Event ID: 1638018
Event Started: 11/8/2010 7:45:59 AM ET
Douglas Throckmorton, MD
Thank you, Leonard. While my slides are coming up, let me give the introduction. I am given a brief amount of time to talk about a lot of things. My task was to talk to you about the history of drug regulation. To give you some overview of what the Center for drug evaluation research does. If I had a couple of minutes, I wanted to talk a bit about where we are today, regarding your development and -- drug development and how we see our impact on that in the best possible way. Having done that, I am out of my introductory and -- introductories.
Here we go. Drug regulation 101. We will talk briefly about the organization. And about the development of the clinical trial infrastructure. I think that is in the clowning -- crowning achievement of the last decade. It's been a decade of challenging structures. By a sometime, I will present some challenges that we could maybe make some changes to to make the development of products better. Human drugs program is one of several centers within the center of the FDA. You can see, it is the yellow box. It entered the tobacco product. Its mission is to ensure that saved -- safe and effective drugs are available to the American outlook. -- public. We have about 3000 people working on this regulation within the center.
FDA is one of many players in a very public sector of healthcare development regulation and delivery. We recommend the what we do sometimes does what we want them to be. At other times, we need to work with other partners to accomplish the things that we want to reach. Under our purview, prescription drugs, generic drugs, over-the-counter drugs -- cold and cough preparations that you buy when you children have a fever, they are regulated in the same way that prescription drugs are regular the. -- regulated. Over-the-counter drugs include things such as toothpaste with fluoride. Because it treats gingivitis. Those that treat diseases all within our purview.
We share responsibilities -- responsibility with other centers. We do safety and compliance and quality manufacturing and consumer product safety. We have a response ability to each one of them. They take roughly equal amount of time and resources. We are not overly focused on premarket. We understand post-market safety issues as they come up.
How did CDER get there? Before 1938, we have been around since 1906, but they can only respond to problems. If things were identify, there were no requirements for testing. We could seek to remove misbranded or dangerous products. There were only these endangers cases -- dangerous cases. You are probably familiar with a lot of the. -- a lot of them. There is another classic one. This was used as a classic weight-loss drug in the 1930s. Evidently, he made you really not want to eat much. The challenge was the dose that made you stop eating in the dose that caused cataracts. Was very narrow. In many thousands of people developed serious candidate -- cataracts resulting in significant impairments. We were given in 1938 a requirement to demonstrate safety. Hugo Pratt -- you could put a product on the market but you had to demonstrate it was a. -- it was safe.
When authority to move forward but we had to show they were saved. -- safe. Or if the information was insufficient to be able to otherwise use the product safely. In 1962, we added the efficacy standard. This was in response to a strategy -- to a tragedy. Three important additions. You are familiar with them and you will learn more about them in the next few days. Explicit requirements for informed consent. And they had to give approval for being studied. Second new thing, there was a requirement of a demonstration of the effectiveness.
That was pivotal also. It turned the safety standard into a safety and effectiveness standard that we are familiar with today. The third is to say that we had to give positive approval. You cannot put a product into commerce without the approval of the Food and Drug Administration. That was 1962. That is the basis for everything that happens thereafter. Until recently. Those two things. They were requiring safety and effectiveness. They allowed for the growth of the clinical trials and architecture. Drug development processes in response worked out to incorporate those two requirements. First for safety and second for I think he -- for efficacy. In the 1970s and 1980s, this led to the development of randomization to minimize the random very ability. You are all familiar with the TB drug. That was much later. When it became standard. To randomize trials. Until that time period. Blinding came in in the 1970s and 1980s. To deal with randomness. And there was a bias that need to be minimized. All of these came into being in the 1960s and 70s and 80s.
It was this focus, in the 1970s and 80s am a the focus -- 80s, the focus was on building the science of effectiveness. New assessments in terms of statistical methods. As a consequence, this focus on effectiveness, focused on withdrawal of high focus drugs. They were identified and focus on. -- focused on. But they thought it led to a loss of emphasis on safety. The other thing to happen in the 1970s and 80s was the development of the federal trial ever structure. Particular through the NIH. The NIH setup an extensive enterprise. Recognizing there is a lack of support for a national infrastructure. They worked to go about setting that up.
In some areas like oncology, there seems to be a strong develop an area in NIH for new products and drugs. Clinical trials structure, however, as a consequence, shifted into the private sector. As drug developers said they wanted to be able to develop a new drug, they built the right infrastructures as the national infrastructure became focused within the NIH. The result was two large groups. You had them working with the their Punic -- therapeutic areas and then you had the other infrastructure to make sure they were getting the clinical trials done in a timely manner to get products approved.
Does have consequences which I will get back to. We would -- we lost the national infrastructure. It made it more difficult to develop products outside of the drugs industry. The other thing that happened in the 1970s and 1980s is the rise of the human subject protection ever structure. -- infrastructure. I was part of IRB at that time to make sure that human subjects were protected for drug development. 1980s, they continue to be focused on efficacy. We started to look a particular areas of science. In drug development. Like metabolism. Like targeted organ toxicity. Like cardiac cardiac -- cardiac toxicities. And understanding --
That brought us to a period around 2000.
At the speed and capacity that they wanted] . The critical path is about focusing drug development as a science. Focusing it. Doing that officially in making changes. Other better things we can be doing more efficiently. Do the assumptions that have guided us went 1938 still hold up? Or are there other ways that we can do our business?
The other is 2007 with the FDA amendment act. This grew out of those conservation safety issues.
Best for two 2010. -- Fast forward to 2010.. Understanding in general that they -- one is better than the other. Has taken a great deal of time and a great deal of attention. I will summarize by just saying that we have more certainty about the efficacy and safety based on the development. With regards to statistical methods. They have allowed us to make better understanding than they have previously.
There has been recent focus on -- . Most recently, there has been an increased and a call from society -- . Today, we have the products --. To be able to continue to change how we respond to these challenges. And understand the safety issues. We are out of time.
At the cost of a national infrastructure that could support.
William Maisel, MD
Good morning. I have the advantage of having the same amount of time that the But he gave the abbreviate of the FDA which will give me a few more minutes. To discuss the device world. The Center for devices has some of approach and mission to what CEDAR basis in the drug world. We try to remote public safety by creating safe medical devices. Were charged with overseeing these products as well. We are also very interested in fostering innovation. In the appropriate oversight of medical devices. But also helping to get innovative and important products second benefit the patient to get there as quickly as possible. We would like to provide the public with accurate and science-based information so that healthcare providers and patients can make important decisions.
This is the definition of a device. I will not repeat the whole thing. The goal of this definition is provided by Congress is to make a distinction between drugs and devices. And in machine an implant and in vitro or similar article. Including any component part or test or. I was get down to the part at the bottom. Which does not achieve its primary purpose for man or animal. And is not dependent on being metabolism -- metabolized. The may seem like a very long division and maybe they just would've been better off saying devices or not drugs. The bottom line is that this definition, while amazing complex is very important it helps us decide which center has the primary oversight for these products. There are a number of important differences between devices and drugs.
I have outlined a few here. These are some of the development of features that we want to take a look at these. First of all, the rate of technology change in device is much faster than for drugs. Design changes can occur. The type of products that are used to make devices can change. Or change over time. Manufacturing processes can change. The product lifecycle for a device is much shorter and much quicker than it is for drug. The drug that was approved or proved three decades ago can stay on the market but there can be minor changes to the manufacturing process for prices -- product that caused -- that are constant radiations. The regulatory structure needs to account for that. In vitro assessment of devices is, in some cases, easier. And in some cases can provide her important information. We need to take advantage of that. Reimbursement through clinical trials so that we don't see them -- over see them is more common in the device world. CMS can often pay for devices that are going trials -- undergoing trials.
Device companies can sometimes get reimbursement for the clinical trials. Importantly, the physician using the device or the patient him a visit is a home use device can have important results for ones that are being conducted. This is different from someone who takes the drug were must be infused. Surgically placed device can depend free much on the skill or the surgeon. I can be very difficult to tease out whether it was a bad implant or -- implanter or Blatt -- that device -- or bad devise -- device.
It is hard to sort out whether that is the bypass surgery itself or the device being used in the bypass surgery. One of the interesting things about devices in one of the things that we can take advantage of is that we can often monitor the performance of the device during a clinical trial or after is used. For example, a device that is implanted, we might be able to monitor the function of that device. We can also conduct forensic analysis. We can conduct analysis of products that failed. We need to take advantage of that information if it helps develop these changes. It allows us to better assess the performance of the device.
The regulatory framework differentiates devices in another important way. That is what is considered a happier as an orphan device -- that is what is considered an orphaned device. It is considered to be used in 4000 people or it you are is considered an orphaned device. It has important implications for smaller markets. Smaller populations of people. And portly, -- and importantly, there are different relations for devices of -- classes of devices. Which are used to provide a regulatory framework. Give art he heard -- you have already heard -- On the left is a dental bone wrapped that has a primary growth factor. The secondary action of the drug promoting -- In this case, this product would be regulated as a device and would require a pre-market approval application. Then you need to deliver the drug. The secondary action is to allow the local delivery device. There is an office accommodation products. Store company can go to the office of combination products when they have accommodation product to help determine which center they should be regulated by. Our risk based classification shown here.
On the left, we have three general classes. This was provided by Congress in 1976 with the amendment. They are relatively simple and straightforward. Like plugs and stethoscopes. Their assurance of safety and effectiveness can be reasonably guaranteed by general controls which are things like if you have a sterile product, picture it has good sterile manufacturing processes. Most of these are exempt from premarket submission and just require registration listing with the FDA.
Class two devices which account for about 90% of devices that come in the market -- their safety and effectiveness can be reasonably a short by safety controls and special controls. This pathway is generally called a premarket classification pathway or the 5K pathway. Class III devices are the most complex devices. They include things like different layers and -- defibrillators and breast implants. These require premarket certification.
Is also a classification that is part of the class II classification called the de novo classification. These are far lower risk classification product or which there is not a similar product early on the market. I would play more that in a moment. Importantly, they are getting more complex. In addition to things like molecular medicine and minimally invasive technologies, and miniaturized devices and nanotechnology and wireless systems. There is all kinds of exciting products that are coming on the market that are -- that challenge our current regulatory process. When we are looking at a device, how do we approach safety and effectiveness of the device? We certainly look at design and engineering. We can rely on bench testing in animal testing in clinical data. I want to give you some idea of where we rely on this different type of data. Due to the unique nature of devices, there are questions that are actually answered better than clinical data. Is sometimes get lost in people point to the fact that there wasn't much clinical data. But there are some that the data and analyses that are better performed then on patient's. One of those -- when we look at something like a casemate or, instead of watching the patient for 10 years we're watching thousands of patients for 10 years, companies can do repetitive motion testing that provides much better long-term predictability of how that device will work. It can tell us in the company where the product might fail and how it might fail. You can stress the product to the point of failure to get an idea of how the product is doing. When you make changes to the design of the product, NEC this test are improving, that can give you some idea that the product might perform at her weekly. We can also, in addition --
The 5-10K notification process is for the class to -- two classification. The way billing which is in the radiation is that this establishes -- the company must establish what is called substantial equivalence to a predicate device. If a company already has a device on the market, any company can come along and they just have to show that their new device is essentially equivalent to the previous device that was previously marketed. Needs to have the same general intended use. And technological characteristics. Were that there were different. Six, the company needs to submit evidence to show there are no new issues affecting issues for safety or effectiveness.
This is how we try to strike a balance. In the products that have these changes which have important developments for changes for patience, without requiring a new clinical trial that is large and long everything will time. Usually but not always, this is based on bench data. But about 5% require clinical data. The need for clinical studies is dictated by of product. The ability of the bench or animal testing to into the questions or concerns. In some devices, because of their importance or their risk always need clinical data in this pathway. One example is the blood pressure monitor.
This process also comes under a lot of screen a lately. About one year ago, we started an internal process of this pathway. We posted in August of this year 55 regulations related to the pathway and how we believe it could better meet the needs of the public including in promoting safety. We also commissioned an external review of this program by the Institute of medicine. Which began over one year go. This is expected in the summer of 2011.
There is likely to have changes in this program in the coming months. The premarket approval application process is designed to ensure safety nets and effectiveness. It is based on valid scientific evidence. It generally relies on bench in animal and human data. The clinical studies are to look at the feasibility of the device of pivotal trial in post-market in some cases.
Valid scientific evidence is defined as evidence from well-controlled investigations. Partially controlled studies studies and objective trials without controls well documented cases to by qualified experts and of course a significant human experience in the market place. These are defined by Congress and this is the type of evidence that we can use to evaluate a device. And what we choose to use depends on the device and the indication. Is valid scientific evidence from which we can include by qualified experts that there is reasonable assurance of safety of a device. Under the conditions of these. -- of use. . The existence and adequacy of warnings and other restrictions. And the extent of experience with its use. Reports lucky sufficient details to do scientific evaluation. And unsubstantiated opinions. I think you get into that there are a lot of different types of vice designs. It is all the different than what you see in the drug world because of the different types of devices that we see. Some of the most basic clinical trial design features such as randomization, sometimes are not possible unless you have a very sick patient preparation that they'll medical therapy. And they have no other options.
Sometimes you can do that versus continued medical care be. -- therapy. It is a very difficult child to complete. In other cases, if you're trying to randomize them to a very high risk device, such as an end state -- stage hard condition, it's hard to get them to randomize to a life-threatening procedure. There are certain challenges that we face in trying to evaluate these devices. In the type of data that we can use. Safety is defined as a reasonable assurance that it is safe when it is used to determine scientific evidence that I just showed you. That the top level benefits of health for the use of the device for its intended use and conditions of use when accompanied by adequate directions for unsafe use outweigh probable risk.
We don't have guaranteed. In the FDA device world. That we are trying to make an assessment that the probable benefits outweigh the probable risk. The effectiveness of a device is based on the scientific evidence, a significant portion of the target preparation, the use of the device and intended use, when accompanied by adequate directions will provide clinically result -- significant results. We don't regulate the practice of medicine. Or off label use of a device by an individual physician trying to help their patient. This is a significant person of the target population as defined in the label of the device. Clinical studies subject to device radiation -- regulation include those where the device is being used to study a mass marketing application. Or on the collection of safety information such as new and intended use of a vaguely marketed device or when the study of an unapproved device or new intended use of an approved device.
Again, it is when you are going to try to support a marketing device of a previous device. There are certain studies that are exempt from device regulation. If you already have a 5-10K cleared or it's being used in accordance with its labeling, then that is not the FDA's business. As long as it's not being used to change modification to the label. Consumer preference of marketing devices, combinations of illegally marketed devices, foreign studies etc. are not under FDA purview. Devices, one that ended being investigated, are performed under investigational device functioning. That allows them to be used in clinical studies for super marketing applications.
Exempt them in certain provisions -- it exempts them from certain positions -- provisions. There are certain requirements for informed consent for monitoring these records which basically include clinical trial practice regulations. It requires approval from a local institution review board for significant risk devices. For nonsignificant risk devices, is also require IRB approval but generally do not require a IED before being used. And the difference between significant use in a significant risk and nonsignificant risk. Significant risk devices provide a potential risk to the health subject. It is an implant or is used in supporting or sustaining human life. Or of "essential important in diagnosing or curing or mitigating or treating disease or preventing interment of human health." It is a pretty broad definition. Most of them fall into this category.
When submitting an IED, it is required to have a US sponsored. -- sponsor. To ever report a prior investigations and details of the device manufacturing information and other information, labeling, informed consent etc. etc. All of those developments that would be required have a good clinical trial. I mentioned some of the trials -- such as study design. Another challenge is iterated design. It is common to learn things about your device or in the trial, particularly with a new device. Fidelity penalize companies for making a modification to my make it easier for clinicians to use it or make it more reliable or safer. It is challenging to do this around a clinical trial. And still interpret the safety and effectiveness results. And masking can be a challenge on occasion.
I -- that is important -- that is an important indication for how we determine and interpret the results. The user interface is very important but devices. Unlike drugs, either take it or you don't. Devices can be misused or mishandled or misunderstood by the person trying to use the device. When the device gets on the market -- before we approve or clear the device. And in collecting information with the devices on the market. The goal of this market on a trick is to improve patient safety and striking that right balance is a challenge. We do have certain regulations that allow us to request data once it is on the market.
Obviously, it's an overview of the medical device in the clinical trial regulation. We always have to work with people and encourage people to come forward before the trial has started. And get the device. Thank you.
Karen Midthun, MD
The history of biological regulation is interesting and it relates back to the biologic control act in 1902 and what happened here, a horse, a middle course name to jam was used to make antitoxin to treat diphtheria is and the horse had tetanus on the anti-did. Cash was used to treat children, it killed several children and this led to the biologic control act of 1902 to government control Biologics. This is a far-reaching regulation and that it required the licensure of biological projects and facilities in which they were manufactured in a provided the authority to inspect facilities and to withhold or revoke licenses. And these were very important. So what are Biologics? They are defined as virus, therapeutic serum, toxin, antitoxin, faxing, blood, blood component, allergenic product and newly added to the definition is protein except for any chemically sent sized polypeptide are analogous project. And the products are for prevention and treatment are care of condition of human beings.
These includes vaccines, preventive and therapeutic and most vaccines are preventive vaccines to prevent infections diseases but vaccines for cancer and other kinds of diseases that are under development. Allergenic extracts, cell and gene therapies, transplantation, products, teachers, selected devices. For example, devices used to screen blood donors and blood supply. Whole blood and blood derivatives are factor VIII that might be derived from plasma and blood components, blood cells and platelets.
What are the priorities and street -- strategic focus at the Center for Biologics? They will prepare the infectious diseases, and through global public health for international cooperation, enhance the ability of science and technology to facilitate the development of safe and biological products and ensure the safety of biological products. And also, the bat -- the overall mission is to assure access to save products that we regulate. I think it is interesting, it is important to -- Biologics are drugs. It is interesting to look at differences between what we think of as being more traditional drugs and biological products. I'm not going to go through the whole slide but in general, the synthesizes some important differences. Most traditional drugs or a low molecular weight and whereas most are higher molecular weight and very complex products. Traditional drugs are usually made through organic synthesis, and biological products made with or using cells, organisms, and inherent and contamination risks and a live vaccine, where it might be very well tolerated, most individuals, but some individuals might have an undesirable effect. Certainly an example that comes to mind is the Oreo -- oral polio vaccine and certainly it was a tremendous effective and safe vaccine but very where cases, did cost the vaccine caused -- that is an example of inherent risk. There is an example of contamination and the whole vaccine, the early one that came out was the Salk vaccine that was contaminated with ASP the 40. That is an example of how they are both inherent as well as other kinds of risks to contaminations from these products because of their characteristics. In other examples of traditional drugs tend to be well characterized, biological products are less characterized and they are not well characterized at all. In other examples are drugs are metabolized and biological products are degraded and additional drugs are not immunogenic and they are not immunogenic. That is a good thing. For example the vaccine used to prevent infectious disease, you wanted to be immunogenic and biological products are intended as therapies or they are, you wanted to be at a very low level that does not cause much of a problem. Whether the clinical trial considerations we think about some of the products that we regulate? They really are very different depending on the product and depending on the population that you are targeting so for example one of the products that we regulate our vaccine for healthy children hear the pivotal studies that are conducted prior to licensure are large randomized trials that typically have several thousands of many thousand children an example of a very large trial for those connected with the more recently rotavirus vaccine which has 70,000 infants, roughly 30,000 investable rotavirus vaccine and 35 -- 30,000 with controls in the studies were designed in that fashion because they not only had, trying to determine efficacy but had a primary safety in point was to look at the risk of interception.
Nearly rotavirus vaccine to have improved in the 1990s had a risk of conception that was withdrawn from the market in the studies were made to look at that because it was felt to approve the vaccine and they are -- the disease are looking at does not occur very frequently. An example there was the original pneumococcal conjugate vaccine that was approved around the early to thousands that have 40,000 infants because a trial that large was needed to determine the effectiveness of invasive disease because that was the disease that occurred in one and 15 instances or so. We oftentimes have other large studies. Controls in the vaccine study can be a placebo or an active control, for example, another licensed vaccine that may or not -- may not be a licensed vaccine. And we are trying to evaluate a new vaccine, a vaccine for a condition which does not approve the vaccine and for that instance, you might want to offer those children other vaccines that they might not normally get. For example. Many of the studies for the rotavirus vaccines were connected elsewhere in the hepatitis a was not a typically administered vaccine that was offered as the control. Certainly, when you're using live viral are back -- bacteria that vaccines. You want to assess the potential for shedding issue to the clinical studies and another thing, I think is really underscored by vaccines, for healthy populations, you need to understand how that informs your risk-benefit and you'll be getting something which they may never encounter and another thing they did encounter it in the vaccine works, you're not going to be able to assess the benefit says obviously very important to have been the safety and effectiveness and we also have trials for products that are for where diseases. Here it is really important to consider possible study designs and in some instances, we have had studies where historical control is used and also consideration should be given to sequential trials, adaptive trial design and crossover trials. I think it is interesting to contemplate some of the historical safety incidents that we have experienced some of the biological products that we regulate because they underscore the need for the control of the manufacturing process, product testing, and pre-and post-market safety surveillance and a product of status regarding emerging effective diseases. Are you mentioned, what happened in 19 no one was contaminated area antitoxin.
And the biological control act of 1902 that came out. Another similar event was the 1955 was a cutter incident and this was where the newly approved inactivated polio virus vaccine, there were some lines for those sufficient inactivation of that was polio -- and 200 vaccinees and their contacts. This is an example where the manufacturing and control testing of the product are critical. Another similar that was in the 70s and 80s with the emergence of HIV, there was transmission of HIV through contaminated blood, blood components and plasma derivatives and the testing that was introduced have significantly reduced the risk and the blood is very safe and your risk of having HIV transmitted through the blood was well under one in 1 million today. But again, one has to be vigilant and understand what is happening is sometimes you may be in a situation where you don't have a test that can screen for this and the deferral process is very important and what happened in the 1990s, and it was recognized that perhaps it could be transferred through blood and blood products and in response to that, the process was put into place word individuals that have learnt over a certain period of time in the UK or Europe from donating blood, has subsequently around 2003 or 2004, they actually recognize, where there have been cases of -- which were highly likely to have been transferred through blood components and this is an example where you have to be doing horizon scanning and recognize these are things that can impact blood and blood products which we regulate want to break away the safety of another example that comes to mind is the West Nile virus were that emerged in 1999 and we recognize again that could be a threat and that is an interesting example where we worked together with blood establishments, device manufacturers and other multiple individuals and we started to scream the blood supply through use of investigations devices and those were used at a dozen cases of West Nile virus and ultimately we were able to test for West Nile virus. And in 1999, a year after we approved the first rotavirus vaccine, the vaccine was associated with the inception of the good news was it was picked up with it nine months of the vaccine being licensed and that led to the first month withdrawal recommendation used to lead to large studies with the rotavirus vaccines that imagine. These are examples of how you want to be looking throughout the lifecycle of your product. And I think that others, I have alluded to this in their presentation but you need to be looking at your product as you are developing it prior to approval and you need to keep looking at it as a licensed product for and certainly, important tools, safety surveillance and they had verse reporting system, errors, active surveillance is an important tool. And active surveillance may be may be -- are the case of vaccines, the CDC manages the vaccine data language has it been a wonderful tool for doing observational studies and for example is very important to signal -- in the first rotavirus vaccine, many of the other epidemiological studies were done with the vaccine safety data link and it is also used to look at the safety of a lot of the recently licensed vaccines as well and the biannual inspections that we do are very important and most of the products that we regulate our subject to the release of that is important to the overarching safety paradigm.
I thought it was interesting to look at the complexity of the manufacturing that we have with some of our products and to imagine how he might have a lot more trouble having a product that is highly consistent with product to product or lots to lots of here is an example of gene therapy we might take the DNC, you might select T. 34 cells and transfuse them using a …
Alleged a tremendous affirmation and multi-arcade fire and the aftermath the investigational study is adequate and whether the information that was a real event had been considered and those are obviously very serious issues and that the more one learns about a particular kind of product the more the risk, great benefit, as a trial for gene therapy for -- it was conducted. These verse conducted in UK and France and the -- involves 20 patients in five out of the 20 children who were treated developed leukemia and actually four were treated as successfully brought into remission so clearly those kinds of efforts are underway 12 to 20 lost their -- even after stem cell transplantation so clearly these are investigative products. There are great potential benefits but also risks that need to be managed. Also they have some interesting complex and Dr. Mizell there is development of matrix for wonder. Cardiovascular repair and these are examples of investigative process that are highly complex and that are being investigated. I think I am running a little short on time. How my doing, Leonard? Stop. I am out of time. Let me come to my summary. What I hoped was able to share with you, Biologics are diverse complex products for the treatment and prevention, and and rare diseases. There are processes used in the manufacture and product testing and evaluation of safety and efficacy. Many products are targeted for healthy individuals and this needs to inform the risk benefit for this kind of population and are highly innovative products that have great potential but it benefit but the risks are not fully defined and the clinical design might vary with the product. Thank you.