certain conditions, to make post-marketing safety-related labelling changes; to perform post-marketing studies and clinical trials to answer drug safety questions; and to implement risk evaluation and mitigation strategies for prescription products.

In addition, this legislation directs FDA to evaluate formally the safety of new drugs 18 months after they have been on the market, or after 10,000 patients have been treated. We are currently in the process of implementing these and other drug-safety-related provisions of this law.

To ensure that the public is aware of our safety findings, we have embarked on many efforts to enhance our public communications of safety-related findings. These include labelling information specifically directed toward patients, communication of new safety findings before the product label has been changed, and the publication of a quarterly drug safety newsletter. The Food and Drug Administration Amendments Act also includes provisions for providing information to the public.

Finally, but not least importantly, drug safety is a global activity. At FDA, our relations with our international counterparts are very important to us. We have especially close and productive relations with our colleagues at Health Canada in a multitude of settings, including at World Health Organization meetings, other international meetings, bilateral meetings, and routine information exchanges.

I'm happy to answer any questions you may have. Thank you.

[The Chair, Conservative, Joy Smith]

Thank you, Dr. Dal Pan. It's been very interesting to hear what you had to say.

I should have introduced myself. I'm Joy Smith, the chair of this committee, and we have members from all sides of the House who are very anxious to ask you questions.

In the first round we have seven minutes per person for them to ask the question and for you to answer it. I want to thank you, before we get into the questions, particularly for all your insightful comments to the committee, which are very helpful to us. Thank you.

We will start off with Dr. Bennett.

[Carolyn Bennett, Liberal, St. Paul's, ON]

Thanks very much.

Even before we get to post-market, I was interested in what the FDA had, because I understood that in the case of drugs for which most of the research and approvals were done in other countries, such as the EU or Japan or other places, there'd be a committee of stakeholders that could fast-track a drug into the market, and then you would watch it in a post-market way. Is that true, or was that an experiment? How did that go?

[Dr. Gerald Dal Pan]

I'm not responsible for the pre-market review of drugs. We can certainly get an answer to that question for you.

We do, however, in broad terms, review all drug applications, regardless of whether they've been approved in another country first or if the United States is the first approval. We often take the data that form the basis of approval to a public advisory committee, and that can happen whether the drug has been previously approved in another country and approved in the United States, or whether the first approval is in the United States.

With regard to your specific question, I'm not familiar with the program you're talking about, but I can certainly have my colleagues here look into that, and we can forward an answer to the clerk.

[Carolyn Bennett, Liberal, St. Paul's, ON]

Thank you very much.

In terms of the life-cycle approach and real-world safety, would you consider what you have in the United States to be progressive licensing?

[Dr. Gerald Dal Pan]

“Progressive licensing” is not a term we use here. I believe it is a term that's used in Canada, and I've heard that term presented at meetings before. When we license a product, it can be marketed, but we continue to watch it closely. Our new legislation puts in a formal requirement for a review 18 months after a drug is on the market, or after 10,000 patients have used it. But once the product comes to market, it's marketed. It's a licensed product.

[Carolyn Bennett, Liberal, St. Paul's, ON]

We're wondering if it's like a learner's permit for a driver's licence, and whether you don't get your learner's permit until you have the 10,000 patients or whatever.

On the issue of post-market surveillance in watching for counterfeit drugs, I understand that last year at a conference the FDA was quite concerned about the resources it had, and that it was only able to inspect about 1% of the drugs coming into the United States. Are you doing things like spot checks and using other ways to determine counterfeit drugs in the pharmacies in the United States?

[Dr. Gerald Dal Pan]

We have a large field organization here at FDA that's present at many borders. We also have an office of compliance in the Center for Drugs. My office works closely with them. We can get an answer to you on that question as well. Counterfeit drugs are of great importance to us, and we can get specific information about those programs to you. They do not fall under my office's purview.

[Carolyn Bennett, Liberal, St. Paul's, ON]

If you had an adverse reaction, how would you know if this was a counterfeit drug or the real thing? We have had some deaths here in Canada, specifically one in British Columbia, where someone bought from an Internet pharmacy. We also have a problem with Internet pharmacies with Canadian flags all over them that aren't from Canada. They sell drugs and say they're from Canada, but they may well be counterfeit. How would you suggest that you check an adverse reaction for whether it was the real thing or counterfeit?

[Dr. Gerald Dal Pan]

That's an important question; it's often difficult. You are probably aware that we have been experiencing a problem with the drug called heparin in the United States. Heparin is a drug that's been available for decades. It's one of the oldest drugs we have, and its safety profile is relatively well known because it has been around so long and has been so widely used. Last November and December there were clusters of outbreaks in dialysis centres around the United States. Multiple patients were getting allergic reactions. Although in rare cases patients receiving heparin can get an allergic reaction, these clusters were particularly unusual.

Our Centers for Disease Control and Prevention, another government health agency, did an outbreak investigation and determined that it was the heparin from one particular manufacturer that was responsible for the outbreak. The heparin was put through very complicated testing and it turned out to be contaminated, even though it came from the manufacturer. In these cases, we're not really dealing with a counterfeit product but with a contaminant. Since this was a relatively widespread problem, we were able to identify both the cause, which was this particular manufacturer's heparin, and the contaminant.

It may not always be easy to determine that an adverse reaction is caused by counterfeit drug rather than a properly manufactured one. If the drug safety profile is well known and the drug has been around a long time and you start seeing adverse reactions that don't fit the pattern, you might suspect the counterfeit, but it would be difficult. If you don't have the actual medication to test, it would be even more difficult.

[Carolyn Bennett, Liberal, St. Paul's, ON]

Does that apply for natural health products as well?

[Dr. Gerald Dal Pan]

Natural health products such as dietary supplements fall under different regulations. They are regulated by our Centers for Food, which could provide you with some information on this. We could ask them to send a response to that question.

[The Chair, Conservative, Joy Smith]

Thank you, Dr. Dal Pan.

Madame Gagnon.

[Christiane Gagnon, Bloc, Québec, QC]

Good morning, Doctor Dal Pan.

How do you determine whether a drug is safe for the public? We read in the newspapers that a number of drugs have been pulled off the market, and that there should have been a much more proactive approach to avoid deaths and detrimental effects, which have a measurable impact on the public.

There were a few deaths reported among girls who had been given the Gardasil vaccine. But no country has called for a moratorium on the mass vaccinations carried out by various public health authorities.

Under your drug safety oversight system, how is a moratorium issued regarding a given drug? What are your parameters? It seems difficult to initiate a drug recall. There have to be a lot of cases in order for a drug to be pulled off the market. In the case of Gardasil, it seems that the clinical trials were improperly done or carried out hastily so that the drug could get to market more quickly.

[Dr. Gerald Dal Pan]

Gardasil is a vaccine, and vaccines are regulated somewhere else in FDA. But let me answer the question about drugs, because I think your comments about gardasil are relevant to many drugs as well.

First of all, when a drug comes to market, we know there are still certain things we will be learning about the drug safety profile. As I mentioned in my opening remarks, it's really impossible to know everything about a drug once it comes on the market. We approve drugs because we believe the potential benefits exceed the potential risks, and our monitoring of drugs throughout their life cycle is aimed at ensuring that the potential benefits exceed the risks. We do much more monitoring in the post-approval period to monitor potential risks than we do to monitor potential benefits or new benefits.

That balance is often difficult to determine, the balance between the benefit and the risk, and in some cases we bring this to public advisory committees. Our new program in the last eight or ten years to have risk management programs is really designed to ensure that certain drugs whose benefits exceed the risks in certain narrowly defined conditions adhere to those conditions so the benefits do exceed the risks. But learning about the safety of drugs once they're on the market is a complex process. One of the complexities is to determine if the adverse reactions we're seeing are actually due to the drug or if they're due to patients' underlying diseases or to other factors. So it's never a particularly easy question.

[Christiane Gagnon, Bloc, Québec, QC]

We were hearing earlier about the issue of speeding up the drug approval process. The United States is taking part in the international conference to harmonize the technical requirements. I would like your comments on the objectives of that conference, which is to accelerate the drug approval process.

What impact would that have on drug safety? Would you like to see the United States approve shortcuts in the drug evaluation process?

[Dr. Gerald Dal Pan]

Again, I'm not in the unit that approves drugs. In the United States our goal is to approve most drugs in a ten-month timeline. For certain drugs that are for serious or life-threatening diseases, we can do it on an accelerated pace in a six-month timeline. But we always ensure that the review of safety is completed before we make a decision to approve a drug. If we need to ask the company for more information, we will.

I'm not aware of the particular conference you're discussing, but we can try to get some information on that for you.

[Christiane Gagnon, Bloc, Québec, QC]

I would appreciate that, since we are studying this issue. We would like to know about more effective approaches to ensure drug safety, both before and after they are put on the market.

If the approval process is shortened in order to get a drug to market, there may be impacts, and we will have to react after the fact. That might mean that people will die or suffer irreversible health consequences, such as blood clots, aneurysms or other serious effects.

Could shortening the approval process have a direct impact on people's health?