Taking Advantage of the Orphan Drug Act – Webinar

In this webinar, Marla Scarola, M.S., Senior Consultant, The Weinberg Group, helps senior life science executives understand how to best take advantage of the significant opportunities provided by the Orphan Drug Act.

“KRISTEN BOOTH: Good morning and good afternoon, everyone, and thank you for joining our webinar. My name is Kristin Booth from the Weinberg Group and I will be moderating this presentation titled, “Taking Advantage of the Orphan Drug Act.” The Weinberg Group is a leading food and drug consultancy with headquarters in Washington DC as well as an office in San Francisco. The speaker on today’s webinar is Marla Scarola, a senior consultant at The Weinberg Group. Ms. Scarola earned her Masters in Biotech at Johns Hopkins University. During her time at The Weinberg Group has assisted in the development of countless regulatory strategies as well as the preparation of the QA of regulatory submissions in both the US and EU. During the course of today’s presentation, you will be able to submit questions to be answered by Miss Scorola at the end of the presentation. We will try to get as many as many questions as possible answered today. However, if we can’t get to all of them we will email the answers along with the copy of the sides to you within a week of the presentation. With that, we will begin the webinar.

MARLA SCAROLA: Today’s webinar, I plan to cover some of the basics of the Orphan Drug Act. So we’ll talk about what types of drugs are eligible, what some of the benefits are. I’m also going to go into some specifics about how you file an Orphan Drug designation request.Then I’ll talk about the approval criteria for orphan products and how they compared to your more traditional products, your not-orphaned products. I’ll raise some of the challenges that companies should be aware of, or some of the nuance at least when considering an orphan drug pathway. And then lastly, I’ll just briefly mention a couple of other programs that are available for rare diseases or conditions. The Orphan Drug Act was enacted in 1983. The intention was to create incentives for sponsors to pursue development of product that will help only a small population of patients. So while it’s called the Orphan Drug Act, the program program actually applies to not only small molecules but also biologics. The orphan terminology derived from the many drugs that were known to be potentially effective for rare diseases but had been eventually abandoned during development for the lack of profitability. This situation led to a lot of frustrated patients and caregivers who could look in the published literature and find there are certain drugs that showed promise as treatment for rare diseases but they were no longer being pursued by any pharmaceutical companies.

So how many orphans are out there? In the United States there are as many as 7,000 rare diseases in total and they afflict anywhere from 25 to 30 million Americans. So that comes out to more than one in every ten Americans. So while each individual disease affects few people, many people really do suffer if Orphan drugs in general are not being developed. And this was the case before the Orphan Drug Act was enacted so you can see in this figure before 1983, there were only 10 drugs for rare conditions approved. But then once the OIrphan Drug Act came into place and implemented, the number of designations has now reached almost 3,000. And at the end of 2013, the end of last year, 457 products has been approved. This slide shows the worldwide orphan designations. You’re looking at EU, U.S., and Japan. So based on the successes of the U.S. program, some other regulatory agencies worldwide now also offer orphan drug programs. So this slide is showing the number of orphan designation per year and you can see the US in blue, the EU in red, and Japan is in green. And the increase over time is especially dramatic when you look at the United States and Europe in the last decade or so.

So why consider pursuing an orphan drug? The Orphan Drug Act provides a number of key incentives to sponsors to facilitate the development of treatment for rare disease. The first is seven years of marketing exclusivity. During this seven years, the FDA will not approve the same drugs for the same orphan indication. And we’ll go into a bit more detail later on in the presentation about what FDA really means when they say drug in the context of orphans. And also talked about some ways that competitors potentially get around this policy. The FDA also offers protocol assistance. The responsibility for providing advice on orphan drug protocols rest with whatever review division you’re working with, in whatever category your drug falls into, you’ll be working with that review division. However, the Office of Orphan Product Development act as an advocate for the sponsor by monitoring the protocol review and asking to resolve any issues that may arise.

Sponsors can also take advantage of a tax credit. And this covers up to 50% of clinical trial costs and can be applied to federal taxes that were incurred in the prior-year, prior to approval, or you can hold on to it and then use it against future taxes for anywhere up to 20 years. It is important to note that the credit does not apply to testing that is done outside of the United States. And the only way around that is if you can prove that the available testing population in the United States is insufficient and you had to branch out and go into other regions of the world To be able to get sufficient numbers of patients to study.

The FDA also offers research grants to help fund the clinical investigation for orphaned products. Although you don’t have to have the orphan designation at the time you apply for and receive the grant. So they’re focused on rare diseases but the designation doesn’t have to be in place before you get those grants. The grants are meant for studies that are being conducted under an active IND and they must be providing data that will advance the product toward market approval. Funding each year depends on Congressional Appropriations so it can fluctuate a bit. Early in the program, the funding rarely exceeded 2 million dollars but the current annual budget is now about 14 million dollars so it has grown over time. The grants are generally given they last three to four years and use it anywhere from 60 to 85 grants that are funded any given time.

And the last incentive products are also waved from having to pay the PDUFA application fee. And this is really a substantial savings considering that in 2014, so currently the fee for an application with clinical data is now nearly 2.2 million dollars.

So now, you’re probably thinking: Well, this all sounds great so where do I sign up? I want to take advantage of these incentives. But first, you have to figure out whether your product and your indication is eligible for orphan status. To determine whether an indication would be considered orphan, you have to determine the size of the affected population. The disease or condition needs impact fewer than 200,000 people in the United States. Drugs can still qualify for orphan status if the indication affects more than 200,000 people but in those cases the applicant has to show that they won’t be able to recoup the cost associated with research and development of the product within the first 7 years following FDA approval. That option is very rarely used. Usually, people just go in based on the prevalence estimate. The option with recouping the cost of investment is just really difficult to prove so it’s rarely, rarely used.

When evaluating whether your proposed indication affects fewer than 200,000 There are a few key considerations that need to be made the first is whether it’s an acute or chronic condition. So if it’s an acute condition, something like malaria, you’re going to want to determine the incidence. But if instead, you’re focused on a chronic condition, and this is where the majority of orphan indications fall into the group of chronic indications, then you’re going to need to count everyone who has the disease at any given point in time. And you can use a variety of sources to justify your prevalence estimate. Typically, the data can be found in the published literature or there may be certain registries or databases that track the prevalence of the condition. If there are no good data available to you, as a last resort an option is to get three independent expert opinions and those can be submitted as justification. But like I said, that really should be seen as a last resort when you’re reviewing all of these different data estimates provided in the literature. The databases, or whatever, you’re going to likely end up with a range of estimates. They’re all not going to be the same, obviously, and it’s the upper end of that range that matters. So it’s not just the average; you can’t take the middle point if the upper end of the range exceeds 200 thousand. Then you won’t qualify for orphan designation.

If the disease or condition is common, orphan designation can still actually be granted if the drug is only for use in a certain subset of the disease population. So, for example, the drug may treat a certain cancer but it’s only affected in patients with a specific genetic mutation. Another way to think about it is if the toxicity of the product is too high to be tolerated in the broader patient population but it is reasonable for a subset of patients that are suffering from more severe disease. So that higher toxicity would be tolerated.

You want to keep in mind that the subset needs to be medically plausible. So you can’t just salami slice the population of this referred to, meaning, sort of cut it up, just to create a small enough subset to qualify for orphan designation. It has to be there has to be a good medical reason for why you’re considering that population to be distinct.

So you’re going to need to provide some type of evidence that demonstrates why your product would not be useful in the broad. So, again, this could be based on toxicity or the specific mechanism of action or just your clinical experience in what population the product works best. Then, as I said, when the FDA grants market exclusivity for an orphan drug, that means they will not approve the same drug for the same indication for seven years. So whether two drugs are different is determined entirely by the active moiety. So two different salt forms of the same active ingredient are considered to be the same as our two peptides with only minor changes in amino acid composition. So this is a little different from other areas of FDA in considering whether two drugs are the same. There can be more differences between two drugs and the orphan office will consider them to be the same even if another orphan product considered to be the same as yours has already received market approval for the same indication you’re seeking.

You may still be eligible for approval and the benefits afforded to orphan products. So this can occur on the basis of clinical superiority to the product already on the market and this is the loophole of sorts that I was referring to when I said that, generally, the market exclusivity will prevent the same drug for the same indication from being approved. So the superiority can be based on advocacy or safety or it can be based on the product providing a major contribution to patient care. In this latter case, the improvement in patient care cannot be accompanied by a loss in efficacy or safety. So you have to be at least effective and at least as safe as the currently approved product and then you also have to add on top of that some major contributions to patient care.

So some examples of what would be considered major contributions to patient care would include changes in your formulations like changing from an injection to an oral product or decreasing the frequency of dosing but more along the lines of going from maybe a once per day dose to per month dose. Going just from like a three times per day to a once per day is likely not enough of the change to be considered a major contribution.

In the case where drug has already been approved for an orphan indication, subsequent drugs with the same active moiety may be granted an orphan designation on the basis of a plausible hypothesis of clinical superiority. But to obtain approval for the same indication and orphan benefits, the clinical superiority to the approved drug needs to actually be demonstrated in the eventual marketing application. So in the NDA or PLA.

So it’s not clear yet whether this means you have to conduct head-to-head clinical trials. There is this added burden beyond merely showing efficacy and safety for the orphan product. So this may mean that comparison to placebo and clinical trials is not enough and an active comparator will need to be included in your trial.

So what do you actually need to include in this application? In general, there are two major elements. You need to demonstrate plausibility for the drugs expected benefit. So this could be based on clinical data or even animal studies or in vitro data that show mechanism of action, a proof of concept kind of thing.

So, typically, applications with clinical data are more successful but there have been sponsors that have received designations on the basis of just the animal or in vitro studies alone. The clinical data that you submit can be very preliminary. You know, you’re simply showing that the drug might be effective. You’re not proving efficacy at this point. You don’t have to do big studies with lots of patients and that would be difficult to do anyway often in these orphan populations. You don’t even need safety studies at this point. Remember, this is just for the designation; it has nothing to do with what the requirements for the market approval would be which will certainly be much more rigorous.

And then of course application must also contain your complete argument that demonstrates that less than 200,000 people in the United States are in the indicated population. And this is, arguably, the most important element of the application. There’s no 505(b)(2) type of option here. What I mean by that is you can’t simply reference somebody else’s designation or approval. So you need to provide your own argument here with your own data support, do your own analysis of the data that are out there and present that to the FDA.

The specific contents of the application are listed in the CFR in section 31620 and there are eight parts and FDA recommends that you number the sections in your application to match the numbering in the CFR. So don’t get creative and kind of create your own outline of format. Instead, just follow what they’ve provided here for you.

So the first part is a statement of request for designation indicating the specific rare disease for which the designation is being sought. The second part is simple; it’s the contact information for the sponsor. You also want to provide the identification of the drug and its source if it’s different from the sponsor. You, then, in part three, want a description of the rare diseases proposed indication and the reason why the therapy is needed. And then four is the scientific rationale for the use of the drug. So this should be a description of the drug. It would include the active moiety or the principal molecular structural features, depending on what type of products you have.

If you can provide the drugs physical and chemical properties, then you should include those as well, sort of depends where you are in your development. And then you need a discussion of the scientific rationale to establish the medically plausible basis for the use of the drug for the rare disease or condition. So you want to include all the relevant data from your in vitro lab studies, your preclinical efficacy studies, that are using an animal model for the human disease. And then you’re also wanting to include the clinical experience with the drug, anything that’s available for the sponsor. So really, this should be all-inclusive. You want to present anything you can find whether it’s positive, negative, or inconclusive. The one thing you don’t need to provide, at this point, are the animal talk studies.

And then part 5, if you’re claiming clinical superiority to an already proved drug, then you’re going to have to include the basis for that conclusion in this part 5. If you’re not, then you could just leave it like it’s not applicable. If you’re claiming that the drugs will be used by only a subset of patients from the broader indication, in part 6, you’re going to have to provide that argument and demonstrate that the patients in the broader population would not be appropriate candidates for the drug.

In part 7, you need to provide a summary of the regulatory status and marketing history of your product. So this should include activities that are occurring both inside of the United States and in other parts of the world.

And then part 8, last but certainly not least, is where you need to provide support for the conclusion that prevalence is fewer than 200,000 people in the United States.

Your application can be provided in hard copy, in which case two copies need to be submitted. Or, you have the option of just submitting one CD with an electronic version of the application. But you also need to submit a hard copy of the cover letter along with the CD. And all of the applications should go directly to the Office of Orphan Products’ development, address to the director at the address shown here on this slide.

The question that we get a lot is around the timing of the orphan designation requests and wondering when exactly in development it makes no sense to submit that. There are some things to consider when you’re making that decision. When it comes down to it, you just need to have the designation submitted not even actually approved but just submitted before you get your NDA or BLA filed. So that’s the requirement to get it in before the filing of the market application.

But for some sponsors, it can be beneficial to have the designation earlier in the development process. This allows for more certainty when you’re having discussions with potential partners or investors so you have a better understanding of what it will take to get approval or that you know that you have this orphan designation and you can flaunt that you know what your exclusivity would be if you get approval.

Also allows you to take advantage of some of those incentives that FDA offers that are most helpful during development and that would be like the protocol assistance. One thing to know is that it’s not even necessary to have an IND filed at the time you submit the orphan designation request. So you really could submit the request very early in your development as long as you have enough information to support the medical possibility aspect as argument.

It is important to realize that the application process is confidential.
Once the designation is granted, then it becomes public. So it’s published in an FDA database as well as the Federal Register. So that’s something to consider and multiple sponsors can hold orphan designations for the same drug for the same indication but it’s the first one who gets approval, they’re the only one who will get market exclusivity in the tax credit. So once that designation becomes public, it’s essentially a race to approval for all sponsors who are developing the drug.

Given that development discussions with FDA are generally confidential, you may be wondering why they treat orphans differently. So, normally, when you’re going to your pre-IND meetings, none of that information is public information. But really, for orphans, it all comes down to what is better for the patient. So you have to remember the reason why this legislation exists: it’s there because treatment for rare diseases were incredibly sparse without it. So creating this competition between sponsors speeds the whole development process. Ultimately, it’s seen as benefiting the patient in getting an approved drug on the market faster.

So what happens after this mission goes in? First, it gets assigned a designation application number and it gets logged into the OPD database. At that time, they send out an acknowledgment letter to the sponsor and it just simply lets you know that your application has been received. And then they’ll begin reviewing the application and they’ll often do this in consult with the appropriate review division that might have more knowledge and familiarity with your proposed indication. Then, the typical request review takes about 60 to 90 days. At the end of that time, you’ll receive either a designation letter or a deficiency letter. The issuance of a deficiency letter is relatively new. You used to just either get a letter that would request additional information or just a denial that didn’t provide you really any other details on why you’re getting denied. If your request is denied, you have the opportunity to resubmit it as many times as you’d like up until you submit the marketing application. So that’s the cutoff for when you can’t submit any more and if you submit a number of times, if you keep going back and forth and getting a deficiency letter, FDA might sort of realize that there’s some fundamental misunderstanding of their expectations and, at that point, they could request a meeting just to talk through some of the issues with you.

You’re also welcome to reach out to the Office of Orphan Products with questions at any point along the way. If the deficiency letter is issued, you have one year to respond to it. Unless you request an extension, if you haven’t responded within one year, your request for designation will be withdrawn. If you’ve been granted an orphan designation, so you get the designation letter, you’re required then to submit an annual report within 14 months of designation and then each year thereafter. And that annual report should update the agency on your status and your general progress.

So that annual report submission should include a brief overview of the progress you’ve made in your drug development. So this would include a review of your non-clinical and clinical studies, provide the status of each of those whether it’s planned ongoing completed. and then if available, you can provide a short summary of results.

You also want to include a description of the investigational plan for the coming year. And this would be where you would bring up any anticipated difficulties that you think are going to come into place in your development, in your testing, in your marketing, just to make FDA aware of those issues early on. And much of this information can actually be provided simply by cross-referencing your IND if you have one. And then the last thing you want to include in that annual report is to address any changes that could affect the orphan status of the product. So you’ve likely been in discussions with the review division about your indication and the right design of your clinical trials and all that sort of thing and so you may have actually revised your indication during the course of development and the impact of this change should be discussed in the orphan drug annual report. Because, depending on how much the indication is changed, it could impact your orphan status and so you may need to submit an amendment to your orphan designation request.

As I mentioned, FDA maintains a database of orphan drug designation and eventual approvals. So this slide shows a screen capture of that database. The product name field can be searched on the basis of the generic name or trade name or even just part of the name. And then the designation field is for the indications and that can be searched with just part of a word. If you’re really just interested in seeing a complete list of all of those designations and approvals, you can just leave all of the fields blank or in the default settings and then just click on the run search button. And then you’ll have a full list there that you can review.

As already mentioned, there are some other regulatory agencies that have entered orphan drug programs. One of these is the European agency, the EMA, a joint application is actually available for sponsors who wish to apply for designations in both the United States and the EU. There’s a common form, it’s the FDA form 3671, that can be completed and submitted to both agencies.

It is important to know, however, that the form is not actually current with some of the revisions to the FDA application contents as they’re listed in the CFR and that 316.20. So most notably, FDA no longer requires a statement of interest so that portion of the joint application form can just be left blank for the United States. The prevalence threshold for the EU is slightly different from that of the United States so this is something you’ll have to think about if you’re considering whether you could apply in both regions. So it’s expressed as a rate rather than an absolute number. The threshold is fewer than five and every 10,000 people in the EU. So it’s a rate based on the population of all the Member States of the EU.

There are also more criteria that one must meet to get orphan designation in the EU. So the drug must be intended for the treatment prevention or diagnosis of a disease that is life-threatening or chronically debilitating and that’s a higher bar than what is that in the United States. Also, no satisfactory method of diagnosis, prevention, or treatment of the condition can be approved or, if there is something that’s already approved, the new drug must be a significant benefit to those affected by the condition. So it’s a little bit more strict criteria to get through the orphan designation process and in the EU.

The Japanese regulatory agency has also begun supporting orphan drugs and this is based on the success of the U.S. program. Depending on the timing of the application, the submission is handled either by Japan’s Ministry of Health Labor and Welfare or it could be handled by the pharmaceuticals and medical devices agency. So in Japan, the threshold is like the United States, it’s expressed in absolute terms. And so there, it needs to be fewer than 50,000 patients affected in all of Japan. You must also demonstrate there’s a high medical need for the product. So just that one additional element.

I already talked a bit about the various incentives that come along with orphan designation and approval. While these are all attractive, there are some nuances that sponsors should be aware of. One of those powerful incentives offers through the orphan drug program is the market exclusivity. So as I said, drugs with orphan designations that receive market approval are granted seven years of exclusivity for the orphan indication, just for that indication. It’s important to realize that other sponsors can seek approval of other indications and those products can then be used off-label for the orphan indication. So, because of this, there’s less incentive to study approved drugs for orphan uses because it really increases the chances that a generic drug will come onto the market and be used off-label for the orphan indication. The one way to avoid this is to make changes, significant enough changes, to the dosage form or the strength of the approved product and tailor it to be used for the orphan indication. One drug can hold multiple orphan designations and, ultimately, approval for multiple indications. So each indication receives market exclusivity. So if another sponsor could identify a second orphan indication for a drug and both NDAs could get approval with seven years of exclusivity for essentially interchangeable products.

As I mentioned already, a tax credit covering up to 50% of the clinical trial cost is offered. It can be applied to federal taxes incurred in the year prior to approval or any time in the following twenty years. However, this is only helpful to a company that is actually enjoying taxable income that needs to be offset. For some companies, especially startups, this may not occur anytime in the short-term. So granted, you do have 20 years to use the credit but it’s likely to be most useful early on. So it’s just something to consider.

The improvable requirements are no different for orphan drugs than they are for other drugs. Overall, you must provide substantial evidence of safety and effectiveness. Of course, defining what is substantial is handled on a somewhat case-by-case basis and the FDA is a lot of discretion in determining what data package is necessary for approval. Gathering substantial data can be pretty difficult to do considering that there are significant hurdles associated with studying orphan drugs. Specifically, because the patient populations are so small, you really can encounter a lot of difficulty in trying to recruit patients for your clinical studies. It also can make it really challenging to find clinical investigators who you would consider to be experts in their field, who are also experienced in clinical trials and the principles of good clinical practices. And it may be nearly impossible to find a research center that focuses on the disease of interest. Those are the types of selection criteria you would look for in a clinical trial on a larger scale for non-orphan indication, focusing in on research centers and people who are experts. It’s just harder to find those people. The conditions being studied, the orphan indications, are often chronic, progressive, serious life-limiting and life-threatening diseases with unmet medical means. Diseases like this, it only complicates clinical study design and conduct because these indications have traditionally not received a lot of attention. Often, there isn’t really a go-to for your endpoints, your clinical endpoints, or your outcome measures, tools, instruments, biomarkers. It’s especially important in cases like this to have a good dialogue with the FDA to make sure that you have reached agreement on what the appropriate endpoints are, what the appropriate study design is. And this is why the protocol assistance benefit really does have a lot of value

Because of these hurdles, there’s a need for flexibility in orphan drug development. Some of the areas of possible flexibility that can be negotiated with FDA includes smaller safety databases than would normally be required, limiting your dose ranking studies so you’re able to progress to phase three studies a little bit quicker, using a non validated outcome measure or instrument, providing just one single pivotal efficacy and safety study rather than your traditional two. You can run your studies without concurrent control. In this case, you might be able to identify historical controls from the published literature or you could do case record reviews. You may also be able to generate data to satisfy some of FDA’s concerns entirely from a retrospective review of case studies. So all of these possible “shortcuts” should be discussed with FDA at your milestone meetings or through the available protocol assistance benefit. Whatever approach you take, you want to make sure the FDA agrees with it to avoid getting in a situation where you have to repeat any of your studies.

The requirements for the amount of data necessary to support approval are, like I said, handled on a case-by-case basis and you can see how different the requirements can be from one product to another.

So here’s our two examples. The first one, carglumic acid which treats a rare metabolic disorder. It was approved in 2010 and that was on the basis of just one single study. So the study was an open-label, historically controlled, retrospective case series of just 23 subjects. Now in comparison dalfampridine, which provide relief from multiple sclerosis symptoms, it was also approved in 2010. So this isn’t changing over time but that data package included your more traditional two to randomized placebo-controlled studies with a total of 540 subjects.

The orphan drug program is handled by the Office of Orphan Product Development. The office is housed within the commissioner’s office. Included in the administration of the orphan drug program are the designation, so that’s where you submit your request for designation, the grant also, so the grant applications would go here, and also coordination with the reviewing divisions on any issues relating to the orphan drug process. So this is where the OPD staff come in as advocates for the sponsor in your protocol assistance and discussions with the reviewing divisions. OOTD reports to the office of special medical programs within the Office of the Commissioner.

So this slide shows the orphan drug structure within FDA. So, you can see OOPD under the Office of the Commissioner and then CDER also has a rare diseases group under the Office of New Drugs.

The mission of the CDER Rare Disease Program is to support research, development, regulation, and approval of drugs and biologics for rare diseases. The program coordinates the development of CDER policy procedures and training for the review and approval of treatments for rare disease. They assist in the development and maintenance of good science for rare diseases. They work collaboratively with stakeholders for development of treatments for rare diseases and they also serve as CDER’s focal point to the rare disease drug development community on how best to interact with CDER.

In addition to the drug and biologics orphan designations that we’ve been talking about, there’s a similar program for medical devices and it’s called Humanitarian Use Devices. This program was established in 1990 and it’s for devices intended to treat or diagnose diseases or conditions that affect fewer than 4000 people the United States per year. So the information that needs to be submitted in a humanitarian use device application is similar to what is submitted for drugs and biologics. So you have to provide data demonstrating that the population estimate is fewer than 4,000 per year. Again, this can be a subset of a broader population but in that case, the rationale has to be provided explaining why the device isn’t meant for use in the bigger population. The application should also contain a description of the rare disease and a description of the device and the scientific rationale for its use. Devices that receive the humanitarian use designation can then apply for marketing approval with a humanitarian device exemption application. So this application is similar to a PMA, pre-market approval, but rather than submitting data in support of both safety and efficacy, with the humanitarian device exception, you can just provide information on the safety of the device and you don’t need to prove the efficacy of the device.

One last program that I wanted to talk about today is an incentive available to sponsors with drugs that treat rare diseases but, specifically, it’s for rare pediatric diseases and it’s a Priority Review Voucher Program. So this program is modeled after the Priority Review Voucher Program that’s awarded for drugs that treat neglected tropical diseases. So if you get a drug approved that treats one of these neglected tropical diseases, they’ll then give you a voucher for priority review of another product. So the Pediatric Disease Priority Review voucher was established in 2012 as part of the FDA Safety Information Act and the purpose of it, overall, is to incentivize development of drugs for rare pediatric diseases. So you can earn a voucher by receiving approval of an NME, a New Molecular Entity, that qualifies for orphan status for a disease that primarily affects individuals aged from birth to 18 years.

The voucher is then used to guarantee you priority review. So this takes your review clock down from the normal ten or twelve months, depending on whether your product is an NME, down to six months. So this is really a significant reduction in the amount of time that your application is under FDA review. So the obvious appeal here is that it allows the sponsor to get that first-to-market advantage. The vouchers can be sold from one company to another and they can be used for any drug. It’s not just for drugs that treat rare diseases. It’s not just for drugs that warrant expedited review. It really can be used for anything at all that’s in your pipeline. So you really could use this as a strategic opportunity to get your application in and approved ahead of another company who you might be racing to approval.

The priority reviews also comes with an additional fee. The fee for 2014, for this year, is 2,324,000 dollars. And this extra fee is on top of any other fee that would normally apply. So if you’re already paying the full fee for an application that contains the clinical data, you’re already paying over two million dollars to file your NDA and then this would be on top of it. So you’re paying well over four million dollars to get your application reviewed. So far, no vouchers have been awarded. The program is still in a testing phase. The plan now is that once the first three vouchers are issued, they’ll start a clock and at the end of one year they’re not going to issue any more vouchers. So, at that time, they’re going to stop issuing the vouchers and then the Government Accountability Office will come in and really assess the success of the program and determine whether or not they’re going to continue it in the future.

KRISTEN BOOTH: Thanks, Marla. That concludes the webinar. We have a number of questions and the first is: “Can a drug approved for a non-orphan indication be then approved for an orphan under the same NDA? Will it gain additional exclusivity?”

MARLA SCAROLA: Yeah, that’s a good question. Yes, you can have a drug that’s approved for both a non-orphan indication and an orphan indication and you’ll always get that exclusivity, the seven years marketing exclusivity for the orphan indication. A good example of this would be Viagra which was obviously originally approved for erectile dysfunction which is not an orphan indication but then it also received an orphan designation for pediatric pulmonary arterial hypertension. So that was, you know, just one of its indications or orphan and, on top of that, too, one single drug can have multiple orphan designations and orphan indication approvals and each sponsor will get the exclusivity for their specific indication. But, obviously, if there are other indications that don’t have any kind of market protection, at that point, generic could come into the market against one of the other indicated products and be used off-label for the orphan indication. So that’s something to think about, too.

KRISTEN BOOTH: Okay, great. The next question is: “How do I file my orphan drug to my existing IND?”

MARLA SCAROLA: The orphan designation process is sort of completely separate from your IND filing. So it’s handled by the Office of Orphan Drugs and there’s a place, I think, on the 1571 that you’ll submit with any IND submissions, where you can list whether you have an orphan designation and you can put your orphan designation number in there. But nothing is actually filed to the IND for the orphan drug designation. That request just goes straight to the to the office of orphan drug development. The other thing to note is that you don’t even actually have to have an IND at the time that you submit an orphan designation request. So you don’t have to have those linked in any way.

KRISTEN BOOTH: Okay, good. We have another one here and the question is: “Is there an appeal function if the sponsor disagrees with a negative decision?”

MARLA SCAROLA: Yeah, essentially there, your ability to resubmit your application is basically the way that you would appeal the decision. So FDA will issue a deficiency letter that lists out the reasons for why they’re denying your orphan drug designation request and then you have a year to take a look at that letter and figure out how you can respond to it. If you need to add more data or find some new literature to reference or something like that. If you don’t get back to the FDA within a year of getting the Division 2 letter, they’re going to just consider it to be withdrawn but you can go back and forth with them as many times as you want. I think I mentioned this already during the presentation. At some point, FDA might think,”This has gone back and forth too many times. Maybe we just need to have a telecon or a meeting to talk through some of these issues.” That will be done on their behalf but I think you could also probably request to get some advice and converse with the people in the Orphan Drug Office to get a better understanding of how you could address the deficiencies.

KRISTEN BOOTH: Okay, great. I think we have time for a few more questions and the next one is: “For joint FDA EMA review, will the decision for orphan designation be taken jointly?”

MARLA SCAROLA: No. So the joint part of that FDA EMA relationship is just in the application. So you can file just one application. You know, it’s the same application that you can file to both agencies but requirements for orphan drug designation are a little bit different for the FDA. It’s that absolute population estimate of less than 200,000 people. Whereas in the European Union, it’s based on the population. So it’s less than five in 10,000. So the prevalence could differ a little bit in the two regions and you’re also focusing on the prevalence of the condition in that specific region. So for the FDA, they want to know how many people in the United States have that condition not worldwide so you won’t necessarily qualify in both regions. Often, people do. Often, drugs will qualify in those places but it’s not a given. The EMA also has some additional requirements that have do with the seriousness of the condition that you’re treating and also whether there are any other therapies on the market and if there are then the new one needs to provide some sort of benefit over what’s already approved.

KRISTEN BOOTH: Alright,t thank you. Our next question is about submissions format. The person is wondering; “If you can elaborate more on the format, should it be paper CD DVD or both and is it possible to do an East mission?”

MARLA SCAROLA: Sure, yeah, FDA asked for two paper copies of the submission that go directly to the Office of Orphan Drug Development but you could also submit a single CD that has an electronic version of the applications. All of your files would be on there electronically. You just need one CD submitted but you’re also going to want to submit a hard copy of a cover letter along with that submission. So it doesn’t go through the electronic gateway. So it’s not necessarily an e-submission but you do have that ability to submit something just in electronic format. In Europe, you have to submit one paper copy and also two electronic copies. So you don’t really have the choice between the paper or electronic over there.

KRISTEN BOOTH: Okay, thank you. Our next question is: “Could an ODD be requested during review of an NDA?”

MARLA SCAROLA: No. so the cutoff for requesting your orphan designation is prior to the filing of an NDA or BLA. You don’t have to have the approval in time for the NDA filing so you could have submitted your designation request right before you filed your NDA but you have to have at least filed the designation request before the NDA went in.

KRISTEN BOOTH: Okay, great. Well, I think we are just about out of time so I’ll ask you one more question. And that is: “Once one applies for orphan status, how long does it take for review and approval?”

MARLA SCAROLA: Well, there aren’t any sort of PDUFA review timelines associated with the orphan designation request process but, generally, FDA will get back to you anywhere within like a 60 to 90-day window. Rarely do they take longer than 90 days to review the request.

KRISTEN BOOTH: Well, thank you so much, Marla, for your presentation and for your answers to these questions. It looks like we are out of time and we do have a few remaining questions which we will answer an email to you along with the slides within the next week. In addition, we would appreciate it if you could take a minute to fill out the evaluation survey on the left side of your screen and we thank you all for enjoying the presentation.”