Single and Shared REMS Systems: The Past, Present and Future Webinar

In this webinar, Emily Krulewitz, Research Associate, The Weinberg Group, helps senior life science executives understand the complex elements of REMS and prepare for the creation and implementation of a single or shared system REMS.

“CLAIRE ROBERTSON: Good morning and good afternoon, everyone. Thank you for joining our webinar my name is Claire Robertson from The Weinberg Group and I will be moderating this presentation titled “Single and Shared REMS Systems: The Past, Present, and Future.” The Weinberg Group is the leading food and drug consultancy with headquarters in DC as well as an office in San Francisco. The speaker on today’s webinar is Emily Krulewitz, a research associate at The Weinberg Group. Ms. Krulewitz graduated Phi Beta Kappa from Northwestern with a double major in Chemistry and Integrated Arts. At The Weinberg Group, Emily assists in the coordination and compilation of regulatory submissions, provides support in responding to various legislative challenges consumer and industrial products and is responsible for the management dissemination and review of scientific literature. During the course of today’s presentation, you will be able to submit questions to be answered by Ms. Krulewitz at the end of the presentation. We will try to answer as many questions as possible during the presentation today. However, if we are unable to get to all of them, we will email the answers along with the slides within a week. With that we will begin the webinar.

EMILY KRULEWITZ: Thanks, Claire. So today, we’ll be talking about REMS or Risk Evaluation and Mitigation Strategies. We’ll cover the history and context of rams and other FDA risk management programs as well as explain who is affected by REMS requirements. We’ll also talk through and give examples of the five basic components of REMS programs. Additionally, we’ll discussed shared system REMS and look at them to the lens of an FDA response to a citizen petition to learn about creating shared systems. We’ll also talk about the shared system waiver and some other special REMS topics. Finally, we’ll take a look at the direction FDA is moving with regards to REMS and talk about the upcoming guidances to be released this year.

REMS is, of course, a risk management program but it’s not the first from FDA. Initially, FDA did not have one system for risk management but rather required some drugs to have risk management programs individually. Clozapine, Thalidomide, and Isotretinoin are three examples of independent risk management programs.

In 1990, FDA implemented the no blood no drugs program for clozapine. Clozapine was found to reduce the levels of certain white blood cells to dangerously low levels. To prevent patient harm, patients’ pharmacists and physicians were enrolled in the program registry and patients were required to have regular blood tests to check their blood cell counts.

Thalidomide became over the counter in Germany in the late 1950s. The use of thalidomide by pregnant women for nausea and morning sickness led to thousands of infant’s form with severe birth defects. When thalidomide was approved in the U.S. in 1998, the S.T.E.P.S. program, which stands for System for Thalidomide Education and Prescribing Safety was implemented. Among other things, the program required women to use two methods of birth control and show a negative pregnancy test within 24 hours before beginning therapy and periodically during therapy.

Isotretinoin, strong teratogen like thalidomide, had the SMART programs, or System to Manage Accutane related Teratogenicity, to prevent pregnant women from using the drug.

RiskMAP which stands for Risk Minimization Action Plans was the first real precursor to REMS. Even though FDA had a few individual risk management plans, RiskMAP was the first time FDA brought them all under one regulatory roof. While RiskMAP was largely an FDA driven program, REMS was formally established by Congress in the Food and Drug Administration Amendments Act of 2007, specifically sections 90 1904 and 909. REMS required risk management plans beyond professional labeling to ensure that the benefits of the drug outweigh the risks. REMS also was new source for increased legal liability as those who are found non-compliant could be fined or issued an injunction. The establishment of REMS by Congress really underscored FDA’s authority to require enforceable risk management programs.

One of the most significant changes from RiskMAPS is that all REMS are required to have continued assessment to evaluate if the program is working which is helpful to ensure that the program is accomplishing what it was designed to do. The implementation of REMS programs was important because they not only affected pharmaceutical companies and patients but they had an impact on the entire health care system.

Many different healthcare and drug supply chain entities are affected by REMS including manufacturers, prescribers, patients, pharmacies, and insurance providers. Because of the significant amount of work required to design, carry out, and participate in a REMS program, the sponsors aren’t the only entities eho aren’t thrilled by the idea of REMS. Pharmacy groups have emphasized the workflow implications for pharmacists and stated that REMS has added to existing confusion and opened the door to potential medical mistakes. Similarly, even though REMS regulations may be put in place, that doesn’t mean everyone will be willing to participate. A 2011 survey of 250 physicians regarding opioid rims showed that only about fifty percent were willing to comply with the patient education and complete the required training. As a result, prescribers may choose not to provide the drugs and participate in the REMS programs. The authors of the study note that REMS could have an unintended consequence of decreasing access to these medications for legitimate medical purposes if a particular patients’ doctor chooses not to participate in REMS programs.

Title 21 of the Code of Federal Regulations specifies the criteria for determining when FDA can require a REMS though these guidelines are very broad and, of course, left up to interpretation by FDA. Size of population, whether the drug is a new molecular entity, severity of the disease, and potential adverse events, as well as the expected benefit and duration of treatment all, go into FDA’s decision to require or not require a REMS programs. REMS programs can also be required pre or post-approval.

In a pre-approval situation, FDA would deem a REMS to be necessary because, without a REMS, the risk of the drug would be greater than the benefits. In this case, the REMS program would be approved with the drug approval letter. This can be very positive for a drug company. In the past, they may have been given a complete response letter and told that, so far, there is an unacceptable risk-benefit profile and more data would be required for an approval. Now, FDA may approve the drug with an appropriate REMS program instead of letting it sit in regulatory on approvable limbo.

Post-approval REMS can be required if FDA becomes aware of new safety information. New safety information often arises through adverse event reporting after a drug’s approval since the number of patients using the drug is greatly increased. In the case of the drugs with RiskMAP programs, most of these were converted to REMS after the establishment of REM. Tysabri, a multiple sclerosis drug, is a perfect example of a REMS that resulted from new safety concerns after the drug was marketed. Tysabri was approved in 2004 but was later withdrawn from the market after it was linked to cases of a rare neurological and sometimes fatal disease called Progressive Multifocal Leukoencephalopathy or PML. Tysabri was re-released in 2006 with a special prescription program and this later evolved into the REMS program initially approved in 2011.

Here is an introductory table with the basic components of REMS and whether or not they are included in a REMS for an NDA, BLA, or ANDA. The five basic components of REMS are Timetable for Submission of Assessments, Medication Guide, Elements to Assure Safe Use often referred to as ETASU, new Implementation Systems, and Communication Plans. We’ll talk a bit about these different REMS components now starting with the Timetable for Assessments.

The Timetable for Assessments lays out when sponsors must assess how well the REMS is working and report back to FDA when a REM program is constructed. They must include certain specific goals that can be used as evaluation metrics. These REMS assessments compare the results of the program to the initial goals set by the rest. Minimum requirements are 18 months, 3 years, and 7 years that can be more frequent especially with REMS including a tossing.

Sponsors often use surveys to see how much the patients and prescribers enrolled in their REMS program know about the specifics of the program. Many assessments use a metric called a “knowledge rate” which takes the number of correct answers divided by the number of respondents to the question. For example, if a question asked about an adverse event and only 10 physicians out of a hundred responded correctly, the knowledge rate would be 0.1 and would be considered quite low. Based on this low rate FDA and the sponsor might work together to revise the REM program to make it more effective.

Adverse event summaries are also used to assess how well the REMS is working. If the REMS was designed to reduce the rate of a certain disease, sponsors would collect adverse event information on how many patients developed or showed symptoms of this disease. Other assessment examples include rate of compliance, prescriber certification, or patient serious adverse event monitoring. These assessments, as I mentioned earlier, will sometimes result in the modification of a REMS program so the program can better serve the patients.

The requirements for medication guides are laid out in the Code of Federal Regulation. Medication guides can be required if a medication guide could help serious adverse events. The patient should know about serious side effects before deciding to use a drug or a product. Adherence is essential to the drug’s effectiveness since medication guides are meant to be read and understood by the average patient. They must be written in non-technical language.

Chantix, for example, is a drug which is used to help patients quit smoking. The medication guide informed patients that some users of Chantix had experienced depression or suicidal thoughts while taking Chantix. The medication guide serves to inform patients of this risk so that of the patient, or family and friends of the patients, notice depression or suicidal tendencies, a doctor can be alerted immediately. A patient may choose not to take this drug after reading the medication guide they’ve previously suffered from depression or suicidal thoughts.

Another example is Opsumit, a drug used to treat pulmonary arterial hypertension or high blood pressure in the arteries of the lungs. The medication guide warns of serious birth defects when taken during pregnancy. This medication guide contains important information that might affect patients’ decision to use as a patient may not begin treatment with Opsumit but they are planning on becoming pregnant in the near future.

FDA’s opinion on medication guides has changed since the establishment of REMS. In the past, many REMS programs for medication guide only. In a 2011 guidance, FDA stated that they may approve a medication guide without requiring a REMS when that alone is adequate to address the serious and significant public health concern. FDA was basically saying that it didn’t make sense to require every drug have a full REMS program if the medication guide sufficiently informed users of the risk. When a drug is released from the REMS requirements, FDA still has authority to require a medication guide, but this medication guide would not be in the context of an overall REMS program.

Now, this can get a little confusing, so I want to make sure I’m clear. Drugs that have medication guides within REMS must have an approved REMS program including clear REMS goals and a timetable for submission of assessments. These drugs are listed on as having an approved REMS programs and an approved medication guide. Drugs that have medication guides outside of a REMS program must only have an approved medication guide. They are not listed on as having an approved REMS program but are listed as having an approved medication guide.

This graph shows the drugs that have been released from their REMS programs each year. The red parts of the bar graph represent the drugs that are no longer part of the REMS program but still require a medication guide. The green parts are the drugs that were released from both their REMS and their medication guides if a medication guide was initially prescribed by the specific REMS. In total, there have been over 140 drugs released from their REMS programs and the vast majority of them still require a medication guide. What this graph really demonstrates is that in 2011, FDA made an effort to remove medication guide only REMS from the program. If you recall, a few slides back when we discussed how every REMS must include a timetable for assessment, you can see how releasing medication guide only REMS from the programs significantly reduced FDA’s workflows.

As I just mentioned, FDA removed many medication guide only REMS in 2011 and so most drams programs today have more elements than just a medication guide. Of the 69 REMS programs today, eight of them are medication guide, only 32 of them are medication guides plus at least one additional REMS element, and 29 of them have no medication guides would include other rams components. If the effort to reduce all of the medication guide only REMS had not occurred, FDA would be tasked with overseeing over 200 REMS programs and the medication guide only piece of the pie would be much larger.

A communication plan serves to educate and raise awareness of risk. Communication plans are similar to medication guides except communication plans are designed for healthcare providers while medication guides are designed for patients. Communication plans can also serve to alert healthcare professionals of any changes in the REMS program that they may need to know in order to properly care for their patients taking a specific drug or determine which patients are a good fit for the specific drug.

One of the key aspects of the communication plan is sending letters to health care providers which includes pharmacists, physicians, and any other relevant healthcare professionals. Communication plans often include distribution of the informational materials through professional society. For example, Tanzeum, a new drug for diabetes, will be issuing information to general organizations such as the American College of Physicians and American Academy of Nurse Practitioners as well as the diabetes-specific organizations such as the American Diabetes Association and the American Association of Diabetes Educators. Distributing this information to both healthcare providers and relevant professional societies increases the chances that a prescriber will be informed about the risks associated with any drug. With the communication plan, there are many different elements to ETASU and they vary widely. Many ETASU requirements focus on actions that are performed prior to dispensing or prescribing the drug to a patient such as certifications and dispense only requirements. Other elements may be required for the duration of the treatment such as patient monitoring. Certifications are common ETASU element. This can include certification of healthcare providers by requiring those who may prescribe the drug to be familiar with educational materials and risks. This certification ensures that health care providers are aware of any serious risks and know how to look for and control potential adverse events associated with the drug. REMS programs can also require a pharmacist or anyone else who dispenses the drugs, perhaps a nurse in a hospital, to be certified. Dispensed only in certain healthcare settings may be relevant if the drug is only meant to be given by healthcare providers. For example, an infusion rather than a tablet that could be easily taken at home. For example, Aranesp, an intravenous drug for anemia due to chemotherapy, can only be dispensed to a hospital or private practice clinic and cannot be dispensed to a patient at a local pharmacy. Many of the drugs that had RiskMAPS before the establishment of REMS programs, which we talked about earlier, had requirements which would fall under ETASU. This is because the ETASU elements represent the most restrictive REMS elements and therefore it makes sense that the first few risk management programs initiated by FDA are for very serious risks. An example is Clozapine which has now been converted to a REMS program. Clozapine has one element of ETASU that requires patients to register and submit to blood monitoring before and during treatment. In some cases, ETASU requirements have caused problems for generic companies trying to obtain reference listed drug for conducting bioequivalence studies. Even though this is prohibited by the law, we will discuss this further a bit later in the presentation.

The last possible remedy requirement is an implementation system which may be required to monitor and track certain ETASU elements. Implementation systems are designed to assist with ETASU. So no REMS programs without ETASU will have an implementation system. This chart describes some of the scenarios where an ETASY element might require supporting implementation system. The REMS for the anti-cancer drug Caprelsa, for example, requires Astrazeneca to maintain validated databases of certified entities, such as health care providers and pharmacies, monitor distribution of the drugs, maintain a call center to support patients, prescribers, and pharmacies, and conduct audits of distributors. As you can see in the above table, in limitation systems are highly dependent on ETASU elements for each particular REMS program. Currently, 40 REMS have ETASU and 35 of them have an implementation system which means that the majority of REMS with ETASU also have an implementation system.

I just wanted to take a minute to talk a little bit about REMS audits as an implementation system requirement. As conducting audits can be a challenging aspect of REMS, there are many different types of audits such as hospital or pharmacy audits and vendor audits. Hospital or pharmacy audits are conducted to make sure they are complying with dispense only and certification rule. In shared systems, vendor audits are common in order to make sure companies managing things like websites, telephone helpline, and adverse event reporting systems are complying with any guidelines. Compliance is one of the reasons REMS audits can be problematic. If a sponsor needs to conduct an audit of a pharmacy or hospital and can’t because they won’t cooperate, this could be a problem for the sponsor. Further, FDA may not be able to force these third parties to comply. Of course in the case of a vendor audit, one could simply choose another company to work with if the initial third-party won’t comply but it isn’t quite so simple with hospitals and healthcare providers since it is beneficial to have them provide and prescribe the drug. Stephen Barlas published on this topic and expressed great concern that auditing of health care professionals could lead to what he called an “Inappropriate Intrusion Into Healthcare Delivery.” He also mentioned that forcing drug companies to look at patient records which could be necessary to fulfill an audit requirement may create privacy concerns for patients. It is possible that certain REMS elements could result in a violation of the Health Insurance Portability and Accountability Act, more commonly known as HIPAA.

In shared system REMS, which we will talk about later, multiple sponsors participate in the same REMS program. Problems can arise when it comes to auditing and so a sponsor may choose an independent auditor rather than an internal auditor as is done for the extended release long-acting opioid analgesics shared REMS systems.

This table is a review of the five elements we’ve discussed. If you recall, medication guides and communication plans are both spent to inform parties about the drug risk, but one target the patients while the other targets health care providers. ETASU was very broad and can include many elements but is generally used when a medication guide and communication plan aren’t sufficient to mitigate risk. Some elements of the medication guide and communication plan can also end up in ETASU. For example, Aranesp, a drug to treat anemia, does not have a communication plan but it does include a Dear Healthcare Provider letter in the ETASU. The implementation system is meant to monitor and track the ETASU program. Finally, the timetable for submission of assessments is where the sponsors can evaluate the whole REMS programs and report if successes to FDA.

A shared system REMS is a REMS program that is approved for multiple sponsors. If the REMS has or will have ETASU, having shared system REMS makes things easier for both FDA and the participating healthcare providers and patients as it eliminates redundant elements. Shared systems generally applied when there is a generic and brand-name version of the same drugs but can also apply to different active pharmaceutical ingredients in the same class. Shared system REMS were designed to eliminate duplicative elements in ETASU. For example, if an ETASU element to require the healthcare providers be certified before prescribing, it would not make sense to have separate certification programs for both the generic and brand-name drugs. Five of the six approved shares REM systems are for generic and brand-name drugs with the same active pharmaceutical ingredients. Since pharmacists can substitute the generic for brand names it is logical that all the REMS precautions and elements should be consistent. The size of these shared REMS programs varies between programs. The smallest shared REM system is for Rosiglitazone and has two sponsors.

The sponsor of the reference listed drug has three NDAs for different formulations and combinations of the API while the generic sponsor has a single NDA for one tablet formulation. In this case, the initial REMS was approved in December 2018 as a single system which means the brand name sponsor developed the REMS program alone. When the generic was approved in 2013, the REMS was converted to a shared system. Only one shared REMS exists for a class of drugs and this REMS is for extended-release long-acting opioid analgesics. This REMS currently has 24 sponsors.

Now there is a way out of the creation of a shared REM system. Part of the FD&C Act states that the requirement may be waived and the AMD a sponsor may be permitted to use different but comparable aspects of ETASU if one of two conditions apply. The two conditions are listed on the slide and are: if the burden of the single shared system outweighs the benefits or if an aspect of the ETASU is claimed by a patent or the trade secrets and the ANDA applicant was unable to obtain a license. What both of these conditions mean in practice is not totally clear since FDA has only granted one waiver. It is especially hard for outsiders to get an idea of how FDA will measure if the burden of creating a single system outweighs the benefits of a single system. FDA does provide some guidance on waiver requirements and other aspects of creating a shared REM system in the FDA response to the Prometheus Laboratories citizens additions.

Before we can talk about FDA’s response to the Prometheus citizen petition, we should go over the background. I’ve included the docket number on this slide and I encourage anyone who is actively involved in developing a shared system to take a look at these documents. The story is this: Prometheus Laboratories had a product called Lotronex which treats irritable bowel syndrome. Roxane Laboratories have filed an ANDA for a generic version of Lotronex with a paragraph IV patent certification. This certification means that Roxanne does not believe they are infringing on Prometheus’s patent or that they believe the patent itself is invalid. Prometheus subsequently sued Roxane and as of May 2013, no trial date had been set.

Now, as we will learn from this petition, the development of a shared REM system begins as soon as the ANDA is accepted for filing. This puts Prometheus in a tough spot. They were expected to work with Roxane to convert the already established REMS into a shared system concurrently with ongoing litigation to resolve the patent dispute. After some discussions with Roxane that all failed to result in any agreements between the parties, Prometheus has filed this citizen petition to gain guidance on how to create a shared REMS system. FDA’s response, which came five months later, didn’t agree to notice and comment rulemaking, as was requested by Prometheus, but did give some advice that is informative for both Prometheus and Roxane and for other sponsors involved in creating a shared system.

In the response, FDA covers many different aspects of shared system REMS. For the timeline, FDA states the timeline for developing a shared system will begin when the generic application is found acceptable for filing. FDA will then notify the ANDA applicant of the shared system requirement and direct them to contact the sponsor of the reference listed drug. FDA expects that negotiations of the shared REM system would begin promptly thereafter and would proceed concurrently with the review of the ANDA application. The next thing FDA recommends is the creation of an industry working group when several companies are impacted by a single shared REMS system. FDA states that in the past, industry working groups have identified a single point of contact to FDA. FDA states they have typically monitored the group’s progress through regular teleconferences and face-to-face meetings. Though not mentioned in the response, oftentimes, the group of sponsors will appoint a third party to manage an industry working group which can make all the sponsors feel a little better than if one of the sponsors were in control of the groups. In the response, FDA suggests that they will act as a mediator, stating that when one company has been unreceptive or unresponsive to working together, FDA has held teleconferences or in-person meetings to help facilitate any issues in terms of the approval of the shared REMS. FDA details that the single shared proposal should be submitted to the agency for review as part of the overall ANDA. FDA states that shared REMS systems are subject to the same ETASU implementation system and timeline for assessments requirements but also notes that some sponsors have worked together to form website training materials and other documents for use by all participants in the REMS system. FDA notes that they are not involved with cost sharing governments and other business issues of the REMS and that those are to be negotiated independently by the sponsors. FDA talks a little about modifying REMS but also notes that they are in the process of developing guidance on this issue.

Finally, FDA talks a bit about the shared system waiver, stating that companies are welcome to provide input on whether the burdens outweigh the benefits. They also stated that FDA may request additional information if they feel it is needed or FDA can decide on their own that a waiver is necessary. FDA recommends that Prometheus submits this sort of information to FDA in its application but doesn’t provide any more details.

Next, we’ll examine the first system waiver decision and see what we can learn from it. The first shared system waiver results in the creation of the Buprenorphine Transmucosal Product Shared REMS programs which, at the time of its creation, only included ANDA without the innovator drug. The innovator drug was produced by a company called Reckitt Benckiser. FDA released a response to a citizen petition from Reckitt on the same day as two ANDAs were approved with the new shared REMS though the citizen petition was otherwise unrelated to the waiver decision. The details of these products is a little complicated and not really relevant so anyone interested should look up the docket number above and check out the initial citizen petition and full response.

The quotes above are taken from FDA response to Reckitt’s citizen application and instead of providing any details about why the waiver was granted, FDA simply states that statutory criteria were met.

The second quote referring to the effort to secure Reckitt’s participation in the shared systems suggests that FDA tried to get Reckitt to come in on this shared system but, for some reason, it didn’t work out. It’s very interesting but unfortunately not very helpful to sponsors. It remains to be seen if more waivers will be granted in the future and if a lack of cooperation by the innovator company may result in a waiver. One hot legal issues surrounding REMS is the idea of using REMS programs to block generic entry to the market. A great summary of the current issues surrounding using REMS to block generics was published in the New England Journal of Medicine in April titled, “Using a Drug Safety Tool to Prevent Competitions” and this slide is adapted from the article.

Even though the law states that REMS requirements should not be used to block or delay approval of generic drugs, this appears to be happening. One method for a sponsor to use REMS potentially block generic entry is demonstrated by the Actelion case against Apotex and Roxanne. Actelion sued two generic companies and stated that because the distribution of the drug in question, in this case, Tracleer, a drug to treat pulmonary hypertension was restricted to pharmacies under the access programs, Actelion could not provide the generic manufacturers with samples of the drugs. Those of you familiar with the approval process for generic drugs know that the would-be-generic needs to obtain samples of the reference listed drug in order to conduct bioequivalence testings. No legal judgment was made here since the case was settled outside court.

Another way to potentially block the generic entry is demonstrated in the Celgene vs Barr case when Barr tried to market a generic version of Thalidomide, Celgene, who holds the NDA for the reference list of drugs sued. When Celgene created the step system we discussed earlier as part of their REMS programs, they obtained numerous patents on this system. Celgene said in the lawsuit that approving Barr’s application would infringe on Celgene’s patents. If you recall our discussion of the shared system REMS waivers, recall that a drug can be granted a waiver if an aspect of the ETASU is claimed by a patent that is not expired which appears to be the case here. However, Celgene followed this lawsuit up with a citizen petition to FDA claiming that any non-patent infringing REMS would pose unacceptable risks. Almost six months following the citizen petition, FDA responded saying they had not yet reached a decision because of the need to address other agency priorities and the complexity of the issues raised by the petition. While this would have been very interesting to watch play out in court, Barr withdrew their application to market the Thalidomide. The New England Journal of Medicine article suggests that it may be necessary for Congress to revisit the REMS legislation to prevent REMS patents from preventing the entry of generic competitors to the market.

Now we’ve seen all the different components of a single and shared REMS program and can get an idea of the effort required to design and execute a successful program, one important question to ask is: Are REMS programs working? Unfortunately, a 2013 reports from the Office of the Inspector General titled, “FDA Lacks Comprehensive Data to Determine Whether Risk Evaluation and Mitigation Strategy Has Improved Drug Safety” found that REMS programs are not meeting their goals. The report reviewed programs from 2008 to 2011 and found that nearly half of the assessments for missing information and that 10 of the 49 reviewed programs were not submitted on time. They found that only seven of the programs met all their goals and stated that FDA had not identified reliable methods to assess the effectiveness of REMS programs. But this report doesn’t mean FDA isn’t trying to improve REMS. In fact, the REMS integration initiative was created just for that purpose. The REMS integration initiative was created in 2011 in order to evaluate and improve REMS program. The goals are: to develop guidance on how to apply the statutory criteria to determine when a REMS is required, to improve standardization and assessment of REMS, and to improve the integration of REMS into the existing and evolving healthcare system. FDA has created three workgroups to assist with the REMS integration initiative: the policy group will develop guidances about how FDA determines when a REMS is required, the design and standardization work group is working to standardize REMS tools and integrate REMS into the healthcare systems. The work group held a public meeting in July 2013 to obtain input on issues and challenges regarding REMS standardization and integrations. A report of findings will be developed from the results of this meeting and from public comments to the related doc. Finally, the evaluation work group is working towards developing an evidence-based approach to assessing the effectiveness and burdens of REMS. This group held a workshop to discuss social science methodologies on how to construct a survey that will be effective in reporting the relevant information. This group will also be developing a guidance on different types of evaluations and relevant methodologies.

So now we’ve discussed the precursors to REMS like risk maps, the current state of individual and shared REM system, and some special REMS topics including legal issues and the shared system waivers, we’ll shift gears again to the future of REMS programs. As you’re all aware, it is not easy to predict the future but we can look at CDER’s list of planned guidances to gain clues. According to the FDA’s guidance agenda, CDER, the Center for Drug Evaluation and Research, is planning on releasing five guidances for REMS this calendar year. We are more than halfway through 2014 and haven’t seen any of the guidances yet. We are hoping that these guidances will be informative and help make managing REMS easier for sponsors. The first two guidances listed under procedural look like they may be a result of the different work groups for the REMS integration initiatives. If you recall the policy work group was tasked with developing criteria for when a REMS is necessary and the evaluation work group was to develop a guidance on evaluation methodologies. The guidance that looks the most interesting is the one referring to a master file for shared REMS systems. In this case, sponsors will likely be able to reference the updated master file when changes are made rather than individually submitting the changes to their NDA, ANDA, or BLA when a REMS program is updated. It will be interesting to see who the owner of a REMS master file will be considering there will be multiple sponsors invested in the REMS. Unfortunately, it doesn’t look like the question of “How can my company obtain a shared system waiver?” will be addressed this year.

Every day, the exclusivity and patent clock are running down for new drugs. As generic drugs the single REMS system enter the market, it is likely that more and more REM systems will be converted to shared REMS programs. The question then becomes how can companies prepare for the entrance of a generic into the market. The first thing may be obvious: what sponsors of the reference listed drugs need to know the patents and exclusivity expiration dates to predict when a generic may enter the market and prepare accordingly.

To prepare for generic entries, brand name sponsors should be mindful in creating their initial round system as part of their NDA. Though the idea of a generic may seem far away when applying for FDA approval of a new drug, it would be wise to consider how other generics would be able to fit into the REMS program without causing much disruptions. Something this simple may prevent a lot of headache down the road. If the idea of making your REMS program easily convertible to a shared system wasn’t considered during the initial approval, sponsors could try to revise the REMS program now and make it easier for generic interest doing from now may give you an advantage in the negotiations later and allow you to take a lead but it would also require a potentially significant financial and manpower investment. This decision will likely be a joint business and regulatory decision about which is more appropriate for your company, given your specific REMS program and drugs. Sponsors of generic drugs cannot prepare quite as much as a sponsor of the reference listed drugs but they should make themselves very familiar with the sponsors REMS programs before submitting their application.

Since REMS negotiations start as soon as the ANDA is accepted for filing, it would be useful for the generic sponsor to be prepared with a list of suggestions on how to transform the individual REMS into a single shared system. So whether you are the sponsor of the reference listed drug or a generic, there is plenty to do to prepare for your drug friends programs and sponsors shouldn’t waste any time getting started.

This concludes our REMS presentation and I will hand it back over to Claire to answer some questions.

CLAIRE ROBERTSON: Thanks, Emily. This concludes the webinar. We have a number of questions and the first is: One of your slides lists the possible REMS requirements for ANDAs and I noticed that a communication plan wasn’t an option for ANDAs. Why is this?

EMILY KRULEWITZ: That’s a great question. I believe this is actually addressed in the Code of Federal Regulations. It says that when an ANDA is approved, the FDA will take over any communication plan for the drugs rather than having the NDA or ANDA holder carry out the communication plans. This is the same reason that if you look at the REMS elements of shared systems, none of them include a communication plans. I can go ahead and find the statutory reference to this and include it in the QA we’ll send out later.

CLAIRE ROBERTSON: Okay, great. The next question is: You said a majority of REMS with ETASU have implementation systems. Why don’t the others have implementation systems and what makes them different?

EMILY KRULEWITZ: These REMS generally have less complicated ETASU systems. If you look at the five ETASU REMS that don’t have implementation systems, you generally only have one ETASU element which, I believe, is often certain training or certification for health care providers. More ETASU elements are added to the REMS, the implementation system becomes more necessary for managing it.

CLAIRE ROBERTSON: Okay, great. I think we have time for a few more questions so we’ll move on to the next question which is: You said that an ANDA, NDA, or BLA could be required to have a REMS program. For an ANDA, would they only be required if NDA has a REMS?

EMILY KRULEWITZ: In almost all cases, this would be correct when laying out the requirements for REMS programs. It’s specified that the ANDA is subject to the elements required for the applicable listed drugs. This makes sense since the NDA and the related ANDA are supposed to be therapeutically equivalent. So, requiring an NDA to have a REMS program when the NDA does not need a REMS doesn’t make much sense. One could imagine, however, a situation where a reference listed drug is discontinued and an ANDA becomes the reference listed drugs and then new safety information results in a need for a REMS. Additionally, the new proposed legislation that an ANDA must revise its label if they get reports of adverse events even if the NDA holder doesn’t may have an impact on differential REMS requirements in the future.

CLAIRE ROBERTSON: Okay, great, thanks for clearing that up. The next question is: You had mentioned that it was explicitly stated that a REMS couldn’t be used to block entry of a generic drug. Do you know if this applies to 505(b)(2) applications which may need to reference and do testing with a reference listed drug but won’t be considered ANDA their generics?

EMILY KRULEWITZ: Yes, the statement mentioned both sections B2 and J which correspond to 505(b)(2)s and ANDAs or 505(j)(s).

CLAIRE ROBERTSON: Alright, well, it looks like we only have time for one more question so we’ll get to it. The next question is: When is the best time to bring up REMS with FDA? Should we wait for them to mention it? What do you recommend?

EMILY KRULEWITZ: This question may have some legal implications as it could raise product liability issues. However, it is always better to preempt an FDA action instead of waiting until they force an onerous burden on you. If you believe your product may require a REMS, it is best to bring it up early on in the drug approval process so there is ample time to develop a program that is satisfactory to both your company and the FDA.

CALIRE ROBERTSON: Alright, well, thanks again Emily. It looks like we’re out of time for today. We will answer the remaining questions within the next week and email them to you along with a copy of the slides. In addition, we would appreciate it if you could please take a minute to fill out the brief evaluation survey on the left side of your screen. Thank you for joining our presentation.”