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Four Considerations for Every Rare Disease Development Program: Summary of CBI’s Rare Disease Clinical Development and Access Summit

Posted by Meagan Spychala & Karl Whitney on Thu, Jan 23, 2020 @ 09:17 AM
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Rho representatives joined regulators, industry scientists, and numerous patient-advocacy groups at CBI’s Rare Disease Clinical Development and Access Summit in Washington this past December. Attendees were able to share best practices in product development for rare disease programs in formal presentations and through informal networking. The following are 4 considerations for your development program that were highlighted during the conference.

1)  Seek early engagement for patient and caregiver perspectives and with key  payers.
Sponsors need patient and caregiver perspectives in order to ensure clinical studies are properly designed to provide evidence speaking to issues that truly matter to patients and their caregivers. These interactions should start as early on in the process as possible, even as early as initial animal proof-of-concept stage. Patient advocates advised companies to be open, transparent, and humble in approaching their communities for these insights; patients and caregivers want their perspectives heard and know that increasingly they have great influence in shaping product development for their conditions. Because of this increasing influence, some patient groups are not waiting for outreach from product developers, and have conducted or are planning formal Patient-Focused Drug Development or FDA listening sessions so that the community can proactively shape FDA’s understanding of key concerns Young pretty girl giving the sick woman glass of waterand priorities for product development.

It's also important to engage with key payers such as Centers for Medicare and Medicaid Services (CMS) no later than End of Phase 2 so that the pivotal studies can provide data that will support reimbursement. Often this means exploring persistence of effect in a longer study than might be minimally required by FDA. And, on that note, don't forget the perspectives of payers outside the US, including via the Health Technology Assessment processes in EU member states.

2)  Regulatory authority investment in rare disease development programs means more opportunities for dialog between regulators and sponsors: prepare for and embrace the increased access.
It is useful to note that in all these discussions about the development program, sponsors should make the most of milestone meetings and other opportunities to gain consensus with FDA on your plans. In 2018, 58% of the approvals were for rare disease indications and FDA speakers shared freely about how important and exciting this time is for them, patients, and industry. Precisely because FDA and similar stakeholders are so invested in these programs, and because these programs often include novel or challenging development issues, an iterative process in arriving at agreements should be expected. This will particularly be the case for topics lacking clear precedent owing to the rare nature of the disease in question. Therefore, it is imperative to identify key development questions and discuss them transparently with FDA and in hopes of settling key program questions by End of Phase 2.

3)  Plan early for Chemistry Manufacturing Controls (CMC).
Once your lead is selected, it's critical to provide sufficient resources and advanced planning to the CMC development program. All too often, especially for a program benefiting from enhanced support and guidance from FDA via Breakthrough Therapy or Regenerative medical pills industry  factory and production indoorMedicine Advanced Therapy designations, sponsors find themselves with near-complete clinical programs backed by incomplete CMC packages. Proper planning and support is the only way to ensure nimble scale-up as development proceeds and as the team begins to prepare for marketing. In that light, as much as possible, avoid tweaks to the investigational product to avoid having an even higher hill to climb for the CMC program. By the same token, if the product needs a specialized delivery device, work to settle the design and performance features of this as early as possible to allow the team to focus on other things like running efficient trials. Finally, the same plan-ahead advice likely applies to the nonclinical program. Interested in knowing more about how to plan for your CMC development program? In the near future, another blog post will address this topic, so be on the look-out.                                                                    

4)  Strategize for how to streamline your clinical trials while still supporting your claims.
In rare disease, recruitment and retention for clinical trials can be increasingly difficult due to the small population size. Creating a streamlined program strategy that will support your potential label will assist in a more efficient product development program. If the disease course, genotype, and phenotype are poorly understood, a natural history study is an absolute must to gain valuable information about the disease and potential endpoints that would be of value to your proposed claims. Remember that the first-in-human study may end up being the pivotal study, so it has to be well designed and as flawlessly executed as possible to deliver the best possible data. Perhaps this is easier said than done, but it's a fundamental pillar of successful product development, particularly for rare diseases. Even if your first-in-human study does not become your pivotal, you should look into alternative study designs that can reduce your sample size and discuss with the agency the composition of the program to understand the expectations for that indication and claim.

Topical, targeted industry meetings like this are excellent opportunities to share ideas and best practices in a small setting with a wide range of highly experienced people, which is why Rho staff regularly attend and contribute to such meetings. No meeting can offer a comprehensive view of everything that can come up in your development program or risks and opportunities to consider, which is why having an expert partner can be invaluable to your program. Contact us at any point in your development program for a free expert consultation; you'll be pleased with our team's thoughtful and creative review.

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Meagan Spychala, PhD, Assistant Vice President of Patient Engagement and Program Strategy at Rho, serves as Rho’s expert on patient-focused clinical research activities and incorporates the patient and caregiver voice and experience into the clinical development program.  She recognizes the uniqueness of each clinical trial, which is especially true within rare disease clinical research, and understands the importance of each patient in the development program.

karlKarl Whitney, PhD., Assistant Vice President of Product Development, leads multiple integrated drug development programs spanning the development spectrum by planning, managing, and overseeing concurrent manufacturing, nonclinical, clinical, and regulatory activities. Dr. Whitney has also contributed to preparation of many regulatory submissions,  clinical protocols and amendments, and numerous other documents. 

 

Current Gene Therapy Landscape:  Overview, Challenges, and Benefits

Posted by Kristin Gabor on Wed, Jan 15, 2020 @ 11:22 AM
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In 2017, the US Food and Drug Administration (FDA) approved its first gene therapy, a chimeric antigen receptor T-cell (CAR-T) product to fight acute lymphoblastic leukemia (Kymriah). That same year, another CAR-T therapy was approved to fight certain types of B-cell lymphoma (Yescarta). Since then, 4 additional products have been approved to treat serious diseases such as B-thalassemia, spinal muscular atrophy, a rare form of vision loss and a rare form of primary immunodeficiency. There are currently over 450 gene therapy and gene-based medicine companies worldwide and around 800 gene therapy and gene-modified cell therapy clinical trials being conducted (ARM Q3 update).

Significant progress has been made in developing safe gene therapy products in recent years. Just over 20 years ago, the tragic case of 19-year old Jesse Gelsinger who died during a gene therapy trial led to a temporary collapse in the gene therapy field. Since then, the gene therapy industry has come a long way. In a joint statement made in January 2019, FDA Commissioner Scott Gottlieb and CBER Director Peter Marks noted that based on an assessment of the current pipeline and clinical success rates of gene therapy products, the FDA anticipates that by 2020 they will be receiving more than 200 INDs per year for cell-based or directly administered gene therapies and by 2025 the FDA will be approving 10 to 20 cell and gene therapy products a year.

The basics – what is gene therapy?kristin1

Gene mutations can be inherited or occur as cells age or become exposed to certain chemicals. Small changes to our genetic material can have large impacts on cellular function.

Gene therapy products mediate their effect by transfer of genes or alteration of human genetic sequences. It can be thought of as the introduction, removal, or change of genetic material within patient cells – for instance, repairing a faulty gene in order to produce new or modified proteins, increase proteins that will fight disease, or reduce proteins that cause disease. This can be achieved by gene replacement, gene silencing, gene addition, or gene editing.

The genetic material is typically transferred into patient cells using a specific type of delivery mechanism (described below). Once inside the cell, the gene will make functional protein or target the disease-causing gene.

Gene Delivery Mechanisms

Gene therapy administration can occur via ex vivo or in vivo mechanisms. With ex vivo gene therapy, targeted cells (eg, chimeric antigen receptors (CAR) T cell therapies, T cell receptor (TCR) therapies) are extracted from the patient and the cells are genetically modified in vitro before they are transferred back into the patient. In vivo administration occurs via direct delivery to the patient using a viral or non-viral vector and the target cells remain in the body of the patient.kristin2

Vectors (carriers of the gene), can come in the form of viral vectors, which are genetically engineered viruses that replace the virus genome with the therapeutic gene. Examples of viral vectors are retroviruses, lentiviruses, and adeno-associated virus (AAV; of note, the AAV method is believed by many to be the future of gene therapy). Plasmids (small DNA circles or “naked” DNA), engineered bacteria, and liposomes are other vectors of gene therapy administration to either carry and deliver a replacement gene or to help or silence an existing gene.

Another type of gene therapy product is genome edited cells, which can be generated using zinc finger nucleases (ZFNs); transcription activator-like effector-based nucleases (TALEN), or nucleases such as Cas9 and Cas12a that derive from the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas). For instance, one company is using a genome editing platform called ARCUS derived from a natural genome editing enzyme called a homing endonuclease in their CAR-T development programs.

Challenges and Benefits in Developing Gene Therapies

The unique benefits of gene therapy are that it targets the cause of the disease and has the ability to treat or maybe even cure rare, debilitating diseases that have few to no treatment options, often with a single administration. Over time, the high price tag of gene therapy could reduce or eliminate the need for a lifetime of expensive and/or painful ongoing treatments that many in this patient population would require.

Although gene therapy offers a number of unique benefits, a number of challenges exist that make the development of gene therapies difficult as well as expensive. Those include:

• Length of clinical trial process – long term safety follow up due to uncertainty surrounding the potential durability of effect and long-term safety effects or complications;
• Manufacturing is complex and time intensive, and many sponsors have faced capacity constraints due to the difficulty in mass production (of viral particles, for instance);
• Individual response variability;
• Some conditions have many mutations leading to a given disease and one gene therapy approach may only work for a subset of affected individuals;
• May stabilize disease pathology but not actually reverse existing damage;
• The efficiency of gene transfer with vectors and the limited control over where integrating viral vectors will integrate;
• Dose of vectors may be high and large doses may be needed to reach target tissues; vectors could be filtered out in the liver or cleared by an immune response;
• Unlike other therapeutics, once administered there is no dose titration and no ability to control expression levels; gene therapy cannot be turned on or off. It is also very likely that there is no ability to do repeat dosing due to immunity developed during initial treatment.

An Advancing Field

Gene therapy offers the potential for significant breakthroughs and a lot of exciting progress hBlue DNA helix background-1as been made with scientific advances in gene therapy and the recent FDA approvals. Their complexity to develop should not be underestimated, as evidenced by the FDA’s release of 6 additional guidances in 2018 intended to help product developers. The gene therapy industry is poised for the future, but due to its complexity the development process needs to be thoughtfully planned and managed. Critical to the success of the field will be the capacity to scale up for AAV manufacturing or other gene therapy manufacturing factories and a streamlined regulatory landscape.

Rho Can Help

There are several unique aspects of gene therapy clinical trials. Rho is currently leading several gene therapy studies and has conducted over 20 gene/cellular therapy trials in over 1000 patients.  One of our sponsors commented, “Our collaborative relationship with Rho has been instrumental in the implementation of a complex and rigorous first in human genetic medicine study, including strategic solutions for unique challenges faced in rare disease gene therapy trials.  Rho has leveraged existing relationships with patient advocacy organizations and worked closely with a centralized biosafety review partner early in study startup to help identify and mitigate potential challenges. “   

From both a clinical and regulatory standpoint, our experts can offer advice on your gene therapy trial from the preclinical phase through post-submission. For additional gene therapy considerations from our experts, please view our webinar, "Development Advice for Gene Therapy Products"  and for regulatory considerations,  David Shoemaker's article, "The Gene Therapy Product Development Process."

Need support designing and executing your next gene therapy trial? Ask our experts for help.

Kristin Gabor smallKristin Gabor, PhD, RAC, Research Scientist, has experience in both regulatory submissions and clinical operations management, with over 10 years of experience in scientific writing and editing clinical and nonclinical documents, which includes numerous publications in peer-reviewed scientific journals.  Dr. Gabor has led and participated in the authoring, review, and preparation of several regulatory and clinical documents, including protocols, clinical study reports, annual safety reports, modules of regulatory submissions (NDA, IND, etc.), and other regulatory documents in a variety of therapeutic areas at various stages of integrated product development programs. Her experience spans a spectrum of therapeutic areas, including cystic fibrosis, sickle cell disease, inflammation and immunology, infectious diseases, atopic dermatitis, multiple sclerosis, and rare diseases. Dr. Gabor earned an interdisciplinary PhD in Functional Genomics from the University of Maine and subsequently received an Intramural Research Training award from the NIH/NIEHS for her postdoctoral studies investigating the role of cholesterol metabolism and cell membrane perturbations in regulating the innate immune response in a rare genetic disease.  Dr. Gabor received her Regulatory Affairs Certification from the Regulatory Affairs Professionals Society (RAPS) in 2018 and is a current member of RAPS and the North Carolina Regulatory Affairs Forum (NCRAF).

 

Is a Target Product Profile Worth the Effort?

Posted by David Shoemaker on Wed, Dec 18, 2019 @ 09:32 AM
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David2

David Shoemaker, PhD, SVP R&D, has over 25 years of experience in pharmaceutical product development. He has served as a Program Leader or Advisor for multi-disciplinary program teams and has been involved with ensuring products meet regulatory standards at all stages of the development process.

A recent study by the MIT Sloan School of Management determined only 14 percent of clinical studies succeed, indicating there is room for vast improvement in the pharmaceutical industry’s ability to develop needed therapeutics more efficiently1. Inasmuch as the clinical develop program for a product comprises several to dozens of clinical studies to achieve marketing approval, chances are that one or more studies will fail during development. Coincidentally, this success rate of 14 percent approximates the age-old estimate that 10 to 20 percent of products that enter human studies make it to the market2,3. However, an eventual failure rate of 80 to 90 percent for products entering Phase 1 speaks to more than simply clinical study failure rate. The failure rate indicates an overall development process shortcoming that begins during the preclinical stage and destines product development programs for failure. This is due in part to the fact that companies are in many cases not doing the correct clinical study on an efficient path to marketing a needed therapeutic product. They do not possess a road map for success.

As a contract research organization who works extensively with late stage development companies collaborating on the preparation of their marketing applications, Rho continually observes product sponsors who fail during late stage development due to preventable missteps with their product development program. We are always buoyed by starting a new relationship with a company who has taken the time to prepare a Target Product Profile (TPP) because we know we have a client who understands the importance that prescribing information and market position play in the ultimate approval of a product by the regulatory authorities and the commensurate successful market capture. Simply achieving marketing approval is not the goal. The goal is to provide a useful therapy that will meet the needs of patients, physicians, and payers and hopefully advance current therapeutic options. The TPP provides a road map for development of a product, laying out all the key development performance criteria that the investigational product must meet in order to ultimately become the useful therapy the sponsor wants it to be; failure to meet any of these key criteria means the investigational product will not succeed as a useful marketed product and development should be abandoned or somehow re-engineered.

The crafting of a TPP is enabled by a detailed understanding of not only the disease and its associated market, but also unmet patient, physician and payer needs. The goal posts for each of the stakeholders need to be determined by identifying the minimal and the optimal characteristics for a variety of TPP elements. The major criteria to meet patients’ needs reside primarily in efficacy and safety elements, but satisfying dosage, route of administration, and specific patient reported outcomes also must be considered. Obviously physicians’ primary needs will be met if the patients are satisfied but there may be additional considerations regarding route of administration as well as ease and efficiency of therapy. Payer value is derived from beneficial differentiation of efficacy and safety but there may also be differential market forces to consider based on geographical regions (e.g., free market, US; clinical effectiveness, France and Germany; cost effectiveness, UK and Canada). If it becomes clear at any point in development that you will fail to meet the minimal criteria for your product to satisfy any one of these stakeholders’ regulatory or commercial requirements, a company is well advised to abandon development. Also, it is simply common sense for companies to Data analysis chart and graphs-2identify their principal competitive product on the market as well as potential competitive products in development prior beginning their development program in earnest. A comprehensive TPP should contain all of these elements.

The organization of the TPP is understandably varied across the industry with some people using the US Prescribing Information as a template and others adopting the European Summary of Product Characteristics. The FDA even issued guidance back in 2007 advocating the use of the US Prescribing Information organization (https://www.fda.gov/media/72566/download). The advantages of these strategies include the fact that you are effectively preparing your US annotated package insert during your development plan. These documents help both with minimizing and focusing development activities and organizing your marketing application, and they are in a format optimal for discussions with regulators. However, a complete TPP should still include an independent payer assessment that is of no interest to regulators. Other companies prefer more general categories than are found in product labeling such as efficacy, safety, payer value, dosage, indication, population and juxtapose these elements with the attributes of their target competitive product for a more commercially oriented TPP. This allows one to easily see when your product comes up short against a competitor thereby rendering a course correction or a No Go decision.

By focusing both the developmental and marketing goals in the TPP at the preclinical stage a company is able to build a commercial differentiation strategy into their early development plan. Preclinical studies are a lot less expensive to conduct than clinical studies and hypotheses can be tested versus competitive products efficiently. These preclinical experiments may or may not lead to earlier examination of active comparator studies in the clinic. However, it will most certainly enforce the understanding that validating a novel mechanism of action is less important than clinical differentiation from a competitive product. These experiments may allow a company to distinguish between competitors and identify the key competitive product to compete against. Demonstrating proof of concept in no way guarantees profit on return, so it is imperative that companies explore pharmacodynamic activity versus competitive products in their preclinical development programs.

A common reason small or inexperienced companies do not prepare a TPP is the proposed cost and amount of time that must be devoted to its preparation. Companies with an exit strategy at proof of concept or prior to phase 3 often claim the cost is not justifiable. However, the value created by a well-run development program that checks all the boxes for an intelligent investor is worth much more than the cost invested in the preparation of the TPP. Investment firms and big pharma are primarily looking for investments where the risks have been minimized and a program that has been conducted efficiently focusing on the ultimate appropriate indication and patient population while examining carefully the commercial landscape holds enormous value.

Perhaps the greatest value of the TPP is as a communication tool. The ultimate goal of the communications-networkdevelopment program is shared clearly and continually with all the company disciplines, e.g., clinical, preclinical, chemistry manufacturing and controls, regulatory, and marketing. The TPP is also able to be used as an external communication tool that facilitates interactions with regulatory authorities, investors, and the media. The document can be used to help structure regulatory and investor briefing documents as well as press releases. The TPP’s additional use as a communication tool is as an educational document for new team members whether they are within the company or at regulatory authorities.

The bottom line is, you must prepare a TPP early and revise it continually during development if you wish to bring a successful therapeutic to market to advance patient treatment or you are left relying on nothing more than good fortune.

1 Wong, C.H, Siah, K.W., and Lo, A.W. Biostatistics. 2019; 20(2): 273 – 286.
2 https://www.reuters.com/article/us-pharmaceuticals-success/success-rates-for-experimental-drugs-falls-study-idUSTRE71D2U920110214
3 https://www.policymed.com/2014/12/a-tough-road-cost-to-develop-one-new-drug-is-26-billion-approval-rate-for-drugs-entering-clinical-de.html

 

Orphan Drugs and Single Trials

Posted by Joseph Watson on Thu, Dec 12, 2019 @ 09:00 AM
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Joseph Watson, PhD, RAC, Research Scientist at Rho, has experience in both regulatory submissions and clinical document preparation, with over fifteen years of experience in scientific writing and editing jwatsonclinical and nonclinical documents, including numerous publications in peer-reviewed journals.  Dr. Watson has led the preparation, review, and coordination of a variety of regulatory and clinical documents, including protocols; clinical study reports; integrated summaries of biopharmaceutics, safety, and efficacy; CMC and nonclinical documents; draft product labels; and 120‑day safety updates.  His writing and editing experience covers a broad range of therapeutic areas, including drug addiction, middle ear disorders, infectious diseases, psychiatric disorders, acute and chronic pain, multiple sclerosis, hemophilia, and oncology. 

Since the enactment of the Orphan Drug Act in 1983, the number of orphan drug approvals has risen steadily. In 2018 alone, 34 out of 59 approved novel medications were for orphan diseases. Consistent with the increase in orphan applications reviewed by the Agency, Rho has received an increasing number of sponsor requests for support of programs working towards an orphan drug approval. Our sponsors often think that their product can be approved with support from a single trial, but how realistic is this stance? To better understand when a single trial approval is possible, we look to FDA guidances.Conceptual image with ladder reaching increasing graph-1

In the 1998 Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, FDA spells out the potential circumstances in which a single clinical trial for a novel therapeutic could be sufficient to support an efficacy claim. The guidance states “reliance on only a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible.”

The key points outlined in the guidance are:

1.   The condition must be serious. If the FDA doesn’t believe the condition is serious, they will not consider a single adequate and well controlled trial for a novel therapy.
2.   A second adequate and well-controlled trial is practically or ethically impossible to conduct. This situation could apply for an orphan indication given limited patient populations (and likely assuming point 1 above).

Both points could apply to an orphan indication; an orphan indication has, by definition, a limited patient population, and many orphan indications are serious. A serious orphan indication falls into the “sweet spot” in which FDA may be willing to show flexibility and accept a single adequate and well-controlled trial.

After considering points 1 and 2 below, FDA must review the single adequate and well controlled trial to determine if it is sufficiently robust and compelling; i.e., does it feature any of 5 characteristics that could make it adequate to support an effectiveness claim (in other words, sufficiently robust & persuasive; FDA’s typical prior to reviewing the data is that the determination will be a review issue):

1.   A large multicenter study
2.   Consistency across study subsets (large trial)
3.   Multiple studies in a single study (e.g., properly designed factorial studies)
4.   Multiple endpoints involving different events (i.e., prospectively identified primary and  secondary endpoints representing different beneficial effects)
5.   Statistically very persuasive findings

For orphan indications, characteristics 1 and 2 are difficult to achieve due to the need for large trials. Characteristic 3 is situational; the example provided by FDA highlights a combination therapy tested as both the combination and as individual parts. Characteristic 4 is typically incorporated into the study designs Rho reviews. Often, this item can be interpreted by sponsors as the “everything but the kitchen sink” approach. In our experience, multiple well thought out, differentiated endpoints can help FDA assess approvability; however, FDA will stress that these endpoints should be independent of each other.

Additionally, FDA will often request that the endpoints be hierarchically ranked; this preserves the overall alpha for the study by preventing companies from fishing for an acceptable endpoint should the primary fail. If the program hits on multiple, well-thought out, agreed upon endpoints, improves significantly on current therapies, and the disease is serious, FDA may consider a single trial appropriate.

Clinical Trial written in search barCharacteristic 5 is likely the most realistic situation orphan drug sponsors can achieve, in spite of the small sample sizes typically observed in orphan trials. Assuming the orphan indication is for a serious indication (as defined above), FDA will at times negotiate with a sponsor those outcomes considered sufficient to support approval with a single clinical trial. Such a strategy should be discussed prospectively with FDA prior to initiating the pivotal trial; assuming FDA agrees with the design, FDA may be willing to consider allowing the filing to proceed if either 1) a highly statistically persuasive and clinically meaningful outcome is achieved or 2) at FDA’s discretion, dependent on FDA’s review of the efficacy data, the severity of the disease, and medical need. In practice, this approach has a high chance of failure, as most companies who work on orphan products move into their pivotal study with either 1) very small proof of concept Phase 1/2 trials that hint at efficacy but are not robust or 2) uncontrolled Phase 2 studies that show efficacy versus natural history data but fail to achieve statistically significant results when conducted as randomized, double-blind studies.

That aside, recently, FDA has taken an active approach for approving products based on a single trial with certain therapeutic paths, particularly anti-infectives. The Limited Population Antibacterial Drug (LPAD) pathway allows antibiotics to be approved and labeled for small populations with unmet needs. As of October 2019, two products have been approved using this pathway with single clinical studies:

•   Arikayce (amikacin liposome inhalation suspension), for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex, in a limited population of patients with the disease who do not respond to conventional treatment, approved with a single trial on a surrogate endpoint (sputum conversion); and
•   Pretomanid Tablets in combination with bedaquiline and linezolid for the treatment of a specific type of highly treatment-resistant tuberculosis of the lungs, which was approved with a single trial that showed significant benefit relative to historical controls.

The success of these programs demonstrates FDA’s willingness to be flexible when the benefit can be properly assessed and truly outweighs the risk in a specific patient population. However, companies should be cautious when developing an orphan product. Prospectively planning to properly assess efficacy outcomes in reasonably sized, randomized, double-blind Phase 2 trials will help companies make appropriate go/no go decisions earlier in a product’s life cycle, ultimately helping companies spend less time and money on unapprovable products.

North American Cystic Fibrosis Conference: Key Takeaways

Posted by Lisa Payne on Thu, Dec 05, 2019 @ 09:00 AM
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The 33rd Annual NACF conference continues to be an action packed 3 days bringing together scientists, clinicians, health care providers, and caregivers to discuss the latest advances in CF research, care, and drug development.  These are our top 3 takeaways from the meeting and how they will impact clinical research moving forward.

We’ve come a long way, baby.

In the plenary talk on the first day, Marie Egan, M.D., provided an important overview of how far CF research has come over the past 30 years in her talk, “Emerging Technologies for CFTR Restoration in All People with CF”. This talk highlighted innovative technologies, including RNA therapies, gene therapies, and gene editing technology that hold potential to finding a cure. Dr. Egan also discussed the challenges and opportunities presented by these novel therapies as they advance toward the clinical study phases of development. Some of these challenges are very similar to what other rare disease communities are facing as the research of gene therapies increases. For clinical research, recruitment and retention in these trials (that can have a follow-up time of at least 5 years) need to be broached carefully, so participants understand the potential benefits and risks that await.

Excitement around Trikafta approval.

A week and a half before the conference, FDA’s approval of Vertex’s Trikafta was announced. With this approval, 90% of the CF community have a treatment option, which is an outstanding achievement. There was excitement around the approval and what this means to those with CF. What we are hearing from sites is that this also means ongoing clinical research studies are likely to have some delayed enrollment as patients start taking Trikafta. The delay will typically be the result of getting on to a stable dose to meet inclusion criteria, in addition to reduced resources at the site, as more patients are requesting appointments to switch onto Trikafta.

Medical News on Multicolor Puzzle on White Background.In the second plenary, Jane Davies, MD, MBChB, MRCP outlined the progress and promise of highly effective CFTR modulator therapies and the potential impact that Trikafta could have on this population. Whilst celebrating the success of effective modulator therapy, Dr. Davies also discussed challenges that remain, including treatments for people with rare mutations, caring for a patient population that has grown and aged, and providing access to CFTR modulators in more regions of the world.

CFTR modulators are not expected to eliminate the need for additional chronic therapies and drugs. While there is potential that CFTR modulators offer an opportunity to restore function earlier in life and alleviate a lifetime of lung damage that patients fight into adulthood, patients and families have expressed that reducing the treatment burden is a high priority and even patients on effective modulator therapies are not commonly reducing their other treatments. So while daily care has become increasingly effective, it remains complex and burdensome. This highlights the need for additional treatments and a cure for those with CF.

We will not stop until CF stands for Cure Found.

Current NIH director Francis Collins and his team helped discover the cystic fibrosis gene and he emphasized that the recent approval of Trikafta means that 90% of the community have the potential to receive a remarkable treatment; however, there are still patients with CF who might not benefit from this new therapy (including individuals with rare and nonsense mutations) and we must not abandon the 10% of people for whom these drugs will not provide benefit. Work towards finding a cure for all is just getting started.

A new era in CF research is beginning. The CF Foundation recently unveiled the “Path to a Cure” initiative, which will focus on finding treatments for the underlying cause of CF and a cure for every person with CF. The CFF is challenging academia and industry to accelerate progress in CF drug discovery and development. To help this ambitious initiative, the foundation intends to allocate $500 million to the effort through 2025.

This new era means that other recruitment strategies and study designs should be considered to enroll and execute a successful trial. Understanding the new patient population will be critical, and will require being cognizant that the baseline disease severity will vary across the population. New clinical trials in the era of modulator therapy may also require new endpoints,Medicine doctor hand working with modern computer interface as medical concept-1 as incidence or severity of common endpoints such as pulmonary exacerbations may change. Innovative study designs should be considered, but will require an increased amount of regulatory interaction.

Despite this remarkable progress there are significant needs that remain. As the CFF president and CEO, Preston W. Campbell, III, M.D, stated “Don’t stop dreaming of a day when all people with CF can say, ‘I used to have CF’.” Prioritizing innovative approaches to find a cure is at the forefront of the CFF’s mind and a recurring theme at the conference was the sentiment that the most important and challenging work lies ahead – until CF stands for Cure Found.

Need support designing and executing your next CF trial? Ask our experts for help.

JamieA3Jamie Arnott, RN, BSN, OCN®, Rho Project Director, received her undergraduate degree in Nursing from the University of North Carolina at Chapel Hill.  She has extensive experience from both the CRO and sponsor perspectives in the oversight and management of clinical trial operations and outsourcing with more than 12 years’ experience in project management and over 20 years’ experience in healthcare as a practitioner and manager.  Prior to her tenure at Rho, Ms. Arnott was the Director of Clinical Trial Operations for a biotechnology company where she provided oversight and management for all clinical activity for up to four concurrent INDs.  Ms. Arnott has broad therapeutic experience with ENT indications, cystic fibrosis, and multiple oncology indications, including ovarian cancer, hematological malignancies, and advanced solid tumors; she has pediatric experience both within the oncology field as well as orphan diseases. 

Kristin Gabor-2-1Kristin Gabor, PhD, RAC, Research Scientist, has over a decade of experience in writing and editing scientific documents and publications across a variety of biological, clinical, and regulatory fields, which includes several publications in peer-reviewed scientific journals.  Dr. Gabor has led and participated in the authoring and preparation of clinical study reports, clinical protocols, annual safety reports, modules of regulatory submissions (NDA, IND, etc.), and other regulatory documents in a variety of therapeutic areas.  She has also coordinated document review for regulatory submissions and led the management of safety review committees for clinical studies.  She has experience in a broad range of therapeutic areas, including sickle cell disease, allergy, inflammation, and immunology, infectious diseases, rare diseases, atopic dermatitis, multiple sclerosis, and cystic fibrosis.  Dr. Gabor earned an interdisciplinary PhD in Functional Genomics from the University of Maine and subsequently received an Intramural Research Training award from the NIH/NIEHS for her postdoctoral studies investigating the role of cholesterol metabolism and cell membrane perturbations in regulating the innate immune response in a rare genetic disease.  Dr. Gabor received her Regulatory Affairs Certification from the Regulatory Affairs Professionals Society (RAPS) in 2018 and is a current member of RAPS and the North Carolina Regulatory Affairs Forum (NCRAF).

NancyWsmallNancy Woody, MA, PMP, Senior Project Manager, has over eight years of project management experience in a clinical research organization (CRO) supporting and leading Phase 1 through 4 global and regional trials. Prior to working at Rho, Ms. Woody worked primarily on late phase and real-world evidence research studies and the collection of patient outcomes in standard of care settings and existing data sources. She has provided leadership to cross-functional clinical research projects and teams, virtually and co-located, in a wide variety of indications including Rare Disease (cystic fibrosis), CNS (Alzheimer’s, Multiple Sclerosis, spine pain, women’s pain, etc.), endocrinology (Diabetes) and oncology (Multiple Myeloma). As the project manager, Ms. Woody’s responsibilities include the creation and maintenance of project management plans, advising on operational strategies and mitigation plans, close collaboration with sponsor contact, and management of vendors, study team resources, timelines and budgets. She has a background in intercultural training and conflict resolution, which has helped to inform her work in risk management and mitigation on complex trials and within diverse teams. Ms. Woody is a certified Project Management Professional and received her Master’s degree in Intercultural Relations from Lesley University and a B.A. in Communication Studies from the University of North Carolina at Chapel Hill.

Patient-Focused Drug Development: Incorporating the Patient’s and Caregivers’ Perspectives into Product Development

Posted by Lisa Payne on Mon, Nov 18, 2019 @ 10:30 AM
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Meagan3-1 Meagan Spychala, Ph.D., Assistant Vice President of Patient Engagement and Program Strategy at Rho, serves as Rho’s expert on patient-focused clinical research activities and incorporates the patient and caregiver voice and experience into the clinical development program.

 

karl

Karl Whitney, Ph.D., Assistant Vice President of Product Development, leads multiple integrated drug development programs spanning the development spectrum by planning, managing, and overseeing concurrent manufacturing, nonclinical, clinical, and regulatory activities.

Patient-centricity and family-centricity has been a hot topic for the past few years in clinical research, as more groups in pharmaceutical companies and CROs are working on patient engagement and patient-centric approaches to clinical research programs. Recruitment and retention are one part of patient-centricity, but the more important up-front and overarching aspect of patient-centric research comes from Patient-Focused Drug Development (PFDD). PFDD is a systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated into the development and evaluation of medical products throughout the product life-cycle. Patients and caregivers know the disease and understand what would have the biggest impact to their lives; this wisdom can and should significantly inform the clinical research being conducted. If done correctly, the research will collect data on outcomes that matter most to the patient community. Using a PFDD approach to engage patients and caregivers throughout the product development process can lead to better study designs, more relevant data, better trial enrollment, and ultimately better products.

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Since 2012, several key pieces of legislation have been signed into law to support performing more patient-focused research. The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, the 21st Century Cures Act of 2016, and the FDA Reauthorization Act of 2017 collectively position FDA to learn about, promote, and encourage the integration of patient perspectives into the development of drugs, biologics, and devices. FDA has been pursuing a number of initiatives under the auspices of this legislation (see links and references below); one being conducting PFDD meetings, of which there have now been 24. In a parallel development, in 2018 the FDA entered into an understanding (MOU) with the National Organization for Rare Disorders (NORD) to conduct pilot listening sessions to enhance the incorporation of the patient experience into regulatory discussions. Twelve listening sessions have been conducted under the MOU since October 2018 and more are currently being scheduled for 2020.

The FDA is working to collate the principles and insights gleaned across these PFDD meetings into 4 formal guidance documents. Collectively, these guidances will describe the steps, processes, and considerations to bear in mind when collecting information from patients and caregivers. This includes discerning what is most salient, important, and impactful to them; using this information to create or use COA or PRO tools; and potentially validating new tools to be used as endpoints for clinical research. The first draft guidance was issued mid-2018 and focused on who to get input from and how to collect the information needed. This is intentionally an initial overview; therefore, it is a high-level view of key philosophies about patient involvement via providing patient experience data to guide a product development program into using the most sensitive and clinically meaningful endpoints. The second draft guidance, issued October 2019, provided methods for eliciting information from the patient population. Three main methods of research for obtaining information to understand what matters most to patients living with a disease and their caregivers were detailed: qualitative Research - Wordcloud Concept. The Word in Red Color, Surrounded by a Cloud of Blue Words.research, quantitative research and mixed-methods research. Each type has strengths and limitations, so deciding on which method to use to support a research program depends on the patient population and research objectives. No matter what type of research method used, a research protocol, interview or survey guide, training materials, glossary, data management plan, and data analysis plan are needed before proceeding with collecting information and the protocol should be reviewed in a meeting with the FDA.

While it will likely take some time until all four guidance documents are complete, we eagerly await the third and fourth draft guidances, as patient advocacy groups and product development organizations are already moving forward with PFDD and need additional FDA guidance and advice on how to incorporate the patient perspective into clinical research. Even though these documents are not completed, ongoing development programs should still strive to be patient-focused. We have seen from having conducted natural history studies and other patient-centric work how important it can be to have a clear understanding of the disease and patients’ (and caregivers’) perspectives; absent such understanding, it is hard to plan and execute sound development programs that result in products the patients need and benefit from.

Want advice on how to proceed with a PFDD approach? Rho has the scientific, operational, and regulatory strategy experience needed to support your PFDD program.

References:

Guidances:

Other references:


 

FDA’s Project Orbis:  Trendsetter or One-off

Posted by Brook White on Thu, Sep 26, 2019 @ 01:58 PM
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David Shoemaker, PhD, SVP R&DDavid Shoemaker, PhD, SVP R&D, has over 25 years of experience in pharmaceutical product development. He has served as a Program Leader or Advisor for multi-disciplinary program teams and has been involved with ensuring products meet regulatory standards at all stages of the development process.

 

working togetherWith the announcement of Project Orbis, FDA’s Oncology Center of Excellence (OCE) excited both patients and the pharmaceutical industry with the program’s future possibilities for collaborative regulatory authority interaction in accelerating product approvals worldwide. The intent of Project Orbis is to provide a structure for collaboration between international regulatory authorities on the evaluation and marketing approval of oncology drugs and this possibility was first manifest by the simultaneous approval by the US FDA, Health Canada (HC), and Australian Therapeutic Goods Administration (TGA) of a combination regimen of two oncology drugs, Lenvima (lenvatinib) and Keytruda (pembrolizumab), for the treatment of advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.

collaborationThe three regulatory authorities involved are to be congratulated for accomplishing this feat for a high profile program where patients are in dire need of the regimen. These two drugs were approved by the accelerated approval pathway in the US using the Real-Time Oncology Review pilot and its accompanying Assessment Aid program and provisional pathway in Australia. The approval was based on tumor response rate and durability of response. Patients were treated with 20 mg lenvatinib orally once daily in combination with 200 mg pembrolizumab intravenously every three weeks until treatment termination due to toxicity or disease progression.

So the question immediately comes to mind as to whether this is the tip of the iceberg for process improvement for future coordinated international regulatory marketing approvals or is this an isolated incident where all the stars were aligned. Inasmuch as these products were already approved on their own merits for treatment of several different types of cancer including differentiated thyroid, liver, and renal in combination with everolimus in the case of lenvatinib and melanoma, metastatic non-small cell lung, head and neck squamous cell, classical Hodgkin Lymphoma, urothelial, microsatellite instability-high, gastric, small cell lung, primary mediastinal large B-cell lymphoma, esophageal, cervical, hepatocellular, merkel cell, and renal in the case of pembrolizumab, this is a case where regulatory authorities have a great deal of familiarity with these compounds and coordinated expedited approval between international regulators should be expected.

Of course the question of how much interaction these different regulatory authorities have with one another is critical to determining how likely these coordinated approvals will be regardless of their familiarity with the compound. This collaboration between the US, Canadian, and Australian regulatory authorities was no doubt facilitated by the monthly Oncology International Cluster Calls held between the FDA, European Medicines Agency, HC, Japan’s Pharmaceuticals and Medical Device Agency, Swissmedic, and the TGA. It seems that while this is a wonderful milestone of having a life-saving regimen approved simultaneously by three international regulatory bodies, the likelihood is it will be a long time before this coordination is repeated for any initial marketing applications in a therapeutic indication other than oncology. Nonetheless, the OCE is once again paving the way for innovation at the FDA.

Risk Evaluation and Mitigation Strategies:  FDA Guidances for Assessing Effectiveness

Posted by Brook White on Wed, Mar 27, 2019 @ 08:56 AM
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Samantha Hoopes, PhD, RACSamantha Hoopes, PhD, RAC is a Research Scientist at Rho involved in clinical operations management and regulatory submissions.  Samantha has over 10 years of scientific writing and editing experience and has served as lead author on clinical and regulatory documents for product development programs for a variety of therapeutic areas.

In January 2019, the Food and Drug Administration (FDA) released 2 draft guidance documents regarding assessment of Risk Evaluation and Mitigation Strategies (REMS).  Both of these draft guidances are under a comment period through 02 April 2019.  These documents are meant to provide industry additional information to more accurately assess the effectiveness of their REMS.  

risk evaluation and mitigation strategiesThe Food and Drug Administration Amendments Act (FDAAA) created section 505-1 of the Food, Drug, and Cosmetic (FD&C) Act, which authorizes FDA to require Risk Evaluation and Mitigation Strategies for certain prescription drug and biologic products if the FDA determines that it is needed to ensure the benefits of the drug/biologic outweigh the risks (FDA REMS history webpage).  REMS are required in cases where there are specific serious risks related to a product and are not meant as a means to mitigate all adverse events.  Risk Evaluation and Mitigation Strategies can consist of a Medication Guide, a package insert, and/or a communication plan to inform key audiences about the risks of the product.  A REMS should be designed with specific risk mitigation goals consisting of specific objectives and safety-related outcomes.  The objectives should include metrics to indicate the program is meeting its goals when a goal cannot be measured directly.  As of 05 March 2019, FDA has approved 76 REMS.  Assessments evaluating the effectiveness of the REMS must be submitted 18 months, 3 years, and 7 years after the strategy is approved, or at other intervals specified in the strategy.  While REMS assessments are required in accordance with 505-1 of the FD&C Act, it does not describe how to design and conduct these assessments.

One of the recently released draft guidance documents, “REMS Assessment:  Planning and Reporting Guidance for Industry,” describes how to develop a REMS Assessment Plan.  A REMS Assessment Plan is a specific plan for how the applicant intends to assess the performance of the REMS in meeting its risk mitigation goals and objectives.  A REMS Assessment Plan should include the categories for evaluation and proposed process and/or outcome metrics.  The categories and some example metrics are provided in the table below.  

Category Definition Example Metrics
Program outreach and communication Measures of the extent to which the REMS materials reached the intended stakeholders. Numbers of specific REMS materials that were distributed to, and the proportion of these that were subsequently opened or read by, the targeted audiences.
Program implementation and operations  Measures of the extent to which the intended stakeholders are participating in the program; how effectively the REMS program is being implemented, including the extent of use of REMS materials and compliance with REMS requirements; and any unintended consequences that could affect patient access or potential burden to the healthcare system related to the program operations. Number of prescribers, health care settings, and/or pharmacies that have certified or undergone training in the REMS program; the number of contacts to the call center and a summary of the reason for the contact; number and results of audits of certified health care settings; and the number of shipments of the drug to non-certified settings.
Knowledge Measures of the extent of stakeholders’ (e.g., patient/caregiver, prescriber, pharmacist) knowledge about the REMS-related risk or knowledge of any safe use conditions that are needed in order to mitigate the risk. Stakeholder understanding of the risks and safe use of the drug;  the draft guidance for industry “Survey Methodologies to Assess REMS Goals that Relate to Knowledge” provides further recommendations on using surveys to evaluate knowledge of REMS risks and safe use conditions.
Safe use behaviors Measures of the extent to which safe use conditions are being adopted or followed (e.g., how often a required laboratory test is conducted prior to dispensing of the medication). Evaluation of prescribing patterns and the proportion of patients who were counseled prior to initiating a drug, as evidenced by the use of a REMS material, such as a patient counseling tool or patient-provider agreement form.
Health outcomes and/or surrogates of health outcomes Measures of the safety-related health outcome of interest (e.g., a reduction in the number of serious outcomes associated with a particular adverse event) or a surrogate of a health outcome (e.g., a reduction in the number or proportion of patients at greatest risk of an adverse event who are prescribed a drug). Numbers and/or rates of a specific adverse event of interest such as rates of serious bleeds or severe neutropenia;  surrogate metrics could include the number of inadvertent fetal exposures or the number of prevented fetal exposures to the teratogenic drug.

 

While the above categories are meant to be broadly applied to REMS, there are some products for which a REMS with elements to assure safe use (ETASU) are required to allow patients safe access to drugs with known serious risks that would otherwise not be approved.  The FD&C Act states that the ETASU should not be unduly burdensome on patient access and the burden on the health care delivery system should be minimized.  This draft guidance also provides information on how to specifically assess both barriers to patient assess and burden on the health care delivery system when ETASU is required with a REMS.

Performance thresholds related to metrics should be specified in order to assess whether the REMS is meeting its goals and objectives.  The REMS Assessment Plan should specify a performance threshold for each health outcome of interest, if feasible.  If the health outcomes of interest for the REMS are difficult to measure directly, performance thresholds should be specified for surrogate metrics.  Proposed steps to achieve the performance threshold should also be noted in the event results indicate the threshold was not met. 

One or more data sources may inform the different categories in a REMS Assessment Plan.  Description and justification of the data source(s) and methodological approaches for assessing specific REMS goals and objectives should also be submitted to the FDA in support of the assessment plan.  Some sources of data could include:

  • Applicant’s REMS data  
    • Data may come from a database of certified/enrolled prescribers, dispensers, healthcare settings, distributors, or patients that may be required with the REMS.
  • Drug utilization data
    • If a drug utilization study is included in a REMS Assessment Plan, it should describe the source of the data, rationale for use of the data source, data collection methodology, design and analytical approaches, and any limitations.
  • Postmarketing adverse event data
    • Postmarketing adverse event data to be collected should be specified in the REMS Assessment Plan and focus on further characterizing the risk, capturing patient outcomes, and determining whether safe use conditions were met.
  • Observational/epidemiology data
    • This guidance does not recommend a specific pharmaco-epidemiology study design as FDA intends to exercise a flexible approach; however, any potential challenges and limitations should be clearly stated in the study proposal.
  • Root cause analysis data
    • FDA states that root cause analysis best practices consist of the development and use of a predefined protocol and a team-based reconstruction of each issue via retrospective review and interviews.
  • Stakeholder outreach data
    • The guidance states that data from key stakeholders, such as prescribers, pharmacists, other healthcare professionals, and patients can inform the applicant and FDA about the impact of the program on the healthcare delivery system, patient access to the drug, and opportunities for improvement.  
  • Surveys
    • Surveys are commonly used to evaluate provider and patient understanding of the serious risks associated with, and safe use of, the product. 

The “REMS Assessment:  Planning and Reporting Guidance for Industry” draft guidance also addresses how to submit the REMS Assessment Plan and REMS Assessment Reports to the FDA.  Appendices in this draft guidance include an example REMS Assessment Plan overview and additional examples of metrics.

Another draft guidance, “Survey Methodologies to Assess REMS Goals that Relate to Knowledge,” was recently released and provides best practices for survey design, conduct, and data analysis, to evaluate knowledge of REMS risks and safe use conditions.  This guidance describes the key information that should be included in the assessment survey protocol and the survey report of the results.  The guidance discusses endpoints, sample populations, sample size, participant recruitment, statistical considerations, and factors that may influence selection of survey administration modality, either self-administration or use of a trained interviewer.  Recommendations are provided for development of the survey questionnaire, including specific considerations for both patient and health care provider surveys.  

It is important to note that FDA acknowledges there are limitations to assessments in cases of infrequently prescribed products, safety outcomes that occur rarely, and REMS establishment at initial approval where there may not be relevant baseline data for comparison (e.g., incidence of risk associated with the drug or drug use patterns).  REMS Assessment Plans should be developed to thoroughly assess effectiveness of the REMS by including more than 1 metric, data source, and methodology, and also acknowledging limitations and potential challenges.  FDA encourages anyone preparing a REMS to develop novel methods for assessing REMS effectiveness that may be appropriate for their specific product. 

The FDA is accepting comments on both of these draft guidance documents, “REMS Assessment:  Planning and Reporting Guidance for Industry” and “Survey Methodologies to Assess REMS Goals that Relate to Knowledge,” through 02 April 2019. 

Master Protocols and the New FDA Guidance

Posted by Brook White on Tue, Jan 15, 2019 @ 09:53 AM
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Kevin Barber, Vice President, Regulatory Strategy & SubmissionsKevin Barber, PhD, VP, Regulatory Strategy & Submissions, has more than 20 years of experience in regulatory affairs and product development, working for both sponsor companies and CROs, across all stages of development from pre-clinical through product launch and post-approval life cycle management. He has lead the preparation and execution of integrated regulatory strategy and clinical development plans for drug, biologic, and medical device products. 

In September of 2018, FDA released a new FDA guidance on master protocols.  So, what are master protocols, how can they benefit sponsors and patients, and what are the challenges?

Benefits of a master protocol design

endpoint-resized-600parallel studiesThrough an over-arching infrastructure, trial design, and protocol with multiple sub-studies run simultaneously, a master protocol is intended to run continuously to evaluate and assess a single investigational drug for multiple indications or patient populations, or multiple drug candidates for the same indication.  Over the past several years, FDA has been encouraging sponsors of clinical development programs in areas such as oncology and pediatrics to consider using a master protocol approach to expedite and streamline mid- to late-stage drug development.  If well-executed, a master protocol approach can reduce study overhead and duplication of activities, reduce patient exposure to control arms through use of a single common control arm, and most importantly, generate data to address multiple questions regarding the safety and efficacy of drug candidate(s) in parallel rather than sequentially.

Master protocol implementation challenges

Planning, executing and monitoring the simultaneous sub-studies under a master protocol require a great deal of coordination and the appropriate trial infrastructure, so a sponsor has to have sufficient resources and well-trained personnel. For example, the draft guidance notes that sponsors should have medical monitors with appropriate training and experience in the conduct of clinical trials and the indications under study, given the potential for rapid patient accrual with increased risks to patients if adverse events are not promptly identified.

Furthermore, FDA acknowledges that one of the challenges for master protocols is related to assessment of safety of the investigational product(s) under the protocol. With multiple arms assessing a single product across multiple patient populations or multiple products across a given patient population, there could be difficulty in attributing adverse events appropriately to the investigational drugs.safety-signals-1

FDA also cautions that multiple study groups under a master protocol could result in over-interpretation of findings, such as falsely identifying a responder population based on multiple between-arm comparisons. Therefore, sponsors should take a great deal of care and consideration in the design and execution of the statistical analysis plan for a master protocol.
There are additional regulatory considerations and activities for a master protocol, because sponsors should submit each master protocol as a new IND to FDA, with the master protocol as the only trial to be conducted under the IND. The requirement to submit a new IND does afford the sponsor an opportunity to request a pre-IND meeting to reach agreement on the design and conduct of the master protocol.

Final Thoughts

Although implementing a master protocol could accelerate a drug development program, a sponsor should carefully consider the potential advantages and challenges to determine whether a master protocol is appropriate.  The guidance provides useful considerations and examples, but most importantly, the sponsor should follow the recommendations to meet with and gain agreement with FDA regarding key features of the master protocol design and analysis plan.  This is especially critical for a master protocol intended to generate adequate safety and efficacy data to support a marketing application.

Download: 10-Step Protocol Authoring Guide

Accentuate the. . . Negative: The Importance of Publishing Negative Clinical Study Results

Posted by Brook White on Wed, Nov 28, 2018 @ 11:36 AM
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Jamison Chang, MD, Medical OfficerJamison Chang, MD, medical officer, is a board-certified internist with over 15 years of clinical experience with a broad range of disease entities in both the ambulatory and hospital settings. After completing his residency and chief residency at UNC Chapel Hill, he obtained additional training in nephrology as well as a master’s degree in clinical research (MS-CR). These experiences allow Dr. Chang to meld clinical pragmatism with scientific rigor to help plan and conduct high quality clinical trials. 

 balancing positive and negative“Stop being so negative about things” or “if you had a less negative attitude, things would go better for you.”  No matter the setting, there tends to be a strong distaste for negativity within our culture.  One notable exception to this is in pursuit of scientific progress.   Here, at least in theory, a negative finding (something does not work) should garner as much attention as a positive finding (something works).  Ideally, a scientific discipline then takes the balance of both supporting and refuting evidence to decide on the current state of knowledge.  This is science at its best.  When the scientific community falls short of this ideal by failing to consider the entirety of scientific evidence, the quality of scientific research can fall.  Lower quality research can result in poorly informed policies, wasted resources and in the extreme cases, harm.  While not the only scientific discipline affected, clinical research has well-documented cases of not devoting equal attention to both negative and positive findings.  The remainder of this post will discuss supporting evidence for this claim, attempt to explain why this may be occurring, explain the effects of this phenomenon on the clinical research enterprise, and then offer a few solutions on how we can start righting the ship.

The asymmetry in reporting positive and negative outcomes was recently highlighted by Aaron Carroll, MD, a professor of pediatrics who recently published an editorial in the NY Times (Sept 24,2018) titled “Congratulations Your Study Went Nowhere.”  Dr. Carroll cites a recent study in Psychological Medicine whose purpose was to explore possible biases in medical research related to antidepressants.  This group evaluated 105 antidepressant studies registered with the FDA. Half of these studies were “positive” and half were “negative” according to the FDA. Whether a study is generally declared positive or negative is based whether or not the study achieves or does not achieve the primary outcome or primary goal.  In these depression studies, a common primary goal is often to determine if there is an improvement in depression using commonly accepted scales. Notably of the 105 trials reviewed, 98% of the positive trials were published while only 48% of the negative trials were published.  Studies may also look at other outcomes, so called secondary outcomes or endpoints. In the case of depression trials, some examples of secondary outcomes may include hours of sleep or change in weight.  Clinical trials are unable to provide similar levels of statistical certainty regarding secondary vs primary outcomes.  Rather, these secondary outcomes are used to generate hypotheses for future trials.   Despite this well-accepted convention, the study in Psychological Medicine noted 10 of 25 trials considered negative by the FDA were reported as positive by researchers who appeared to shift the focus from a negative primary outcome to a favorable secondary outcome.   Dr. Carroll also cites a 2004 JAMA study where researchers reviewed more than 100 trials approved by a scientific community in Demark that resulted in 122 publications and over 3000 outcomes.  Half of these outcomes on whether drugs worked were not reported and two-thirds of cases of possible harm were not reported.  

This is not to cast a negative light on scientists or entities that do not fully report outcomes in clinical trials.  While there may be instances of deliberately not reporting certain findings, underreporting of outcomes likely derives from a collective “Eh” regarding negative trials from the clinical research collective.  Biomedical journals, grant funding agencies and biomedical scientists seem to lean more favorably toward studies that demonstrate an effect versus those that don’t show one.  Pick up any major medical journal and this phenomenon will be readily apparent.  Go to any major medical conference and you will witness hundreds of posters showing positive results to every 10 showing negative results.  Journals more often bolster their reputation by publishing breakthrough articles that more often demonstrate the effectiveness of a new therapy rather than a lack of effectiveness.  There is something inherently more attractive about reporting positive results than negative results in the current clinical research environment.  Unfortunately, this is doing a disservice to the quality of clinical research as a whole and potentially limiting our ability to further improve the health and well-being of patients.   

positive resultsSelective reporting has major implications for the current clinical research enterprise.  Starting with the most obvious implication: if more positive results are reported than negative results, new therapies or devices may actually be less effective in practice than in published literature supports.  There are major financial implications to this, with both insurers and payers utilizing resources on these therapies that might be better apportioned elsewhere.  Underreporting of negative trials and/or outcomes also greatly hinders one of the most critical aspects of scientific research: learning from both the past successes and the failures of other scientists. If this knowledge is not widely available to the scientific community, we are more likely to repeat the same mistakes, utilizing scarce resources inefficiently and hindering future scientific progress.  

Given the high stakes of underreporting the results of negative trials and outcomes, how might we go about addressing these issues?  Many governing bodies including the Food and Drug Administration (FDA) in the US have mandated registering clinical trials at ClinicalTrials.gov.  The requirements have evolved over the years but most of the requirements focus on disclosing details of the design of the trial including the primary endpoints, secondary endpoints and analysis plan.  The intent here is for more transparency so that stakeholders can validate whether a trial was carried out properly.  Inadequately conducted clinical trials can lead to erroneous conclusions about the effectiveness (or lack thereof) of a product. In other words, trials may be falsely negative (the new therapy may be effective but errors in trial conduct obscured this effect) or falsely positive (the new therapy does not work but improper trial conduct results in it appearing better than it actually is). The FDA further tightened reporting requirements in 2017 with the FDA Final Rule 42 CFR 11 (the National Institutes of Health (NIH) published similar regulations).  The results of these regulations are encouraging. From 2007 to 2017, major university reporting when from around 28% to 78% with a 20% improvement (58 to 78%) between 2015 and 2017 (1). Increased regulation has been helpful but other changes are cultural.  Fundamentally, we need to celebrate and encourage the reporting of important negative results as we do positive results.  We should implore journals to publish negative results so that the clinical research community can learn from and improve upon what has been done previously.   Reporting negative results may seem less newsworthy and to some, boring, but if that is the price of better science and better treatments for patients, maybe we should consider boring over bling? 

The scientific method is an enduring achievement that continues to benefit us.  However, the magnitude of this benefit is significantly curtailed when this method is not employed as it was intended.  In the case of clinical research, there appears to be an inherent bias toward popularizing and publishing things that “work” in lieu of things that didn’t “work”.  This asymmetry of accentuating the positive not only potentially leads to erroneous conclusions about current therapies but also impacts the direction and success of future biomedical research.   We need to urge culture change within the clinical research space.   “Accentuating the negative and not just the positive” might be an appropriate mantra for this culture change as we move forward emphasizing the need to place both positive and negative findings on equally footing.  In this way, we maximize our ability to obtain the best possible answers to our research questions and hopefully deliver the greatest benefits to patients. 

Acknowledgements: Many thanks to Dr. Aaron Carroll whose editorial in the NY Times helped clarify my thinking on this issue.  Thank you to Dr. Jack Modell for further clarifying the important issues. 

  1. Piller C and Bronshtein T.  Faced with public pressure, research institutions step up reporting of clinical trial results. STAT Jan 19, 2018.