The FDA's Drug Approval Process

the center of Drug Evaluation and Research is one of the centers within the FDA structure and it is in this Center where the office of new drugs resides and within the office of new drugs we are divided into several scientific review divisions which are based on disease specific areas and so the division in which the pulmonary fibrosis drugs are largely reviewed are the division of pulmonary allergy and Rheumatology products which is where I work and so within our division we are a division of multiple disciplines including medical doctors not only pulmonologist but critical care doctors internal medicine doctors pediatricians but we also have pharmacologist and toxicologists that work with us to look at the animal data that's generated prior to going into humans and we have a large host of support staff including our regulatory project managers which really help us to implement the regulation in order to review drug applications so that's where the division fits into the whole organizational structure within the division I'm a clinical team leader which means I I am one of the Supervisory staff that is involved in the review activities of drugs all along their development pathway so that's a little bit about the organization of the FDA where our division falls in and my role within the division and I think you also asked a little bit about a history of you know where what we do in the FDA comes from and the history can be very long very interesting so I'll try to summarize it briefly you know the modern area era of the FDA really dates back to 19:06 when the Pure Food and Drug Act was passed and this was something this was an act that added regulatory function to the agency scientific mission it prohibited interstate transport of unlawful food and drugs under penalty of seizure but important as it was it was fraught with shortcoming because it didn't regulate medical devices or cosmetics and it didn't give the FDA any explicit authority to inspect factories to prosecute false therapeutic claims and it really didn't give us any control over what drugs could be marketed and so really what came to what came to happen in shortly after in 1937 really was defining and in in 1937 there was a company that tried to introduce an elixir of sulfanilamide and it was a flavorful oral dosage form and it was a new anti-infective that was supposed to be a wonder drug which was a disaster the firm used an untested solvent which was dialing glycol which is chemically related to antifreeze and by the time FDA became aware of that problem and removed the product from the pharmacy shell the preparation had caused over a hundred deaths including many children so that disaster actually reinvigorated a bill to replace the 1906 Pure Food and Drug Act which had been languishing in Congress for the past four or five years and so at that point in 1938 President Roosevelt actually signed Food Drug and Cosmetic Act into law and among many provisions it required that firms had to proved FDA that a new drug was safe before it could be marketed and this was really the birth of what we call the NBA or the new drug application and this new law covered cosmetics and medical devices and authorized factory inspections and outlawed bogus therapeutic claims or drugs and it was really there so that someone could review these claims prior to marketing and so with that we took one step closer to having drugs having to be safe before they were marketed and then we went even one step closer to what where we are now or to where we are now which is a new drug law called in the ketha ver how Harris amendments and this was again an act that came on the heels of a disaster that was narrowly averted a solidified in this case was a sedative that was never approved in this country but produced thousands of grossly to form newborns outside the United States and so this new mandated efficacy law this new law mandated efficacy as well as safety before the drug could be marketed and a required FDA to assess the efficacy of all drugs and instituted stricter control over drug trials so this is where the this is where the work that we currently do as the FDA comes from in terms of determining the efficacy and safety of drugs prior to going to market thank you that that was fantastic and very helpful kind of sets the frame for my next question which is now with all of the the regulation and and fantastic work the FDA does we want to understand how this happens you know what what is that what are the FDA requirements for a drug to be approved what is the the burden of evidence that you want to see so again the FDA requirements for drug approval are actually codified in the Code of Federal Regulations and so everything we do is mandated by regulation and by law and in general terms approval of an application requires that the application meets the requirements for safety efficacy manufacturing controls and labeling so different disciplines within the agency review each of these broad areas so the clinical teams and the statistical teams are looking at efficacy and safety but we have a large team of chemists and and also labeling consultants within the agency that are making sure that all of these four components in terms of manufacturing controls labeling labeling safety and efficacy are all met and I'll speak I'll speak less about the the manufacturing and controls today because that's not really my area of expertise and these types of things are usually handled by the chemist within the agency but I'll speak more to the efficacy and safety because those are the things that are clinically reviewed and so the efficacy standard that we abide by states that substan program must provide substantial evidence consisting of adequate and well controlled investigations that a drug product will have the effect that it purports or is represented to have under the conditions of use prescribed recommended or suggested in the proposed labeling and this is our efficacy standard you know I think depending on the disease area and depending on the number of patients that are available to study and certain disease areas substantial evidence is definitely something that is can be flexible it usually means and has usually been interpreted to mean to adequate and well controlled investigations but there are cases within the agency where you know the results of one robust study can also be considered a substantial evidence so this really does become an issue that is disk with sponsors at the time during development so that's the efficacy standard and then the safety standard is again the the Code of Federal Regulations is written in a way that is you know what what would cause one to refuse to approve an application based on safety so this safety standard explains that an application wouldn't be approved if it didn't include all the tests adequate test by all methods reasonably applicable to show whether the drug is safe for use if the results of the test showed that the drug is unsafe for use or if there's insufficient information to determine whether the product is safe so the safety standard is sort of more general and and this is very closely reviewed by the review divisions in terms of the safety data that the sponsors provide to us and then finally I'll just say that you know we do have a we use this as part of our regulatory framework when we're making decisions about whether or not drugs have met the efficacy and safety standards as codified within the Code of Federal Regulations and we take all of these things together and really try to make a benefit risk assessment and one of the things that patients will see with the new reviews that are coming out with drugs that are being approved is a real push to summarize what the benefit risk assessment is and all of our reviews are now opened with what's called a benefit risk assessment table which really summarizes what the benefits of the drug are what the risks to the patients are and what the agency's assessment of that of that balance is either supporting or not supporting approval of the drug thanks for that that was that was very very helpful and so we have another question up here which is very cool related and I think you've addressed some of this the question is what are the steps taken by drug developers and by the FDA to lead to FDA approval and maybe what I could ask you to summarize here are the the different phases of clinical trials I think a lot of listeners aren't certain what phase one and phase two and phase three and perhaps even phase four clinical trials are would you would you be able to educate our listeners on that absolutely so even though the FDA is often involved even prior to the traditional clinical phases of development so I will certainly summarize phase two phase one through phase four trials but we are often involved in consulting with companies regarding development of their products even when they're just starting off their non clinical testing either you know in vitro or in animal studies so these these this work will come before the phase one human studies and is really used to define doses that would be safe to administer to to patients and these consists of various tests and to evaluate safety prior to proceeding in human subjects so with that information in hand and knowing which doses will be safe at least using the animal data to go into humans the phase one portion of a clinical development program usually consists of first in human studies and and really studies to in to define what the safety and tolerability of doses administered to humans would be so in these studies we typically look at multiple doses in both single doses and short multiple dose repeated doses to see what the safety and tolerability profile are what the drug exposure in terms of blood levels is in in human patients as we have some of that information from the animals and to see if that's comparable or not and we're really trying to by a safe and tolerable dose prior to proceed proceeding into the next phase of development once phase one studies are completed phase two and again this is along a continuum phase to begin the Phase two development program typically includes dose ranging so we have an idea of the doses that are tolerated but we don't know which doses will be the most effective in treating the disease at hand so we asked sponsors conduct robust dose ranging studies so that when we can be sure that the the most the dose with the best risk benefit assessment is being carried forward so that usually occurs in phase 2 and phase 2 it and as part of that is really a proof of concept phase so we know that we can safely give this drug to humans but we want to show now that it actually is going to do what we think is going to do and so that's really what's established in phase 2 phase 3 is typically defined as the pivotal the pivotal studies in a clinical program to phase 3 studies these are the studies that patients will see in support of marketing of a drug that will appear in the product label and these are you know again rigorously designed and conducted studies that with pre specified statistical analysis plans that will be analyzed by the agency to support the marketing of the product and then finally drugs may be approved with certain questions still remaining especially regarding long-term safety outcomes and that's where the phase for clinical development comes in and these are studies that may be required or done post marketing of a product to further elucidate any remaining safety questions that might have arisen during the three program thank you that I think that's very helpful I think I even learned a couple a couple of things in there so you now one of the very common questions we get through our patient communication center is is about the different designations that are given during the drug development process and I think some of these terms get folks really excited that a drug might be on the verge of being approved or that the drug is effective and I'd love to have you clarify for us there are five different terms and maybe you can you can give us all all insight and understanding about these so they're two up on the screen right now our orphan drug status and the term fast-track can you address both of those for us sure so I think we have them split up onto two different slides here but really I think probably fast-track belongs on the next slide and so I'll I'll address orphan drug status and then I'll sort of go through fast-track breakthrough therapy accelerated approval and priority review because really there is a distinction and so the orphan drug status or orphan drug designation as we call it is a program that provides what we call orphan status to drugs and biologics and these are defined as those drugs which are intended for the safe and effective treatment diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States or that they affect more than 200,000 persons but are not expected to recover the cost of developing and marketing a treatment drug so what this status really when this status is conveyed to a drug it's really defining not only in a drug but the disease that its treating it's a rare disease that it's treating and the reason that you know one of the the orphan there's an act under from which this designation comes is called the Orphan Drug Act and it provides for granting special status to drugs or biologic products upon request of a sponsor and this is really done if the specific disease or condition criteria are met and this qualifies the sponsor for various development incentives including financial incentives qualified clinical testing and for those listeners who aren't aware when sponsors submit typically when sponsors submit a new drug application a marketing application to review for review to the agency they pay a fee in order for their drug application to be reviewed a drug that's granted orphan drug designation isn't subject to this user fee unless it unless other criteria are met but for sort of the simplest if you have if you if your drug has orphan drug designation the fee is basically waived and so this is really to incentivize sponsors to develop drugs for these rare diseases and orphan populations which really there may not be a financial incentive on their part to develop drugs fir for these conditions so that is really a status and can be granted basically at any time for a drug that is determined to treat a rare disease and again that's affecting fewer than 200,000 people in the United States we have a an office that reviews those those designation requests – to see if the disease actually does meet that criteria so the other four that are listed and maybe we can I don't know if you want to move on to the next slide but I won't forget that fast track show so FastTrack and breakthrough therapy accelerated approval and priority review again these are what we call within the agency are expedited programs for serious conditions and these programs are really intended to facility and expedite development and review of new drugs and address unmet medical needs in the treatment of serious or life-threatening conditions such as IPS for example and so these are the four programs fast track designation breakthrough therapy designation accelerated approval and Priority Review and so these these programs are really intended to help ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the therapies benefits justify their risk and so all for expedited programs represent efforts to address an unmet medical need in the treatment of a serious condition and as with everything all of these terms are explicitly defined so again we interpret the term serious to be a disease or condition associated with morbidity that has substantial impact on day to day functioning and short-lived and self-limiting morbidity look usually not be sufficient but the morbidity need not be irreversible if it's persistent or recurrent so we have also determined what and again you know these are programs that sponsors apply for for their drugs again and I understand that when something receives you know breakthrough therapy designation or fast track designation it can be interpreted in a number of ways I want to provide what is actually required for each of these programs what criteria is required so that you know we can understand and maybe sort way what each of these designations really need so with that I'll start with fast track so the qualifying criteria for some for a program to meet fast track or to be granted fast track designation is that it's intended to treat a serious condition and non clinical or clinical data demonstrate the potential to address unmet medical need so I'll contrast this with breakthrough therapy designation which is one of our newer expedited program and breakthrough therapy requires that the drug is also intended to treat a serious condition but there should be preliminary clinical evidence that indicates that the drug may demonstrate substantial improvement on clinically significant endpoints over available therapies so you can see that the the criteria for being designated a breakthrough therapy product are much more stringent than the criteria required for gaining fast track designation so in general we consider that IPS we consider IPS to be a serious condition and if a sponsor could come in with you know even some non clinical data that suggests that this drug attenuates lung fibrosis be very likely that they would be granted fast track designation however if they don't have preliminary clinical evidence that shows that their drug is substantially better over available therapies they wouldn't be designated as a breakthrough therapy so the breakthrough therapy requirements are higher look the criteria is more stringent and we need more data to look at and review prior to granting breakthrough therapy designation I'll skip over a caller ages approval for a second I'll go to priority review because this is also what's another designation so it's that's assigned to an application whereas accelerated approval is more of an approval pathway so Priority Review is granted or a program can be designated as a primary priority review if it's an application for a drug again that treats a serious condition that's sort of the common thread through all of these expedited programs and what provides and would provide a significant improvement in safety or effectiveness over our I'll stop there significant improvement in safety or effectiveness and so this is a designation that is given right before a marketing application comes in or at the time a marketing application comes in they might believe that they fulfill this criteria and they would ask FDA if we would grant them a priority review and what this means is that we would conduct our review activities on a shortened timeline so for the most part new molecular entities are reviewed over the course of 10 to 12 months and Priority Review applications are reviewed in six months and so this would this designation would be granted to those applications which we believed fulfill these criteria and in which we would be shortening our time clock to get the drug approved faster and available to patients and so for people who remember back to 2014 the offe s and s brihat been intended and presented own applications were submitted to the agency in May of 2014 and we committed to priority reviews for those two applications and in fact they were reviewed under the six-month time clock so we do exercise regulatory flexibility when we see that there are drugs out there that have the potential to really fulfill an unmet medical need and we have the data in hand to approve those drugs so that those are the three designation fast rap fast track breakthrough therapy and Priority Review and then finally accelerated approval which is also described in this guidance document that I am referring to and I can provide for listeners it's available on our website is an approval pathway and so this is a little bit different than three other programs and again it it it is offered to again those drugs that treat serious condition and generally provide a meaningful advantage over available therapies but the difference in this in this program is that the approval basically takes place using what's called a surrogate endpoint and this is an endpoint that FDA believes is reasonably likely to predict clinical benefit or a clinical endpoint that can be measured earlier than irreversible morbidity or mortality and it's reasonably likely to predict the effect of the investigational treatment or other clinical benefit so the difference in this expedited program is we're using this surrogate endpoint for approval but then we would want to see confirmatory trials afterwards to confirm and verify to describe the B that the effect that the surrogate endpoint actually demonstrated was followed up and confirmed by more definitive clinical endpoints so this approval pathway is not something that we have historically used in our division this is more often used in oncology where you know the surrogate endpoint might be tumor shrinkage and and then the confirmatory trials are followed up to me to ensure that clinical benefit follows along with that you know for to bring it back to idiopathic pulmonary fibrosis think we've come down to or you know with the review of the applications of pro phenytoin an incentive and you know review of the literature and where everyone has the thinking academic thinking is sort of gone we have accepted lung function as a clinically meaningful endpoint and so if one were to say that that was a surrogate further trials would be required and so in this case we're saying that that it's a traditional approval pathway that is the endpoint and no further confirmatory trials are required thank you for that so you mentioned the two drugs that are approved yeah by the FDA in the US for IPF which are antennae they've been prevented own so we we have a couple of questions at our focus more on interstitial lung disease and related forms of pulmonary fibrosis on the first is about patient-centered outcomes you actually just address this with with the you know the FCC measure that that's been used in in outcomes so can you just maybe build on that or reiterate just a little bit about how the FDA's perspective on safe in this case what I would call a physiological endpoint meaning you know a measurement of lung function versus a biomarker versus what we tend to call patient-centered outcomes and I'll let you elaborate on that yeah I mean you know this is this is a really important question and you know based on the approval of the two drugs that we're talking about presented and presented on and in tentative looking at lung function the physiologic endpoint of forced vital capacity is is sort of the current approval pathway what's the ideal approval pathway survival you know survival benefit would be the ideal approval pathway but those studies are difficult if not impractical to do and and even with lung function as a physiologic endpoint that we've sort of it's did based on our experience with the obstructive lung diseases you can imagine that to show a benefit in lung function really does still require long studies and you know we're not a hundred percent sure that it tracks with how patients are feeling or functioning or surviving we we can maybe make that jump theoretically logically but we don't know that and so we really have come you know to rely and to really see the importance of patient-centered outcomes in in interstitial lung disease and and you know an IPF specifically because this is something that is tangible to patients the drug is making them feel better it's making them function better and so we we really do see the importance of this and as you know we we held a patient-centered drug development workshop in September 2014 right before the two IPF drugs were approved and you know this really was helpful to us because we had patients providers even sponsors come out to listen and we really wanted to engage the wider community to discuss how we could approach these meetings so that we could collect systematic data and maybe provide a framework for others to collect this data systematically too so that we could sort of advance the science of patient input and you know while we're limited in our resources at FDA in order to take this information and really go forward and develop instruments we really thought that this input from the patient community would support drug development more broadly and really help identify specific areas of unmet need by listening to what patients were suffering from the most and also you know help identify outcome measures that could be developed for clinical trials so you know we were really using that forum to communicate to sponsors and developers of instruments because we think that you know we have endpoints for now are they the ideal endpoints you know they're I think it could be better and I think that the patient-centered outcomes are the way that we could improve the drug development for IPF thank you for that I certainly share your sentiments about that we certainly want drugs that help people live longer and healthier and better lives and the open forum you mentioned I think it was in 2014 what a fantastic thing that the FDA has been doing with that in many different disease states that was a that was a great forum I remember it very very well hearing the panelists had patients and advocates and family members on a couple of panels who just really communicated I think the disease state very very well and I'm glad and I heard you speak there and you were you're very eloquent and and wonderful things to say so maybe we'll see more of those then down the road so you know we do have a question what's that know I hope so me too so we do have a question about profanity and in ten of them you have already talked about this is there anything you want to add to the discussion we've already had are there any other unique aspects or anything else that would be of interest to our listeners or do you think we've covered it you know I think we've covered most of it I think that you know the I was involved in the in the review of both applications I think that you know there were one of the aspects specifically to me that was unique was that we had both applications in-house at the same time which very rarely happened and so we really were able to review and concert these two these two entities on and I think one of the other you know very unique aspects was this you know the approval of these two drugs really did establish the precedent that we would look at lung function in IPS specifically for vital capacity as an you know as a clinically meaningful endpoint and as a basis for approval and so I think having both applications in-house at the same time and you know taking and it allowed us to find using this endpoint to be acceptable and to gain comfort with this as an endpoint for approval it was it was a very concentrated but very intense it was a very concentrated an intense experience because in a very short timeframe we spoke with experts we convened advisory committees and really got a lot of input from both internally and externally so it was a an example of how the FDA really can do things quickly when it's necessary yeah I agree with that that was very impressive I don't know effect listeners know but the results of these clinical trials were published in May of 2014 and the drug was approved in October 2014 of course FDA certainly had had the data before it was published but that was that was very quick and very rewarding experience I think in that in the whole community pulmonary fibrosis well let's let's move on and tackle two additional terms or well just leave leave them to you to define and help us understand one is expanded access which has been around for a while and the other is right to try which is a little bit newer and I'm hoping you can shed some light on these for our listeners these are questions we get quite commonly so expanded access is a program that has has that we have been operating under for many many years it's not a new program and this really is meant to provide patients with access to drugs that that may currently be under review or on their way to approval and so and a lot of sponsors will actually ask for permission to have expanded access programs while their new drug applications are being reviewed and this is just so that as the application is being reviewed because as the listeners have heard you know we have timelines under which we review these applications and while we try to be as expeditious as possible again you know we do take time and we don't want you know patients who were participating in clinical trials and gaining benefit from a drug and a drug that's likely headed towards approval to be cut off from receiving that drug and so under expanded access programs they're able to continue to receive the drug while FDA is reviewing the efficacy and safety of the application the right to try legislation is something that just came into effect and this legislation gives terminally ill patients the right to use experimental medications that have not been approved by the FDA and so as many of the listeners may be aware the President signed this law the right to try act of 2017 and this new law amends what I talked about earlier which is the Federal Food Drug and Cosmetic Act and it's intended to increase access to certain unapproved investigational treatment either drugs or biological products for patients that are diagnosed with life-threatening diseases or conditions who have exhausted approved treatment option and are unable to participate in the Clinton a clinical trial involving the investigational drug as certified by a physician so an eligible patient under this right to try act would be one with a life-threatening disease again this is defined in the Code of Federal Regulations and who meets certain other conditions that are set forth in the statute and the investigational drug or biological product can only be provided under light to try if it's not approved or licensed for any use it's completed just a phase one trial so if listeners remember back to phase one that means that it was basically just given to humans found to be safe and tolerable but there hasn't been any investigation into its proof of concept of whether it works or not yet and then and if it is also the subject of a new drug application or a biologic application filed with us at the FDA or is a subject of an active IND which is an investigational new drug application which is basically what all drugs are before they come in for marketing and it's under investigation in a clinical trial that's intended to inform the primary basis of a claim of efficacy so to contrast it with expanded access expanded access often has more data associated with it the right to try drugs will have you know less data in terms of their efficacy available for review and again it has it has to be a drug that's actively being developed in that the development ongoing and not discontinued and it's not on what we call clinical hold and for a lot of along different drug development pathways if at any point we find a clinical trial at FDA to be unsafe we put the application on what's called a clinical hold which means it's there at that point the sponsor may no longer conduct studies so in order for a drug to be accessed under the right to try it cannot be on clinical hold and so you know we're still trying to work out how we are going to how we at the FDA are going to deal with this right to try act we are reviewing the legislation internally and you know we're working to implement it in a manner that's consistent with the congressional intent and with FDA's Public Health mission and we receive a lot of questions about the process and how you know patients should go about inquiring about this or figuring out whether they are eligible or whether a drug qualifies under the right to try Act two to to be administered and you know at this point in time I don't have a definitive answer for patients but all I can say is we are really working as fast as we can to develop further information on how to respond to patient inquiries and so at this point we really do believe that sponsors who are developing the drugs are in the best position to provide information of the development status of their products and I mean that's really one of the key determinants to whether the drug is eligible for use under the right to try act and whether they the sponsor intends to make an investigational product available under the right to try at so we at the FDA are just we're just we're working currently to figure out how this fits into our regulatory framework and into our review processes but you know we encourage patients if they have questions about certain drugs or questions about whether they would qualify to reach out to the sponsors of those drugs thank you that definitely clarifies it for everyone and just for our listeners when when we say sponsor we mean that the drug developer which might in many cases be a pharmaceutical company that is our last slide yes that is our last slide our last question I know a few of you have put some questions into the chat box we're not going to be able to address them but I do encourage you to email them to the pulmonary fibrosis foundation you can reach our patient communication center at PCC at pulmonary fibrosis org and we will do our best to to give you all the information you want or need and dr. creamy Shaw I want to thank you so much this was a fantastic webinar it was extremely informative answered a lot of questions we get so now we have a lot of information we can provide to the patient community when they reach out to us with questions and I hope in the year or two you'll come back and and share some more important information with with us thank you so much you're very welcome thank you so much for having me okay and thank you to our listener

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